Plant

Secondary
Metabolism
 ine of
Plant Secondar
y Metabolism

chlorophyll + C 0 + light
2

cyclitols, polyols
photosynthesis^
C C -compounds
6 1

t
glycosides
carbohydrates

pentose phosphate
shikimi c acid
erythrose 4-phosphate

I glycolysis

chorismic acid phosphoenol pyruvate

£so-chorismic cyanogenic glycosides

acid * glucosinolates
peptides • proteins
non-protein amino acids

f tricarboxyli c acid
amino acids cycle acids

alkaloids
t e
r^ °
alkaloids
n i d

s-
ternenes ^ roev . .

^ ^ / / waxes

I acetylenes

rotenoids / hydrocarbons
flavonoids polyketides
• phenols
phenylpropanoid \ naphthoquinones
coumarins compounds \ anthraquinones
Iigni n lignans condense
d tannins
 Plant
Secondary
Metabolism
]David S. Seigler
Department of Plant Biology
University of Illinois, Urbana

SPRINGER SCIENCE+BUSINESS M E D I A , L L C
Library of Congress Cataloging-in-Publication Data

Seigler, David S.
Plant secondary metabolism / David S. Seigler.
p. em.
Includes bibliographical references.
ISBN 978-1-4613-7228-8 ISBN 978-1-4615-4913-0 (eBook)
DOI 10.1007/978-1-4615-4913-0
1. Plants--Metabolism. 2. Metabolism, Secondary. 3. Botanical
chemistry. r. Title.
QK887.538 1995
581.1'33--DC20 89-70112
CIP

Copyright © 1998 by Springer Science+ Business Media New York

Originally published by Kluwer Academic Publishers in 1998
Softcm-er reprint of the hardcover 1st edition 1998
All rights reserved. No part of this publication may be reproduced, stored in a retrieval
system or transmitted in any form, or by any means, mechanical, photocopying, recording,
or otherwise, without the prior written permission of the publisher.

Printed on acid-free paper.

This printing is a digital duplication of the original edition.

Table of Contents

Preface vii Chapter 21 Sesquiterpenes 367

Acknowledgments ix Chapter 22 Diterpenes and Sesterterpenes 398
Chapter 1 Introduction 1 Chapter 23 Triterpenes and Steroids 427
Chapter 2 Fatty Acids 16 Chapter 24 Saponins and Cardenolides 456
Chapter 3 Acetylenic Compounds 42 Chapter 25 Limonoids, Quassinoid., and Related
Chapter 4 Plant Waxes 51 Compound. 473
Chapter 5 Polyketides 56 Chapter 26 Tetraterpenes or Carotenoids 486
Chapter 6 Benzoquinones, Naphthquinones, and Chapter 27 Introduction to Alkaloids 506
Anthraquinones 76 Chapter 28 Simple Amines, Simple Aromatic and
Chapter 7 Shikimic Acid Pathway 94 Pyridine Alkaloids 513
Chapter 8 Phenylpropanoids 106 Chapter 29 Pyrrolidine, Tropane, Piperidine, and
Chapter 9 Coumarins 130 Polyketide Alkaloids 531
Chapter 10 2-Pyrones, Stilbenes, Chapter 30 Pyrrolizidine, Quinolizidine, and
Dihydrophenanthrenes, and Xanthones 139 Indolizidine Alkaloids 546
Chapter 11 F1avonoids 151 Chapter 31 Alkaloids Derived from Anthranilic
Chapter 12 Tanuins 193 Acid 568
Chapter 13 Nonprotein Amino Acids 215 Chapter 32 Isoquinoline and Benzylisoquinoline
Chapter 14 Peptide. 234 Alkaloids 578
Chapter 15 Carbohydrate. 247 Chapter 33 Alkaloids Derived from Both Tyrosine
Chapter 16 Cyanogenic Glycosides and and Phenylalanine 617
Cyanolipids 273 Chapter 34 Indole Alkaloids 628
Chapter 17 Glucosinolates 300 Chapter 35 Ergot and Other Indole Alkaloids 655
Chapter 18 Introduction to Terpenes 312 Chapter 36 Alkaloids of Terpenoid Origin 668
Chapter 19 Monoterpenes 324 Chapter 37 Miscellaneous Types of Alkaloids 692
Chapter 20 Iridoid Monoterpenes 353 Index 713
Preface
Life has evolved as a unified system; no organism exists
alone, but each is in intimate contact with other organisms
and its environment. Historically, it was easier for workers
in various disciplines to delimit artificially their respective
areas of research, rather than attempt to understand the entire
system of living organisms. This was a pragmatic and neces-
sary way to develop an understanding for the various parts.
We are now at a point, however, where we need to investi-
gate those things common to the parts and, specifically, those
things that unify the parts. The fundamental aspects of many
of these interactions are chemical in nature. Plants constitute
an essential part of all life systems; phytochemistry provides
a medium for linking several fields of study.
It is partially through teaching a course in phytochemistry
that I have come to realize more fully the potential of phyto-
chemical studies to unite and integrate a vast amount of
material from different disciplines. The diversity of students
that have taken this course and their research interests also
reflects the utility and value of this type of information.
Among the fields represented are Biology (Ecology, Ento-
mology, Plant Biology, Botany, Physiology, Microbiology,
and Zoology), Geology (Organic Geochemistry), Chemistry
(Organic Chemistry, Biochemistry, and Analytical Chemis-
try), Agriculture (Horticulture, Animal Science, Dairy Sci-
ence, Forestry, Agronomy, and Plant Pathology), Veterinary
Medicine, and Food Science. Possibly because of the diffi-
culties involved in integrating such a diversity of interests,
no adequate text presently exists for this course.
In this text, I propose to survey our present knowledge
of the phytochemistry and the role that secondary metabo-
lites play in biological relationships. These relationships bas-
ically fall into two categories: the first concerns the function
and value of the compounds within the plants themselves.
Many compounds are catabolized for energy or used to fulfill
other requirements that involve nitrogen. For example, fatty
acids from triglycerides have long been recognized as energy
sources for the embryo of a germinating seed. Recently, a
similar role also has been suggested for fatty acids from
cyanolipids. Nonprotein amino acids, cyanogenic glyco-
sides, and the non-fatty-acid portion of cyanolipids also are
incorporated into primary metabolites during germination.
Secondary metabolites of these structural types are accumu-
lated in large quantities in the seeds of several plant groups
where they probably fulfill an additional function as deter-
rents to general predation.
The second type of relationship involves interaction of
plants with other organisms and with their environment. Bio-
logical interactions must be viewed in the light of evolution-
ary change and the coadaptation, or perhaps coevolution, of
organisms. A plant that possesses the ability to synthesize
a compound that disturbs the physiological functions of a
herbivore may have a selective advantage over one that does
not. The chemical abilities of the plant may be utilized to
establish interlocking relationships within the contexts of
pollination, seed dispersal, establishment of mycorrhizal
fungi, or protection of the plant by another organism, such
as ants. The "advantage" gained from such interactions may
be offset by metabolic cost or self-toxicity, but the process
of natural selection optimizes these interacting factors. Thus,
assuming the system remains stable for a sufficient time,
eqnilibrium will be reached. Finally, it must be remembered
that all organisms in a given system are evolving. Interacting
organisms have the ability to adapt to changes in plant chem-
istry and morphology, and may eventually ntilize plant hosts
that were formerly unacceptable. Host selection, food prefer-
ences, taste, toxicity, wounding responses, allelopathy, and a
vast array of other topics are the results of these evolutionary
processes.
An understanding of the biosynthetic pathways leading
to secondary metabolites and a recognition of the chemical
structural types present and their distribution among plant
groups have proven useful for the study of biosystematic
problems and for achieving an understanding of plant phylo-
vii
viii Preface
geny. The predictive value of chemotaxonomic information
has been recognized by natural products chemists.
Plant secondary compounds play an important role in in-
dustry and medicine. Many industries are based on flavoring
agents and perfumes, rubber, and naval stores. Several sec-
ondary compounds are physiologically active, which results
in their use as insecticides, medicinal agents, or biological
probes or "tools." Plant compounds that are toxic to man
and domestic livestock are widespread and may be responsi-
ble not only for accidental but also for chronic poisoning by
common foods such as cassava, sago, lima, and fava beans.
Subjects are grouped on the basis of major chemical struc-
tural types. Each will be discussed in terms of biosynthesis
and distribution, diversity of known structures, taxonomic
application, biological function, toxicity, and medicinal and
industrial uses. I do not present an encyclopedic coverage
of all available literature. Rather, the goal is a readable, inte-
grated text that will be suitable for instruction at the ad-
vanced undergraduate as well as the graduate level. In gen-
eral, only phytochemical (Le., plant chemical) data has been
included, although information about the chemistry of in-
sects, marine organisms, bacteria, fungi, and other organisms
has been incorporated where warranted.
No attempt has been made to reference exhaustively all
information cited in the text. Many references given are to
review articles and in many instances are not those of the
workers who carried out the original work. Although an at-
tempt has been made to give the structures of most com-
pounds given in the text, some are not included. Further, the
structures of some representative compounds are included
in figures, but, as they are not specifically cited in the text,
they are not given numbers.
I apologize to authors inadvertently misquoted and will
attempt to correct errors in any future editions. As it is diffi-
cult to locate many references dealing with topics discussed
in this text, I solicit comments and any pertinent information
that may be useful for correction of errors or for the prepara-
tion of further editions and wish to thank those who have
already provided me with manuscripts, reprints, unpublished
material, suggestions, and assistance in preparing this pres-
ent manuscript. ffitimately, of course, I stand responsible
for the conclusions and statements made in this text.
Acknowledgments
I wish to thank Anita Brinker, H. David Clarke, Ute Ecken-
bach, Richard Lindroth, Karin Readel, and Kurt Potgieter
for reading earlier versions of portions or the entire manu-
script and making suggestions for improvement. The techni-
cal assistance of Susan Gibbons, Elizabeth Bartlett, Cheryl
Frankfater, Nathaniel Ohler, and Ulrike Nolte also is greatly
appreciated. The comments of J. Balsevich, K. Brown, S.
A. Brown, E. E. Conn, K. R. Downum, G. Cordell, D. Gian-
nasi, J. Gershenzon, J. B. Harbome, E. Leistner, S. Mole,
A. Nahrstedt, R. G. Powell, P. Reichard, G. A. Rosenthal,
T. J. Simpson, K. Schreiber, P. Waterman, and anonymous
reviewers have been extremely useful in revising the manu-
script. Greg Payne of Chapman & Hall has provided many
helpful suggestions.
In a number of cases, topics were reviewed in term p'apers
submitted by students of the Plant Secondary Metabolites
or the Chemical Ecology course. Information from these
papers was extremely helpful and I especially wish to thank
the following stndents: John Andersen, Du-Jong Baek,
David C. Breeden, Anita Brinker, Stacie E. Canaan, H.
David Clarke, Paul R. Connelly, Katherine Dowd, Thomas
Dudman, Nicole Duffee, Candace Easter, Robert J. Eilers,
John Gerlits, Peter Gottschalk, Mark Hediger, Ellen Hei-
ninger, Tricia HooChung, Han-Young Kang, Frederick J.
Lang, Wei Jane Liao, Hengchen Lin, Vincent Ling, Randall
A. Lovell, John Martini, Susan McCarthy, John Ng, James
Nitao, Paul Ode, Mark S. Pavlin, Raymond Pedersen, Char-
lotte Read, Karin Readel, Nelson T. Rotto, Claire Rutledge,
Michael J. Sophia, Andrew L. Staley, Larry J. Thompson,
Martin B. Wolk, and Craig M. vanZyl.
This work would not be possible if it were not for some
of my former teachers and mentors including Allie Marie
Hobbs, Donald Hamm, Jordan J. Bloomfield, Leon Cieres-
zko, Eric Conn, Dale M. Smith and Tom Mabry.
I also wish to express my appreciation to my wife Janice
for her patience during the preparation of this book. She bas
assisted in many ways to further this work.
Ix
1
Introduction
Developments in the Study of Plant Secondary
Compounds
What Is a Secondary Metabolite?
The Origin of Plant Secondary Pathways and Compounds
The "Waste Product" Hypothesis
Internal Functions of Plant Secondary Compounds
The "Overflow" or Excess Primary Metabolism
Hypothesis
The "Increase in Fitness" Hypothesis
The "Cost" of Secondary Metabolite Synthesis
Variation of Secondary Compounds
Site of Synthesis and Accumulation of Secondary
Compounds
Interactive Roles of Plant Secondary Compounds
Patterns of Simultaneous Evolution of Plants and Other
Organisms
Evolution of Chemical Pathways
The Value of Plant Secondary Chemistty for
Understanding Evolutionary Relationships and
Phylogeny of Plants
Why Study Secondary Compounds?
References
DEVELOPMENTS 1l'I11fE SnIDV OF PLAl'IT
SECOl'lDAKV COMPOUNDS
Formerly, relatively large amounts of plant materials were
needed to isolate, purify, and characterize most secondary
compounds. Only those compounds that crystallized readily,
were biologically active, colored, or were present in excep-
tionally large amounts tended to be studied. Recent advances
in chemical microtechniques permit studies of the chemical
composition of individuals of plants and other organisms. It
has become feasible to examine patterns of variation within
and among populations of naturally occurring organisms that
previously were not amenable to study. Among the tech-
niques used to separate complex mixtures of plant com-
pounds are paper (PC), thin-layer (TLC), column (CC), liq-
uid (HPLC and MPLC) and several types of countercurrent
chromatography. Newer techniques for the identification and
characterization of compounds include lH and l3C-nuciear
magnetic resonance (NMR) (Derome, 1989; Sadler, 1988;
Simpson, 1986), mass spectrometty (MS), ultraviolet (UV),
and infrared (IR) spectrophotometty, and x-ray crystallogra-
phy. Development of computerized techniques has permitted
utilization of Fourier transform methods for acquisition of
spectra and greatly increased the capabilities of these meth-
ods. Today, it is possible to isolate, purify, and characterize
amounts as small as several nanograms of secondary com-
pounds from complex mixtures.
At the same time that individual plants may be studied,
various plant organs and tissues can be examined. Immuno-
logical methods and radioactive labeling techniques can be
used to detect compounds at the cellular level. ELISA (en-
zyme-linked immunosorbent assay) serves to localize the
site of accumulation of secondary metabolites by binding
specific antibodies to a solid surface (Wilkinson et al., 1992).
The development of plant cell culture techniques has fa-
cilitated major breakthroughs in the study of the biosynthesis
of plant secondary compounds (Barz and Ellis, 1981; Ellis,
1988; Flores, 1987; Hutchinson, 1986; Wink, 1987). None-
theless, many cultures either do not produce secondary me-
tabolites or produce an array that differs from that found in
the plant. Thus, there are still many questions to be answered.
In instances where a culture fails to produce a particular
chemical, it is often assumed that the enzymes of the path-
way are not formed, but, sometimes, only one enzyme is
repressed or there is no product formation because of poor
precursor supply, lack of storage capacity, or product degra-
dation (Wink, 1987). The addition of exogenous precursors
to the culture medium may increase product yield. For exam-
ple, many plants appear to contain an L-alanine:aldehyde
aminotransferase that results in amine formation; the supply
 Introduction
of substrate appears to be the controlling step in this reaction.
Cultures of lupines rarely accumulate the levels of quinolizi-
dine alkaloids found in the intact plants; in this example,
alkaloids are formed, but are rapidly degraded (Barz and
Koster, 1981; Wink, 1987). Isolation and use of protoplasts
(cells of bacteria, fungi, or plants from which the cell walls
have been removed) for biosynthetic studies sometimes
modifies restrictions on the rate or extent of the uptake of
precursors (Hutchinson, 1986).
In order to understand many of the biosynthetic pathways
described in this text fully, it will be necessary to isolate and
purify many of the enzymes of the pathways to homogeneity.
This has not been completed for any major pathway, al-
though significant steps have been taken for a number of
types of secondary metabolites (Hutchinson, 1986).
Most of the recent progress in alkaloid enzymology has
been made possible by purified enzymes that catalyze the
respective steps of alkaloid biosynthesis. This is illustrated
by the application of these techniques to alkaloid biosyn-
thesis. For example, formation of ajmalicine (1) from its
precursors, tryptamine (2) and secologanin (3), involves four
key intermediates (Fig. 1.1).
The first enzyme of the pathway, strictosidine synthase,
has been purified from Catharanthus roseus about 50-fold.
~H
~HN) ~
5SH~ 2 H"'"
.:'::::.""O-glllCOSYI
+ ~ 0 strictosidine (4)
CH,02C
tryptamine (2) seco-Ioganin (3)
4,21-dihydro-
geissoschizine
(7)
HO
HO
geissoschizine (8)
Fig. 1.1. Biosynthesis of ajmalicine (Hutchinson, 1986; modified and used with pennission of the copyright owner, the Royal Society of Chemistry).
In this case, tissue cultures contained 116 times more of the
enzyme than the roots of the plant, clearly demonstrating
an advantage to plant tissue culture methods. The partially
purified enzyme was immobilized, which increased its tem-
perature stability and permitted the synthesis of strictosidine
(4) (the first of the intermediates mentioned above) (Hutch-
inson, 1986). Two glucosidases were isolated which had
strict substrate specificity for strictosidine. Reduction of
4,21-dihydrogeissoschizine (7) gives geissoschizine (8),
which had previously been thought to be an precursor to
ajmalicine. However, the study of the metabolism of this
compound in vitro revealed that it is a shunt product of the
pathway (Hutchinson, 1986). Study of the enzymes has clari-
fied the early stages of events in this complex pathway (see
Chapter 34).
As another example of the value of enzymological stud-
ies, the major enzymes of the benzylisoquinoline alkaloid
pathway have also been isolated from plant tissue culture
and studied by Zenk and co-workers (see Chapter 34) (Fig.
1.2). An enzyme, (S)-noriaudanosoline synthase, which cat-
alyzes the conversion of dopamine and (3,4-dihydroxyphen-
yl)acetaldehyde (9) into (S)-noriaudanosoline (10) has been
purified about 40-fold from cell suspension cultures of
Eschscholtzia tenuifolia (see also chapter 32 for up-dated in-
__
HN
ajmalacine (1) cathenamine

H0X)! H0)CJ(0 HO~
HO~I :H
I:
HO
CHO
HO
I:
(3,4-dihydroxyphenyl)acetaldehyde (9) (3,4-dihydroxyphenyl)pyrovale (11)
Fig. 1.2. Some intermediates in the biosynthesis of benzylisoquinoline alkaloids.
fonnation). The properties of this enzyme indicate that (3,4-
dihydroxyphenyl)acetaldehyde is the actual precursor for
this series of alkaloids rather than (3,4-dihydroxyphenyl)py-
ruvate (11), as previously suggested (Hutchinson, 1986) (see
Chapter 32).
Because it is often difficult to obtain the quantity of pro-
teins, especially enzymes, needed to study individual steps
of biosynthetic pathways, or those involved in transport or
accumulation of plant secondary metabolites, DNA recombi-
nant methods hold great promise for future studies. In in-
stances where the gene can be cloned and expressed in bacte-
rial cells, it frequently becomes possible to obtain relatively
large amounts of pure, biologically active protein (McPher-
son and Parish, 1987). In order for this method to be more
widely applicable, however, additional knowledge about the
regulation of developmental genes and the control of gene
expression is needed.
WHAT IS A SECONDARY l'IETABOLlm?
The compounds in living organisms may be divided into two
major groups: primary and secondary metabolites. Primary
metabolites are those produced by and involved in primary
metabolic processes such as respiration and photosynthesis,
whereas others, including many pathways clearly derived
from primary metabolic pathways, are considered "second-
ary." In practice, there is overlap between the two tenns
and, other than providing a pragmatic way to identify a large
body of compounds, pathways and literature, too much sig-
nificance should not be attached to the definitions.
Primary metabolites, as mentioned above, include the
components of processes such as glycolysis, the Krebs or
citric acid cycle, and, in photosynthetic organisms, photo-
synthesis and associated pathways. Primary metabolites,
which are virtually identical in most organisms, include
Ubiquitous small molecules such as sugars, amino acids, tri-
carboxylic acids, or Krebs cycle intennediates, the universal
building blocks and energy sources-as well as proteins,
nucleic acids, and polysaccharides, that differ in structural
detail from one organism to another, but which appear to
have universal functions as enzymes, structural, and heredi-
tary materials. Many sugars (such as glucose), protein amino
acids, low-molecular-weight organic acids, many fatty acids,
Introduction
CO2- HO
HO
,;7
~
I
(S)-norlaudanosoline (10)
and some proteins are identical in animals, bacteria, fungi,
plants, and other organisms. Nonetheless, differences in the
pathways leading to these primary metabolites and the actual
compounds involved in some fundamental processes differ
in some instances (Haslam, 1986).
Secondary metabolites, produced by pathways derived
from primary metabolic routes, are numerous and wide-
spread, especially in higher plants. More than 20,000 were
known in 1985 (Hartruann, 1985), and at least 1000 addi-
tional compounds. are described each year. In practice, the
difference between the primary and secondary metabolites
is fuzzy. Plant honnones such as gibberellic acid, indoleace-
tic acid (auxin), ethylene, kinetin, and abscisic acid, as well
as compounds involved in plant cell wall structure such as
cinnamic acid and its polymeric derivative, lignin, are inter-
mediate between primary and secondary metabolism (Birch,
1973). In some instances, compounds nonnally considered
primary metabolites may accumulate in large amounts and
behave in a manner usually associated with secondary me-
tabolites. Entities such as shikimic acid and squalene, which
initially were considered secondary metabolites, were subse-
quently shown to be important intennediates in the fonnation
of primary metabolites (phenylalanine, tyrosine and trypto-
phan, and steroids, respectively).
The amount of any plant secondary compound found in
an organism is the result of an equilibrium among synthesis,
storage, and degradation. Regulation of secondary metabo-
lism is complex. The onset of secondary metabolism is
linked to the developmental stage of the organism and is
often closely linked to morphological and cytological
changes (Haslam, 1986). In general, the fonnation of prod-
ucts in secondary metabolism appears to be enzyme limited,
but the level of substrates present influences the production
of other secondary metabolites, especially in artificial culture
(Bu'Lock, 1980). The degree to which anyone prevails often
depends on the developmental stage of the plant and a variety
of other factors. In the fungal genus Claviceps, biosynthesis
of the alkaloids begins shortly after fonnation of two key
enzymes, DMAT synthetase (tryptophan dimethylallytransf-
erase) and chanoclavine cyclase, at the beginning of the sta-
tionary phase of growth. The rate of synthesis is detennined
by the first of these enzymes; L-tryptophan, a substrate of
this enzyme, must be added early in the growth phase to
serve as a precursor (Haslam, 1986).
 Introduction
In another example of the complex sequences of factors
controlling secondary metabolite biosynthesis, the enzyme
phenylalanine ammonia-lyase (PAL) in higher plants is often
associated with the rate of accumulation of flavonoids and
has been considered by many to be the principal regulating
factor in the synthesis of phenylpropanoids. However, in
parsley cell cultures, two groups of enzymes can be distin-
guished: enzymes of general phenylpropanoid metabolism
(including PAL) and those specific to pathways leading to
flavones and flavonol glycosides. Both are induced by irra-
diation with UV light, but the first group reaches maximal
activity several hours before the second and then declines
more rapidly than the latter group. However, the level of
free phenylalanine normally is very low. Hence, in this in-
stance, the amount of phenylalanine is more likely to be
limiting than the level of enzymes (Haslam, 1986).
Several new approaches to the study of the variation of
plant secondary compounds have been undertaken by Som-
erville and Browse (1991). More than 10,000 individuals of
Arabidopsis thaliana (Brassicaceae) have been screened for
mutants in the pathways of lipid metabolism, and mutants
of at least 12 steps have been identified. None of these mu-
tants can be distinguished from the wild type by visual in-
spection under normal growth conditions. Most mutations
cause a loss or reduction in the amount of an unsaturated acid
and affect the accumulation of a less saturated precursor. By
this approach, it has been confirmed that, except for <l.9-
unsaturated C 18 fatty acids, double bonds are introduced into
fatty acids that are esterified to lipids rather than the acyl-
CoA or acyl-ACP derivatives of the acids. At least eight of
these genes now are known to control specific desaturases
in this species. The mutations have been genetically mapped
and this information forms the basis to isolate the corre-
sponding genes (Somerville and Browse, 1991). Analysis of
these mutations has provided insight into the regulation of
membrane lipid desaturation. Other mutants had defects in
genes involved in fatty acid elongation. The availability of
specific alterations in membrane fatty acid composition pro-
vides another method to examine the physiological conse-
quences in variation of lipid unsaturation. Certain types of
unsaturation are directly linked to cold tolerance. These stud-
ies promise to shed light, not only on the biosynthesis but
also control of synthesis and accumulation, as well as the
influence of plant secondary compounds on the physiology
and ecology of the plant (Somerville and Browse, 1991).
Our knowledge of secondary compounds is limited
mostly to those that are accumulated, but, in some instances,
compounds normally not thought to be present have been
found at very low levels. For example, azetidine-2-carbox-
ylic acid, normally found in the Liliaceae and in some leg-
umes, has been isolated from amino acid fractions of sugar
beets (Beta vulgaris, Chenopodiaceae) isolated as a by-prod-
uct of sugar manufacture. A number of other unusual amino
acids also were isolated from the mixture. About 500 kg
of these fractions is obtained from 106 tons of sugar beets
(Fowden, 1972). The formation of quinolizidine alkaloids
in cell cultures of Lupinus polyphyllus (a legume), Conium
maculatum (Apiaceae), Daucus carota (Apiaceae), Atropa
belladonna (Solanaceae), Chenopodium rubrum (Cheno-
podiaceae), Spinacia oleracea (Chenopodiaceae), and Sym-
phytum officinale (Boraginaceae) was induced by adding
foreigu alkaloids and a number of other "disturbances"
(Wink and Witte, 1983) (see Chapter 30). Of these, only the
legume would normally be expected to contain quinolizidine
alkaloids. These and other studies suggest that we do not
know the full biochemical potential of any plant.
THE ORIOIN OF SECOl'lDAKY PAntWAYS
Al'ID CO!IfPOUl'lDS
The ultimate origin of secondary compounds in all organ-
isms is based on accumulation of changes (or mutations) of
genetic materials originally associated with primary meta-
bolic pathways. Although the process probably is not en-
tirely random, changes in DNA-RNA responsible for the
formation of particular types of secondary compound are
more or less accidental. Most of the products of altered path-
ways are deleterious to the producing organism and, if ex-
pressed, the organisms (and the genes).that produce them
are quickly reduced in frequency or eliminated by natural
selection. Changes in secondary metabolic pathways and the
resultant compounds generally are tolerated more readily
than changes in primary pathways and compounds. The ef-
fects of these changes may be witnessed as "modified en-
zyme specificity," availability of substrates, production of
a modified structure, or a variety of other factors (Haslam,
1986).
Most prokaryotic organisms have relatively simple path-
ways for respiration and synthesis of food materials. These
organisms have a single copy of most genes, and any changes
that occur in the genetic information are expressed. Most of
these changes are probably lethal, but some have selective
advantage and are maintained. The number of compounds
other than primary metabolites (those involved in respiration
and/or synthesis) produced by prokaryotic organisms is lim-
ited. Much of our knowledge of the origin of secondary
metabolites in prokaryotic organisms is based on bacteria
and blue-green algae in culture, and few studies have been
made of metabolism in their natural habitats. There is evi-
dence, however, for antagonisms among soil organisms and
the antibiotics produced by some species appear to bind spe-
cifically to receptors in other microbes (Williams et al.,
1989). Although microorganisms have been used exten-
sively for the study of the biosynthesis and catabolism of
secondary metabolites, the extent to which identical se-
quences occur in plants varies.
In contrast, the amount of genetic material in plants and
other eukaryotic organisms is greater than in prokaryotic
organisms and is organized into chromosomes. Because
there are two copies of each chromosome for diploid stages
of organisms, the accumulation of recessive characters is

possible and many changes are not expressed immediately.
In addition. the existence of multiple copies of genetic mate-
rial produced by polyploidy or increase in the amount of
chromosomal material promotes the accumulation of genetic
variation at particular alleles, because one of a group of
multiple copies of a gene may change without a significant
effect on other copies or on primary metabolic pathways.
Many plant enzymes occur as mixtures of closely related
but distinct proteins (isozymes) that presumably originated
from genetic material altered in the manner described above.
If a particular metabolite can be tolerated, or its synthesis
is favored, the necessary mechanisms that pennit "pools"
of compounds to fonn also must exist, if the compound is
to be accumulated.
Selection against deleterious modifications may lead to
an apparent increase in those changes with "positive" ad-
vantage for a particular organisms under a particular set of
circumstances. Much confusion has been brought about by
"teleological" statements concerning the origin of second-
ary metabolites that have been suggested to play roles in
plants and their interactions with other organisms. The origin
of secondary metabolites and the capability of an organism
to accumulate them is detennined largely by stochastic
events influenced by preexisting starting materials (for in-
stance, the initial pathways and precursors available for
modification, whereas accumulation of secondary com-
pounds with functions in living organisms is directed largely
by natural selection. The parameters involved in the process
of natural selection which lead to this accumulation undoubt-
edly are many and poorly understood. Attempts to account
for the mixtures of secondary metabolites found in many
organisms, without considering the complexity of the bio-
logical and physical environment in which these organisms
arose and exist, in some simple "satisfactory" or "explicit"
manner seem naive. Several hypotheses about the origin and
accumulation of secondary compounds have been proposed.
TUB "WASTE PRODUCT" HYPOTHESIS
The relatively large number and amount of secondary metab-
olites observed in nature and the notion that these com-
pounds arose from' 'errors" in primary metabolism, coupled
with the apparent absence of excretory mechanisms in
plants, led to the idea that secondary compounds arise and
accumulate as "waste products" (Luckner, 1972, 1990;
Luckner et aI., 1976; Mothes, 1966c, 1976; Paech, 1950).
Mothes originally felt that secondary plant substances are
not essential to the existence of plants. In support of this
idea, he observed that they can be missing from individual
members of a related group (of plants) and that they are
not an "inherent taxonomic characteristic" (Mothes, 1966a,
I 966b, 1966c).
Several types of data suggest that the "waste product
hypothesis" is not a likely explanation for the origin of sec-
ondary compounds. For example, the idea that plants cannot
excrete secondary compounds has been disproved. Many
Introduction
compounds are leached from the above ground parts of
plants by precipitation. Others are exuded from roots of
plants (Tukey, 1970). Well-organized enzyme complexes in-
volving channeling of precursors are involved in the biosyn-
thesis of many types of secondary compounds (Hrazdina and
Jensen, 1992). The synthesis of these compounds requires
many kilobases of DNA. To suggest that such highly ordered
processes arose from a series of neutral mutations that have
accumulated contradicts the accepted basis of evolutionary
changes (Williams et aI., 1989). Further, it is now known
that many secondary metabolites exist in a state of dynamic
equilibrium Of "turnover" in which compounds are con-
stantly being synthesized and broken down by anabolic and
catabolic enzymes (Barz and Koster, 1981). It has been pos-
tulated that this process may involve further biosynthetic
transfonnation, polymerization, or catabolism to yield pri-
mary metabolic consituents (Haslam, 1986). Feeding of ra-
dioactively labeled precursors indicates that the half-lives of
many of these secondary metabolites are between 6 and 24
h. Other compounds, particularly those of strnctural materi-
als and from storage tissues/organs such as seeds tum over
at much lower rates. The pathways by which "turnover"
occurs are known in few plants. Some interesting examples
are known from the work of Croteau and Gershenzon on
monoterpenes in mints (see Chapter 19) and from the work
of Lieberei and Selmar (Selmar, 1989; Selmar et aI., 1988)
on cyanogenic glycosides in Hevea brasiliensis, and Gander
(1962) on the cyanogenic glycoside dhurrin (see Chapter
16).
The origin of certain types of compounds such as glyco-
sides and methylated derivatives has been ascribed to cata-
bolic changes and detoxication mechanisms (Hartmann,
1985; Luckner, 1972). Indeed, there are marked differences
in the biological activities of aglycones and the correspond-
ing glycosides and methylated derivatives (e.g., see Chapter
11). However, detoxification seems inadequate to explain
the variety of secondary metabolites found in plants (Wil-
liams et aI., 1989).
The line between catabolic and anabolic activity is as
nebulous as that between primary and secondary metabo-
lism. The mycotoxins aflatoxin and patulin give every ap-
pearance of being catabolic in nature (Haslam, 1986). Many
secondary metabolites possess elements of structure that di-
rectly parallel those observed in the catabolism of primary
metabolites such as a-amino acids (Haslam, 1986).
If secondary metabolites are "waste products" and the
"expense" involved in making, accumulating, and maintain-
ing these compounds is significant (see below), plants that
make them would be at a considerable selective disadvantage
with regard to plants that do not. Less efficient organisms are
often eliminated in the process of natural selection.
INTERNAL FUNCTIONS OF PLANT SECONDARY
COMPOUNDS
Others have suggested that secondary metabolites once
played a metabolic role in the organisms prOducing them or
that they were primary metabolites in the past (Williams
 Introduction
et al., 1989). Many compounds do have roles intermediate
between primary and secondary metabolism. For instance,
some plant secondary compounds (e.g., the gibberellins, ab-
scisic acid, ethylene, indole acetic acid, kinetin, and a num-
ber of other plant hormones) are associated with plant growth
and development.
Other secondary metabolites serve as reserves of energy
and as precursors of important organic compormds or
sources of nitrogen and may be recycled within the plant
(Rosenthal, 1982). As nitrogen is often a limiting factor for
the growth of plants, it is not surprising that plants use it
"economically"; for this reason, many nitrogenous com-
pounds appear to be involved in multiple functions in plants,
which include storage of nitrogen, plant defense, and regula-
tory roles (Jones, 1979; Seigler and Price, 1976; Swain,
1976). For example, nonprotein amino acids accumulated in
legume seeds disappear upon germination of the seeds, and
the nitrogen appears to be reused (Rosenthal, 1982). Cyanol-
ipids, which make up about 15% of the total biomass of the
seeds of Ungnadia speciosa, are mobilized and disappear in
about 2 days during germination (Selmar et al., 1990); the
nitrogen again appears to be reutilized, although in this in-
stance, it may be transferred to cyanogenic glycosides. Simi-
lar changes occur in instances when alkaloids are accumu-
lated in seeds. They undoubtedly play a defensive role but
are mobilized and recycled during germination (Waller and
Nowacki, 1978; Wink, 1987).
Modified secondary metabolites have different solubility
and other physical properties than the parental compounds
and may be involved in transport and accumulation mecha-
nisms in plants (Wink, 1987). Nonetheless, there is little
evidence to support the notion that most or all secondary
metabolites once had primary roles (Williams et al., 1989).
THE "OVERFLOW" OR EXCESS PRIJIIARY
I'IETABOLISJllIIYFOTHESIS
In instances of unbalanced growth, secondary metabolites
have been envisioned by some as shunt metabolites produced
in order to reduce abnormal concentrations of normal cellu-
lar constituents~ The synthesis of enzymes designed to carry
out secondary metabolism permits primary metabolic en-
zymes to continue to function until such time as circum-
stances are propitious for renewed metabolic activity and
growth. For example, this could be linked to the depletion
of nutrients such as phosphorus or nitrogen (Bu'Lock, 1980;
Haslam, 1986).
Phosphoenolpyruvate, pyruvate, acetyl coenzyme A, and
a number of amino acids involved in the biosynthesis of
cyanogenic glycosides, alkaloids, glucosinolates, and antibi-
otics are linked to the final portion of the glycolytic sequence
and immediately prior to entry into the Krebs cycle. A shift
from normal sustained growth to that in which there is a
decreased uptake of acetyl coenzyme A in the Krebs cycle
may reflect a diminished requirement for nucleotide triphos-
phates (e.g., ATP). In this way, the synthesis of secondary
compounds is interpreted as an "overproduction" of metab-
olites (Haslam, 1986).
The addition of exogenous substrates of primary metabo-
lites to organisms in culture (or blocking of particular steps
of biosynthetic pathways) can result in "overproduction"
of either primary or secondary compounds. Gross primary
production by plants exceeds net primary production. Addi-
tionally as much as 38% of carbon fixed by photosynthesis
may be lost through photorespiration. The process of cya-
nide-resistant respiration represents an obvious nonaccumu-
lative mechanism by which plants can divide any overflow
into carbon dioxide (Waterman and Mole, 1989).
Although "overflow" may occur in some instances,
many plants that would not experience overflow possess a
variety of secondary metabolites and this theory does not
explain adequately the vast number of secondary metabolites
known to occur. Neither does it address the functions many
of these compounds are now known to possess (Williams et
al., 1989).
THE "II'ICREASE II'I FITl'lESS" HYPOTHESIS
Many, especially a number of ecologists, have come to ac-
cept the hypothesis that secondary metabolites increase the
"fitness" of individuals that possess them and that those
individuals have been favored by the process of natural se-
lection (Harbone, 1986; Rosenthal and Jansen, 1979; Swain,
1977). Not all of the large number of compounds in any
particular plant will have obvious benefits. These benefits
simply may not be recognized at present, although it has
been suggested that "mechanisms must have evolved that
ensure generation and retention of chemical diversity." Re-
tention of inactive compounds is one way of increasing
chemical diversity and the probability of producing active
compormds in the face of consumer adaptation" (Jones and
Firn, 1991). The "increase in fitness" hypothesis is the ouly
one that accounts for the fact that many natural products
trigger very specific physiological responses in other organ-
isms and, in many cases, bind to receptors with a remarkable
complementarity (Williams et al., 1989). These workers sug-
gested that "natural products may ... aid an organism's sur-
vival in the absence of an immune system."
However, one of the key considerations in the hypothesis
is that there can be evolutionary selection against those indi-
viduals in popUlations of organisms that lack certain second-
ary metabolites and, in that manner, those organisms that
have secondary metabolites with beneficial aspects are fa-
vored. Accordingly, those compounds which impart benefit
to plants have become prominent. Metabolites with "neu-
tral" functions may be selected against because of the' 'met-
abolic cost" associated with their production, but if the cost
of production is sufficiently low, many relatively inactive
compounds could be tolerated for a period of time (Jones
and Fim, 1991).
 Introduction

THE "COST" OF SECOl'lDAKY METABOLITE In a genetically based series of experiments, seed produc-
SYNfHESIS tion of the tall morning glory, Ipomoea purpurea, was used
as a measure of fitness. No observable reduction in fitness
was observed in the presence of the herbivore sweet potato
The concept of "cost" in terms of metabolic energy, avail-
flea beetle, Chaetocnema confinis (Simms and Rausher,
ability of precursors and limiting factors, as well as ecologi-
1987). On the other hand, the magnitude of cost of produc-
cal considerations and evolutionary fitness has engendered
tion of furocoumarins in the wild parsnip, Pastinaca sativa,
a large body of literature. Many factors that must be consid-
in terms of umbel production, is significant (Berenbaum et
ered in making cost estimates have been discussed and evalu-
al., 1986).
ated (Chew and Rodman, 1979). Estimates of the energetic
Metabolic inefficiency, as implied by the waste product
outlay to produce and maintain plant secondary compounds
hypothesis, seems unlikely if a significant cost is associated
vary widely, from perhaps 8-10% of a plant's total meta-
with the production of secondary metabolites. Most plants
bolic efforts (Robinson, 1974, 1980) to nothing (Simms and
produce and accumulate relatively large amounts of mixtures
Rausher, 1987). Carbon usually is not limiting in plant bio-
of secondary compounds, despite any metabolic cost of syn-
synthesis, and formation of carbon-based compounds may
thesis and accumulation. The cost of maintenance of cata-
play a beneficial role to plants under high light conditions,
bolic enzymes must also be considered. Further, plants can
by helping to dissipate excess energy associated with photo-
excrete most of the compounds produced andlor limit their
synthesis. This may be a major function of photorespiration
production by other means. All these factors suggest that
(Selmar, 1992). In general, synthesis of secondary metabo-
plants with secondary compounds are at a selective advan-
lites containing limiting elements, such as nitrogen, incur
tage.
higher costs. Most approaches to estimate "cost" or "ex-
In summary, the cost of production of secondary metabo-
pense" attempt to assess the physiological cost to the plant
lites is difficult to estimate. The physiological cost of pro-
but fail to evaluate the effects of resistance on fitness or
duction varies for different secondary compounds; costs for
fecundity (Bazzaz et al., 1987), and, hence, the constraints
compounds containing limiting elements such as nitrogen
on the evolution of defense.
may be especially sensitive to enviromnental fluctuations in
Several theories related to the distribution of plant sec-
these nutrients. Physiological cost and evolutionary success
ondary compounds for defensive purposes have been pro-
are not linked in linear fashion; for evolutionary considera-
posed (Feeny, 1990). Many "qualitative" or "mobile" de-
tions, some estimate of cost linked to fitness is essential.
fensive compounds contain nitrogen, whereas most of the
Many aspects of the origin of secondary metabolites and
"quantitative" or "immobile" compounds do not (Coley et
their accumulation remain obscure. No one theory can ac-
al., 1985; Feeny, 1990; McKey, 1974, 1979). McKey (1974)
count for all the problems inherent to resolving this enigma.
proposed that the amount of defensive compounds in particu-
When all the possibilities are examined, some examples can
lar tissues should reflect the value of those tissues to the
be found that can be explained by each of the hypotheses.
plant. In practice, however, plants are subject to a variety
Further, some compounds may have arisen by different path-
of physiological constraints that vary with the availability
ways in an assortment of organisms in response to a variety
of resources and alter the relative costs of different types of
of factors.
defense (Feeny, 1990). Plants which are adapted to high light
intensities in nutrient-poor habitats, for example, are likely
to have a relative surplus of carbon and, hence, to deploy
carbon-based defenses (Bryant et al., 1983). Unless con- V ARIATIOl'l OF SECOl'lDAKY COMPOUl'lDS
strained by other factors, plants should maximize the bene-
fits conferred by secondary metabolites relative to the cost Genotypic variation gnarantees diversity in both murpholog-
of reclaiming or replacing them (McKey, 1979). In studies ical and chemical characters. In addition, more complex pat-
of light gap species in a lowland rain forest in Panama, Coley terns of variation or polymorphism occur in many plants;
concluded that "pioneers" or "light gap specialists" were individuals from natural populations of plants often differ in
grazed more than "persistents" that could tolerate only low the amounts and types of compound present. Roots, leaves,
light levels and grew in the shade. The former produced stems, seeds, fruit walls, flowers, and buds frequently differ
relatively fewer defensive compounds. She proposed that in chemical composition. Further, each of these parts may
plants adapted to favorable areas (such as light gaps) can vary at different stages of development and at various times
grow fast enough to escape the relatively high levels of dam- of the year (Luckner, 1990; Waterman and Mole, 1989;
age resulting from low levels of defense. Plants that typically Wink, 1987). Daily (diurnal) variation of many compounds
occupy unfavorable habitats are limited in their productivity, also occurs (Fliick, 1963; Luckner, 1990). The reasons that
cannot grow rapidly, and must rely on greater resistance to plants fail to produce or accumulate compounds are numer-
herbivores. She further stated that the availability of re- ous, but include regulatory processes, blockage of pathways
sources in the environment is the major determinant of both by mutations, and the absence of precursors at the site of
the amount and type of plant defense (Coley et al., 1985; synthesis.
Feeny, 1990). Plants are often quite "plastic." They vary in complex
 Introduction
ways, not only because of genetic differences as discussed
above but also in response to environmental factors. Both
qualitative and quantitative variation of secondary metabo-
lites is known to occur in response to various types of stress
(Waterman and Mole, 1989). Among these are biological
stresses such as attack by fungi, bacteria, nematodes, insects,
or by grazing by mammals, and abiotic stress such as ex-
tremes of temperature and moisture, shading, presence of
heavy metals, and injury (Fliick, 1963; Gershenzon, 1984).
Formation of many secondary compounds is influenced
by environmental stress in both general and specific manners
(Waterman and Mole, 1989). Plant secondary metabolites
respond to changes or differences in soil nutrients, but not
all plants respond in similar ways. In general, production of
non-nitrogenous shikimic-acid-derived metabolites is in-
creased-when plants are grown under nutrient-deficient con-
ditions (Waterman and Mole, 1989). Compounds from mev-
alonic acid pathways do not show consistent relationships.
An increase in light intensity tends to produce increases in
phenolic compounds and terpenoids. Water stress has been
reported to lead to increases in cyanogenic glycosides, glu-
cosinolates, terpenoids, alkaloids, and condensed tannins
(Waterman and Mole, 1989). Grazing is known to increase
the amounts of many secondary compounds in plants; the
changes observed are similar to general wound responses,
although insect grazing caused more widespread and greater
response in birch than artificial damage (Waterman and
Mole, 1989).
Other responses, such as formation of phytoalexins, are
more specific (Chappell and Hahlbrock, 1984; Luckner,
1980). It has been shown that production of secondary com-
pounds in cell cultures also can be enhanced by environmen-
tal stress. Treatment of cell cultures with fungal, bacterial,
or plant cell wall materials often results in the formation of a
number of flavonoids, stilbenes, terpenoids, anthraquinones,
rutacridone alkaloids, sanguinarine, and gossypol (Eilert,
1987; Heinstein 1985). In some cases, production of these
metabolites is transient. Clearly, we need more information
on the basic principles of the defensive response, such as
structures and perception of defensive signals, transduction,
and translation of these signals into a response (Luckner,
1980; Wink, 1987).
Especially complex variation arises in situations in which
hybridization or the combination of two genetically different
groups exists. In some plants, "additive" chemistry, appar-
ently produced by the presence of two sets of enzyme sys-
tems, has been observed. In hybrids of Baptisia leucophaea
and B. spherocarpa, the appearance of a hybrid compound
(a 7-0-glucoside-3-0-rutinoside) can be explained as such
an additive combination (one parental type produced the 7-
O-glucoside, whereas the other produced the 3-0-gluco-
side). Other compounds, predicted on the basis of the chem-
istry of the putative parents, are mysteriously absent (Alston
et al., 1965; Markham and Mabry, 1968).
"Races" or chemically distinct populations of plants
often are observed when a plant species is studied over a
great geographic distance. In contrast, examination of popu-
lations of other plant species often reveals a gradual variation
in plant chemistry over a distance. These racial or elinal
shifts in chemistry usually parallel changes in other charac-
teristics of the plant involved.
When plants reproduce elonally or vegetatively, the
amount of variation in plant chemistry may be quite small.
SITE OF SYl'ITIIESIS Al'ID ACClJlllULATlOI'l
OF SECOl'lDARY COJIIPOV1'lDS
Although all cells of a plant harbor the genes for synthesis
of a particular secondary metabolite, ouly a limited number
express them and produce the enzymes needed to make the
compound. This temporal and spatial expression of genes is
a typical feature of eukaryotes (Kutchan, 1983; Wierman,
1981; Wink, 1987). For example, highly colored flavonoids
and anthocyanins are typically formed in flowers or fruits.
Further, this compartmentation is observed within single
cells (Luckner, 1990; Matile, 1978; Wink, 1987). However,
even if a particular secondary metabolite is found in an organ
or tissue, this does not necessarily mean that the compound
was formed there. Long-distance transport must also be con-
sidered (Sehnar, 1989; Sehnar et al., 1988). This is particu-
larly true in epidermal cells. Many secondary metabolites
are synthesized elsewhere and transported to these cells
which form an early line of defense for the plant (Luckner,
1990; Wink, 1987).
Lupine alkaloids are formed in the green, aerial parts of
Lupinus polyphyllus that incorporate labeled cadaverine into
the lupanine skeleton, consistent with the fact that the en-
zymes of alkaloid biosynthesis, in this case, are located in
the chloroplast stroma (Hartmann, 1985). Roots of the intact
plants or in vitro cultured roots do not. A similar sitoation
obtains for coniine in Conium maculalum, where the en-
zymes occur in both the chloroplasts and mitochondria.
However, alkaloids are rarely formed in plastids (Hartmann,
1985), but are usually formed in the cytoplasm. Chloroplasts
are not only the site of photosynthesis, but also of lipid,
amino acid, and terpenoid biosynthesis (Schultz et al., 1985;
Wink,1987).
All these factors are important for the development of
plant cell cultures. For example, cultures of Lupinus poly-
phyllus only synthesize alkaloids when kept in the light and
alkaloid content is correlated with chlorophyll content. This
may be explained by a better supply of lysine (formed in
the chloroplasts), the fact that the enzymes of alkaloid bio-
synthesis have a pH optimum of about pH 8, which is created
in the chloroplast stroma only in the light, and that the en-
zymes are subject to activation by reduced thioredoxin which
is generated only in the light (Wink, 1987). The alkaloids
of Peganum harmala, which are formed in the roots of the
plant, act in an opposing manner. Cultures maintained in the
light fail to produce the alkaloids, whereas those kept in
the dark synthesize harman alkaloids (Barz and Hiisemann,

1982). Similar effects have been observed with antbraqui-
nones and lipoquinones in Morinda Lucida cell cultures
(Schultz et al., 1985). The presence of tissue-specific "pro-
moters" is linked to expression of secondary compounds in
many tissues. All these data indicate the need to understand
the basic biochemistry and physiology of the biosynthesis
of secondary compounds before it will be possible to initiate
synthesis in cell cultures in a controlled manner{Hutchinson,
1986; Rosahl et al., 1986).
In addition to these factors, the mechanisms for product
accumulation and storage are of prime importance, but little
studied (James, 1950; Matile, 1978, 1984; Wink, 1987). In
general, there are few data concerning the site of storage of
secondary compounds within the plant. As observed above,
storage at a particular site does not necessarily imply that
the compound was synthesized there. For example, lupine
alkaloids are accumulated in epidermal cells (which lack
chloroplasts) but synthesized in mesophyll cells. The alka-
loids are transported to the epidermis via the phloem. Accu-
mulation depends on the season and developmental stage of
the plant (James, 1950; Mothes, 1955). Sites of synthesis
and accumulation often are separated in cells by compart-
mentation. Lipophilic compounds tend to be accumulated
in membranes, vesicles, dead cells, or extracellular sites.
Hydrophilic compounds tend to be stored in an aqueous envi-
ronment, typically the vacuole (Matile, 1978, 1984; Wink,
1987).
Improvements in techniques for isolation of protoplasts
(plant cells without the cell wall) and vacuoles have facili-
tated studies of the uptake of plant secondary compounds.
The concentrations of secondary metabolites in the vacuole
may be higher than 500 mmollL. Compounds are usually
stored in the vacuole against a concentration gradient; the
tonoplast membrane (the membrane surrounding the cell
vacuole) appears to contain a number of active proton-trans-
locating ATPases and pyrophosphatases. Import of com-
pounds into the vacuole is achieved by an H+-substrate anti-
port mechanism (Sze, 1984; Thom and Komor, 1984). These
mechanisms for import of alkaloids into the vacuole are
highly specific. In Fumaria capreolata vacuoles, (S)-scoule-
rine and reticuline are transported, whereas the R-forms are
not. This transport is activated by ATP, displays saturation
kinetics, depends on hydrogen ion concentration, and is sen-
sitive to inhibitors (Deus-Neumann and Zenk, 1984, 1986).
In suspension cultures of cells of Lupinus polyphyllus, spar-
teine and lupanine are accumulated. The vacuoles take up
these compounds (which are normally produced in the plant)
but discriminate against other alkaloids. The system is also
pH and temperature dependent and can be activated by ATP
and KCI. In other plants, a variety of secondary compounds
such as coumaryl glycosides, flavonoids, and cardenolides
appear to be taken up by similar mechanisms (Matern et al.,
1986; Werner and Matile, 1985; Wink, 1987).
Long-distance transport in plants is undoubtedly impor-
tant, but little studied. The mechanisms involved are not
elucidated. Interestingly, few (if any) cell cultures produce
Introduction
a secondary metabolite that is subject to long-distance trans-
port in the differentiated plant (Wink, 1987).
IN'mRACTIVE ROLES OF PLANT SECOl'IDAKY
COMPOUl'lDS
Plants exist in contact with a changing array of animals
(mammals, insects, and nematodes), plants (algae, bry-
ophytes, ferns, and higher plants), fungi (mycorrhizal associ-
ates, pathogens, etc.), and bacteria. Secondary compounds
(allelochemics) are involved in interactions with and be-
tween these organisms (Nordland et al., 1981; Swain, 1977;
Whittaker and Feeny, 1971). Many appear to confer protec-
tion to the plants that produce them (allomones); others are
involved in processes such as pollination and fruit/seed dis-
persal (synomones); and yet others are used by the interact-
ing organism to locate the plant host (kairomones). Similar
considerations apply for insects which now are being recog-
nized as rich sources of secondary metabolites. Although
insects sequester plant-derived compounds, there is now
considerable evidence that many compounds can be synthe-
sized de novo by the insects (Nahrstedt, 1989; Pasteels et
al., 1988, 1989, 1990). For example, larvae of the burnet
moth, Zygaena trifolii, feed on plants that produce the cyano-
genic glycosides linamarin and lotaustralin. Studies of incor-
poration of labeled precursors indicate that this insect both
sequesters and synthesizes the compounds (Nahrstedt,
1989). The origin of the pathways leading to these com-
pounds is an important unanswered question. Some products
and steps of the pathways are similar, suggesting a degree
of homology between insect and plant enzymes. Did these
pathways and compounds arise independently within the two
groups or have they been transferred from plants to insects?
Although either alternative would seem unlikely, recent
work suggesting that mites have transferred transposable ele-
ments between insects makes interspecies transfer of genetic
material a more acceptable possibility (Houck et al., 1991;
Robertson, 1993).
PAtTERNS OF SIMULTANEOUS EVOLUTION
OF PLANTS Al'ID OTHER OROAl'llSIIIS
As observed above, the chemistry and morphology of indi-
viduals in most populations of any organism are variable.
In response to selection pressures such as herbivory, the
abundance of certain phenotypes of plants within a given
population will be reduced. If selection pressure is sufficient
and is maintained for a sufficient period of time, plants of
this phenotype may become greatly reduced in number
within the population or, in extreme cases, disappear. In
response, the numbers of the herbivore will decrease (assum-
ing that the herbivore is limited to this plant). If a plant
phenotype that is avoided by the herbivore exists within the
population (or is formed by a mutation or by some new
10 Introduction
genetic combination), a gradual shift toward that phenotype
will occur.
Variability occurs in both plant and herbivore popula-
tions. As a particular plant phenotype increases in numbers,
any phenotypes of interacting herbivores which exist or arise
and are capable of utilizing the plants will be favored also.
This type of interaction probably is and has been very
common in the course of evolution. As all organisms have
evolved in the presence of other organisms, it is difficult
to imagine circumstances in which this situation does not
prevail.
One ofthe classic systems of this type involved butterflies
and plants and, in particular, insect herbivores on Passiflora
species (Ehrlich and Raven, 1964). From a systematic evalu-
ation of the kinds of plants fed upon by the larvae of certain
groups of butterflies, these authors concluded that plant sec-
ondary substances played the leading role in determining
patterns of utilization. They felt that this was true for other
groups of insects that were phytophagous or parasitic on
plants as well. In general, whenever a plant produces chemi-
cal products that are deleterious or repellent to an insect (or
other herbivore) in some way, the plant is at least partially
protected (Bemays and Chapman, 1987a,b; Jermy, 1976;
Jermy and Szentesi, 1978; Nahrstedt, 1989; Spencer, 1988).
Past evolutionary patterns have resulted in a great diversity
of plant secondary compounds and the herbivores on most
plants represent only a small fraction of the total herbivores
possible. These herbivores often appear to be "coadapted"
or "coevolved" although some herbivores are generalist
feeders and have the ability to consume a broad range of
plants. If a recombinant or mutation appears in an insect
population (or is selected from a variation that already exists)
that permits the insect to feed on some previously protected
plant group, selection will carry the line into a new adaptive
zone. Thus, the diversity of plants not only will tend to aug-
ment the diversity of insects, but the converse also appears
to be true. Changes in food source would be especially fa-
vored in situations where the supply of the "preferred" food
plant is limited. In some instances, formerly repellent sub-
stances (allomones) might become cues that help the insects
to locate the host plant (kairomones). Of course, the com-
pounds may at the same time be allomones to noncoadapted
insects. If the newly adapted insect herbivore is too success-
ful, selection for new resistant chemical variants in the plant
will be favored. Thus, plant secondary chemistry appears to
have played a strong role in the radiation of both plants
and herbivores. Clearly, other factors are involved and plant
chemistry is not the dominant driving force for diversifica-
tion in many instances (Luckner et al., 1976).
Why do we have so many secondary compounds? Radia-
tion of chemically distinct plant popnlations in response to
herbivores and concurrent proliferation of herbivores with
different abilities to tolerate the presence of the resulting
compounds illustrates at least one major way by which large
numbers of plant secondary metabolites could have arisen.
In instances in which the second organism (here, the her-
bivore) further causes a change in gene frequency of the first
(the plant), the phenomenon is sometimes called coevolution
(Berenbaum, 1983; FutuymaandKeese, 1992; Futuymaand
Slatkin, 1983). Few, if any, proven examples exist in which
a one-on-one gene relationship of such changes has been
demonstrated.
As the basic biochemical systems (including respiration
and detoxication of various compounds) are similar in many
animals, it is not surprising that a large number of plant
secondary compounds are deleterious to the growth and de-
velopment of many animals. The toxicity or poisonous prop-
erties of plants, in many cases, are determined by whether
the animal has previously become coadapted to the plant
compounds. In some cases, medicinally useful compounds
(coincidentally?) modify the physiology of other organisms
in a beneficial way (Swain, 1972; Wagner and Hiirhammer,
1971). A new area of research involving examination of
the role of the chemical "messages" involved in biological
interactions has emerged. A number of examples from this
new area of research, often called "chemical ecology," will
be presented in this text.
BVOLUI10N OF CHBlIUCAL PATHWAYS
As changes in secondary metabolism have occurred, new
pathways have been elaborated. Modifications that involve
relatively simple shifts of secondary metabolic pathways are
encountered frequently. Precursors that are found in most
(if not all) plants, such as the compounds leading to gibberel-
lins, carotenoids, or steroids, can serve as sources of many
new secondary metabolites. Changes that parallel those pro-
duced by widely distributed primary enzymes should be
more likely than those for which new enzymes would be
required.
In general, simply derived secondary compounds are
more widely distributed than complex secondary compounds
(Le., those involving numerous steps in their derivation from
primary compounds or readily available precursors, or in-
volving complex or chemically difficult steps) (Fig. 1.1). For
example, simple amines such as tryptamine (2) are widely
distributed; alkaloids of greater complexity are less widely
distributed. Harmine (13), a J3-carboline alkaloid, is found
in at least 20 plant families (Downum et al., 1991), several
of which are not closely related. Even more complex com-
pounds such as ajmalacine (1) are less widely distributed.
This alkaloid has been only isolated from three plant fami-
lies. Quinine (14), an alkaloid derived from the same precur-
sor as ajmalacine and the product of a long pathway involv-
ing many complex steps, is known only from two or three
genera in the family Rubiaceae (Fig. 1.3) (Hansel, 1956;
Waller and Nowacki, 1978).
As a generality, evolutionarily "advanced" organisms
have more "advanced" secondary compounds; that is, they
are structurally and substitutionally more complex and more
highly altered in comparison to the structure of the precursor.

0----0
~HN) ~ H2
CH,-O
tryptamine (2)
found in at least 20 families, some not
widespread
ajmalacine (1)
found in 3 closely related
families
Fig. 1.3. More complex members of series of plant secondary metabolites have restricted distribution.
There are many exceptions to these general observations.
Small changes greatly affect the secondary compounds pro-
duced, if they occur early in the biosynthetic route. Further,
it is easier to lose than to gain the ability to synthesize and
accumulate a particular compound. Thus, it is not surprising
to find many instances of apparent reversals in biosynthetic
capacity. This should particularly be troe in instances where
the initial selection pressures that favored the presence of the
compounds have disappeared. Species of plants that occur on
islands (presumably with lower herbivore pressures) often
have reduced secondary compound production and accumu-
lation in comparison to mainland species of the same genus
(Mabry, 1973; Seeligmann and Alston, 1967).
In instances where breakage of a biosynthetic route oc-
curs, precursors may be shunted into completely different
routes that may not have appeared in the particular species
previously or may be accumulated (Birch, 1973).
Lignification, based on phenylpropanoid metabolites, is
associated with the advent of land plants. It is thought by
many that early land plants were woody. In evolutionarily
advanced plant groups, there is a tendency toward herba-
ceousness, or a decrease in the synthesis and accumulation
of lignin. In some of these plants, lignin precursors may
serve as the starting point for such secondary metabolites as
phenylpropanoids, lignans, flavonoids, and alkaloids. Some
plants of the family Rutaceae accumulate alkaloids derived
from phenylpropanoid precursors, but these compounds ap-
pear to have been lost and replaced by alkaloids based on
anthranilic acid in some more evolutionarily advanced mem-
Introduction 11
CeQ
I~
~
I
HN
"""N
harmine (13)
closely related
CH3 0
quinine (14)
found in 2 or 3 closely
related genera of the Rubiaceae
bers of the family (Gottlieb, 1980, 1989; Kubitzki and Got-
tlieb, 1984, Kubitzki, 1987). Anthranilic acid is derived from
a precursor of the shikimic acid pathway previous to those
leading to the phenylpropanoids which serve as lignin pre-
cursors. It is argued that because the pathway to lignins was
blocked, the precursors were shunted into alkaloids and other
compounds. As the pathways to these alkaloids became
blocked, intermediates earlier in the pathway were shunted
into anthranilate-derived alkaloids. There was a concom-
mitant increase in the role of mevalonate (terpenoid) path-
ways in more advanced groups; terpenoids (limonoids) and
coumarins replaced many compounds based on the shikimic
acid pathway in the course of evolution (Gottlieb, 1980,
1989, 1990).
THE VALUE OF PLAl'IT SECOI'IDAKY
CHEJllISTRY FOR Ul'lDERSTAl'lDIl'IG
EVOLUfIONARY RELATIONSHIPS OR
PHYLOGEl'IY OF PLAl'ITS
Many simply derived secondary compounds are widespread
and have limited usefulness for understanding the relation-
ship of higher taxonomic groups of plants (Hegnauer, 1986).
Compounds derived from more complex pathways, how-
ever, are often restricted in distribution and can be valuable
in this regard. Whereas simply derived compounds (espe-
cially those involving common chemical steps from wide-
spread precursors) could have evolved several or even many
12 Introduction
times in the evolution or plants (or perhaps were present in
the ancestors of all modem plants), more complex com-
pounds with restricted distribution are less likely to have
arisen in this manner. Thus, plants that share these complex
compounds are more likely to be related in an evolutionary
sense than those which share simple compounds.
Certain groups of compounds characteristically are ob-
served to occur in specific groups of plants. The patterns
of distribution and information related to the biosynthetic
pathways responsible for secondary compounds have proven
useful for understanding evolutionary relationships of plants.
In some instances, the same molecular structure is known
to arise by different biochemical pathways (convergence)
and it is important to know not only the structure but also
the route of origin (Birch, 1973). Plants may appear to have
regressed as a result of mutations that block past evolution-
ary transformations (Birch, 1973).
Secondary compounds are not, of course, the only fea-
tures of plants that have evolved. Many morphological and
anatomical characteristics also have been modified in the
process of evolution. Studies in which a number of different
aspects of evolutionary change are examined are especially
desirable, as different aspects of plants are under different
selection pressures, and examination of several features will
be expected to give a more complete picture of the evolution-
ary history involved.
As one compares major groups of plants, it is clear that
no one line of secondary compounds has evolved indefi-
nitely. Most major biosynthetic pathways are replaced even-
tually in more highly derived plant groups by other second-
ary metabolic pathways. In some instances, these may have
provided more effective systems of chemical defense. For
example, in relatively primitive plants of the Rutaceae, ben-
zylisoquinoline alkaloids are common. In more advanced
groups within this family, acridone alkaloids almost com-
pletely replace the former type of alkaloids. In a similar
manner, condensed tannins are replaced by hydrolyzable tan-
nins among the more highly advanced groups of angio-
sperms (Gottlieb, 1980; Kubitzki and Gottlieb, 1984; Kubit-
zki, 1987).
Although the study of plant secondary metabolites has
been of value for understanding the phylogeny of higher
plants, the reverse is true also. Knowledge of plant systemat-
ics and phylogeny has considerable predictive value for the
study of secondary metabolites.
WHY STUDY PLAl'IT SECOl'IDAKY COl'lPOUl'IDS?
In the past, secondary compounds from plants have been
major targets for both structural and synthetic studies of or-
ganic chemists and have provided interesting challenges to
biochemists in the areas of biosynthesis and enzymology. A
knowledge of the distribution of these compounds has
proven useful to plant systematists and taxonomists and has
shed light on the phylogeny of plants and fungi. The role
of these compounds as "chemical messages" has proven
important to our understanding of many ecological problems
and has led to the development of "chemical ecology."
Plant secondary metabolites are not just randomly pro-
duced compounds, but ones that have been shaped and opti-
mized during evolution. It is not surprising that many are
used by man as pharmaceuticals, spices, fragrances, pesti-
cides, poisons, hallucinogens, stimulants, or colors (Barz and
Ellis, 1981; Luckner, 1990; Wink, 1988). Many of the com-
pounds also are important as medicines, pharmaceutical and
industrial precursors, fuels, pesticides, flavurings, perfumery
ingredients, plant hormones, adhesives, and drugs of abuse.
Some still play exotic roles in other cultures as arrow poi-
sons, piscicides (fish poisons), and hallucinogens.
The data provided by study of plant secondary metabo-
lites have proven important in linking various aspects of
ecology, organic chemistry, biochemistry, both animal and
plant systematics, mycology, phycology, plant physiology,
and evolutionary studies. There are important implications
of these data for food science, range science, nutrition, an-
thropology, archaeology, agronomy, horticulture, dairy sci-
ence, geology, and plant pathology.
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Introduction 15
WHIITAKER, R. H. and P. P. FEENY, Allelochemics: Chemical inter·
actions between species, Science, 171, 757-770 (1971).
WIERMANN, R., Secondary products and cell and tissue differentia-
tion, in The Biochemistry of Plants, Vol. 7 (E. E. Conn, ed.),
85-115, Academic Press, New York, 1981.
WILKINSON, A. P., C. M. WARD, and M. R. A. MORGAN, Immuno-
logical analysis of mycotoxins, in Plant Toxin Analysis (H. F.
Linskens and J. F. Jackson, eds.), Modem Methods of Plant
Analysis, VoL 13, 185-225, Springer-Verlag, Berlin, 1992.
WILLIAMS, D. H., M. 1. STONE, P. R. HAUCK, and S. K. RAHMAN,
Why are secondary metabolites (natural products) biosynthes-
ized?, J. Nat. Prod., 52,1189-1208 (1989).
WINK, M., Physiology of the accumulation of secondary metabo-
lites with special reference to alkaloids, in Cell Culture and
Somatic Cen Genetics of Plants, Vol. 4 (F. Constabel and I. K.
Vasil, eds.), 17-42, Academic Press, San Diego, CA, 1987.
WINK, M., Plant breeding: Importance of plant secondary metabo-
lites for protection against pathogens and herbivores, Theoret.
AppL Genet., 75, 225-233 (1988).
WINK, M. and L. WIITE, Evidence for a wide-spread occurrence
of the genes of quinoIizidine alkaloid biosynthesis, FEBS Lett.,
159, 196-200 (1983).
2
Fatty Acids

Introduction INlKODUCTlOI'l
Primary Fatty Acids
Fatty Acids of Plant Vegetative Parts Most fatty acids occur in nature as esters of glycerol (com-
monly called triglycerides or triacylglycerols). These esters
Biosynthesis
Fatty Acid Biosynthesis are found in most living organisms and playa role in energy
storage. The molecular shapes of lipid molecules affect the
The Two-Pathway Model of Lipid Biosynthesis
biogenesis and function of various cell membranes (Browse
The Second 3-Ketoacyl ACP Synthase Isozyme
~d Somerville, 1991). Both phosphoinositides and methyl
Biosynthesis of Unsaturated Fatty Acids
Jasmonate are involved in signal transduction. Because of
The Prokaryotic Pathway
their economic and dietary impottance, triglycerides of seeds
The Eukaryotic Pathway
and the corresponding fatty acid derivatives have been inves-
Biosynthesis of Triacylglycerides
tigated extensively; there have been comparatively few stud-
Degradation of Fatty Acids
ies of glycerides and fatty acids from other plant palls. The
Unusual Fatty Acids in Plants
biochemistry of fatty acids, glycerides, and related com-
Fatty Acids from Unusual Starter Units
pounds has been reviewed (Browse and Somerville, 1991;
Fatty Acids with Unusual Patterns of Unsaturation
Goodwin and Mercer, 1983; Lie Ken Jie, 1989; Stumpf,
Hydroxy Fatty Acids
1976).
Epoxy Fatty Acids
Glycerides are major components of edible oils. Those
Methyl Branched, Cyclopropanoid, and Cyclopropenoid
which contain fatty acids with a relatively high degree of
Fatty Acids
unsaturation are thought to provide benefits in the diet. The
Cyclopentenoid Fatty Acids
ability of highly unsaturated oils to polymerize in the pres-
Fluoro Fatty Acids
ence of air has made them useful for paints. Glycerides that
Other Unusual Lipids
contain a predominance of saturated fatty acids can be con-
Metabolically Altered Fatty Acids
verted to salts by treatment with bases (saponification). So-
The Green Leaf Volatile Complex
dium and potassium salts are usefnI for soaps, whereas lith-
Functions of Fatty Acids and Their Derivatives in Plants
ium salts are components of lubricants. Triglycerides from
Jasmonic Acid and Related Compounds
seed oils possibly represent the most likely substitute for
The Requirement for Unsaturated Fatty Acids in the
petroleum in the future.
Diet of Animals Fatty acids also are stored as components of phospholip-
Effects of Fatty Acids and Their Derivatives on ids, glycolipids, and waxes, or converted to alcohols, alde-
Animals hydes, olefins, hydrocarbons, acetylenic compounds, and
Fatty Acids with Biological Activity other secondary metabolites.
Insect Pheromones Derived from Fatty Acids
Mammalian Pheromones Frimary Fatty Acids
Analysis of Fatty Acids ~any fatty acid.s are primary metabolites; that is, they
References are Involved In resprration and energy storage and are ubiqui-

16
 Fatty Acids 17

~CO,H capric acid

CO,H lauric acid (6)

CO,H myristic acid (7)

CO,H palmitic acid (1)

H H
CO,H palmitoleic
acid (13)
CO,H stearic acid (2)

H H
CO,H oleic acid (3)

CO,H eJaidic acid

H H H H

C01H linoleic acid

(4)
H H H H H H

CO,H linolenic acid

(5)

CO,H arachidic acid

(25)

H HH HH HH H
CO,H arichidonic acid
(61)

Fig. 2.1. Some naturally occurring primary fatty acids.

tous in plants. Among these are palmitic (1), stearic (2), oleic
(3), linoleic (4), and linolenic acids (5) (Fig. 2.1). Others,
such as lauric (6) and myristic acid (7) also are widely dis-
tributed in nature.
Chain lengths of 16 and 18 are common for most animals,
microbes, and plants. This may be because these chain
lengths provide optimal physical properties of bilayer mem-
branes (Ohlrogge et al., 1993).
Fatty Adds of Plant Vegetative Parts
Whereas plant seeds contain a wide variety of fatty acids,
fatty acids from leaf tissue are closely linked with the pres-
ence and number of chloroplasts and are remarkably con-
stant. Plant membranes differ in composition from those of
animals and fungi. This is especially seen in the composition
of chloroplast membranes which consist largely of glycolip-
ids. The lipid composition of plant chloroplasts is similar to
that of cyanobacterial membranes (Somerville and Browse,
1991). About 70% of the fatty acids ofleaves are linoleic and
a-linolenic acids with smaller amounts of oleic, palmitic,
palmitoleic, and (E)- or trans-3-hexadecenoic acid (8) (Fig.
2.14) (found only in chloroplasts). Some plants contain siza-
ble quantities of hexadecatrienoic acid. Lipids are responsi-
ble for about 7% of the total weight of many plant leaves.
About 30% of these leaf lipids are comprised of phospholip-
ids (including glycerophospholipids), glycolipids (Joyard
and Douce, 1987), and waxes (Harwood, 1980) (Fig. 2.2).
Phosphatidylglycerol (9) makes up as much as 20% of the
total phospholipids of thylakoids and envelope membranes
(Lawlor, 1993); monogalactosyl and digalactosyl diglycer-
ides (10, 11) may represent 20-45% of the total leaf lipids
(Elbein, 1980). Complex glycolipids appear to be wide-
spread among plants (Kojima et al" 1990). No triacylglycer-
ols and only minor amounts of phospholipids occur in chlo-
roplasts (Stumpf, 1976), where as much as 30% of the total
lipids may be monogalactosyl diglycerides (Elbein, 1980).
18 Fatty Acids

o o

{ O~R
R = alkyl group II
O--1L. R OJLR

RTo {
0
R---,rO
II II
0
R---,ro{
II
0
II
CH CH
,~+ 3
o O~R O O-P-O'
I
0 O-p-O............. "CH
I 'V' 3
O·

triglyceride phosphatidic acid (19)0' pbospbatidylcholine (23)

o 0
~ {O~R O~R
R 0{0 0 R RIIO ~ RT O { ~ ~
IoI "
0-P·0~NH3
+0 O-P·O"'-"'" /"OH
,,(
0 O-P'O--v'O'P-O}
O' OH·' 0
6. o· OH 0 O..lLR
Rlr°
o
pbosphatidyletbanolamine (29) pbosphatidylglycerol (9) diphosphatidylglycerol

monogalactosyl dlgaJacrosyl sulfoquinovosyl

diacylglycerol (10) diacylglycerol (11) diglyccride (12)

Fig. 2.2. Glyceropho'phatid, and glycolipid, from plants. [Reprinted in modified form from Stumpf (1976).]

Glycolipids of this type are synthesized in the chloroplast
(Lawlor, 1993). Sulfoquinovosyl diglyceride (12) is wide·
spread in leaves but usually occurs at low concentrations
(Stumpf, 1976). This lipid is linked to S04 - reduction in
the chloroplast (Lawlor, 1993). Sterol esters and acylated
steryl glycosides are also found in leaf lipids.
Unusual fatty acid structures, often found in seed oils,
are rarely encountered in leaves. The presence of cyclopro·
penoid fatty acids in leaves of plants of the Malvaceae and
related families and conjugated unsaturated fatty acids in
leaves of plants of the Boraginaceae appear to be exceptions
(Shoriand, 1963).
In general, the linolenic acid of leaves is replaced by
linoleic acid in roots.
BIOSYNI'HESIS
In tissues that nonnally do not store triacylglycerols, for
example, leaf cells, the chloroplast is the primary source of
fatty acids (Browse and Somerville, 1991). The endoplasmic
reticulum in the cell cytosol is involved in further modifica·
tions of the acyl moiety. In tissues high in oil content, the
proplastid is the source of the primary fatty acids. The endo·
plasmic reticulum is the site of further structural modifica·
tions and/or the fonnation of the oil storage organelle or
oil droplet (which contains only triacylglycerols) (Stumpf,
1980, 1987). Some evidence suggests that lipid biosynthesis
also may occur in mitochondria (Shintani and Ohlrogge,
1994).
Fatty acids and lipids usually are not transported between
the cells of higher plants, but are transported within cells
from chloroplasts to sites on the endoplasmic reticulum and
back into the chloroplasts (Somerville and Browse, 1991).
The Two·Pathway Model of Lipid
Biosynthesis
Research since about 1980 indicates that the leaves of
higher plants utilize two distinctive pathways for glyceroli·
pid biosynthesis. Palmitoleic acid (C I.) (13) and oleic acid
(CIS,I) (3) are synthesized de novo in the chloroplast and
may be used directly for the biosynthesis of chloroplast lipids
via the prokaryotic pathway (see below) or exported from
the chloroplast as CoA esters that are used in the eukaryotic
pathway primarily at sites on the endoplasmic reticulum
(Browse and Somerville, 1991). However, in all higher
plants, a proportion of the diglycerol moiety of phosphatidyl·
choline, synthesized by the eukaryotic pathway, again enters
the chloroplast where it contributes to the production of thy-
lakoid membranes (Browse and Somerville, 1991).

In many families of angiospenns, phosphatidylglycerol
(9) is the only major product of the prokaryotic pathway.
Other chloroplast lipids in these plants are synthesized only
by the eukaryotic pathway. In some primitive angiospenn
families, both pathways contribute to the synthesis of mono-
galactosyldiacylglycerol (10) and other lipids (Browse and
Somerville, 1991).
Fatty Acid Biosynthesis
Fatty acids in plants are synthesized by a series of reac-
tions similar to those for fatty acid biosynthesis in animals,
yeasts, bacteria, and other organisms. The synthetases of
prokaryotic cytoplasmic systems are freely soluble and read-
ily separable as discrete proteins; those in mammalian sys-
tems are localized in the cytoplasm as large soluble synthe-
tase complexes. The exact nature of association of the
enzymes in plants is unknown (Ohlrogge et al., 1993). The
reactions of plant fatty acid biosynthesis are catalyzed by
individual polypeptides (Somerville and Browse, 1991);
once organelles are disrupted, the enzymes also are soluble
and may be isolated (Somerville and Browse, 1991; Stumpf,
1976). In contrast to mammalian systems, plant fatty acid
synthetases are plastid localized.
Synthesis of fatty acids occurs in the stroma but involves
mitochondria and the cytosol (Lawlor, 1993). Dihydroxyace-
tone phosphate (DHAP) moves from the stroma to the cyto-
sol. Pyruvate is fonned from the triosephosphate DHAP and
enters the mitochondria where acetyl-CoA and acetate are
produced. This reaction also produces NADH, which pro-
vides part of the reducing power needed for later reactions
in the sequence. Acetate returns to the chloroplasts where
acetyl-CoA again is synthesized (Lawlor, 1993). Because
acetyl-CoA does not cross membranes, this molecule must
be resynthesized in plastids to provide the carbon precursors
for fatty acid biosynthesis (Ohlrogge et al., 1993).
Plastids of oil seeds appear to have a complete glycolytic
pathway, which together with pyruvate dehydrogenase, can
result in the conversion of glucose to acetyl-CoA. Chloro-
plasts and plastids of oilseeds may use different pathways
to provide the necessary substrates and cofactors (Ohlrogge
et al., 1993).
The synthesis of malonyl-CoA (14) from acetyl-CoA
(15), which also occurs in the stroma, with acetyl-CoA car-
boxylase (ACCase) is the first committed step of fatty acid
biosynthesis (Fig. 2.3). Malonyl-CoA produced by plastids
primarily is used for fatty acid biosynthesis (Ohlrogge et al.,
1993).
Malonyl-CoA condenses with an acyl carrier protein
(ACP). This reaction is catalyzed by malonyl-CoA ACP
trans acylase, an enzyme that has been purified from several
plants (Ohlrogge et al., 1993). ACP is a relatively small
heat-stable protein of 9000 molecular weight that occurs in
several isofonns (Browse and Somerville, 1991; Lehninger,
1982). Both ACP and coenzyme A have a 4'-phosphopan-
tetheine prosthetic group (Ohlrogge et aI., 1993). Amino acid
sequences for ACP molecules from more than 15 plants,
including both monocots and dicots, are available. The
Fatty Acids 19
NH,
l):)
HO ~ o-p-o-p-o~~
~ ~
I I
0
o OH OH CH NH)
S
Ho-Lo OH O=\H
~H
acetyl-CoA (15) S-COCH,
'yO acetyl·CoA carboxylase ~"
S·CoA
S·CoA
acetyl·CoA (15) malonyl·CoA (14)
Fig. 2.3. Acetyl-CoA and the origin of malonyl-CoA.
amino acid sequence surrounding the prosthetic group to
which acyl groups are attached is highly conserved. Further,
from other studies, it appears that precursors to ACP units
contain chloroplast transit peptides. Thus, ACPs are nuclear-
encoded proteins that must be imported into the plastid from
their site of synthesis on cytoplasmic ribosomes (Ohlrogge
et al., 1993).
In subsequent steps of fatty acid synthesis, a fatty acyl
group that is linked by a thioester bond to the active site
of 3-ketoacyl-ACP synthase condenses with malonyl·ACP.
One molecule of CO2 is liberated (Browse and Somerville,
1991 Conn and Stumpt, 1972, Lehninger, 1982) (Fig. 2.4).
Although acetyl-ACP has been considered to condense ini-
tially with malonyl-ACP, recent work indicates that the
product of the first condensation, butyryl-ACP, is fonned
by the condensation of acetyl-CoA and malonyl-ACP and
that acetyl-ACP is a minor participant in fatty acid biosyn-
thesis (Jaworski et aI., 1993).
Three forms of 3-ketoacyl-ACP synthase have been dis-
covered in plants. These fonns may be distinguished by their
substrate specificity; they are homodimers with molecular
weights of 43,000 to 45,000 per subunit. One, KAS III, ap-
pears to be responsible for the first condensation of acetyl-
CoA and malonyl·ACP (Browse and Somerville, 1991; Ohl·
rogge et al., 1993). The activity of this enzyme in plants
seems to bypass the need for acetyl-ACP, although that mol-
ecule is fonned and accumulated in some plants (Ohlrogge
et al., 1993). KAS I or 3-ketoacyl-ACP synthase elongates
the acyl chain to palmitoyl-ACP, whereas KAS II converts
palmitoyl-ACP to stearoyl-ACP (Ohlrogge et al., 1993).
The acetoacetate ester fonned in the initial condensation
step is reduced by 3-ketoacyl·ACP reductase in the presence
20 Fatty Acids

malonyl trausaeylase
malonyl-CoA + ACP-SH • malonyl-S-ACP + CoA

acetyl-CoA + malonyl-S-ACP - - - - - - - _ aeetoaeetyl-S-ACP + CO2

3-ketoaeyl-ACP reductase
acetoacetyl-S-ACP + NADPH + H+ • D(-)-3-hydroxybutyryl-S-ACP + NADP+
3-hydroxy-ACP dehydratase
D(-)-§-hydroxybutyryl-S-ACP • E-Ll.2-butenoyl-S-ACP + H 20
enoyl ACP reductase
E-Ll.'-butenoyl-S-ACP + NADPH + H+ • butyryl-S-ACP + NADP+

butyryl-S-ACP + e n z ( * ) - - - - - - - - - . butyryl-S-enz (0) + ACP

butyryl-S-enz(*) + malonyl-S-ACP - - - - - - . . 3-ketohexanoyl-S-ACP + enz(.) + CO2 etc_

enz(*) = 3-ketoacyl-ACP synthetase

Fig. 2.4. Summary of reactions leading to fatty acid biosynthesis.

ofNADPH to fonn 0-3-hydroxybutyryl-S-ACP. Isofonns of
the enzyme require either NADPH (the dominant fonn) or
NADH. The native enzyme appears to be a tetramer with a
molecular weight of 130,000 (Ohlrogge et al., 1993). 0-3-
Hydroxyburyryl-S-ACP is dehydrated by 3-hydroxyacyl-
ACP dehydratase to yield E-t.. 2-butenoyl-S-ACP. This en-
zyme has a molecular weight of 85,000 and appears to be
a homotetramer (Ohlrogge et al., 1993). The olefin produced
is reduced by NADPH in the presence of enoyl-ACP re-
ductase to fonn buryryl-S-ACP (Fig. 2.5) (Lehninger, 1982).

~ ~CO~cc_ase
)Vl
0 0

ACP-SH~ SCoA ACP-SH

o COA~ AD~O 1 CO~-SHO
A
ATP SCoA 0

~YI-COA:ACP
transacylase malonyl-CoA:ACP
~ ~ /~
II
S-ACP HO S-ACP
malonyl-ACP

CO2 +
ACP-SHor
o o 0 CoA-SH
_ II KAS·I
~S-A-C-P-----=;::'::""'----
AAS-ACP
aeyl.ACP 3-keloaeyl-ACP
A enoyl-ACP reductase H20 3-ketoacyl-ACP reductase

NADP+" 0 ~ OH 0 ~NADPH
NADPH _ II - 1 I NADP·
/~S-ACP /~S-ACP
enoyl-ACP 3·hydroxyaeyl-ACP 3-bydroxy-ACP
dehydrase
Fig. 2.S. Reactions of fatty acid biosynthesis (Ohlrogge et aI., 1993; modified and used with pennission of the copyright owner, CRe Press, Boca
Raton, Florida. © 1993).

biotin
O=<
B: \ OH carboxylation
~ retention
~
COA
'H
'H
o
o 0
./JlX JL. . . NADPH
3 H 2H
SCoA - - - - +
H 0
~SCOA
'H
(17)
Fig. 2.6. Stereochemistry of fatty acid biosynthesis (Torssell. 1983; modified and used with permission of the copyright owner, John Wiley and Sons,
Ltd., Chichester. © 1983).
This reductase has two isoforms, one of which is specific
for NADPH and exists as a homotetramer with a molecular
weight of 115,000 to 140,000 (Ohlrogge et aI., 1993).
To begin the next series of reactions, a malonyl unit is
transferred from malonyl-CoA to the phosphopantotheine
site of ACP. In a manner similar to the initial condensation,
the homolog containing two additional carbons (in this case,
butyryl-ACP) reacts with the malonyl unit, displaces CO2 ,
and is reduced in the next three steps of the reaction sequence
(Fig. 2.5). Energy is required to provide the NADPH reduc-
tant and (as ATP) to regenerate the thioester linkage of ace-
tyl-CoA, and for formation of malonyl-CoA (Lehninger,
1982). The cycle continues until palmitoyl-ACP is produced.
A number of conclusions concerning the stereochemistry
of the condensation have been established (Fig. 2.6). The hy-
droxy acyl intermediate (16) has a (3R)-configuration. Upon
loss of water, the E- or trans-enoate (17) is preferentially
formed. As the 'H derivative of (2R,3R)-3-hydroxy-2-'H-bu-
tenoate (16) gave trans-butenoate (17) with retention of 'H,
elimination must have occurred in a syn-fashion and the initial
condensation must have proceeded with inversion of configu-
ration (Fig. 2.6) (Simpson, 1984; Torsseli, 1983).
Tbe Second 3·Ketoacyl ACP Synthase
Isozyme
Palmitoyl-ACP is subsequently elongated to stearoyl-
ACP in another biosynthetic system associated with the en-
Fatty Acids 21
o 0
H~COA acylation
H 'H ~SR inversion
(28) ~
HQ~
'y·
/' ,)\! 'SCoA
elimination
3H2H
(lR,3R) (16)
o
NADPH
~SCOA'H H
doplasmic reticulum which involves the second isozyme of
3-ketoacyl ACP synthase (KAS TI) (Browse and Somerville,
1991; Lehninger, 1982; Somerville and Browse, 1991). This
system requires only NADPH and palmitoyl-ACP. Malonyl-
ACP is the specific C-2 substrate. Paimitoyl-CoA cannot
serve as a substrate in this system (Browse and Somerville,
1991; Stumpf, 1976).
Both the de novo synthesis and the elongation step (i.e.,
the systems that involve isozyme I and II of 3-ketoacyl ACP
synthase) occur as ACP-derivatives (Fig. 2.7).
These chain lengths may be maintained by the combined
action of the three keto-acyl synthase enzymes (KAS I-III),
and relatively specific thioesterases that convert acyl-ACP
molecules to the corresponding CoA derivatives. Most
plants have an acyl-ACP thioesterase with the highest activ-
ity for oleyl-ACP. Chain termination also may occur when
fatty acids are transferred from ACP to glycerol-3-phosphate
by acyltransferases (Ohlrogge et al., 1993) (see below).
Biosynthesis of Unsaturated Fatty Acids
Desaturation of stearoyl-ACP (18), which requires the
soluble enzyme stearoyl desaturase, is probably the primary
route for the synthesis of oleic acid (3) in .plants (Browse
and Somerville, 1991; Ohlrogge et ai., 1993; Somerville and
Browse, 1991). Stearoyl desaturase is a homodimer with a
molecular weight of 68,000 (Ohlrogge et ai., 1993). The
22 Fatty Acids

--
KAS·II stearoyl-ACP
KAS·II1
elongation desaturase
C2 + 7C3 C16·ACP~ C1s-ACP - - - + C 18:r ACP
system

thioesterases
.~-j ~-j ~o~j
.wj
16:0 18:0 18:1

thiokinases CoA
.wj "'j CoA CoA

ff
16:0·CoA 18:O-CoA

j j 18:2 oA

metabolic pool: acylation of polar lipids, etc.

Fig. 2.7. The interrelationship between acyl-ACPs and acyl-eoAs in plants (modified from Stumpf, 1976; modified and used with permission of the
copyright owner, Academic Press, Orlando).

enzyme is highly specific for stearoyl·ACP. This aerobic
mechanism for desaturation of fatty acids, found in all eukar-
yotic cells, involves molecular oxygen and a reductant. Z-
or cis-elimination of two hydrogens occurs to form a Z-
double-bond system. The oxidative desaturase is associated
with microsomal or membranous particles and requires
NADPH or NADH and O 2 • Cytochrome b5 is the electron
carrier coupling the reductant with the desatorase (Fig. 2.8)
(Browse and Somerville, 1991).
Lipids from the prokaryotic pathway of both leaves and
seeds contain only oleic and palmitic acids when they are
first synthesized in the chloroplast or proplastid (Browse and
Somerville, 1991).
The mechanism for desaturation of oleic acid (3) to lino-
leic (4) and linolenic acids (5) in plants is not well under-
stood, partially because the enzyme systems are membrane
bound, which has made them difficult to study (Browse and
Somerville, 1991; Jaworski, 1987). Microsomal membrane
preparations from the developing endosperm of castor bean
catalyzed the transfer of oleate from oleyl-CoA to phosphati-
dyl choline (Bafor et aI., 1991). There is strong evidence for
the intermediacy of an a- or f3·oleyl phosphatidylcholine
intermediate in the formation of a-linoleyl phosphatidylcho·
line. Oleyl-CoA is a very effective and highly specific sub-
strate for these same systems. Once linoleic acid (4) is syn-
thesized, it is further desaturated to a-linolenic acid (5)
(Stumpf, 1976).
In anaerobic bacteria, unsaturated fatly acids can be syn-
thesized in the absence of oxygen (Fig. 2.9), but only monoe-
noid fatty acids are produced. It seems likely that a branching

O,INADPH Z
CH,(CH')16COSX CH,(CH,J,CH=CH(CH,),cOSX
stearate (2) oleate (3)

O,INADPH z Z
CH,(CH,J.CH=CHCH,CH=CH(CH,J,COSX

linoleate (3)

O,INADPH z z z
CH,CH,CH=CHCH,CH=CHCH,CH=CH(CH,J,COSX

a-Iinolenate (4)

Fig. 2.8. Desaturation of stearoyl-ACP to oleyl-ACP and linoleyl-ACP.


SEnz
o H
H>=(,[ _
If X "SEnz
H D
Fig. 2.9. Desaturation of stearic acid to oleic acid in a bacterial system (Simpson, 1984; modified and used with pennission of the copyright owner, the
Royal Society of Chemistry. London).
point in the synthesis occurs at C8 or C w and that the desatu-
ration occurs at this stage followed by chain elongation to
produce acids with 18 carbon atoms (Mann, 1987; Sedgwick,
1973). Oleic acid (3) synthesized from [2-2H21 malonyl-CoA
contained no deuterium at C w . As deuterium at that position
in the precursor is known to occupy the pro-S-position, that
deuterium atom must have been abstracted in the fonnation
of the olefm_ Further analysis showed that the deuterium at
position C8 was in the pro-2R position and a proton must
have been added to the 2-si face (Fig. 2.9) (Gunstone, 1984;
Simpson, 1984).
The Prokaryotic Pathway
In most higher plants, the first enzyme on the prokaryotic
pathway, the stromal acyl-ACP:glycerol-3-phosphate acyl-
transferase is highly specific for oleyl-ACP, whereas the
second acylation, catalyzed by a membrane-bound acyl-
ACP-l : lysophosphatidic acid acyltransferase specifically
uses palmityl-ACP to yield 1-0Ieyl-2-palmitylphosphatidic
acid (Browse and Somerville, 1991). Much of the palmitic
acid (30-70%) at the sn-2 position ofphosphatidylglycerol
(9) is converted to the a 3 -isomer (8) (Fig. 2.14). Chloroplast
phosphatidylglycerol is synthesized from phosphatidic acid
(19) in all higher plants. In C 16,3 plants, a prokaryotic diacyl-
glycerol pool is fonned by the action of phosphatidic acid
phosphatase_ In C 18 ,3 plants, only prokaryotic phosphatidyl-
glycerol is found, and a eukaryotic pool of diacylglycerol is
used to synthesize chloroplast lipids. The most abundant
chloroplast lipid, monogalactosyldiacylglycerol (10), is
fonned from diacylglycerol by action of UDP-galactose: dia-
cylglycerol galactosyltransferase (Browse and Somerville,
1991). .-
The Eukaryotic Pathway
The first committed step of the eukaryotic pathway is the
hydrolysis of C I6 acid and C 18 ,I-ACP to the free fatty acids.
These free fatty acids move through the two membranes of
Fatty Acids 23
-
H D D
-H,O
),6~
'1,) lr _
--,SEn.
K-
0
H+
CO,H
H D D D D
(3)
the chloroplast and are converted into palmitoyl and oleoyl-
CoA derivatives, respectively, by the action of thioesterases,
thiokinases, CoA, and ATP in the outer envelope (Browse
and Somerville, 1991). The resulting soluble CoA esters are
used for the synthesis of phosphatidic acid (19) at the endo-
plasmic reticulum. However, in contrast to the prokaryotic
pathway, the acyltransferases of the endoplasmic reticulum
synthesize phosphatidic acid (19) with a C I8 fatty acid at
the sn-2 position.
Biosynthesis of Triacylglycerides
The synthesis of triacylglycerides is located in the micro-
somal fraction of the cell. The fonnation of sn-glycerol 3-
phosphate (19) (Fig. 2.2) from free glycerol and ATP is
essential for this synthesis. The glycerokinase that catalyzes
this reaction occurs as a soluble chloroplast enzyme in the
cell. The thiokinases and the acylating enzyme appear to be
associated with microsomal particles (Stymne and Stobart,
1987). Chain termination also may occur when fatty acids
are transferted from ACP to glycerol-3-phosphate by acyl-
transferases (Ohlrogge et al., 1993). There are two enzymes
in the plastid that carry out this reaction. One is a soluble
enzyme that prefers oleoyl-ACP as the substrate and trans-
fers the oleoyl group specifically to the sn-l-position of glyc-
erol-3-phosphate. The second enzyme is located on the inner
membrane of the chloroplast envelope and is specific for
palmitoyl-ACP. This enzyme transfers the palmitoyl unit to
the sn-2-position of 1-acyl-glycerol-3-phosphate (OhIrogge
et ai., 1993).
sn-G1ycerol 3-phosphate is acylated by acyl-CoA in two
steps to yield diacylglycerol3-phosphate (phosphatidic acid)
(Fig. 2.10), which is dephosphorylated to give diacylglyc-
erols. The synthesis of phosphatidylcholine (23) (Fig. 2.2)
from diacylglycerols (20) by choline phosphotransferase is
reversible and phosphatidylcholine is a direct precursor of
highly unsaturated diacylglycerols in seeds (Browse and
Somerville, 1991). A specific a l2 fatty acid hydrolyase from
castor bean (Ricinus communis) endospenn converts phos-
24 Fatty Acids
o i
II
R ~O -
~
sn-3
CH,--OH
o ,
R.---lL.o_l_
H HO--C--H
diacylglycerol (20)
Fig. 2.10. Triacylglycerol structure (modified from Stymne and Stobart. 1987; used with pennission of the copyright owner, Academic Press. New
York).
phatidylcholine containing oleic acid at the sn-2 position
into ricinoleyl phosphatidylcholine. A specific phospholi-
pase hydrolyzes ricinoleyl phosphatidylcholine into phos-
phatidylcholine and ricinoleic acid (24) (Fig. 2.15). The ri-
cinoleic acid is then converted to ricinoleyl-CoA which is,
in sequence, converted into diacylglycerols (Bafor et ai.,
1991). Diacylglycerols are further acylated in the presence
of acyl-CoA and diacylglycerol acyltransferase to produce
triacylglycerides (25) (Bafor et al., 1991; Stumpf, 1976;
Stymne and Stobart, 1987). In the system from castor bean
endosperm, the enzymes exhibited selectivity for ricinoleyl-
containing diacylglycerols (Bafor et al., 1991). In instances
where the three acyl substituents differ, the product usually
is optically active, and specificity as to the position of attach-
ment of particular fatty acids is exhibited (Fig. 2.10) (Good-
win and Mercer, 1983; Styrnne and Stobart, 1987).
DEGRADATION OF FArrY ACIDS
When a seed germinates, lipids disappear and sugars appear
rapidly. Lipase activity rises sharply and participates in the
stepwise hydrolysis of triacylglycerols to diacylglycerols
and monoacylglycerols, ultimately leading to glycerol and
free fatty acids. Once fatty acids are formed by lipase action
(Huang, 1987), they may be oxidized by several mecha-
nisms, the principal being a- and (3-oxidation (Kindl, 1987;
Stumpf, 1976).
Free fatty acids from C I2 to CIS may be attacked readily
to yield either a fatty acid with one less carbon atom and
CO2, or a n-a-hydroxy fatty acid. Molecular oxygen is re-
sn-! 0
~H,-O.--lL.R
i
/'-2
C- H triacylglycerol (22)
1 0
!H,-O.--lL. R
CH,--OH
I
I
0
CH,-o-_.JJII_- R
monoacylglycerol (21)
quired for this process. The small amounts of odd-chain fatty
acids found in nature may be formed by this pathway, but
a-oxidation is not a major route of metabolism of fatty acid
in most plants.
The principal mechanism by which fatty acids are broken
down in plants is (3-oxidation (Fig. 2.11) (Kindl, 1987). On
germination, seeds with high oil content form glyoxysomes
that contain the enzymes of (3-oxidation. In this process,
much of the energy stored in the lipids is converted to acetyl-
CoA and is trapped in the thioester bond. Acetyl-CoA then
enters the tricarboxylic acid cycle (TCA). (3-0xidation in
plants appears to be identical to that of animals.
Palmitoleic (13) and similar acids may arise by (3-oxida-
tion of oleic acid (3).
The Z,z-methylene-interrupted system oflinoleic (4) and
linolenic acid (5) is readily susceptible to attack by lipoxy-
genase. This enzyme catalyzes the direct addition of oxygen
to the system with the formation of a Z,E-I,3-butadiene hy-
droperoxide. Lipoxygenase has been found widely in plant
seeds and leaf tissues. This enzyme serves as a starting point
for the breakdown of multiply unsaturated fatty acids and
gives rise to a host of compounds (Goodwin and Mercer,
1983; Hamberg and Gardner, 1992; Stumpf, 1976).
Ul'IUSVAL FArrY ACIDS Il'I PLA1"ITS
Most plants have the standard complement of stearic, palmi-
tic, oleic, linoleic, and linolenic acids, a certain number of
lower-molecular-weight acids (lauric, myristic, palmi-
tooleic), and occasional higher-molecular-weight homologs
 Fatty Acids 25

~\o
R.CH,.CH,.CO,H ATP

\\OCOASH
II
t-
CO,
~ CH3·C·SCoA
II
R·CH,·C·SCoA
+0

II
several repetitions
(d;!n)lt
R·C·SCoA
sucrose COAS~ ,,~ 0
H
R·G=CH·C·SCoA
II
" "
R·C·CH,·C·SCoA H,OJ
/ )

~
·2H R.CHOH.CH,.C.SCoA
II
(pyridine nucleotide)
Fig. 2.11. The j)Moxidation cycle in plants (Stumpf, 1976; modified and used with pennission of the copyright owner, Academic Press, New York).

such as arachidic acid (25), (Fig. 2.1). These acids all are
primary metabolites.
Some groups of plants accumulate unusual quantities of
primary fatty acids. For example, myristic acid (C I4 ) is
found in the seeds of Myristica fragrans (nutmeg) as a com·
ponent of the triacylglycerol, trimyristicin. Plant lipids often
contain small amounts of fatty acids that differ from common
primary fatty acids only in chain length. Usually, these com·
pounds represent a small percentage of the total fatty acid
content and are overlooked or ignored in analyses, but they
may be major constituents. For example, C l2 (6) and C l4
(7) fatty acids occur in large quantities in the seeds of many
groups of palms (Arecaceae), and these two acids may com·
prise more than 50% of the total fatty acids of the oils. Coco·
nut oil contains high percentages of hexanoic, octanoic, and
decanoic (capric) acids. Most other fatty acids have limited
distribution among plants (Harwood, 1980; Smith, 1970).
Unusual fatty acids typically are found in seed glycerides
(often as major components) along with common fatty acids.
Fatty Acids from Unusual Starter Units
In certain cases, starter molecules other than acetyl·CoA
are utilized. Small amounts of isa· and anteisa-fatty acids
which co-occur with normal fatty acids in most plants arise
from precursors (26) and (27), respectively (Fig. 2.12). Fatty

JySCOA

(3) (4)

CO,H

an isofatty acid

CO,H
an anteisofatty acid

CO,H

a fatty acid based on a cyciohexylMCoA starter unit

Fig. 2.12. Fatty acids derived from iso, anteiso, and cyc10hexyl starter units.
26 Fatty Acids
acids with highly restricted distribution are found in the ther-
mophilic prokaryotic organism Bacillus acidocaldarius, in
which the CoA derivative of cyclohexylcarboxylic acid is
an acceptable starting unit. In a group of closely related
higher plants, cyclopentenoid fatty acids are synthesized
from a cyclopentenecarboxylic acid starting unit (aleprolic
acid) (see Fig. 2.18 and discussion below).
Fatty Acids with Unusual Patterns of
Unsaturation
Chloroplasts from photosynthetic tissues of higher plants
and algae contain E-3-hexadecenoate (8) (Fig. 2.13), an unu-
sual palmitate-derived fatty acid. Desaturation of the 3-posi-
tion requires light and may occur after the palmitic acid
precursor is attached to the acyl moiety. This acid is found
almost entirely at the 2-position of phosphatidyl glycerol (9)
(Fig. 2.2).
Fatty acids with unsaturation in positions other than the
characteristic 9,1 O-position probably arise, in most in-
stances, from modified A-9 desatorases. Petroselinic acid
(28), a C'8-monounsatorated acid with the double bond in the
A6-position, from developing endosperm of carrot, Daucus
carota, and coriander, Coriandrum sativum (Apiaceae),
comprised 70-75 mol% of the fatty acids of the triacylglyc-
erols, but only about JO mo1% of the phosphatidylcholine
(23) and phosphatidylethanolamine (29) (Fig. 2.2) fractions
(Cahoon and Ohlrogge, 1994). However, introduction of la-
beled acetate indicated that there was rapid incorporation
into phosphatidylcholine and that most of this was in the
form of petroselenic acid. In time course stodies, the radiola-
bel initially entered phosphatidylcholine at the highest rates,
but later accumulated in triacylglycerols. Petroselenic acid,
in this instance, was readily incorporated into both the sn-
1 and sn-2 positions of triacylglycerols (Cahoon and Ohl-
rogge, 1994). The coding of a cDNA for this desatorase has
about 65% sequence identity with the A9 -desaturase (Ohl-
rogge et aI., 1993).
Conjugated ethylenic acids (31-38) may arise from lino-
leic acid (18: 2,9Z,I2Z) and its Z,E- or E,E-isomers (Fig.
2.14) (Hitchcock and Nichols, 1971). The two hydroxy
dienes (37 and 38) could arise directly from linoleic acid (or
its isomers) and give rise to the conjugated dienes, or more
H H
petroselenicacld(l8}
{E).3.hexedeeeno!e acid (8)
Fig. 2.13. (E)·3-Hexadecenoic acid and petroselenic acid.
likely, an intermediate in the lipoxygenase-type reaction
might stabilize in a number of ways, each leading to the
accumulation of a diene, dienol, or triene. Thus, 9Z, I 2Z-
linoleic acid (4) gives either coriolic acid (l3-hydroxy, 9Z,
liE) (38) or a-dirnorphecolic acid (9-hydroxy, JOE, 12Z)
(37), the 12Z-family (the 12Z-compounds of 31 and 35), and
the 9Z-derivatives of 33, 34, and 36. The 9Z, 12E-isomer of
linoleic acid yields the 12E-compounds of 31, 32 and 35
and the 9Z, 13E-compounds 34 and 36, whereas 9E, 12E-
linoleate gives rise to 12E-compounds of 31, 32, and 35,
and the 9E-forms of 33,34, and 36. Significantly, the inter-
mediates postolated occur in the same tissues in many cases.
The production of isomers with E-double-bonds remains
unexplained (Hitchcock and Nichols, 1971).
Hydroxy Fatty Acids
Hydroxy fatty acids appear to derive from multiple routes
(Butt and Lamb, 1981). Ricinoleic acid (24) (Fig. 2.15), for
example, arises in the embryo (to a lesser extent in the endos-
perm) of the castor bean, Ricinus communis. Synthesis be-
gins about 12 days after pollination and ceases about 6 weeks
after flowering. At that time, ricinoleic acid accounts for
about 90% of the fatty acids in the triacylglycerols. Proplas-
tids isolated from developing castor bean endosperm synthe-
size only oleic acid (3), although the major product of fatty
acid synthesis in these seeds is triricinoleoylglycerol. Oleic
acid is exported from the plastid, where it is synthesized to
the cytosol and activated to oleyl-CoA. An acyl-CoA: Iyso-
phosphotidylcholine acyltransferase transfers the oleate
from oleyl-CoA to Iyso-phosphatidylcholine to form oleyl
phosphatidylcholine. A specific A12-fatty acid hydroxylase
catalyzes the conversion of oleyl phosphatidylcholine into
ricinoleyl phosphatidyIcholine, mainly at position sn-2 (see
triglycerol synthesis above) (Baforetal., 1991). Synthesis of
ricinoleic acid (24) involves microsomal action (presumably
endoplasmic reticulum) that hydroxylates oleyl-CoA to ri-
cinoleyl-CoA; this product is then channeled into triacyl-
glycerides and storage oil droplets (Stompf, 1980). The en-
zyme requires NADH and molecular oxygen. Oleyl-CoA
was the only reactive substrate (Stompf, 1976); notably pal-
mitate, stearate, or linoleate do not serve as precursors. Re-
tention of label in the carboxyl group of ricinoleate demon-
strated that the compound was not made by breakdown and
resynthesis. In contrast, ricinoleic acid in ergot oil (produced
by the fungus Claviceps) apparently arises by hydration of
the double bond of linoleic acid.
12,13-Dihydroxyoleic acid (30) (Fig. 2.15) is formed
from vemolic acid (39) (which, in tom, is formed from lino-
leic acid) in crushed seeds of Xeranthemum annuum (As-
teraceae) and Euphorbia lagascae (Euphorbiaceae).
Laetisaric acid (9Z,I2Z,8-hydroxyoctadecadienoic acid)
(40) from the soil-dwelling fungus Laetisaria arvalis has
allelopathic activity and inhibits growth of the major root
pathogen Pythium ultimum (Bowers et aI., 1986). An anti-
fungal compound from taro, Colocasia antiquorum, infected
 Fatty Acids 27

?H
t
ZIE E
- CH= CH- CH= CH- CH- CH,- dlmorphecolic acid
• 12 1" • (9·hydroxy,10E,12Z) (37)

OOH
ZIE E I
-CH= CH- CH=CH-CH- CH,-

ZlE E Z
-CH= CH- CH=CH- CH=CH-
ZIE E E
-CH=CH- CH=CH- CH=CH-
"
(35)
\
--CH==CH--CH==CH--C--CH--
. / (31)

/ ZIE Z
-CH=CH-CH=CH-CH-CH-
\
ZIE ZIE (32)
-CH= CH-CH,-CH=CH-CH,-
Il 12 It 10 !II 8
linoleic acid (4)
E ZIE
(18:2,9Z,I2Z) -CH-CH--CH=CH-CH=CH-
:~ (33)

• E ZlE
--CH--C--CH==CH--CH==CH--

~~L~'~'~~\
-CH";'C-C~CH-CH~CH-
(36) ~.
OH
I -CH~C-C~CH-CH~ECH- •~ (34)

_ CH1-
I
C_
E ZIE
CH=CH- CH=CH-
I I'
cor 0 IC aCI
'd (38)
Il It !II (13·hydroxy,9Z,11E)

Fig. 2.14. Possible mechanism of biosynthesis of conjugated fatty acids.

with the pathogen Ceratocystis Jimbriata proved to be Methyl·BranchecL Cyc:lopropanoicL and

9,12, 13·trihydroxy-(E)-1 O-octadecenoic acid. Cyc:lopropenoid Fatty Acids

Epoxy Fatty Acids
Epoxy fatty acids also are found as components of triglyc-
erides of the seed oils (Smith, 1970). This unusual fatty acid
type is sporadically distributed in species of several taxo-
nomically unrelated plant families. 2-12, 13-Epoxyoleic acid
(vemolic acid) (39) (Fig. 2.15) is biosynthesized from lino-
leic acid in the seeds of Xeranthemum annuum and Euphor·
bia lagascae (Hitchcock and Nichols, 1971). This compound
and 2-9, lO-epoxystearate are synthesized by the introduction
of oxygen from O2 across the double bonds of linoleic and
oleic acids, respectively (Butt and Lamb, 1981; Morris,
1970). The biosynthesis of epoxy fatty acids is related to
that of dihydroxy fatty acids, and epoxy fatty acids may
serve as precursors for the latter type of compound.
Several naturally occurring fatty acids contain additional
methyl groups andlor cyclopropyl rings. In some cases,
cyclopropyl fatty acids arise from starter units such as propi-
onyl-CoA, but in others, the extra atoms are derived from
S-adenosylmethionine (Buist and Findlay, 1985). DeRosa et
al. (1974) suggested that tuberculostearic acid (41) is fonned
from oleic acid and S-adenosylmethionine (Fig. 2.16). Cy-
clopropane containing fatty acids are probably fonned by a
related process. Lactobacillic acid (42) and tuberculostearic
acid are both known from bacteria; other cyclopropanoid
and cyclopropenoid fatty acids also are known from higher
plants. Sterculic acid (43) is fonned by oxidation of the
cyclopropanoid fatty acid (44) derived from oleic acid
(Mann, 1987). Cyclopropenoid fatty acids are found com-
28 Fatty Acids

H H

CO,H

ricinoleic acid (24) vaccenic acid (64)

H H
CO,H

lactobaclllic acid (42)

vernollc add (39)
R CO,H

sterculic acid (43)

OH
12,13 . cUbydroxyoielc acid (30)
CO,H
OH OH
dihydrosterculic acid

OR
laellsaric acid (40) CO,H
Fig. 2.1S. Selected hydroxy fatty acids.

monly in seed oils of the families Malvaceae, Stercuiiaceae,

and Bombacaceae (Fig. 2.17).

Cydopentenoid Fatty Adds

The nonprotein amino acid cyclopentenylglycine (45) is sterculynic acid
a constitnent of the free-amino-acid pool in seeds and leaves Fig. 2.17. Cyclopropanoid and cyclopropenoid fatty acids from plants.
of Hydnocarpus anthelminthica and Caloncoba echinata
(FJacourtiaceae), where it comprises up to 2% of the total
free amino acids. This unusnal compound is derived via the
pathway presented in Fig. 2.18. This amino acid is then con-
verted to cyclopentenylcarboxylic acid (aleprolic acid) (46)

CO,H
CO,H

sterculic acid (43)

tuberculostearic acid (41)

Fig. 2.16. Proposed biosynthesis of methyl, cyc1opropenyl, and cyclopropyl fatty acids in bacteria and in plants.
 Fatty Acids 29

a-ketoglutaric
acid
r~H3COSCOA
(

CO,"
CO,

""::::">-"","--,,.c!::...
f"
CO,"

T" --
CO,"

(45)

CO,H

aleprolic acid (46)

chaulmoogric acid (47)

CO,H

hydnocarpic acid H H

CO,H

Fig. 2.18. Biosynthesis of cyclopentenoid fatty acids (modified from Mangold and Spener, 1980; used with permission of Academic Press, Orlando,
FL).

which serves as a starter unit for the synthesis of cyclopen-
tenoid fatty acids such as chaulmoogric acid (47) and gorlic
acid (48), found in the family Flacourtiaceae. Cyc!openten-
oid fatty acids also have been reported from red algae (Mira-
lie et aI., 1990). The cyclopentenoid unit in higher plants
apparently is synthesized by the following pathway (Fig.
2.18) (Mangold and Spener, 1980).
Fatty acids with structures resembling those of prosta-
glandins have been isolated from Lemna species (Fig. 2.19)
(Monaco and Previtera, 1987; Previtera and Monaco, 1987).
F1uorofatty Acids
A number of w-fluorofatty acids are known to occur in
seeds of species of the genus Dichapetalum, especially in Di-
chapetalum toxicarium (Dichapetalaceae) in west Africa
(Sierra Leone) (Meyer and O'Hagan, 1992; Smith, 1970).
This shrub is known to be highly toxic to livestock; it contains
w-fluorooctadec-Z-9-enoic acid, w-fluorooleic acid (49), and
w-fluoropa1mitic acids (Fig. 2.20). Although even-numbered
compounds are highly toxic (they are metabolized to fluoroa"
cetic acid), odd-numbered chains are much less so.
Fluoroacetate is found in at least 34 species of Gastrolob-
ium and Oxylobium (Fabaceae) in Australia, and occurs to
the extent of 0.25% of the fresh weight. Bush rats and rat
kangaroos in the areas where these plants grow are resistant
to poisoning, whereas those from other areas are not (Har-
borne, 1986).
The caterpillars of Sindris albimaculatus, which consume
30 Fatty Acids
U U
(12S)-hydroxyhexadeca-SZ,IOE,l4Z-trienoic acid
co,U
Fig. 2.19. Prostaglandin-like fatty acids from Lemna species.
the flowers, fruits, and young leaves of Dichapetalum cymo-
sum, accumulate the toxin fluoroacetate as a defense against
predators (Meyer and O'Hagan, 1992).
other Unusual Upids
Although glyceride structures with sugar substitutions,
especially galactoglycerols, are not uncommonly encoun-
tered as components of plant leaf lipids, a number of grasses
accumulate digalactosylglycerols in their seeds (Joyard and
Douce, 1987). These compounds are partly responsible for
the physical properties of flours and make them useful for
breadmaking. Compounds of this type have been isolated
from Briza spicata (50) (Fig. 2.21) (Smith and Wolff, 1996).
In seeds of some species of the Convolvulaceae, normal
glycerides are replaced by glycolipids (e.g., 51) (Fig. 2.21)
(Smith et aI., 1964). 6-D-Glucopyranosyl esters of palmitic,
oleic, linoleic, and linolenic acids occur in rape, Brassica
napus, pollen (Grove et aI., 1978).
METABOLICALLY ALTERED FATTY ACIDS
Metabolically altered fatty acids (i.e., fatty acids that have
been reduced in chain length by (X- and/or f3-oxidation and
have undergone various processes of oxidation or reduction)
occur in many essential oils. Many of these intermediary
metabolites are converted ultimately to esters, acids, alco-
hols, aldehydes, alkenes, and alkanes (Fig. 2.22). These fatty
acid derivatives are relatively volatile and occur widely as
components of the essences of flowers, fruits, stems, leaves,
U U
F
m·Ouorooleic acid (49)
Fig. 2.20. ro-Fluorooleic acid.
CU,
U I
~
o ~
-J(CU,).
~
o
ou uo ouol
U H (CH,),
OH I
CO,H
E
lipid from Ipomoea parasitlca seeds (51)
O_galaciOSYI
O-galactosyl
O.C16,C18 fatty acids
(SO)
Fig. 2.21. Glycolipids from Briza spicata and Ipomoea parasitica
seeds.
and roots. To cite but one example, the flavor of Bartlett
pears (44) (Fig. 2.22) is due in part to esters. Analysis of
these metabolically altered fatty acids is usually effected by
GC/MS (gas chromatography/mass spectruscopy) methods
(Buttery et aI., 1987; Kameoka, 1986).
Essential oils often are important as synomones (com-
pounds that are of benefit to both the sending and receiving
organism) in mutualistic relationships between plants and
animals (especially insects). Synomones are especially im-
portant for pollination and fruit and seed dissemination.
The volatile resin exuded from the stem bark of Commi-
phora rostrata (Burseraceae) consists mainly of 2-decanone,
2-undecanone, 2-dodecanone, and hexadecanal. This sub-
stance seems to be involved in limiting herbivory on this
small tree. When branches or twigs are bent or cut, a resin
is released that rapidly covers the area around the injury
(McDowell et aI., 1988).
The wild tomato, Lycopersicon hirsutum f. glabratum
(Solanaceae), is covered with trichomes which contain 2-
tridecanone (53) (Williams et aI., 1980). The level of this
compound is much lower in the domesticated tomato, L.
esculentum. The exudate is toxic to Manduca sexta (tobacco
homworm) and to Helicoverpa zea (the cotton bud worm).
The density of glandular trichomes was influenced by an
interaction between day length and light intensity; the toxic
plant compound was significantly more abundant on foliage
of plants grown under long-day regimes. This fmding is of
considerable importance, as there is a possibility of intruduc-
ing this resistance into acceptable tomato cultivars (Kennedy
et aI., 1981; Williams et aI., 1980; Zamir et aI., 1984). The
sesquiterpene zingiberene was found in Lycopersicon hirsu-
tum f. hirsutum and its presence coincided with resistance
to the Colorado potato beetle (Carter et aI., 1989).

~ ~O~
o
3·octanone
~OH~CHO
I-octano)
~~OH
2-undecanone
2-tridecan.ne (53)
H H
~COlCH3.rClH'-
(52)
Fig. 2.22. Metabolically altered fatty acid derivatives.
Plant-derived compounds such as (3Z)-hexenyl acetate,
(3Z)-hexen-I-ol, (2E)-hexenal, (3E)-hexenal, 4-methyl-3-
heptanol, (llZ)-hexadecenal, (9Z)-hexadecenal, and (7Z)-
hexadecenal are used by parasitoids to locate the host habitat
(Elzen et al., 1984; Kennedy, 1984; Turlings et al., 1991;
Wickremasighe and Emden, 1992). (2E)-Hexenal was
strongly inhibitory to tomato seed germination at concentra-
tions as low as 6.9 fJM (Bradow and Connick, 1990).
Tbe Green Leaf Volatile Complex
The leafy or grass-like smell of most green leaves is due
to the presence of a series of aldehydes and alcohols derived
by oxidative degradation of fatty acids. (see Fig. 2.23.) The
relative proportion of these compounds varies among plant
species and often seasonally within the same species. The
composition of mixtures of these compounds also is affected
by aging and injury.
In electroantennogram responses of the Mediterranean
fruit fly, Ceratitis capitata, to a spectrum of plant volatiles,
Fatty Acids 31
octyl acetate
octanal
I-dodecanol
IO-undecen·l·o1
the strongest responses were obtained for the monoenoic C.
alcohols and aldehydes which make up much of the green
leaf volatile complex of many plants (Light et al., 1988).
Humans respond in a similar way; oct-l-ene-3-01 and (3Z)-
hexenol contribute much of the characteristically pleasant
"green odor" to the fruits of chayote (Sechium edule, Cu-
curbitaceae) (MacLeod, 1990).
Compounds such as E-2-hexen-I-ol, I-hexanol, Z-3-
hexen-I-ol, and E-2-hexenol and linalool (a monoterpene)
are involved in the olfactory orientation of the Colorado
potato beetle, Leptinotarsa decimlineata, to the foliage of the
potato, Solanum tuberosum (Solanaceae). However, none of
the individual components alone was attractive; the beetle
was attracted only to a mixture similar to that of the host
plant (Visser and Ave, 1978; Visser et al., 1979). A similar
complement of compounds seems to be involved in attrac-
tion of the alfalfa seed chalcid (Bruchophagus roddi) to al-
falfa (Medicago sativa, Fabaceae) (Buttery and Karnm,
1980).
Whereas undamaged plants emit low levels of green leaf
32 Fatty Acids
acyl hydrolases
leaf lipids - - - - - -•.,
oxidatio,:--- linolenic acid (18:3) /
¥'
~CHO
3Z·hexenal ---------...
i 2E-hexenal
3Z-hexenol
,
~CH,OH
3E-hexenol
Fig. 2.23. Proposed biosynthesis of green leaf volatile complex.
volatiles, caterpillar-damaged plants emit higher levels. Fe-
male braconid parasitoids, Micropiitis croceipes and female
ichneumonid parasitoids, Netelia heroica, oriented to the
compounds and damaged plants in a wind tunnel, but seldom
to undamaged plants, suggesting that these parasitoids may
orient toward plant damage to locate their caterpillar hosts
(Whitman and Eller, 1990).
f'Ul'ICTIONS OF FATTY ACIDS Al'ID THEIR
DERIVATIVES Il'I PLANTS
Many functions of fatty acids in plants have been reviewed
(Fuller and Nes, 1987). The most important role of fatty
acids is as a component of energy storage systems in plant
seeds and other lipid-accumulating organs and as compo-
nents of plant membranes. Upon germination of the seed,
fatty acids are usually broken down to smaller compounds
and utilized by the plant. On a percent weight basis, glycer-
ides are the most efficient energy storage material commonly
used by plants. Most plants store energy as either glycerides
or carbohydrates, but few produce large quantities of both.
Seed lipids provide an excellent source of food not only for
plant embryos, but also for a variety of animals, fungi, and
bacteria. Thus, there has been evolutionary selection to pro-
tect seeds from predation by several mechanisms including
accumulation of toxic secondary metabolites in the seeds
(Levin, 1974). In some instances, the poisonous materials
are modified fatty acids stored in the seeds. These com-
pounds are later catabolized when needed as energy or nu-
trient reserves.
A wound hormone in plants, traumatin or l-decene-1, 10-
dicarboxylic acid, was first isolated from bean pods. This
substance is capable of inducing renewed cell division and
free fatty acids - - - - . linoleic acid (18:2)
.. oxidation
~CHO
isomerase
~CHO hexanal
~CH,OH
I-hexanol
~CH,OH
2E-hexenol ' ...
~CH,OH
2-Z-hexenol
cell extension activity in the parenchymatous cells of the
bean pod mesocarp (Mandava, 1979).
Modified fatty acids (such as 54 and 55) containing cyclo-
pentenoid rings have been isolated from the alga Eleocharis
mierocarpa and have been suggested to be involved in allelo-
pathic interactions with other aquatic organisms (Fig. 2.25)
(van Aller et a1., 1985). A series of structurally similar com-
pounds that have pheromonal properties is known from
brown algae (Fig. 2.24) (Jaenicke, 1974, 1991). In addition
to pheromonal properties, a mixture of two of these com-
pounds, dictyopterene A (50) and B (51), inhibits feeding
on the brown alga, Dictyopteris de/ieulata, by reef fish (Hay
et a1., 1988). These substances also may indirectly protect
small marine herbivores that fed on the algae.
Jasmonic Acid and Related Compounds
Perhaps one of the greatest surprises in recent years is
the wide range of physiological activities in plants induced
by the presence of jasmonic acid (59) and structurally related
compounds (Fig. 2.25). Jasmonic acid and the corresponding
methyl ester are fragrant constituents of the essential oils of
fasminum spp. (Oleaceae) as well as other perfumery plants
(Sembdner and Parthier, 1993). These compounds occur in a
large variety of plant species. Jasmonic acid and its relatives
possess structural similarities to prostaglandins from animals
(Fukui et aI., 1977a,b; Gross, 1980).
Jasmonic acid is derived from a-linolenic acid, 13(S)-
hydroperoxylinolenic acid, 12-oxophytodienoic acid, and
phytodienoic acid (Farmer and Ryan, 1990, 1992; Hamberg
and Gardner, 1992). The biosynthesis of jasmonic acid and
related compounds has been reviewed (Sembdner and Par-
thier, 1993).
(- )-Jasmonic acid (59) and its methyl ester are wide-
spread among plants and have demonstrated growth-inhibit-

ing capabilities in plants (Dathe et aI., 1991) (Fig. 2.24). A
structurally similar group of compounds including cucurbic
acid has been isolated from pumpkin (Cucurbita pepo, Cu-
curbitaceae) and other plants (Dathe et aI., 1991). Cucurbic
acid, (lS,2S,3S)-3-hydroxy-2-(2'-cis-pentenyl) cyclopen-
tane-I-acetic acid (60), and the co-occuring 3-0-f3-D-gluco-
side and methyl ester possess growth inhibiting ability in
rice, but lack activity in Avena coleoptile bioassays.
The phytohormone effects of jasmonic acid are similar
to those of abscisic acid, an established phytohormone; it
has been argued that jasmonic acid should be recognized as a
representative of a unique class of phytohormones (Hamberg
and Gardner, 1992; Sembdner and Parthier, 1993; Staswick,
1992). Jasmonic acid is more effective than abscisic acid in
promoting senescence, induces the expression of a specific
set of proteins (jips or jasmonate-induced proteins) in differ-
ent plants (Sembdner and Parthier, 1993; Staswick, 1992),
and, in some instances, may be involved with the induction
of the formation of seed storage proteins. This compound
linolenic acid
~-~
OH
O2
~CO,H_""-",,,-_....
opP
(a) ~ •
Ov_~ __ ~,==
~~g: dictyopterene B (51)
~Al
H~
(b) (+homosirene
Fig. 2.24(a & b). Patty acid-derived phennones from brown algae (Modified from Jaenicke, 1974; used with pennission of the copyright owner,
Springer-Verlag, Berlin),
Fatty Adds 33
seems to be involved with tuber formation in both yam (Di-
oscorea) and potato (Hamberg and Gardner, 1992). Jas-
monic acid may be active in the process of tendril coiling in
some lianas (Hamberg and Gardner, 1992; Staswick, 1992).
When methyl jasmonate was applied to the surface of
tomato plants, the synthesis of a defensive proteinase inhibi-
tor protein was induced, not only in the plant to which the
application was made but also in nearby plants. In subse-
quent studies, this compound was shown to have a similar
effect with plants of other families as well (Farmer and Ryan,
1990; Pearce et aI., 1991). In a series of experiments, it was
demonstrated that methyl jasmonate can be a component of
interplant communication systems. Octadecanoid precursors
of jasmonic acid were able to activate the synthesis of
wound-inducible proteinase inhibitors (Crombie and Mistry,
1991; Farmer and Ryan, 1992). Jasmonic acid is a signal
transducer in elicitor-induced plant cultures of Rauvolfia
canescens and Eschscholtzia californica. Tissue cultures of
36 species of plants could be induced to accumulate second-
OH
~ctor fucoserraiene
COz,HzO
OH
(2ATPlMgH)
\.
V
~
~
/='- --:. . . . -
~~
dictyopterene A (SO)
(+)-ectocarpene
34 Fatty Acids

Methyl jasmonate is a pheromone produced by the male

~CO'H H~~ oriental fruit moth (Staswick, 1992).

~
o
~C01H The Requirement for Unsaturated Fatty
Acids In the Diet of Animals
Although most plants appear to have the ability to make
jasmonic acid (59) cdcurbic acid (60)
linoleic and linoleic acids, animals cannot desaturate posi-
OH tions from C-9 to the methyl terminus of the fatty acid chain,

~CO'H
and must obtain unsaturated fatty acids such as linoleic acid
and linolenic acid from their diet. The requirement for these

~
(55)
o 5,8,1l,14-enoic acid, is formed from Iinoleate by chain ex-
o mammals and other organisms.
Fig. 2.25. Cucurbic, jasmonic acid. and algal cyclopentanoid fatty
acids.
ary metabolites by the presence of methyl jasmonate (Gun-
dlach et aI., 1992).
When cotton seedlings are infested by herbivorous mites,
volatile signals are released that attract additional mites.
Downwind-uninfested plants are made more resistant to mite
attack by contact with these volatile compounds; this system
also seems to involve methyljasmonate (Bruin et al., 1992).
acids involves formation of arachidonic acid (61) and, subse-
quently, prostaglandins. Arachidonic acid, eicosatetra-
tension and by additional desaturation. Prostaglandins (such
as 62 and 63) are derived from eicosatrienoic and eicosate-
traenoic acids, respectively, although the actual path of bio-
synthesis is not completely elucidated (Fig. 2.26). These
compounds have pronounced hormonal and other effects on
A range of prostaglandins have been reported from the
leaves of onions (Allium cepa, Liliaceae) and other plants
(A1-Nagdy et aI., 1986; Levinet al., 1988). Compounds from
Bryonia (Cucurbitaceae) are not structurally similar but have
prostaglandin-like activity in animals (Fig. 2.27) (Panossian
et al., 1983).
Effects of Fatty Acids and Their Derivatives
on Animals
The effect of many toxic secondary metabolites is proba-
bly to prevent or limit feeding rather than to kill the herbivore

HO

HO
~ /
HO
I
arichidonic acid (61) PGF,a(62)
HO

~H ~COzli
l(~~
/ i
HO
I
HO H~
thromboxane A1
PGF",(63)
OH
HO I
\ !

~~ j ! HO 0 I
HO HA H~
thromboxane 8 1

Fig. 2.26. Representative prostaglandins.

 C
OlH
~COlH
OH
s:x
HO A _ HO ~ cic acid (Z-13-docosenoic acid) (66), when fed to rats at as
OH
C
OH
CO,H
COlH
OH
HO 6 OH
HO
HO
OH
Fig. 2.27. Compounds from Bryonia alba (Curcubitaceae) with
prostaglandin activity.
outright, although many compounds could certainly accom-
plish the latter, if enough were consumed. Seeds may be
made "distasteful" or "non-nutritious" by one mechanism
or another.
Triglycerides from most plants are edible to most animals.
In humans, they have mild laxative properties, especially
when consumed in large amounts. Glycerides have been
shown in at least two cases to serve as compounds that elicit
aggregation in insects. l-Palrnitoyl-2,3-diolein, 2-linoleoyl-
1,3-dipalmitin, and I-palmitoyl-2-linoleoyl-3-0Iein were
identified in three active fractions from wheat germ that elicit
aggregation of the confused flour beetle (Seigler, 1979; Ta-
mald et al., 1971). Similarly, 1,3-diolein was shown to "at-
tract" houseflies (Musca domestica) to the fruiting bodies
of Amanita muscaria, and similar fractions were shown to
"attract" houseflies to the fruiting bodies of other mush-
rooms of the Tricholomataceae and Amanitaceae (Seigler,
1979). 1,2-Dioleins are the major attractants for ants in elaio-
somes of a number of ant-dispersed seeds in the northeastern
United States. (Kusmenoglu et aI., 1989).
Fatty acids are known to be feeding stimulants for certain
insects. Linolenic acid (as the free fatty acid) in mulberry
leaves stimulates leaves potent feeding activity in Bombyx
mori, the silkworm. Linoleate and laurate also have activity,
whereas myristate, palmitate, stearate, elaidate, oleate, and
vaccenate (64) (Fig. 2.16) have none. Oleate promotes
growth, but not feeding activity. A synergistic effect of (3-
sitosterol has been observed with linolenate, linoleate, vac-
cenate, and laurate. Linoleic acid and linolenic acids are
phagostimulants for the fire ant, Solenopsis saevissima var.
richter;' Palmitate and stearate produce a positive feeding
response in the hide beetle (Dermestes maculata) and valeric
acid (71) (Fig. 2.29) in the Khapra beetle (Trogoderma gra-
narium). Fatty acids (CS-C ll ) are repellent to the red flour
beetle (Tribolium castaneum). Honey bees are attracted to
clovers by the action of the triene (65) (Mann, 1987).
Fatty Acids with Biological Activity
The antifungal and antibiotic properties of fatty acids and
some derivatives have been studied; monolaurin (the triester
Fatty Acids 3S
of lauric acid and glycerol) is the most potent compound in
this regard (Kabara, 1987; Masui et aI., 1989).
Although similar in structure to common fatty acids, eru-
little as 15% of their caloric intake, produced myocarditis
(accumulation of lipids in the heart) (Fig. 2.28). Eventually,
myocardial fibrosis and other abnormalities were observed.
Because rapeseed oil was widely used for margarine produc-
tion, a breeding program was initiated to produce new vari-
eties in which most or all of the erucic acid is replaced with
oleic acid. This new product is called canola oil. High erucic
rapeseed oil is still used to prepare lubricants (Simpson and
Conner-Ogorzaly, 1986). Both types are cultivated.
A number of mammalian and fungal enzyme systems,
whole cells, and entire animals have been shown to respond
differently to fatty acids that differ in number and position
of double bonds, geometric isomers, or cyclopropyl ring po-
sitions (Seigler, 1983). Few olefinic or acetylenic fatty acids
are highly toxic, although there are large variations in the
ease of utilization by different organisms.
Most unsaturated fatty acids contain Z- or (cis )-double-
bonds. When fatty acids with E- (or trans-) double-bonds
are fed to rats along with adequate amounts of essential fatty
acids, E- or trans-fatty acids have little effect on growth,
longevity, or reproduction, but when fed as the sole source
of lipids, E-fatty acids exaggerate the symptoms of fatty
acid deficiency. An effect on the metabolism of long-chain
polyunsaturated acids was noted, however (Alfin-Slater and
Aftergood, 1979; Seigler, 1983).
A pentane extract of tung (Aleurites fordii, Euphor-
biaceae) that contained a-eleostearic acid [(9Z,l1E,13E)-
octadecatrienoic acid] (67) and erythro-9,1O-dihydroxy-l-
octadecanyl acetate (acetate of 68) was shown to be strongly
repellent to Anthonomis grandis, the boll weevil, as well as
other insects (Jacobson et al., 1981).
Castor oil, which contains up to 90% ricinoleic acid (24)
(Fig. 2.15), possesses cathartic activity in humans, but not
in rats.
Several esters of hydroxy fatty acids (such as 3-acetoxy
fatty acids) are involved in mutualistic relationships of some
plants (such as those of the genus Krameria, Kramericeae)
and their pollinating species. o-3-Hydroxydecanoic acid has
fungicidal properties (Seigler, 1983).
Cyclopropenoid fatty acids (Fig. 2.17) inhibit fatty acid
desaturation in several species, including chicken, rat, pig,
cow, and trout, causing a rise in the stearate to oleate ratio.
This may have an effect on the composition and function of
membranes as variation in lipid composition is known to
alter permeability of membrane systems. Numerous types
of deleterious effects from consumption of seed oils with
cyclopropenoid fatty acids have been observed (Seigler,
1979). A cyclopropene fatty acid from Sterculia foetida oil
was lethal to the larvae of Callosobruchus maculatus at 0.1 %
in artificial diets (Janzen et al., 1977). The most important
edible oil with these compounds is cottonseed oil from Gos-
sypium hirsutum (Malvaceae). Much of the cyclopropenoid
36 Fatty Acids
(65)
(X-eleostearic acid (67)
OH
OH
erythro-9,lO-dihydroxy-l-octadecanol (68)
erucic acid (66)
echinacein (69)
neoherculin (70)
Fig. 2.28. Fatty acids and fatty acid derivatives with biological activity.
content is removed by processing of the oil, especially in
the process of deodorization, but the range of cyclopropenyl
fatty acids in commercial cottonseed oil is from 0.1 % to
0.5%.
Oils containing cyclopentenoid fatty acids such as chaul-
moogric and hydnocarpic acids (Fig. 2.18) have long been
used for the treatment of leprosy.
Amide derivatives of unsaturated fatty acids (CID-C IS )
are especially common in members of the families Aristolo-
chiaceae. Asteraceae, Piperaceae, and Rutaceae; about 140
compounds of this type are known (Greger, 1988). Many
contain only olefinic fatty-acid-derived portions, but those
of the tribes Anthemideae and Heliantheae of the Asteraceae
often contain acetylenic linkages as well. Among these, the
isobutyl amides [such as echinacein (69) and neoherculin
(70)] have pronounced insecticidal activity, others induce
local anesthesia (Greger et aI., 1985). Most of these com-
pounds have not proven practical for insecticides, as they
are highly irritating to mammals and are relatively unstable
(Jacobson, 1971). Leaves and inflorescences of Spilanthes
olearacea (anamafana or anamalaho) that contain com-
pounds of this type are widely used as an herb in Malagasy
cooking. This plant contains both olefinic and acetylenic
isobutylamides (Greger, 1988), which may be responsible
for the tingling sensation in the mouth that is produced by
this herb.
~ CO,H
INSECT PHEROMOrrnS DERIVED FROM
FAITY ACIDS
A number of insect pheromones are derived from fatty acid
metabolism. These are liberated by the female insect to at-
tract the male from a distance and to induce copulation when
at close quarters. In other instances, the males liberate similar
compounds to attract the females. In human terms, these
compounds are equivalent to aphr0disiacs.
The first insect pheromone to be isolated and character-
ized was bombykol (structure 72) from the silk moth, Bom-
byx mori, by Butenandt and co-workers (Kelly, 1990). Pher-
omone glands (500,000) were extracted to yield 12 mg of
the 4'-nitroazobenzene-4-carboxylic acid ester of the volatile
alcohol. As few as 2500 molecules of the pheromone is
enough to elicit behavior in the male moth (Hecker and Bu-
tenandt, 1984; Kelly, 1990).
Pheromones have now been studied and characterized
from many different species and at least 200 female sub-
stances are known from female lepidopterans and at least
60 from males (Fig. 2.29) (Harborne, 1982).
In terms of structure, the simplest is valeric acid (71), the
female pheromone of the sugar beet wire worm. The major-
ity are long-chain unsaturated alcohols, acetates, or carbox-
ylic acids. In anyone insect, the s!mctures ofthe pheromones
are usually quite specific and small changes (position of
 Fatty Acids 37

double bonds, Z versus E double bonds, or stereochemistry}
usually diminish sharply or eliminate any activity. In some
cases, mixtures of compounds occur; the exact ratios must
often be present to maintain activity. Pheromones are usually
active at extremely low concentrations and have generally
proven difficult to study for this reason.
Several aggregation pheromones are metabolically al-
tered fatty acids, or mixtures of these compounds. The most
active attractants for the sawtoothed grain beetle, Orzyaephi-
Ius surinamensis, from oats were (2E}-nonenal and (2E,4E)-
nonadienal (Mikolajczak et al., 1984). The most abundant
compound from a variety of food-related resources with
pheromonal activity for males of the driedfruit beetle,
Carpophilus hemipterus (Coleoptera: Nitidulidae), was
(2E,4E,6E,8E}-3,5,7-trimethyl-2,4,6,8-decatetraene (Bartelt
et aI., 1990).
In a few cases, pheromonal substances are taken from the
plant and used directly (see Shorey and McKelvey, 1977),
but more commonly, pheromones appear to be modified or
synthesized by the insect. The biosynthesis of pheromones
has been discussed (Tumlinson and Teal, 1987).
Brevicomin (73) and frontalin (74), probable products of
fatty acid metabolism, are part of the pheromone system of
bark beetles of the genus Dendroctonus. These compounds
are involved in interactions of these insects with their host
plants, many of which are important softwoods (gymno-
sperms) (Fig. 2.30).
The active constituents of the Dufour's glands of species
of Colletes and Halictus bee species have been studied and
characterized as macrocyclic lactones, such as l8-octadeca-
nolide (75). These compounds also are derived from fatty
acid metabolism (Fig. 2.30).
The European cherry fruit fly, Rhagoletis cerasi, lays a
single egg into half-ripe cherries. An oviposition-deterring
pheromone, which prevents oviposition by a second female
of the same species, was isolated from the feces of the insect.
This compound was characterized as N[15(J3-glucosyl}oxy-
8-hydroxypalmitoyIJ-taurine (76) (Fig. 2.30) (Hurter et aI.,
1987).
MAMMALIAN FHEKOMOrmS
A number of mammalian pheromones are combinations of
low-molecular-weight carboxylic acids. In other mamrnals,
steroids, sulfur-containing compounds, amines, and alcohols
play pheromonal roles; some of these compounds also are
derived from carboxylic acids (Albone, 1984; Harborne,
1982). Macrocyclic lactones such as civetone (77) and mus-
cone (78) are the active odor compounds of the civet cat and
the musk deer, respectively.
ANALYSIS OF FATl'Y ACIDS
Historically, this was one of the most difficult groups of
compounds for chemical examination. Because the intact
glycerides are difficult to purify and to characterize, most

~CO,H valerie acid (71) sugar beet wireworm

Limonius californicus

o
~O"- z-7-dodecenyl acetate cabbage looper
Trichoplusia ni
o
~CO'H E-9-keto-Z-decenoic acid honey bee
Apia mellifern
o
~O~ Z-S-dodecenyl acetate oriental fruit fly
Dacus orienkllis

bombykol (72) silkworm moth

HO

o
/l-o~ red banded leaf roller

I"", I"", CO,H monarch butterfly

H02~

Douglas fir tussock moth

Z-6-heneicosen-ll-ooe Orygia pseudotsugata

Fig. 2.29. Fatty-aeid-derived insect pheromones (modified from Harhorne, 1982).

38 Fllf1.\' AcidJ

frontalin (73) brevicomin (74)

HO _ _<OH ____ 0, fH,

HO~CH(CH,J'<;H(CH,J.CONHCH1CH1SO,H
OH I
OH

N[15(P-glucosyl)oxy-8-hydroxypalmiloyll-taurine (76)

° °

Q
18-octadecanolide (75)

clvetone (77) muscone (78)

Fig. 2.30. Bioactive molecules derived from fatty acids.

studies have been carried out with the fatty acids or esters
derived from them. As is true for most esters, trlacylglycerols
may be hydrolyzed with either acid or base tu yield an alco-
hol (glycerol) and free fatty acids. Glycerides may also be
transesterified to form fatty acid methyl esters.
With the advent of column chromatography, thin-layer
chromatography, and gas liquid chromatography, the analy-
sis offatty acids and their methyl esters has become routine.
GCIMS makes the characterization of most fatty acids a
straightforward procedure.
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3
Acetylenic Compounds
Introduction
Biosynthesis
CIS Acetylenic Fatty Acids
AllyJic Oxidation and Rearrangement
Compounds Derived by Modification of CIS Acetylenic
Fatty Acids
Reduction of Chain Length by Ooe Carbon Atom
Oxidative Cleavage of the Chain
Cyclization of Acetylenic Compounds
Sulfur Derivatives of Acetylenes
Distribution of Acetylenic Compounds in Plants and
Fungi
Physiological and Pharmacological Properties
Biologically Active Acetylenic Compounds
Acetylenes as Phytoalexins
Plant-Insect and Plant-Nematode Relationships
Phototoxic Effects of Acetylenic Compounds
Allenic Fatty Acids
References
INTRODUCTION
Although discovered in the late 1800s, there was little
progress in the study of acetylenic compounds from plants
until the 1950s. These compounds are highly unstable to
light, oxygen, and heat. Plant acetylenes often occur in com-
plex mixtures and the techniques needed to isolate, purify,
and characterize them were not widely available until that
time; UV spectrophotometry permitted workers to assign
structures and was a major breakthrough for study of this
group. Acetylenic compounds are widespread in nature, but
they are concentrated in several groups of plants and fungi.
At present, about 1000 naturally occurring acetylenes are
known.
There are three main types of acetylenic compounds in
plants. Acetylenic acids, usually derived from oleic acid,
42
often occur as part of triacylglyceriiles and are restricted to
seed oils in a few plant families. A second group of acetyle-
nic compounds consists of metabolically altered derivatives
of crepenynic acid. These often are distributed throughout
the plant, although, in some instances, the compounds may
be found only in a single plant part, especially roots. This
second type is often found in the essential oils of plants of
the Apiaceae, Ara1iaceae, and Asteraceae. Other acetylenic
compounds of this origin are found in seeds. A third group
is formed by triple-bond introduction into compounds of
many different biosynthetic origins, such as terpenes. These
compounds are sporadically distributed in diverse plant
groups.
BIOSYl'lTHESIS
CIS Acetylenic Fatty Acids
The facts that radioactively labeled acetate and malonate
label acetylenes in the same manner as fatty acids and that
few branched-chain acetylenic compounds are known
strongly suggest that naturally occurring acetylenes are de-
rived from fatty acids. Additionally, many acetylenic com-
pounds with a Z double bond have the double bond in the
same position as the double bond of oleic acid. In a similar
manner to fatty acids, introduction of double bonds into acet-
ylenic compounds requires molecular oxygen. Although the
triple bond is usually introduced into a position where a
double bond would be expected, in some instances no prior
double-bond formation is observed. The enzymes responsi-
ble for the introduction of triple bonds have been little
studied.
Oleic and linoleic acids are precursors for acetylenes in
microorganisms and plants (Fig. 3.1), but crepenynic and
dehydrocrepenynic acids also are incorporated into most
acetylenic compounds. Crepenynic acid (1) is the first acety-
 AcetyJenic Compounds 43

z z
stearate --+ oleate __ CH3(CH,),CH=CHCH.CH=CH(CH,),COSX

IInoleate

z z
CH3(CH,).CH=CHC=CCH.CH=CH(CH.J,COSX _ CH3(CH,),C:CCH.CH=CH(CH,J,COSX

~ (2) crepenynate (1)

CH3(CH,).C:CC=CCH.CH=CH(CH,J,CO.R _ CH3(CH,).(C=C}zCH=CHCO(CH,),CO,R

1m !~
°II
CH3CH=CH(C:C),CH.CH=CH(CH,J,CO,R CH3CH=CH(C:C).CH=CHCO(CH,),CO.R?

""".00 ..' t.'. . .;--mt

. !
II z z
CH3CH=CH(C:C),CH=CHC(CH,),CO,R CH3CH=CH(C:C),CH=CHCO,CH3

~ Oz matricaria ester (4)

E
CH3(C:ChCH=CHCO.CH3

dehydromatricaria ester (5)

Fig. 3.1. Biogenesis of matricaria ester and dehydromatricaria ester.

lenic fatty acid in the reaction sequence. This compound is

then desaturated to yield dehydrocrepenynic acid (2) which
is, in turn, converted to the corresponding diacetylenic com- z
pound (3). A number of other acetylenic fatty acids are de- CH3(CH,),C:::CCHzCH=CH(CHz)7COzH
rived from both (1) and (2) by reactions involving allylic
oxidation and subsequent rearrangement (Bohlmann and crepenynie aeid (1)
Burkhardt, 1972; Bohlmann et al., 1973; Bu'Lock, 1966).

AllyUc Oxidation and ReillTangement ! [0]

Allylic oxidation is often followed by allylic rearrange-
ment (Fig. 3.2). Oxygen atoms are rarely introduced into
nonallylic positions in these molecules (Bohlmann et al.,
1973).

Compounds Derived by Modification of CIS

Acetylenic Fatty Acids allylie 1 rearrangement

A large series of compounds are derived by modification

of crepenynic acid and related C •• acetylenic fatty acids.
Whereas these acids may be accumulated in seed oils as
E
components of triacylglycerols, modified derivatives USUally CH3(CH,),C=CCH=CHCH(CHz),COzH
are found in vegetative portions of plants. The biosynthesis
of matricaria ester (4) and dehydromatricaria ester (5) (both
I
OH
with 10 carbon atoms in the acid portion of the molecule)
(Fig. 3.1) is typical for this series of compounds. In this from a Helichryaum species (Asterae..e)
instance, fatty acids with chain lengths of less than 18 carbon
atoms do not serve as precursors. Fig. 3.2. Allylic oxidation followed by allylic rearrangement.
44 Acetylenic Compounds

oleic acid

! Z
CH,(CH,J,C=CCH,CH=CH(CH,J,CO,H

/
crepenynic acid (1)

E
CH,(CH,J,C=CCH=CHiH(CHlhC01H

OH

Z
CH,(C=C),CH,CH=CH(CH,J,CO,H

Z / ! Z CH(CH-',CO,H
CH,(""'C_=C),CH1CH-_

1 1
CH,(C:C),CH,CH =CH(CH,),CO,H "

C lO polyacelylenes

C14 polyacetylenes C13 polyacetylenes

Fig. 3.3. Biosynthetic pathways from oleic acid to polyacetylenes (modified from Jente et aI .• 1988).

In the biosynthesis of metabolically altered acetylenic

compounds, various numbers of acetylenic bonds may be R,CHa·YHCOlR ..... R.CHrCHO
inserted and the chain shortened by a- or l3-oxidation or OH
both (Fig. 3.3). Triple bonds are usually introduced in a
conjugated manner, although they may be separated by a
methylene group from the initial double bond of oleic acid.
Other compounds maintain the Z double bond and do not
undergo an allylic rearrangement (Jente et al., 1988). " ~o
'0-
R·CH·CH,.C ~
In some plants, reduction of terminal carboxyl groups to I
the corresponding aldehyde occurs. Aldehydes may then be ( OH

reduced to alcohols, these dehydrated to olefins, and the H<

olefms saturated to hydrocarbons (Fig. 3.4). In other plants, Fig. 3.5. Fonnation of C17-tenninal olefins from Cl8 precursors.
the reverse (degradative metabolism) of this reaction series
occurs. These modifications occur frequently in the acetyle-
nic series and help to explain the large number of compounds
observed.

Reduction of Chain Length by One Carbon

Atom
Various combinations of a- and l3-oxidation lead to short- ----. HOCHl-e=C-R ---+ OCH-CEC·R
ened chain length as previously mentioned. In addition, in-
troduction of an oxygen alpha to the carboxyl group can
lead to the formation of an aldehyde with a chain length of
one carbon atom less (Fig. 3.5). The elimination of one car-
bon atom from the hydrocarbon end of the chain also is
observed (Fig. 3.6).
Introduction of an oxygen at the l3-position can lead to

Fig. 3.6. Possible sequence for fonnation of C17 acetylenes from CIS
precursors.
Fig. 3.4. Oxidation and reduction in biosynthetic sequences.
 ACt'tyfenit: Compounds 45

Cyclization of Acetylenlc Compounds

Extended conjugated acetylenic systems sometimes give
rise to aromatic rings in plants. These compounds usually
co-occur with other acetylenic compounds and have linear
side chains attached to the aromatic rings. (see Fig. 3.9)
Almost all aromatic compounds from acetylenic precursors
are found in the Asteraceae.
Acetate is incorporated in the manner predicted for fatty
acids (Weiss and Edwards, 1980). In some instances, aroma-
tization is known to occur under in vitro conditions and the
probable precursor and the corresponding aromatic com-
pound sometimes occur together in the same plant; for exam-
ple, compounds (6) and (7) often co-occur in Coreopsis spe-
cies (Fig. 3.10).

Sulfur Derivatives of Acetylenes

Conjugated dienes in some plants react with sulfur-con-
taining intennediates to yield thiophenes. In other instances,
methyl thioethers are fonned. Although not known with cer-
tainty, suggested sulfur donors are methionine, S-adenosyl
methionine (SAM), and cysteine.

Fig. 3.7. Baeyer-Villiger type oxidation possibly responsible for DISTRIBUTION OF ACETYLENIC COMPOUNDS
fonnation of CIO compounds.
IN PLANTS AND FUNGI

In contrast to the distribution of most fatty acids, acetylenic

decarboxylation and fonnation of an olefin with one less
compounds are found in a restricted number of plant taxa.
carbon atom. Compounds of both origins may then undergo
Acetylenic acids that are components of triacylglycerides
reduction or oxidation as indicated above (Bohlmann et aI.,
are occasionally found in the seed oils of members of the
1973).
Asteraceae (such as in species of Crepis and Helichrysum),
but are most commonly found in a group of closely related
Oxidative Cleavage of the Chain families: the Loranthaceae, Oiacaceae, Opiliaceae, and San-
talaceae (Order Santalales).
A reaction similar to Baeyer-Villiger oxidation (oxida-
Metabolically altered acetylenic compounds are common
tion adjacent to a carbonyl group) occasionally occurs and
constituents of many plants of the families Apiaceae, Aralia-
may be responsible for the fonnation of several C IO com-
ceae, and Asteraceae, but also occur in the Campanulaceae
pounds (Fig. 3.7).
and Pittosporaceae (Downum and Nemec, 1987). Among
A complex lipid from the seed oil of the Chinese tal-
the fungi, acetylenes of this type are quite common in basidi-
lowtree, Sapium sebiferum (Euphorbiaceae), appears to have
omycetes. Acetylenes usually occur free, are found in di-
arisen in this manner (Fig. 3.8). Although acetylenic com-
verse parts of the organism, and are found frequently as
pounds are not commonly found in the Euphorbiaceae, the
essential oil components. Other acetylenes only are obtained
presence of an aIIenic linkage is suggestive of their presence.
by extraction with nonpolar solvents.
Acetylenic compounds typical of the Apiaceae and Arali-

E
aceae characteristically contain C 17 acetylenes, falcarinone,
°II and related compounds. Those of the Asteraceae usually
O;(CH,J7CH=CHCH,CH :::CHCH,CH=CHCH,CH, have vinyl end groups (Fig. 3.11). Acetylenic compounds
of the Pittosporaceae resemble those of the Apiaceae and
Araliaceae in structure whereas acetylenic compounds of
the Campanulaceae resemble those of the Asteraceae. The
OC(CH,J7CH=CHCH,CH=CH(CH,J.CH,
occurrence of tetrahydropyran derivatives seems to be re-
stricted to the Campanulaceae.
The relationships of several of acetylene-containing fami-
OC(CH,J,CH==HCH,OCCH=CHCH=CH(CH,J.CH, lies (e.g., the Apiaceae, Araliaceae, Asteraceae, Campanu-
laceae, and Pittosporaceae) have long been enigmatic. Many
"o 0
"
Fig. 3.8. An unusual aOerne lipid from Sapium sebiferum seed oil.
of the groups with which the Apiaceae and Araliaceae have
been placed lack acetylenic compounds, but are known to
 0"
46 AcetyJenic Compounds

I (<ZC),CH,

""" CH'C=C~CH=CHCOOCH'

carlina oxide

O-O-CJ
S S S

a·lerlbienyl (15)

-0-
C-C

- C# ~C - -
S

-C:C-C::C- _ -C=CH--C=C--
I
S·CH,

Fig. 3.9. Aromatic acetylenic compounds, thiophenes, and methylthioethers.

possess iridoid monoterpenes. The Apiaceae and Araliaceae
lack the latter group of compounds (Dahlgren et aI., 1981).
Some have felt that the presence of acetylenes (as well
as other shared characters) indicates a relationship of the
Asteraceae, with the Apiaceae and Araliaceae (Dahlgren et
aI., 1981). Similar arguments have been made for the rela-
tionship of the Pittosporaceae with Apiaceae and Araliaceae
(Regnauer, 1969) and the Campanulaceae and Asteraceae
(Mabry and Bohlmann, 1977).
Within the family Asteraceae, acetylenic compounds are
largely absent from the tribe Senecioneae and are most com-
CHz=CHCH=CHC=CC=CC=CCH=CHCH,
(6)
mon in the tribes Reliantheae and Anthemideae (Dahlgren
et aI., 1981).
Acetylenic compounds are widely distributed in the basidi-
omycetes, mostly from families of the Agaricales and Pol-
yporales. Many of these compounds are polar, have extensive
oxygenation, and chain lengths of 10 carbon atoms or less.
The third group of acetylenic compounds is not related
clearly to the first two. Acetylenic linkages are occasionally
introduced into compounds of diverse biosynthetic origin
such as sesqniterpenes, tetraterpenes, and amino acids (Fig.
3.12). These compounds are found in unrelated plant fami-
lies, among them the Annonaceae, Cupressaceae, Euphor-
biaceae, Fabaceae, Lauraceae, Myoporaceae, Sapindaceae,
Simaroubaceae, Sterculiaceae, Valerianaceae, and certain
algae and mosses.

PHYSIOLOGICAL Al'ID PHARMACOLOGICAL

PROPERTIES

The quantity and type of acetylenic compounds present in

(7)
most plants vary considerably at different stages of develop-
Fig. 3.10. Compounds from Coreopsis species. ment and in different plant parts. For example, the roots of
 Acetylenic Compounds 47

Helianthus annuus contain a pentaynene that disappears NH2 NH,

when the fruits begin to ripen. Although Centaurea seeds I I
do not contain acetylenic compounds, I-day-old seedlings HC=CCHCH CHC0 H2 2 HC:CCHCH,CHCO,H
do. The turnover time of many acetylenic compounds in I I
CH,OH OH
plants is 6-48 h. The amount of polyacetylenes in plants
ranges from traces to about I %, but the amounts present
Euphorio longana, Sapindaceae
often vary widely within and between plants.
CH,
Callus cultures of Bidens pilosa which normally produce
no acetylenic compounds could be induced to do so by addi-
o
tion of culture filtrate from the fungus Pythium aphanider-
matum; cultures of this and other Bidens species that had
been transformed with the Ti plasmid of Agrobacterium tu-
mefaciens produced a root type profile of acetylenes (Ellis, Eremophila jreelingii, Myoporaceae
1988). Hairy root cultures of Ambrosia, Bidens, and Tagetes
have similar content of acetylenes as those of normal plant
roots (Flores et al., 1987, 1988).

E E
c 1" CH,(C=C),CH=CHCH=CHCH,CH,CH,OH
Chamaecyparis jormosensis, Cupressaceae

E E E
CH,CH=CH(C:C),CH=CHCH=CHCH,CH,CH,OH

taririe acid

E E Z
CH,CH=CHCH=CHC :CCH,CH=CH(CH,J,CH,OH

E Z
CH,CH=CH(C :C),CH,CH=CH(CH,J,CO,H

E E from a Dichranum species

C17' CH,(C=C),CH=cHCH=CH(CH,J,CH=CH,
E E
CH,(C=C)'CH=CHCH=CHiH(CH,J,CH=cH,
OAc
E E E
CH,CH=CH(C :C),CH=CHCH=CH(CH,J,CH=CH,
Q-(C:C),CIf=CHCH,
Some naturally occurring polyacetylenes of Dahlia species.
Fig. 3.11. Some naturally occurring acetylenic compounds of Dahlia
(Asteraceae) (modified from Lam et al.. 1991; used with pennission of
the copyright owner, Pergamon Press, Oxford).
Fig. 3.12. Compounds of diverse biosynthetic origin that possess
acetylenic linkages.
Biologically Active Acetylenic Compounds
Acetylenic compounds that occur in essential oils proba-
bly contribute to the overall taste-odor properties in several
spices and herbs derived from the Apiaceae. Compound (8)
(Fig. 3.13), in association with monoterpenes, contributes to
the flavor of caraway, Carum carvi.
In contrast, certain other acetylenes are highly toxic to
humans and domestic animals; for instance, the compounds
from Cicuta virosa (water hemlock) (10) and Oenanthe ero-
cata (9). Relatively small variations in structure lead to
nearly nontoxic compounds. Other compounds such as falc-
arinol (11) are less toxic to people, but still possess antifun-
gal properties. Compounds of this type occur widely in mem-
48 Acetylenic Compounds

bers of the Apiaceae and Araliaceae in plants such as carrots
(Daucus carota) and ginseng (Panax quinquefolium). There
do not appear to be enough acetylenic compounds present
in most cultivars of carrots, parsley, or celery roots to be
really dangerous (Yates et al., 1983).
Many isolated acetylenic compounds have pronounced
antifungal activity (and often antibacterial activity), but their
inherent instability limits their usefulness for this purpose.
One example is the antibiotic mycomycin (12) isolated from
a basidiomycete, Nocardia acidophilus (Weiss and Edwards,
1980).
Two African species of Aspilia (Asteraceae) which are
used medicinally by man also are eaten by chimpanzees in
a similar manner. This plant contains a potent antibiotic,
thiarubrine A (13) (Rodriguez et al., 1985). An unusual anti-
viral acetylene, chondriol (Fig. 3.13), and other related com-
pounds have been isolated from a marine algae (Moore,
1978).
Acetylenes as Phytoalexins
Although acetylenic compounds may served as pre-
formed antifungal compounds, the amount of several of
these substances increases rapidly in response to attack by
pathogens and are phytoalexins (Downum and Nemec,
1987). In safflower, Carthamus tinctorius, the amount of
safynol, an ene-triyn-ene-diol (14) (Fig. 3.14), increases 20-
fold when the plant is attacked by the pathogen Phytophthora
drechsleri. The best studied example of acetylenic phyto-
alexins, however, is the broad bean, Vicia faba, which pro-
duces a series of acetylenic furanoid ketones related to wyer-
one after infection with a Botrytis species. Wyerone and
related compounds also are known to occur in the lentil,
Lens culinaris. Although the relationships of the lentil have
been debated, these data suggest an affmity with the broad
bean.
Infection of the African marigold, Tagetes erecta, with
highly pathogenic fungi results in a general decrease in thio-

z
o
II
C7HISCH=CHC(C=C),CCH=CH2
0
I HO)!?1
from Carum carvi (8) chondriol

E E,E E,E
HOCH2CH=CH(C=Clz(CH=CH),CH2CHC2H, HOCH2(CH2)2(C=Clz(CH=CH).CHCH2CH2CH.
I I
OH OH
oenantbetoxin (9) from Cicuta virosa (10)
o
/\
HCH=CHCH(C:C)2CH=CHCH2(CHz),CH. CH.CH2CH2C:CC:CCHCH -GH(CH2),CH=CH2
I
OH
I
OH
falcarinol (11) (SR,9R,IOS)-9,IO-epoxybepladec-I6-ene-4,6-diyne-8-o1 (16)

OH OH
I I z E
CH,(CH2).CH=CHCH(C=C),CHCH=CH2 HC=CC=CCH=C=CHC=CHCH=CHCH2C02H

falcarindiol mycomycin (12)

CH,C=C~C=CC:CCII=CH2
S-S

thiorubrlne A (13) laballenic acid (17)

Fig. 3.13. Some biologically active acetylenic compounds.

CH3CH2CH=CHC=cM-C}-CH=CHC02H
CH3CH2CH=CHC=C~-D-CH=CHC02CH3
E E
CH3CH=CHC:::CC:::CC:::CCH=CHCHCH20H
Fig. 3.14. Wyerone epoxide, wyerone, and safynol.
phene levels, whereas less pathogenic pathogens resulted
in the accumulation of a-terthienyl (15) (Fig. 3.9) and two
bithiophene derivatives above the levels in noninfected
plants. This suggests that highly pathogenic fungi may sup-
press the production of thiophenes (Downum and Nemec,
1987), or possibly that nonpathogenic fungi release sub-
stances that enhance production of thiophenes.
Plant-Insect and Plant-Nematode
Relationships
Many fatty-acid-derived acetylenic compounds in plants
are active in plant-insect relationships. 8-Z-Dihydromatrica-
ria acid, found in the defensive secretion of the soldier beetle
(Chauliognathus lecontei), has been shown subsequently to
have antifeedant properties against Phidippus spp. (jumping
spiders) (Eisner et a!., 1981). Matricaria acid (5) also has
antifeedant properties against the pink bollworm, bollworm,
and tobacco hornworm (Binder et a!., 1979).
Several nematicidal acetylenic compounds have been iso-
lated; most possess thiophene structures and are from mem-
bers of the Asteraceae family. Another recently isolated
compound with this activity is (8R,9R,IOS)-9,IO-epoxyhep-
tadec-16-ene-4,6-diyne-8-01 (16) from Cirsium japonieum
(Kawazu et a!., 1980) (Fig. 3.13).I-Phenylhepta-I,3,5-triyne
and 2-phenyl-5-(l'-propynyl)-thiophene from Coreopsis
laneeolata and Z-dehydromatricaria ester (5) from Solidago
altissima have been shown to be fly ovicidal substances
(Seigler, 1983).
Four of the major acetylenic compounds of Chrysanthe-
mum coronarium (Asteraceae) were insecticidal to the milk
Acefylenic Compounds 49
wyerone acid
wyerone
wyerone epoxide
OH
' safyool (14)
saffiower
weed bug Oneopeltus fasciatus. Upon purification and test-
ing of individual compounds, these were shown to have anti-
juvenile hormone activity (see more discussion in Chapter
18) (Bowers and Aregullin, 1987).
PHOTOTOXIC Bf'FECTS OF ACBTYLBl'IIC
COMPOUl'lDS
In addition to non-light-mediated toxic effects of acetylenic
compounds, many are potent photosensitizers that can enter
an excited state by absorption of light energy. This may
occur in the presence of sunlight or UV -A radiation (Dow-
num and Rodriguez, 1986). In this excited state, such mole-
cules mediate a variety of phototoxic effects through two
major types of action. Straight-chain acetylenic compounds
tend to interact directly with target molecules in the cell,
whereas thiophenes mediate the oxidation of a variety of
biomolecules (membrane lipids and proteins, in particular)
presumably via singlet oxygen generation (Downum and
Nemec, 1987). In addition to killing or inactivating viruses,
bacteria, fungi, and nematodes, herbivorous insects are also
affected (Downum and Rodriguez, 1986).
Despite the fact that acetylenes are found in at least 15
families, phototoxic acetylenic compounds are only found
in the Asteraceae (Downum et a!., 1991).
ALLBl'IIC FATTY ACIDS
Several allenic acids are known. One of these, laballenic
acid (17), is from the seed oil of a mint, Leonotis nepetaefolia
(Fig. 3.13). An unusual allene containing lriacylglycerol is
SO Acetylenic Compounds
found in Sapium sebiferum (Euphorbiaceae) (see Fig. 3.8).
In origin, these unusual compounds are probably related to
acetylenic compounds, although acetylenes are not known
from either the Larniaceae or Euphorbiaceae.
REFERENCES
BINDER, R. G., B. G. CHAN, and C. A. Eu.IGER, Antibiotic effect
of C IO-C 12 fatty acid esters on pink bnllwonn, bnllwonn, and
tobacco budwonn, Agric. Bio!. Chern., 43,2467-2471 (1979).
BOHLMANN, F. and T. BURKHARDT, Zur Biogenese des Matricari-
aesters, Chern. Ber., 105, 521-528 (1972).
BOHLMANN, F., T. BURKHARDT, and C. ZDERO, Naturally Occurring
Acetylenes, Academic Press, New York, 1973.
BOWERS, W. S. and M. AREoUllIN, Discovery and identification
of an antijuvenile honnone from Chrysanthemum coronarium,
Mem. Inst. Oswaldo Cruz, Riodegeneiro, 82, Supp!. 3, 51-54
(1987).
Bu'LoCK, J. D., The biogenesis of natural acetylenes, in Compara-
tive Phytochemistry (T. Swain, ed.), 79-95, Academic Press,
London, 1966.
DAHLGREN, R. M. T., S. ROSENDAL-JENSEN, and B. J. NIELSEN, A
revised classification of the angiospenns with comments on
correlation between chemical and other characters, in Phyto-
chemistry and Plant Phylogeny (D. A. Young and D. S. Seigler,
eds.), 149-204, Praeger, New York, 1981.
DoWNUM, K. R and S. NEMEC, Light-activated antimicrobial chemi-
cals from plants: Their potential role in resistance to disease-
causing organisms, in Light-Activated Pesticides (J. R. Heitz
and K. R. Downum, eds.), ACS Symposium Ser. 339, 281-294,
American Chemical Society, Washington, DC, 1987.
DoWNUM, K. R. and E. RODRiGUEZ, Toxicological action and eco-
logical importance of plant photosensitizers, J. Chern. Bco!.,12,
823-834 (1986).
DOWNUM, K. R., L. A. SWAIN, and L. J. FALEIRo, Influence of light
on plant allelochemicals: A synergistic defense in higher plants,
Arch. Insect Biochem. Physio!., 17, 2011-211 (1991).
EISNER, T., D. lIIll., M. GOETZ, S. JAIN, D. ALsOP, S. CAMIZINE,
and J. MElNwALO, Antifeedant action of Z-dihydromatricaria
acid from soldier beetles (Chlluliognathus spp.), J. Chern. Bco!.,
7, 1149-1158 (1981).
ELus, B. E., Natural products from plant tissue culture, Nat. Prod.
Rep., 5, 581-612 (1988).
FLORES, H. E., M. W. HoY, and J. J. PICKARD, Soluble metabolites
from root cultures, Tibtech, 5, 64-69 (1987).
FLORES, H. E., J. J. PICKARD, and M. W. Hoy, Production of polya-
cetylenes and thiophenes in heterotrophic and photosynthetic
root cultures of Asteraceae, in Naturally Occurring Acetylenes
and Related Compounds (J. Lam, H. Breteler, T. Amason, and
L. Hansen, eds.), 233-254, Elsevier, Amsterdam, 1988.
HEoNAUER, R., Chemical evidence for the classification of some
plant taxa, in Perspectives in Phytochemistry (J. B. Harborne
and T. Swain, eds.), Academic Press, London, 1969.
KAwAZU, K., Y. NISHR, and S. NAKAJIMA, Two nematicidal sub-
stances from roots of Cirsium japonicum, Agric. BioI. Chern.,
44,903-906 (1980).
JENTB, R., E. RICHTER, F. BOSOLD, and G. A. OLANTuNn, Experi-
ments on biosynthesis and metabolism of acetylenes and thio-
phenes, in Chemistry and Biology of Naturally-Occurring Acet-
ylenes and Related Compounds (NOARC) (J. Lam, H. Breteler,
T. Amason, and L. Hansen, eds.), 187-199, Elsevier, Amster-
dam, 1988.
LAM, J., L. P. CHRlSTBNSEN, and T. THOMASEN, Polyacetylenes from
Dahlia species, Phytochemistry, 30, 515-518 (1991).
MABRY, T. J. and F. BOHLMANN, Sununary of the chemistry of the
Compositae, in The Biology and Chemistry of the Compositae,
Vo!. 2 (V. H. Heywood, J. B. Harborne and B. L. Turner, eds.),
Academic Press, London, 1977.
MOORE, R. E., Algal Nonisoprenoids, in Marine Natural Ptoducts,
Vol. I (p. J. Scheuer, ed.), Academic PIess, New York, 1978.
RODIUGUEZ, E., M. AREoULUN, T. NISIDDA, S. UEHARA, R. WRAN-
GHAM, Z. ABRAMowSKI, A. FINLAYSON, and G. H. N. TOWERS,
Thiarubrine A, a bioactive constituent of Aspilia (Asteraceae)
consumed by wild chimpanzees, Experientia, 41, 419-420
(1985).
SBIGLER, D. S.• Role of lipids in plant resistance to insects, in Plant
Resistance to Insects (p. A. Hedin, ed.), ACS Symposium Series
208,303-327, American Chemical Society, Washington, DC,
1983.
WEISS, U. andJ. M. EDWARDS, The Biosynthesis of Aromatic Com-
pounds, Wiley, New York, 1980.
YATES, S. G., R. E. ENGLAND, W. F. KWOLEK, and P. W. SIMON,
Analysis of carrot constituents: Myristicin, falcarinol, and falc-
arindiol, in Xenobiotics in Foods and Feeds, ACS Symposium
Series 234, (J. W. Finley and D. E. Schwass, eds.), 333-344,
American Chemical Society, Washington, DC, 1983.
4
Plant Waxes
Introduction
Biosynthesis
Taxonomic Usefulness
Function of Waxes
Commercial Value of Waxes
Biological Activity
Chemical Fossils and Petroleum
Cutin and Suberin
Analysis of Waxes
References
INTRODUCTION
Plant waxes are complex mixtures of hydrocarbons, alco-
hols, aldehydes, ketones, esters, acids, and combinations of
these that are deposited in a layer outside the epidermal cells.
This complex mixture of lipids probably is synthesized in
the epidermal cells of most plants and exuded onto the sur-
face. Plants usually possess cutin, a layer of cross-esterified
hydroxy fatty acids which is also deposited on the surface
of the epidermal cells (Kolattukudy, 1980). This layer is
impregnated with waxes. The combined lipid covering not
only protects the plant from invasion by foreign organisms
but also helps to regulate transpiration.
Waxes are usually isolated by boiling, scraping, or wash-
ing the outside surface with a nonpolar solvent. Surface lip-
ids differ markedly from both seed lipids and other leaf lip-
ids. (See Chapter 2.)
BIOSYl'l'l1lESIS
Most components of the wax layer are derived from long-
chain fatty acids (C2.-C34 ) formed by chain extension of
shorter-chain fatty acids (Fig. 4.1). The shorter-chain fatty
acid precursor seem to be formed in the same manner as
those previously discussed. Chain elongation requires malo-
nyl-CoA and NADPH as the elongating agent and reductant,
respectively; exogenous stearic acid can be incorporated.
Stearyl-CoA, but not stearyl-ACP, has been demonstrated
to be elongated by endoplasmic reticulum preparations from
the epidermis of leeks, Allium porrum (LiJiaceae). The
length of acids produced depends on the plant species, but
C2., C30 , and C32 acids are commonly encountered (Kolattu-
kudy, 1980).
Long-chain alcohols are formed by reduction of long-
chain fatty acids. A fatty acyl-CoA reductase has been dem-
onstrated in cabbage, Brassica oleracea (Brassicaceae).
Fractionation of the protein fraction isolated in these studies
indicated that one protein fraction catalyzed acyl-CoA re-
duction to the aldehyde stage with NADH as the preferred
reductant and another catalyzed reduction of the aldehyde
to the alcohol with NADPH as the preferred reductant. The
similarity of the naturally occurring fatty aldehydes and fatty
alcohols of a given plant is probably due to the fact that
aldehydes represent intermediates in the synthesis of fatty
alcohols (Kolattukudy, 1980).
Wax esters in plants are formed by the combination of
long-chain alcohols and long-chain acids. Although this can
occur in several ways, it is most probable that, in vivo, these
esters are formed by action of an acyl-CoA alcohol lransacyl-
ase that has been demonstrated to be present by Kolattukudy
(1980).
Wax esters from jojoba (Simmomisia chinensis, Simmonds-
iaceae) consist of molecules with mostly C20 acid (monoene)
esterified with about an equal mixture of Yo and C22 alco-
hols (monoene) (Yermanos, 1978; 1981; Miwa, 1971). In
studies of the biosynthesis of the fatty acids and alcohols in
slices of fresh jojoba cotyledons, a radioactive label from
glucose was incorporated into all carbons of both the C 20
and C22 acids and alcohols. In contrast, exogenous acetate
was used almost entirely for chain elongation from endoge-
51
S2 Plant Waxes
acelyl-CoA fatty acid syntbetase
+ 7 malonyl-CoA
mnlonyl-CoA
-------I.~
NADPH
slearoyl-ACP
stearoyl.CoA
malonyl-CoA
NADPH
-
NADPH
CH3(CH,),.CH,OH
Fig. 4.1. Biosynthesis of long-chain fatty acids, aldehydes, alcohols. and wax esters. (Kolattukudy. 1980 modified and used with pennission of the
copyright owner. Academic Press. Orlando. FL).
nous oleate (pollard et aI., 1978). In this plant, fonnation of
oleic acid occurs on the ACP track. The acid is released and
subsequent reactions leading to the fonnation of C 2G and Y2
fatty acids and alcohols occur as CoA derivatives.
Hydrocarbons found in the wax layer of plants also are
synthesized from long-chain fatty acids. C ,2 , C ,4 , C ,6 , and
C ,S fatty acids are incorporated into Y9 alkanes. Com-
pounds that are efficient precursors for long-chain fatty acids
are also efficient precursors of hydrocarbons. Both groups
of compounds are synthesized in epidennal cells. Exogenous
C3G fatty acid is converted into C29 alkane in cabbage,
Brassica oleracea (Brassicaceae), and similar results have
now been obtained in a number of other plants. Oxygen
is required for this decarboxylation. Further, an <x-hydroxy
intennediate is involved (Kolattukudy, 1980).
Secondary alcohols, ketones, and ketols also are synthe-
sized from long-chain fatty acids. Ketones generally appear
to be synthesized from secondary alcohols by oxidation. The
mechanistic details of these reactions remain obscure.
In an exceptional case, Pinus jeffreyi essential oils consist
of about 98% n-heptane. Acetate can serve as a precursor
for this compound in the plant.
TAXOI'lOI'lIC VSEFULl'IESS
Virtually all plants have hydrocarbons in the same molecu-
lar-weight range; those of C 29 , C3l , and C33 are essentially
ubiquitous. The same is true for wax esters and other long-
chain lipid constituents of plants. Although a small number
of plants have been examined, there appears to be little varia-
tion that would serve to differentiate plant groups (Eglinton
and Hamilton, 1963).
I'Vl'ICDOI'l OF WAXES
As previously mentioned, waxes function primarily to pro-
tect the plant, by preventing entry of foreign organisms and
desiccation of the plant. However, waxes may play other
palmiloyl-ACP
stearic acid
-
CH,(CHzl,.COCoA
- NADH
' " acyl-CoA: alcohol
~ transacylase
wax eslers
roles. For example, in species of Nepenthes, an insectivorous
plant, wax particles inside the "trap" are easily detached
and stick to the feet of insects, preventing them from getting
a foothold inside the trap and escaping.
COl'lllmRCIAL VALVE OF WAXES
Waxes are of considerable commercial importance, as syn-
thetic materials have not been produced at a price that will
allow them tu compete with the natural substances. The most
important natural waxes are camauba from palms of the
genus Copernicia, candelilla from Euphorbia antisyphlitica,
and sugar cane wax-a by-product of the sugar industry
(Schery, 1972).
Camauba wax is comprised mostly of wax esters, cande-
Iilla contains a significant hydrocarbon fraction, and sugar
cane wax is a complex mixture of materials.
For the last several years, there has been mnch interest
in jojoba, Simmondsia chinensis, a plant native to the south-
western United States and Mexico, because of the presence
of liquid wax esters in the seeds (Wisniak, 1988). Numerons
schemes to convert desert land into orchards of these plants
have been proposed. The oil is an excellent lubricant, has
good emollient properties, and may replace spenn whale oil
for many uses. As the fatty acid combination of Limnanthes
douglasii (meadowfoam, Limnanthaceae) is quite similar to
that of jojoba, the synthesis of a similar wax ester by hydroly-
sis and reduction followed by esterification has been pro-
posed (Miwa and Wolff, 1962).
Hexadecanol and octadecanol have been used extensively
in the sonthwestern United States to produce a monolayer
on the top of lakes and other nonfJowing bodies of water to
retard evaporation. These compounds also have potential
agricultural applications (Taylor et aI., 1964). Gennination
of bluegrass seed was increased by application of these mate-
rials to soil (Atsatt and Bliss, 1963).

BIOLOGICAL ACTIVITY
It is generally assumed that long-chain hydrocarbons are
relatively inert and lack pronounced biological activity.
However, octacosanol (C2S ) has androgenic activity in
chicks (measured by comb growth) similar to 11,000 times
the same amount of testosterone propionate.
The application of similar compounds to crop plants has
been conducted (Taylor et aI., 1964). I-Triacontanol, a
straight-chain fatty alcohol, has been isolated from alfalfa
and is sometimes found in other leaf waxes as the palmitate
ester. This compound has been reported to be a powerful
plant growth stimulant. Application of amounts as low as 4
mg per acre can lead to 10-40% increases in growth and
yield of food crops. Application of this compound to corn
and rice plants produces a response within minutes-even
in the dark. Triacontanol increased hypocotyllength of ger-
minating cucumber seeds by 14% over controls, but it
showed inconsistencies in field tests on agricultural crops.
I-Docosanol reportedly stimulates growth in auxin assays.
Lower homologs with 16-28 c",bon atoms and structural
isomers with other hydroxyl substitutions are ineffective
(Gross, 1980).
Surface waxes of plants are important in contact chemore-
ception by insects (Stadler, 1984, 1986). After being at-
tracted to the plant by visual and olfactory cues, the undam-
aged plant surface is normally the first point of contact. The
physical nature of the surface also is important in determin-
ing whether the insect will accept the plant. Long-chain fatty
acids are involved in the biting behavior of Locusta migra-
toria (Chapman, 1977). Undoubtedly, many more volatile
compounds are dissolved in the surface waxes, but the waxes
themselves also are important for sutface recognition.
Some nest parasites in social insects are protected because
their cuticular chemistry is very similar to that of the hosts.
The complex cuticle hydrocarbon blends of parasite and host
are virtually identical and the hosts cannot distinguish the
parasites from conspecifics (Stowe, 1988). Nest parasites
of the genus Trichopsenius biosynthesize their hydrocarbon
mixture; the pattern matches the species-specific mixture of
their termite hosts. In contrast, the scarabaeid beetle, Myr-
mecaphodius excavatacollis, which associates with ants, ac-
quires its hydrocarbons by association with the host and can
invade the nests of several different species of ants with
different hydrocarbon blends (Stowe, 1988). In another bi-
zarre example, larvae of the neuropteran, Chrysopa slosso-
nae, cover themselves with wax plucked from their wax-
coated aphid prey. The ants that tend these aphids fail to
recognize the neuropterans and do not attack them (Stowe,
1988).
The social wasp. Parachartergus aztecus, an ant Pseu-
domyrmex ferrugineus, and the tree they inhabit, Acacia col-
lins;;, exemplify a complex biological interaction (Espelie
and Hermann, 1988). The ants feed on and protect the tree
from herbivory and infringement by other plants and fungi,
the trees provide a place for the ants and wasps to nest,
Plant Waxes 53
and the ants protect the wasps from predators as well. The
cuticular ratios of alkanes and alkenes of the ants and wasps
were found to be identical. The compounds from these two
insect species proved to be identical to the cuticular hydro-
carbons from the spines of the tree (Espelie and Hermann,
1988).
Alkanes also play an important role in nest mate recogni-
tion of wasps (Polistes metricus). However, these same sig-
nals may announce the wasp's presence to possible predators
(Espelie and Hermann, 1990; Espelie et aI., 1990).
CHEMICAL FOSSILS AND PETROLEUM
A major portion of the petroleum used today is derived from
lipids of plants deposited in past eons. The structures of most
compounds isolated from petroleum suggest a derivation
from fatty acids. Various chemical changes have occurred,
mostly reduction and decarboxylation, so that most petro-
leum is comprised of a mixture of odd- and even-chain-
length hydrocarbons. Some petroleums have a variety of
other compounds that appear to be derived from chemical
modification of other types of secondary metabolites.
These compounds may be viewed as chemical fossils. In
some instances, the mixture of compounds may be correlated
with a particular plant or plant groups, although such correla-
tions are usually difficult in coal and in petroleum.
CUTIN AND SUBERIN
Cutin, the lipid that covers the outside of epidermal cells,
and suberin, which is associated with cork cells in plants,
are largely comprised of cross-linked hydroxy fatty acids.
The composition of each type of compound varies from plant
to plant. Generally, cutin is distinct from suberin in the type
of monomeric units present (Harwood, 1980).
Cutin is composed chiefly of a C I6 andlor a CIS family
of monomers (Fig. 4.2). The usual components of the former
are palmitic acid, 16-hydroxypalmitic acid, and 1O,16-dihy-
droxypalmitic andlor its positional isomers in which the mid-
chain hydroxyl group is at C 9 , C g , or C7 • Monomers that
could be derived from the above acids by further oxidation
or reduction also have been found in cutin from some plants.
The C I8 family consists of stearic acid, oleic acid, linoleic
acid, 18-hydroxyoleic acid, 18-hydroxy-9,IO-epoxystearic
acid, and 9,1O,18-trihydroxystearic acid together with their
11.-12 unsaturated analogs. Members of the C I6 family are
the dominant components of the cutin offast-growing plants,
whereas the cutin of slower-growing plants with a thicker
cuticle consists of a mixture of C16 and CIS monomers (Har-
wood, 1980).
The major aliphatic components of suberin are w-hydroxy
acids, the corresponding dicarboxylic acids, very long acids
(greater than Czo), and similarly long alcohols. Among the
w-hydroxy and dicarboxylic acids, monounsaturated CI8 and
54 Plant Waxes
CH,(CH')'4COZH
I
OH
y = 8, 7, 6, or 5
x+y=13
OH
I
HOzC(CH,).CH(CH,).COzH
OHOH
I I
HO(CH,).CH-CH(CH,),COzH
o
II
HO(CH,).C(CHz).COzH
Fig. 4.2. The major components of cutin (Harwood, 1980; Kolattukudy and Espelie, 1985; modified and used with pennission of the copyright owners,
Academic Press, Orlando and Springer-Verlag, Berlin).
saturated C,. acids are often the dominant components (Har-
wood, 1980).
Both cutin and suberin contain phenolic components that
are presumably esterified to the polymeric matrix. p-Coum-
arlc acid and lesser amounts of ferulic acid are found (Kolat-
tukudy and Espelie, 1985). However, a recent reevaluation
of the composition of suberin indicates that there is no solid
evidence for aliphatic-aromatic linkages, nor is it under-
stood how the phenolic units are joined, nor are their identies
clear (Davin and Lewis, 1992).
Al'IALYSIS OF WAXES
Hydrocarbons from waxes are usually removed by dissolu-
tion in a nonpolar solvent such as purified hexane and ana-
lyzed by capillary gas chromatography. Most common hy-
drocarbons can be identified readily by mass spectrometry
(Bagneres and Morgan, 1990). Analysis of wax esters is
more difficult, as several different compounds in the rather
complex mixtures obtained possess the same molecular
weight. Analysis of these mixtures has been effected by tan-
dem mass spectrometry (MS-MS) methods (Spencer and
Plattner, 1984).
REFERENCES
ATSATI, P. R. and L. C. Buss, Some effects of emulsified hexa-
octadecanol on gennination, establishment, and growth of Ken-
tocky bluegrass, Agron. J., 55, 533-537 (1963).
iHZ(CH,),CH=CH(CH,),COZH
OH
CHz(CH,),GH-CH(CHz),COzH
I
OH
"i
CHz(CH,),CH-CH(CHz),COzH
I I I
OH OHOH
i H
OHC(CHz).CH(CHz),COzH
~HIH ~H~H
HO(CH,).CH-CHCHzCH-CH(CHz),COzH
BAGNERES, A. G. and E. D. MORGAN, A simple method for analysis
of insect cuticular hydrocarbons, J. Chem. Ecol., 16. 3263-3276
(1990).
CHAPMAN, R. F., The role of the leaf surface in food selection by
Acridids and other insects, Comportement des insectes et milieu
trophique, Colloques Intern.tionaux CNRS, 265, 133-149
(1977).
DAVIN, L. B. and N. G. LEWIS, Pbenylpropanoid metabolism: Bio-
synthesis of monolignols, lignans and neolignans, lignins and
suberins, in Phenolic Metabolism in Plants (H. A. Stafford and
R. K. Ibrahim, eds.), 325-375, Plenum, New York, 1992.
EGl.INTON, G. and R. J. HAMn.TON, The distribution of alkanes, in
CbenticalPlantTaxonomy (T. Swain, ed.), 187-217, Acadentic
Press, London, 1963.
ESPEUE, K. E. and H. R. lIERMANN, Congroent cuticular hydrocar-
bons: Biochemical convergence of a social wasp, an ant and a
host plant, Biochem. Sys!. Beol., 16, 505-508 (1988).
EsPEUE, K. E. and H. R. lIERMANN, Surface lipids of the social
wasp Polistes annularis (L.) and its nest and nest pedicel, I.
Chern. Ecol.,16. 1841-1852 (1990).
ESPEUE, K. E., J. W. WENZEL, and G. CHANG, Surface lipids of
social wasp Polisites metricus Say and its nest and nest pedicel
and their relation to nesbnate recognition, I. Chern. Ecol., 16.
2229-2241 (1990).
GROSS, D., Wachstumsregulatorisch wirksame Pflanzeninhalts-
stoffe, Z. Chern., 20. 397-406 (1980).
HARWOOD, J. L., Plant .cyllipids: Structore, distribution, and analy-
sis, in Lipids: Structore and Function (p. K. Stumpf, ed.), Vol.
4 of The Biochemistry of Plants (P. K. Stumpf and E. E. Conn,
eds.), I-55, Acadentic Press, New York, 1980.
KOLA'ITUKUDY, P. E., Cutin, suberin, and waxes, in Lipids: Struc-

ture and Function (P. K. Stumpf, ed.), Vol. 4 of The Biochemis-
try of Plants (P. K. Stumpf and E. E. Conn, eds.), 571-645,
Academic Press, New York, 1980.
KOLATIUKUDY, P. E. and K. E. EsPELIE. Biosynthesis of cutin,
suberin, and associated waxes, in Biosynthesis and Biodegrada-
tion of Wood Components (T. Higuchi, ed.), 161-207, Aca-
demic Press, Orlando, FL, 1985.
MrwA, T. K., Jojoba oil wax esters and derived fatty acids and
alcohols: Gas chromatographic analysis, J. Am. Oil Chem. Soc.,
48, 259-264 (1971).
MrwA, T. K. and I. A. WOLFF, Fatty acids, fatty alcohols, and wax
esters from Limnanthes douglasii (meadowfoam) seed oil, J.
Am. Oil Chern. Soc., 39, 320-322 (1962).
POLLARD, M. R., J. B. OHLROGGE, and P. K. STUMPF, Wax ester
formation in the developing jojoba seed, in Proceedings of the
3rd International Conference on Joboba, (D. M. Yermanos, ed.),
71-81, International Committee on Jojoba and the Dept. of
Botany and Plant Science, University of California Press, River-
side, 1978.
SCHERY, R. W., Plants for Man, 2nd ed., Prentice-Hall, Englewood
Cliffs, NJ, 1972.
SPENCER, G. F. and R. D. PLATTNER, Compositional analysis of
natural wax ester mixtures by tandem mass spectrometry. 1.
Am. Oil Chern. Soc., 61, 90-94 (1984).
Plant Waxe,f 55
STADLER, E., Contact chemoreception, in Chemical Ecology of In-
sects (W. J. Bell and R. T. Carde, eds.), 3-35, Chapman &
Hall, London, 1984.
STADLER, E., Oviposition and feeding stimuli in leaf surface waxes,
in Insects and the Plant Surface (B. Juniper and R. Southwood,
eds.), 105-121, Arnold, London, 1986.
STOWE, M. K., Chemical mimicry, in Chemical Mediation of Coe-
volution (K. C. Spencer, ed.), 513-580, Academic Press, San
Diego, CA, 1988.
TAYLOR, S. A., S. R. OLsEN, J. P. VAVRA, W. J. ROBERTS, G. M.
AUBERTlN, G. W. GoRSLINE, J. P. LAw, JR., and F. M. RHOADBS,
Can fatty alcohols reduce water losses?, Crops Soils, 16(8), 7-9
(1964).
WISNIAK, J., The Chemistry of Jojoba, American Oil Chemical
Society, Champaign, JL, 1988.
YERMANOS, D. M. (ed.), Proceedings of the 3rd International Con-
ference on Joboba, International Committee on Jojoba and the
Dept. of Botany and Plant Science, University of California
Press, Riverside, 1978.
YERMANOS, D. M., Jojoba, in Resource Materials (T. A. McClure
and E. S. Lipinsky, eds.), Vol. 2 of Handbook of Biosolar Re-
sources (0. R. Zaborsky, ed.), 245-257, CRC Press, Boca
Raton, FL, 1981.
5
Polyketides

Introduction plants, for example, as flavonoids, naphthoquinones, and an-

Biosynthesis of Polyketides in Plants and Fungi thraquinones.
Tetraketides Many polyketides have pronounced physiological effects
Pentaketides and several are important antibiotics.
Hexaketides
Heptaketides
Octaketides BIOSYl'fl'HESIS OF POLYKETIDES Il'I PLAl'ITS
Tetracyclines Al'ID FUl'IQI
Decaketides
Macrolide Antibiotics Few areas of natural products chemistry have seen as many
Ionophores major advances in the study of biosynthetic pathways as
Acetogenins have occurred in polyketide compounds. Birch and Donovan
Polyketide Compounds from Unusual Starter Units (1953) demonstrated that a wide range of structural types
Methylenebisphloroglucinols and Related Compounds are derived from acetate (later shown to be acetate and malo-
Polyketides from Lichens nate). In experiments with deuterated precursors, acetate
Mycotoxins serves preferentially as a starter unit for the formation of 6-
Functions of Polyketide Compounds methylsalicylic acid in Penicillium griseofulvum (Simpson,
Phytotoxins 1983). Thus, polyketides are derived from the same precur-
Phytoalexins sors as fatty acids and the initial step seems to be similar (Fig.
References 5.1). Extensive purification of 6-methylsalicylate synthetase
from Penicillium patulum has been performed. This enzyme
system is distinct and separable from the co-occurring fatty
Il'ITKODUCTlOI'l acid synthetase and has a molecular weight approximately
half that of the former enzyme. NADPH is required as a
Polyketide or polyacetate compounds are derived from ace- coenzyme for methylsalicylate synthetase from this source
tate-malonate pathways and, in terms of biosynthesis, are (O'Hagan, 1990; Packter, 1980).
related to fatty acids. Polyketides are assembled by conden- In contrast to the reaction sequence observed with fatty
sation of acetate and malonate units; however, in contrast acid synthases, the sequential reduction, elimination, and
to fatty acid biosynthesis, the carbonyl groups may not be reduction of fatty acid biosynthesis does not occur. The re-
reduced and intermediate compounds typically condense to sulting intermediates usually are cyclized into phenolic sys-
produce aromatic ring systems, usually with phenolic substi- tems; although in practice these compounds show varying
tutions (Packter, 1980). degrees of reduction andlor oxygenation (Simpson, 1987).
Many polyketides have restricted patterns of distribution, It has been suggested that as each malonate unit is added,
but members of this group are common in algae, bacteria, the newly added portion may undergo any or none of the
fungi, and lichens. In general, polyketides from these organ- steps above, and in this way, "polyketide precursors,"
isms are water soluble and formed in high yield, late in the which show varying degrees of reduction and deoxygena-
growth cycle. However, polyketides also are found in higher tion, can be assembled in a stepwise manner on the synthase

56
 o
Polyketides 57

o 0
II~ II lie-
CH3C-CoA CH3CCH,C-CoA
on polyketide synthetase
H'cl""",O enzyme complex
H,~
c;:iCOSACP
H/I ......... 0.
u/1n

/r
ACPSCO '-.)'

-
000
II II II
CH3CCH,CCH,CSACP

bound on enzyme surface

from acetyl·CoA
)JL( from the latest
malonyl.ACP added

ACP =acyl carrier protein

Fig. 5.1. Fonnation of polyketide intennediates.

before being released from the enzyme by a stabilizing-ring
condensation (Simpson, 1987). While the intennediate is
still bound, alkylation of some activated methylene groups
may occur. Acyl-CoA species are involved, but the exact
nature of enzyme-bound intennediates has yet to be estab·
lished. Although there is a pronounced "starter effect" in·
volving acetyl CoA, other starter units such as methylmalo·
nate and ethylmalonate occur (Simpson, 1987).
The "chain length" of the polyketide intennediate in-
creases by units of two carbon atoms to various lengths.
Cyclization of intennediates occurs by one of two pathways.
An intramolecular aldol condensation produces aromatic
rings with one substitution pattern (Fig. 5.2) and an intramo-
lecular Claisen condensation produces another (phloroglu-
cinol structures) (Fig. 5.3).
In order for these condensations to occur, the reactive
sites must approach more closely than is possible in a linear
precursor molecule. One proposed mode of action of polyke-
tide synthetase enzymes is to facilitate fonnation of a Z dou-
ble bond into the molecule (Fig. 5.4). In this manner, the
reactive groups for the above types of condensations can
become proximal. This could be accomplished either by eno-
lization of a carbonyl function or by reduction and dehydra-
tion. The fonner process is reversible and should result in
loss of label (by exchange) at position a. Reduction and
dehydration should result in relative loss of label at position

rZ?
oUo
CO,R

000
R
~COzR ---=:::.

HOVOH
R

(yCOZR

HOVOH
tv-
orsellenic acid (2)
Fig. 5.2. Orsellenic acid and aldol~type condensation.

58 Polyketides
_:
0\JR
OO~
_
o~R:~_
o 0
HOXOH
Y OH
Fig. 5.3. Eugenone and Claisen-type condensation.
b. Examples of both mechanisms have been discovered (Fig.
5.4) (Simpson, 1984).
As is true in other groups of secondary metabolites, sev-
eral types of reactions follow the initial cyclizations: addition
and removal of hydroxyl and methoxyl groups, oxidation of
methyl groups to alcohols, aldehydes, and acids, the reverse
of this series, and decarboxylation. Decarboxylation of 13-
keto esters is especially common.
Many recent studies have used precursors labeled with
13C, I·C, 2H, 3H, and 18 0 (Simpson, 1986, .1987). Use of
2H and 180 precursors permits detection of specific hydrogen
and oxygen atoms by means of the isotope shifts that are
induced in I3C-NMR (nuclear magnetic resonance) absorp-
tions. Further, much of the information that formerly re-
quired degradation of compounds can now be obtained by
these nondestructive methods. 3H-NMR spectroscopy has
proven useful as this isotope has a nuclear spin of 112, a
slightly higher sensitivity than IH and gives sharp peaks and
chemical shifts and coupling constants similar to those of
1H. Deuterium is inexpensive, has a nuclear spin of 1, is
stable and nonradioactive, and can be accurately integrated,
but sensitivity is low. 13C also has a spin of 112 and a large
chemical shift range (200 ppm). Sensitivity is also lower
than that for IH, but this is partially compensated by determi-
nation of spectra with proton decoupling (Torssell, 1983).
I3C-NMR spectroscopy is especially useful when it is possi-
ble to introduce precursors enriched in 13C. Determination
of I3C_ 13C spin-spin couplings often provides information
about which intact two-carbon units are present (when
[1,2- 13C2]-acetate is used as a precursor) (Torssell, 1983).
From casual observation of structures in which I3C_I3C
couplings of intact acetate units are marked, it might appear
that all adjacent carbons would be coupled (if all the carbon
atoms in the molecule come from acetate). However, as the
overall percentage oflabeling is relatively low, the statistical
v
('OR
0
R
0
0
-----"'-
'-. - «::""""
o
engenone (8)
odds that a carbon adjacent to a pair of acetate-derived car-
bon atoms in which I3C_I3C is enriched also will be 13C
labeled are low. Because of this, only the I3C_I3C of acetate-
derived groups will be seen. By means of these and a variety
of other isotopic labeling and NMR techniques, details of
many proposed pathways for polyketide compounds have
been investigated (Simpson, 1984; 1987; Torssell, 1983).
TETRAIrnTIDES
Several examples are known in which four C2 units are incor-
porated and cyclized to produce phenolic molecules; 6-meth-
ylsalicylic (I) and orsellenic acid (2) are formed in this man-
ner. In the presence of malonyl-CoA and NADPH, 6-
methylsalicylic acid, triacetic acid, lactone (3), and fatty
acids are produced by an enzyme preparation from Penicil-
lium patu/um. In the absence of NADPH, only the lactone
(3) is formed (Fig. 5.5).
Formation of 6-methylsalicylic acid involves condensa-
tion of an acetyl-CoA unit with three units of malonyl-CoA.
The entire sequence is enzyme bound and intermediates are
not released. Furthermore, attempts to introduce exogenous
intermediates in feeding studies failed. As mentioned above,
extensive purification of 6-methylsalicylate synthetase from
Penicillium patu/um yielded an enzyme complex distinct and
separable from fatty acid synthetase and approximately half
in molecular weight. NADPH is required for production of
6-methylsalicylic acid (packter, 1980). The application of
NMR spectroscopy to study of the biosynthetic steps in the
formation of 6-methylsalicylic acid and other polyketides
has been reviewed (Simpson, 1987).
Some more complex compounds are formed by union of
tetraketide-derived rings. For example, usnic acid (4) is
derived by oxidative coupling of two molecules of methyl-
 Polyketides S9

phloracetophenone (5), each produced from four C2 units
(Fig. 5.6). The enzymes responsible for most in vivo coup-
lings are peroxidases which function in the presence of a
porphyrin cofactor.
Patulin (6), also derived from a tetraketide precursor, is
a potent carcinogen produced by certain Penicillium and As-
pergillus species, sometimes found in moldy apples and a
variety of other fruits, as well as barley (Beier and Nigg,
1992). Patulin inhibits respiration of higher plant cells and
has a neurotoxic effect on animals. 6-Methylsalicyclic acid
(1) (see above) is an intermediate in the biosynthetic pathway
leading to patulin (6) (Fig. 5.7) (Gaucher, 1979; Simpson,
1983; Zamir, 1980). The oxidation steps are carried out by
monooxygenases. The pattern of label introduced from intro-
duction of 14C-labeled acetic acid was of value in the deter-
mination of the reaction path (Fig. 5.8) (Gaucher, 1979).
Another complex polyketide compound, stipitatonic acid
(7), is derived from four C2 units (Fig. 5.9) (Weiss and Ed-
wards, 1980).
A series of lactones from Melodorum fruticosum (Annon-
aceae) may be of tetraketide derivation (Fig. 5.10). These
compounds have cytotoxic activity in the KB and P-338 cell
lines (Tuchinda et aI., 1991).
PENI'AKEnDES
A series of pentaketides derived from five C 2 units is also
known. Eugenone (8) (Fig. 5.3) occurs in the essential oil
of cloves, Syzygium aromaticum (Myrtaceae). Citrinin (9),
a carcinogenic antimicrobial metabolite produced by several

:yY~
R~SEnz
:W· ~SEnz
o 0 ~hYdration !.nolizati:n in D2~
/<:088

u9(oo- R((_---: <xl

~ of protons at position a)

,,_:,.. 0

CR30~Oy
D'8~
OR OR 0
/ 0 0 ~,,:,.,.:.

RO;
Wi
0.3 ~ I
~
0
OR

OR 0
by enolization

o OR 0 OR

CR30:@1 CR30~1
I I 0

0.4 :::,...
I I OR 0.4 ,..
..........
0
OR 0
OR 0 OR ,(6oR OR 0 OR
o ,:y I by enolization
RO :::,.. OR
1

Fig, 5.4. Preliminary steps of polyketide biosynthesis (Simpson, 1984; modified and used with permission of the copyright owner, the Royal Society of
Chemistry. London).
60 Polyketides

.~- -
0 0 HO 0

~-
acetyl·CoA NADPH NADPH

2 malonyl.CoA methylsalicylate
synthetase

/ 1
D V - ~" -
OH

o 0
~
C02H
OH D~
rr2COCOA
(3) SEm
6.methylsalicylic
acid (1) CO..

Fig. 5.5. Proposed biosynthesis of 6-methylsalicylic acid.

oy rs:w
V
o
Y
"(1" .
SCoA

C,' '-r 0

o
. o
---

rY.
COMe OH

.A( ----..~
HOyYOH radical formation

oOXOH

(5)
OH
o
OH HO

.~ovrrOH
"-.J0 ~
0 •

HO~ 0 ~ -
HO 0
o
0
OH HO

- ·H2O

HO 0

usnic acid (4)

Fig. 5.6. Biogenesis of usnic acid (Herbert, 1981; modified and used with pennission of the copyright owner, Chapman & Hall, London).
 Polyketides 61

JyCO'H
acetyl-CoA
3 malonyl-CoA
-- UOH

6-methylsalicylic
acid

V - (r0H
OH OH
oxygenase
¢roo OH

m-cresol OH
m-hydroxybenzyl
alcohol
OH o

N CHO
O~I
Y
O"NADPH
dehydrogenase OH
oxygenase ,f - -
H I
HO' H
OH

genistaldehyde isoepoxydon (49)

(a)

--
phyllostine (55)

HO
D' 0
..

HO
It -:?' h

OH
21"
,r

o
h

OH

isopatulin E-ascladiol patulin (6)

(b)

Fig. 5.7. (a & b) Biogenesis of patulin in Penicillium urticae (modified from Stoessl, 1981; used with pennission of the copyright owner, Academic
Press, New York).

:1'(X
3~"

#7
Ii'

OH
COH--
8 2
8
.7'"
3

5 4 0
2'
.d

1
.,0

OR
7

6-methylsalicylic acid (1) patulin (6)

OH

Fig.5.S. Incorporation of 14C label from carboxyl labeled acetic acid into
6-methylsalicylic acid and patulin (Gaucher, 1979; modified and used with stipitatonic acid (7)
pennission of the copyright owner, the International Association of Milk,
Food, and Environmental Sanitarians, Des Moines, IA). Fig. 5.9. Stipitatonic acid.
62 Polykelides

o ~ O~ 0 -
H
O~
)l
CH,

o O~ "0/ \ "" O~
O~CH' O~

Fig. S.10. Lactones from Meladorumfruticosum.

[1-1"c]-a<etate
OW""·
, ..
.
.
HOC:::"" :::,... 0
OH
C1

0:0:):/'0.. HOW
CH,-CO,Na --+
• elK
0 0
SR
- I 0
""" SR
o 0 HO 0

! C-I reduction

HO

WWW ,p-

"""
HO
I
'-'I ")

(11)
0;-'
\
0

H'
L --
---".
HO 17

"""
HO
I
CHO
OH C-3_
_
reduction
HO 17

"""
HO
(14)
I
CliO
0

O~ O~
~b
OH
(10)
- HO'C~~')
OH citrinin (9)

··.W
R R
HO~
AyJyb
OH 0 OH 0

(IS) (12)R=CH, (13)R=H

Fig. 5.11. Biogenesis of citrinin (Simpson. 1983; modified and used with pennission of the copyright owner. the Royal Society of Chemistry. London).
 Polykerides 63

Aspergillus species and by Penicillium citrinum, also is a
representative of this series, This pentaketide was at least
partly responsible for fatalities caused by "yellow rice dis-
ease" in Japan during the early part of this century and to
a lesser extent following World War II (Ciegler, 1975),
Several of the proposed steps of the biosynthetic pathway
for this compound (Fig, 5.11) have been reexamined. The
fungus that produces citrinin has been grown in media made
with 0 20. By adding normal protium eH)
containing pre-
cursors to the cultures, it is possible to measure incorporation
of that isotope. By study of the extent and sites of incorpora-
tion of protium ('H) with combined I3C_, 2H_ and 'H-NMR
techniques, the origin of various hydrogen atoms in the ci-
trinin molecule could be determined. For example, the hy-
drogen on C-4 of citrinin (9) is acetate derived. The marked
difference in the amount of protium at C-I and C-3 suggests
that reductions at these two sites occur at markedly different
stages in the biosynthesis (Simpson, 1983).
Further, in the I3C-NMR spectrum of [1_I3C, "Oz]-ace-
tate-enriched citrinin, isotopically shifted signals are ob-
served for the resonances due to C-3, C-6, and C-8. This
indicates that oxygen atoms attached to each of these carbons
come from acetate. The quinone-methide structure (as in
compounds 9 and 10) must be formed by the elimination of
hydroxyl (as water ?) from the hemiacetal (11). Compound
(12) was incorporated into citrinin, whereas the correspond-
ing compound (13), without methyl groups, was not. This
suggests that methylation occurs early in the biosynthetic
pathway, probably before aromatization. Compound (12)
was shown by other methods not to be an obligate precursor
of citrinin, however. Compound (14), but not compound
(15), was incorporated into citrinin.
IrnXAKBTJDES
The biosynthesis of ascochitine (16), a phytotoxic hexake-
tide from the fungus Ascochyta labae, has been investigated
by means of I3C-Iabeled acetates and methionine and 14C_
labeled precursors (Ballio, 1981; Stoessl, 1981) (Fig. 5.12).
Ascochitine is derived from a single hexaketide precursor
with introduction of three methyl groups from methionine
via a quinone-methide structure (17) similar to that involved
in the biosynthesis of citrinin. The aldehyde (18) and qui-
none-methide (17) were specifically incorporated.
The naphthoquinones plumbagin (19) from Plumbago
spp. (Plumbaginaceae) and 7-methyljuglone (R = CH3 ) (20)
from Drosera spp. (Droseraceae) are derived from six Cz

0X)):f0 -- H0)O¢D
C,
1\
--+
• ,If
I °
0 0
SR "'" SR
C,
o 0 HO 0

~
O~ HO~ HoxX0
~6 I ~6 I
I °
""
HO
CHO
HO OH
OH
(17) (18)

i
":~
Ho,c~6
OH
I
ascochitine (16)

Fig. 5.12. Biogenesis of ascochitine (Simpson, 1983; modified and used with permission of the copyright owner, the Royal Society of Chemistry,
London).
64 Polyketides

[0] [0] HEPTAKETIDES

! ! Griseofulvin (21), an antifungal antibiotic representative of

W-
the heptaketide series, is obtained from Penicillium griseo-
fulvum and probably is biosynthesized as indicated in (Fig.
o 0
COA ~
y y
5.14). Formation of this molecule involves both a Claisen
and an aldol condensation. The intermediate compound
o
OU OU
griseophenone B (22) is then cyclized via a free-radical
coupling to normethyldidehydrogriseofulvin, as discussed in
o 0
Chapter 6.

W
o

OCTAKETIDES

Although many anthraquinones in plants are derived from

OU 0 shikimic acid pathways (see Chapter 6), others, such as an im-
plumbagiD (19) '-methyljuglone (20)
Fig. 5.13. Biogenesis of plwnbagin and 7·methyljuglone.
units (Fig. 5.13) (Durand and Zenk, 1971; Packler, 1980).
In this unusual instance, the acetate arises from L-tyrosine
(Haslam, 1986). Most naphthoquinones, however, are de-
rived from shikimate pathways and will be discussed in the
following chapter.
portant plant and fungal anthraquinone, emodin (25), are syn-
thesized from octaketide units. This compound is widely dis-
tributed in fungi, especially in the genera Penicillium and
Aspergillus, and is an important intermediate in the biosyn-
thesis of many other fungal metabolites (Sanakawa, 1980).
The biosynthesis of helminthosporin (26) from Helmin-
thosporium gramineum is similar to that of emodin (Fig.
5.15).
Because of secondary reactions (such as loss and/or sub-

OU 0 OU

~O -~
CU,COCoA
r
l
6Cj,COCOA

co,u UO~~ ~OU

O~coAJ-I ..
OU

OU 0 OH OH 0 OCH,

--{()c}1
I ~ - (xJi1
CH,O
I"'"
:::"... OH
.& OH CH,O
~.&
OH OH

griseofulvin C
griseophenone B (22)
(24)

~¢:Y
coupling
CH,o~
OH

CI
I
0

0-
OCH,

0
~
¢0:r
CH,O:::"'"
0CH'

I
0

O. -
OCH,

0
_ _ ~OCH'
0 OCH,

CH,O:::"'"
I
0
0

CI· CI

normethyldidehydrogriseofulvin 5 ,6 -didehydrogriseofulvin griseofulvin (21)

(23)

• label from acetate preferentially incorporated here

Fig. 5.14. Biogenesis of griseofulvin (modified from Vleggaar and Steyn. 1980; used with pennission of the copyright owner, Academic Press. New
York).
 Polyketides 6S

.
-- ~
o 0 O. OH 0 OH

• • •
OSEDZ ~COSEn.
? ~
CH,CO,H • 000 --- I I
o ••• HO% ~

HO~ -
OH OH

~~ HO

1 emodin anlbrone
o
emodin (25)

OH 0 OH o OH
OH

o
helminthosporin (26) alizarin (27)

Fig. 5.15. Probable biosynthesis of emodin and helminthisporin.

sequent addition of hydroxyl and methyl groups), it is some-
times difficult to predict the biosynthetic origin of com-
pounds of this series. Generally, those anthraquinones with
substituents on both A and C rings [such as emodin (25)1
are derived via the acetate-malonate pathway, whereas those
with substituents in only one ring derive from shikimate
and malonate (Fig. 5.15). The structurally similar compound
alizarin (27) is synthesized from iso-chorismic acid, a-keto-
glutarate, and mevalonate. Anthraquinones derived from
shikimate pathways will be discussed in Chapter 6.
toxic and carcinogenic natural products known. Various
strains of Aspergillus (and other fungi) produce these potent
carcinogens, which cause lesions in the mammalian liver
(Beier and Nigg, 1992; Coulombe, 1991; Simpson, 1984;
Steyn, 1980). Aflatoxins are found in many food products,
but are most commonly encountered in corn (Zea mays) and
peanuts (Arachis hypogaea).
MACROLIDE Al'lTlBIOTICS

A number of polyoxygenated fungal metabolites are assem-

bled from c" C 3 , and C. units. Starter units of propionyl-
TETRACYCLIl'IES
CoA and successive additions of methylmalonyl-CoA are
especially important in the formation of many of these com-
Tetracyclines, formed from the condensation of eight C 2
pounds (O'Hagan, 1990). Most of these metabolites possess
units and a malonamide starter, are produced by a number
large rings and are potent antibiotics; they are known collec-
of Streptomyces species from an unusual group of bacteria,
tively as macrocyclic or macrolide antibiotics. One well-
the actinomycetes (Fig. 5.16). Many tetracyclines, such as
known example of this group of compounds is erythromycin
terramycin (28), aureomycin (29), and tetracyline (30), are
A (34) from Streptomyces erythreus (Fig. 5.18) (Omura,
broad-spectrum antibiotics (Thomas and Williams, 1984,
1984; Simpson, 1984). An extensive literature deals with
1985; Weiss and Edwards, 1980).
these antibiotic compounds but is beyond the scope of this
text.

DECAKETIDES
The fungal metabolite aflatoxin B1 (31) is derived from a co-
occurring xanthone sterigmatocystin (32) which is, in turn,
produced by oxidative cleavage of the anthraquinone versi-
colorin A (28) (Fig. 5.17). Aflatoxins are among the most
IOI'lOPHORES
A group of natural products, ionophores, which disrupt nor-
mal ion gradients, function as antibiotics by binding to metal
ions and transporting them across cell membranes. One of
66 Polyketides

CONH, 8 CH,COCoA O~SEnz

tH1COCO; bOi ---- ~NH'--

o 000 0

-+
NH,

OH OH HO HO o OH OH HO HO o

OH ~HO
,:? H
,
O
OH

NH, "I
- . . ..........
" :
1 NH
1

OH OH o o OH 0 OHO 0 0

/
anhydrotetraeycline dehydrotetracycllne

~
~
I
P
I
OH H R H N(CH,),
I! ~ OH «m(
PI'
""-
CI OH
H

""- •
H
-
H N(CH,),
OH
I
NH,
""- ""- • NH, HO
HO OH 0 HO 0 0
OH 0 HO 0 0

R =OH, terramycin (oxytetracycline) (28) aureomycin (29)

R =H, tetracycline (30) (7·chlorotetracycline)

Fig. 5.16. Biogenesis of terramycin, tetracycline, and aureomycin (Thomas and Williams, 1984, modified and used with pennission of the copyright
owner, the Royal Society of C.hemistry, Cambridge),

CH,CO,H - -
O~
0 0 --
HO~""OH
I I
o ""- h
OOCoAOOO OOOHOH

averantin

averufin
--~
HO~I
o
0

0
",,0

OH
0yO
OHH

versiconal hemiacetal acetate

~O~
-
--+

versicolorin A (33) sterigmatocystin (32) aflatoxin B1 (31)

Fig. 5.17. Biogenesis of aflatoxin (Coulombe, 1991; modified and used with pennission of the copyright owner. the CRC Press. Boca Raton, FL. ©
1991).

CH,CH,COCoA
CH,
I
6CHCOCoA
I
co·
Fig. 5.18. Biogenesis of erythromycin.
these compounds, lasalocid A (35) (Fig. 5.19) has complex
stereochemistry and oxygen substitution that serve to coordi-
nate metal ions (Williams et al., 1989).
ACETOGEl'IIl'IS
A series of acetate-derived compounds have been reported
from plants of the family Aunonaceae (Annona cherimolia,
A. muricata, A. squamosa, and other Annona species; Asim-
ina triloba, pawpaw; Goniothalamus giganteus; and several
Rollinia and Uvaria species) (Fig. 5.20) (Alkofahi et al.,
1989; Lieb et al., 1990; Nahrstedt, 1985; Rupprecht et al.,
1986). Most of these compounds exhibit potent antimicro-
bial, antiparasitic, cytotoxic, and antitumor activity (Bories
et al., 1991). For example, asimicin (36), from the bark of
Asimina triloba, is extremely cytotoxic (EDso <10- 7 tJiml
with several cell cultures); fractionation of the plant material
was monitored by the brine shrimp bioassay (AIkofahi et aI.,
1989). This compound also is toxic to the striped cucumber
beetle, Mexican bean beetle, mosquito larvae, blowfly lar-
vae, melon aphid, two spotted spider mite, and the free-
living nematode, Caenorabditis elegans (Rupprecht et al.,
1986).
Iasalocid A (35)
Fig. 5.19. The ionophore antibiotic lasalocid A.
Polyketides 67
dadlno.se
erythromycin A (34)
POLYKETlDE COlllPOUI'IDS FROM UNUSUAL
STARTER Vl'IITS
Many polyphenols are derived from malonate units and a
starter other than acetate. The starter unit for tetracyclines
(previously discussed) is malonamido-CoA (Fig. 5.16).
Members of the Anacardiaceae characteristically produce a
series of compounds based on unsaturated fatty acid precur-
sors. The surface of a number of plants of this family is
covered with a mixture of phenols well known for their irri-
tating properties to humans. Poison ivy, Toxicodendron radi-
cans, commonly is involved in human poisoning in eastern
North America. The family of phenols known as urushiols
are the major irritant constituents (Fig. 5.21), but the CoA
ester of palmitoleic acid usually serves as a precursor of
this group of compounds. The side chain structure of active
compounds is mono-, di-, or triunsaturated, suggesting that
a number of unsaturated acyl-CoA starter units can be em-
ployed. The pure compounds are very active allergens in
man; those compounds with a catechol structure are the most
potent in this regard. Related compounds from Mangifera
indica, the mango, are thought to be responsible for resis-
tance to the fungal pathogen black spot disease, Alternaria
alternata (Harborne, 1989). Similar substances have been
isolated from Amphypterygium atistringens, a plant placed
in the family Julianaceae (Navarette et al., 1989). These and
68 Polyketides

R' other data confinn that this family should be merged with
the Anacardiaceae.
7
Pest-resistant geraniums (Pelargonium species, Gerania-
R" 0
0 ceae) contain primarily C22 and C24 unsaturated anacardic
acids (Walters et aI., 1990). For example, geranicardic acid
(37) and similar compounds from the cultivated geranium
(Pelargonium X hortorum) are largely responsible for resis-
R R R' tance of the plants to the two-spotted spider mite, Tetrany-
R"
asirnjcin (36) OH OH OH chus urticae (Craig et aI., 1986; Gerhold et aI., 1984). In
asimicintriacetate OAc OAc OAc Pelargonium X hortorum. anacardic acids were shown to
uvaridn OAc OH H be biosynthesized from saturated and w-saturated C 16 and
OH CIS fatty acids by chain elongation with three acetate groups
(Walters et aI., 1990).
These and similar compounds are found in the Anacardia-
ceae, Geraniaceae, Ginkgoaceae, Myristicaceae, Myrsina-
ceae, Poaceae (Gramineae), and Proteaceae.

METHYLBNBBISPHLOKOGWCINOLS
OH
colliRODe
AND ReLATBD COMPOUI'IDS

Fig. 5.20. Acetogenins from the Annonaceae. Several ferns, mostly those of the genus Dryopteris, elabo-
rate compounds in which methylated phloroglucinol units
(such as 38) are coupled through methylene groups to yield

Z
CH,(CH,),CH=CH(CH,hCOSCoA

palmitoleic acid

7'0
/CH,-C"-.,
CH,(CH,),CH=CH(CH,),C CH
II / '
0 CH~
/ I 0
COSCoA \ OH

CH'(CH,),CH=CH(CH'h-Q'
- CH,(CH,),CH=CH(CH,),
-Q~
anacardic acid CO2" OH -
\ CO,H OH

j
CH'(CHzl'CH=CH(CHzl,-Q \

urushiol no on
OH

CH,<CHzl,CH=CH(CHzlr-Q CH'(CHzl'CH=CH(CH'),Q

cardanol OR cardol OH

OC
HO
CO'H

'>--
I Z
(CH,),CH=CH(CHzl,CH,

geranicardic acid (37)

Fig. 5.21. Compounds from poison ivy and geranicardic acid (modified from Geissman and Crout, 1969).
 Polyketides 69

compounds such as 39-43 (Fig. 5.22). Each of the phloro-
glucinol molecules is based on a C4 starter unit and subse-
quent addition of three units of malonate. The extensive C-
methylation is derived from S-adenosylmethionine and ap-
pears to occur while the polyketide chain is bound to a pro-
tein surface (Geissman and Crout, 1969).
Even more complex molecules are formed by coupling
of these units. Most of these couplings are through methyl
groups that are ultimately derived from S-adenosylmethio-
nine. Filixic acid (39) is one of the most common of these
compounds. These compounds have been used medicinally
as anthelminthics and purgatives.
A series of compounds which share many structural fea-
tures occur in dicotyledonous plants. Drummondin A, B, and
C [44,45, and 46, respectively, (Fig. 5.23)] from Hypericum
drummondii (Clusiaceae) have significant activity against
the gram-positive bacteria Staphylococcus aureus, Bacillus
subtilis, and the acid-fast bacterium Mycobacterium smeg-
matis. Japonicin A (47), from the same plant, has antimalar-
ial activity. Robustaol A (48), from Eucalyptus robusta
(Myrtaceae), has activity against Plasmodium berghei (Boris
and Schaeffer, 1992). Similar compounds, isolated from
Mallotusjaponicus (Euphorbiaceae), have cytotoxic activity
(Jayasuriya et aI., 1989).

CH,CH,CH,COSCoA
. _ CH,CH=CHCOSCoA
. biotin,COz

ATP

CO,H

.~
(
I
CH,CH=CHCOSCoA
•
--
.
CH,CH,CH,COCH,CH=CHCOSCoA
.
CH CH CH CO-SCoA
3 1 2

oxidation .
CH,CH,CH,COCH,COCH,CH,COSCoA
. C-methylation

hydration malonyl-eoA

.
CH,CH,CH,COCH,COCHCOCH,COSCoA _
. CH,CH,CH,CO - -
•
HOO·OH
~
I
1

:o:56r
CH, OH
(al

H
HO OH 'r OH
1 1 1

¢CO'
CH3CH2CH2CO :::-.. -COCH zCHzCH3
o OH CH
p·aspidin(39)
HO "'" OH "'" OH
H0X)c:(XIHOOH I I
1 1 1 1 CH,CH,CH,CO"'- ~ ~ "cOCH,CH,CH,
CH,CH,CH,CO COCH CH CH OH OH
o 0 2 2 3
margaspidin (41)
albaspidin (40)
CH, CH, :Q:5O:CH'

~ ~I
\/ HO OH"",OH
HO?, 0 0 r OH I I
CH,CH,CH,CO COCH,CH,CH,
CH,CH,CH,CO OH OH COCH,CH,CH, 0 OH
desaspidin (43)
methylenebisaspidinol
(42) COCH,CH,CH,

H000HO~OHH000H filixic acid (38)

CH,CH,CH,C~COCH,CH,CH'
(b)
o OH 0

Fig. 5.22. (3 & b) MetbyJenebispbloroglucinols from ferns (modified from Geissman and Crout, 1969).
70 Polyketides
drummondiD A (44)
drummondln C (46)
robustaol (48)
Fig. 5.23. Antimicrobial compounds of mixed polyketide origin.
POLYKETlDI!S FROM LICHEI'IS
Lichens, organisms in which fungi and algae live in associa-
tion, produce numerous polyketide-derived compounds,
often in very large amounts in proportion to the dry weight
of the organism (Culberson, 1969). In general, it appears
that the fungal member of the pair synthesizes these com-
pounds from carbohydrates provided by the alga. Many of
the compounds also are found in free-living fungi, but only
rarely in algae. A substantial number of these substances are
unique to lichens. These polyketides are used frequently to
assist in the identification of the approximately 18,000
known species of lichens (Culberson, 1969, 1970, 1977).
The chemistry of lichen substances has been reviewed (Elix
et aI., 1984; Huneck and Yoshimura, 1996).
Depsides, in which esterification to links two polyketide-
derived units [such as lecanoric acid (50») (Fig. 5.24), are
quite common among lichens (Weiss and Edwards, 1980).
Many of these compounds are strongly allelopathic and are
responsible for the death of trees inhabited by the dense
growth of lichens (Cutler, 1992).
MYCOTOXJI'IS
Many fungi produce compounds that are highly toxic to man
and his domestic animals. A large number of these are de-
rived from polyketide pathways. Several have been previ-
japonicln (47)
ously discussed, among them are the aflatoxins patulin (6)
and citrinin (9). A few other common and important myco-
toxins are discussed below.
Animals that consume moldy feeds excrete the estrogenic
polyketide mycotoxins zearalenone (51) and zearalenol (52)
in milk and milk products (Fig. 5.24). The same compound
sometimes is found in beer. Zearalenol and zearalenone are
synthesized by Fusarium species; these compounds produce
sterility and other reproductive problems in livestock (Beier
and Nigg, 1992).
Fumonisins are from Fusarium moniliforme, a fungus that
occurs worldwide on a variety of plant hosts, including
wheat, barley, soybeans, rice, maize, and oats (Beier and
Nigg, 1992). Although man and domestic livestock are af-
fected, horses seem to be particularly sensitive. They suffer
a neurotoxic syndrome in which the white matter of one
or both cerebral hemispheres liquifies. Fumonisins also are
highly carcinogenic. Of this group of compounds, fumonisin
B, (53) is the most common, often representing about 70%
of the total fumonisins detected (Plattner et aI., 1992).
Methods for detection and analytical determination of
mycotoxins at low levels have been reviewed (Wilkinson et
aI., 1992).
fUNCTIONS OFPOLYKETlDE COMPOVNDS
Polyketides frequently possess potent physiological activity
which is expressed in a variety of ways. Some compounds
of this group, such as morphogens, appear to be involved in
 Polyketides 71

~y
O~O
OH
(+)-isoepoxydon (49) patulin (6)

1-(3,5-dichloro-2,6-dihydroxy- lecanoric acid (50)

4-melhoxyphenyl}-1 hexanone (53)

HO HO

OH o
zearalenone (51)
zearalenol (52)
OH
~
o
o 0

OH OH o OH

O~OH
fumonisin 8 1 (53)
8 o~A~OH.. 8
Fig. 5.24. Some biologically active polyketides.

fundamental developmental levels, whereas others are in-
volved in biological interactions with other organisms.
Morphogens are signal molecules in embryos that are, as
one example, involved in establishing the spatial pattern of
cells during development. 1-(3,5-Dichloro-2,6-dihydroxy-4-
methoxyphenyl)-I-hexanone (54), apparently derived from
polyketide pathways, is required for producing the
prestalkJprespore pattern in the aggregate formed by cells
of the slime mold Dictyostelium in response to starvation
(Morris et al., 1987). Several homologs and analogs have
since been isolated (Jaenicke, 1991).
Many of the polyketides produced by filamentous fungi
are water soluble, formed in high yield, and removed from
the intracellular pool by excretion into the culture medium.
Although these compounds frequently possess antibiotic ac-
tivity and a number have commercial importance, they sel-
dom exert any apparent function in the physiology of the
producing organism. However, in nature, interactions of
fungi and other organisms are complex and may involve
plants, animals, and other fungi (Wicklow, 1984, 1988). For
example, (+ )-isoepoxydon (49) has been established as the
major causative agent of interference between Poronia punc-
tata, a late fungal colonist of cattle dung, and two earlier
colonists, Ascobolus furfuraceaus and Sordaria fimicola
(Gloer and Truckenbrod, 1988).
Phytotoxins
Phytotoxins, compounds produced by pathogenic organ-
isms that contribute to the death and decomposition of the
host plant (Ballio, 1981; Harborne, 1986, 1989; Stoessl,
1981), are well represented among polyketides.
72 Polyketides
Fig. 5.25. Phytotoxins from the Dutch elm disease fungus, Ceratocystis ulmi.
cytochalasin B (56)
Fig. 5.26. Some representative cytochalasins.
Dutch elm disease, caused by the fungus Ceratoeystis
ulmi, is disseminated by a bark beetIe of the genus Seolytus.
The fungus produces toxins that cause necrotic lesions and
leaf wilting. These toxins consist of a mixture of glycopro-
teins and three low-molecular-weight phenolic compounds
(Fig. 5.25) (Claydon et aI., 1974; Harborne, 1982, 1986;
Wood et aI., 1972).
A compound that serves as an intermediate in the biosyn-
thesis of patulin (6), phyllostine (also known as epoxydon)
(55), (Fig. 5.7) has been identified as a phytotoxin from a
Phyllostieta species that is pathogenic to red clover (Ballio,
1981). Patulin also has been reported to possess phytotoxic
activity (Stoessl, 1981). Further, several structurally related
compounds from a number of different fungal species seem
to be involved in phytotoxicity (Stoessl, 1981).
Cytochalasins, a complex group of polyketide-derived
microbial metabolites, exert profound effects on a variety of
cellular processes (Fig. 5.26) and are used widely as cytolog-
Fig. 5.27. T~Toxins
0
OH
0
HO~
o
cytochalasin D
ical tools. Cytochalasin B (56), for example, disrupts micro-
filament assembly and contractile processes within cells
(Stoessl, 1981). These compounds are both phytotoxins and
mammalian toxins.
Other powerful phytotoxins, T-Toxins from the fungus
Helminthosporium maydis race T, are derived from acetate
(Fig. 5.27) (Kono et aI., 1981).
Phytoalexins
Another group of biologically active compounds, phyto-
alexins, are produced by plants in response to invasion by
foreign organisms, typically fungi and bacteria.
One of the earliest reported phytoalexins was 6-me-
thoxymellein (57) (Fig. 5.28) produced by carrot root slices
after inoculation with Ceratoeystis fimbriata. This fungus,
which causes black rot disease in sweet potatoes (Ipomoea
batatas, Convolvulaceae), is not pathogenic in carrots (Dau-
o 0
from Helminthosporium maydis.

--
co,
4CHj'"'C0,H
enzyme 4CHf"'COEnz
o 0 0 0
~Enz--
HOW
-- 0-- 1.,9
OH 0
Fig. 5.28. 6-Methoxymellein biosynthesis (modified from StoessI. 1981; used with pennission of the copyright owner Academic Press).
cus carota, Apiaceae). Treatment of carrot tissues with ethyl-
ene and a number of other chemicals also has been shown to
induce fOimation of 6-methoxymellein, as do several carrot
storage fungi (Bailey and Mansfield, 1982; Yates, 1987).
REFERENCES
ALKOFAHI, A, 1. K. RupPREClIT, 1. E. ANDERSON, J. L. McLAUG-
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6
Benzoquinones, Naphthoquinones, and
Anthraquinones
Introduction
Benzoquinones
Biosynthesis
Distribution of Benzoquinones Among Higher Plants
Biological Functions of Quinones in Plant-Plant
Interactions
Biological Functions of Quinones in Plant-Animal
Interactions
Naphthoquinones
Biosynthesis of Naphthoquinones
Distribution of Naphthoquinones Among Higher Plants
Biological Functions of Naphthoquinones
Anthraquinones
Biosynthesis of Anthraquinones
Distribution of Anthraquinones
Biological Functions of Anthraquinones
Economic hnportance and Uses
Anthrones and Anthrone Dimers
Hypericin and Anthrone Dimers
References
INl'RODVCTIOI'l
Quinones, naphthoquinones, and anthraquinones are found
in many types of higher plants and fungi. About 600 natu-
rally occurring quinones have been described. More than
half of these are from one plant family, the Rubiaceae (Has-
lam, 1974; Harhorne, 1982). Quinones are cyclic Ol,J3-dike-
tones of such a structure that they are converted by reduction
into hydroquinones, that is, phenols contaiuing two hydroxyl
groups such as (2) (Fig. 6.1) (Morrison and Boyd, 1973).
The reduced and oxidized forms are closely balanced ener-
getically and are easily interconverted.
The highly conjugated oxidized forms of quinones are
colored; for example,p-benzoquinone (1), is yellow. In con-
trast, the reduced forms usually lack color. Many chemical
76
properties of quinones result from their tendency to form the
aromatic hydroquinone system (Morrison and Boyd, 1973).
Both para- (3 and 6) and ortho-quinones (4) (Fig. 6.3) are
known. Quinonoid compounds in which a second aromatic
ring is fused to the benzoquinone ring are called naphthoqui-
nones (6 and 7); those in which an aromatic ring is fused to
both sides of the benzoquinone ring are called anthraqui-
nones (9-11). Anthrones (12) are related structurally tu an-
thraquinones. Anthrones are readily oxidized to anthraqui-
nones (12 is converted to 11).
Many quinones are derived from acetate-malonate path-
ways (discussed in Chapter 5), some from shikimate path-
ways (discussed in Chapter 7), and others are derived by
oxidative modification of secondary metabolites from a vari-
ety of other pathways. Quinones of this last type will be
discussed with the compounds to which they are biosyntheti-
cally related.
Most quinonoid compounds probably occur in plants as
glycosides and many of the benzoquinones, naphthoqui-
nones, and anthraquinones that have been studied are arti-
facts of isolation.
The IH_NMR spectra of anthraquinones and anthraqui-
none glycosides have been discussed (Kalidhar, 1989).
BEl'IZOQVIl'IOl'lES
Simple quinones or benzoquinones are found commonly in
nature. Some quinonoid compounds such as the electron car-
rier ubiquinone (13), sometimes known as coenzyme Q, play
important primary roles in plants. Structurally related plasto-
quinones are important as electron carriers in photosynthesis.
Secondary compounds with similar structures, for exam-
ple, polygonaquinone (5) (Figs. 6.1 and 6.2), are encountered
in species of Fagopyrum (buckwheat), Polygonum (smart-
weed), Rumex (dock), and Rheum (rhubarb) in the Poly-
gonaceae (Mathis, 1966).
 Ben::oquinones. Napluhoquinones, and Anthraquinones 77

o
o

o
OK
reduction ....
"'" oxidation
o OK
p-benzoquin.ne (1) hydroquinone

*?
yellow (1)

W
I
I I
KO
o OK 0

arbutin (14) pyrolatin perez.ne (3) plumbagin (6)

o o

QQ OK 0

jugl.ne (7)
~
~ OK 0
belminth08porin (9)
® OK 0

(8)

~
~
o
emodin (11) emodin anthrone (12) 2-methylanthraquinone
(10)

Fig. 6.1. Quinones from higher plants.

Biosynthesis oxidation of many different types of primary and secondary

As mentioned above, quinones commonly arise by po-
lyketide pathways, by the shikimic acid pathway, and by
oxidation of a number of secondary metabolites of varied
biosynthetic origin. In some instances, the same compound
is known to arise by distinct pathways in different organisms.
In general, polyketide pathways are favored in bacteria,
fungi, and lichens, whereas shikimic acid pathways are fa-
vored in higher plants (Kubitzki and Gottlieb, 1984a,
1984b), although there are many exceptions to this generali-
zation. It is not always possible to determine the pathway
of origin for a particular quinone by structure alone, but a
knowledge of plant families and their relationships permits
an educated guess. In order to be certain, the pathway must
be established by biosynthetic studies in each case.
Distribution of Benzoquinones Among
HlgberFlants
Benzoquinones are widely distributed among higher
plants. Compounds with quinonoid structure may arise by
compounds. For example, hydroquinone and its J3-n-gluco-
side, arbutin (14) (Fig. 6.1), are known to occur in many
plants. This compound appears to arise by oxidative decar-
boxylation of p-hydroxybenzoic acid. Although arbutin is
widespread, it is especially common in the family Ericaceae.
A number of naphthoquinones are also found in this family.
The Myrsinaceae are known to produce and accumulate
many benzoquinones. Among these are embelin (15), rapa-
none (16), and maesaquinone (17) (Fig. 6.2). Maesanin (18),
from the fruit of Maesa lanceolata, is a powerful antibiotic
agent. A hot-water extract of the fruits is used locally in
Africa to prevent cholera (Harbome, 1986).
Many ortho- and para-quinones based on terpenoid struc-
tures are found in the Lamiaceae (Labiatae, the mint family)
especially in the genus Salvia (4, 19,20) (Fig. 6.3), the Mal-
vaceae (Gossypium and Hibiscus), the Bombacaceae (Bom-
bax), Boraginaceae (Cordia, 21-25), the Asteraceae (Cac-
alia) (26, 27), as well as other families. The wood of the
blue mahoe, Hibiscus elatus (Malvaceae), has a dark bluish
78 Benzoquinones, Naphthoquinones, and Anthraquinones

pene from cotton (see Chapter 21), although cotton is not a

~
O.& H host for this parasite. A compound which serves as a germi-
;....- vitamin Kl (37) nation stimulant for seeds of Striga also has been isolated
"" I I 3 from Sorghum bicolor, a normal host for the parasite. This
compound, 2-hydroxy-5-methoxy-3-[ (8'Z, 11 'Z)-8', 11',14'-
o pentadecatrieneJ-p-hydroquinone (28) (Fig. 6.4) and the cor-
° responding p-benzoquinone (29) co-occurred. Only the hy-

::~,
droquinone was biologically active (down to 10-7 M), but
ubiquinone (13) was readily converted to the benzoquinone (Chang et al.,
1986). Haustorium formation is tightly regnlated in Striga.
If the seed germinates and the parasite seedling root does

»N
not approach the root of the host closely within about 5-7
° days, the parasite seedling will die. Haustorial induction
must occur within about 50 f.LIll of the host root for successful
I plastoquinone attachment (Chang and Lynn, 1986, 1987). In experiments
"" H with the roots of Sorghum bicolor and germinating Striga
o ... asiatica seeds, a haustorial inducing substance, 2,6-dimeth-
oxy-p-benzoquinone (30) (Fig. 6.4) was isolated (Chang and
Yr0H {POH {POH Lynn, 1986, 1987). This compound is widespread among
higher plants, has been shown tn have allelopathic proper-
HO~n-Cl1Ra3 Hoyn.CllH23Ho~n.C13H27 ties, and may be involved in host defense. Further, several
0 0 0 fungi release this compound by the action of laccase en-
polygonaqulnone embellin (IS) rapanone (16)
(5)
zymes. It was shown that the meristematic tips of seedlings
of AgaUnis and Striga produce similar laccases (Chang and
o Lynn, 1987). It is proposed that compounds such as syringic
~OH maesaquinone(17)
acid (31) from Sorghum bicolor roots are oxidized by lac-
cases from Striga asiatica roots to produce 2,6-dinlethoxy-
HOY(CH2)13CH=CH(CHV3CH3 p-benzoquinone (30) (Fig. 6.5). Radicle development termi-
o nates with the induction of haustorial development (Chang
o Z and Lynn, 1986, 1987).
CH,o«(CH,)'CH~H(CH')3CH3 The haustorial inducer from Lespedeza sericea for the
I I maesanln (18)
parasite AgaUnis purpurea, however, proved to be a
OH triterpene, soyasapogenol B (Lynn, 1985).
o
Fig. 6.2. Benzoquinones occurring in flowering plants. Biological Functions of Quinones
in Plant-Animal Interactions

gray color that changes to yellow in the presence of light,
which is caused by quinonoid sesquiterpenes present in the
wood (Leistner, 1985).
Biological Functions of Quinones
in P1ant-FJant Interactions
Parasitic plants are known from about 10 families of
higher plants; the Scrophulariaceae and Orobanchaceae con-
tain many parasitic species. Some, such as AgaUnis purpurea
(Scropulariaceae), a hemiparasite, have wide host ranges,
whereas others, such as Striga asiatica (Scropulariaceae), a
holoparasite, are restricted to a single host family, in this
case, grasses. Because Striga attacks cereal grains and sugar
cane (grasses), this parasitic plant has major economic im-
portance. Two levels of recognition of the host plant exist:
one associated with seed germination and the other with
haustorial formation (a haustorium is a specialized attach-
ment organ found in parasitic plants). Germination of Striga
seeds can be induced by compounds such as strigol, a diter-
Although most benzoquinones do not appear to be highly
toxic to other orgauisms, a few, such as arbutin (14) found
in the nectar of Arbutus unedo (Ericaceae), are known to be
involved in biological interactions. Apparently harmless to
man, this compound is toxic to honeybees (Harborne, 1982).
In most plants, arbutin co-occurs with a l3-glucosidase that
converts the glucoside into hydroquinone. Hydroquinone
also is one of a complement of phenolic compounds leached
from the leaves of chaparral plants (in particular from Arc-
tostaphylos and Arbutus species, Ericaceae) in the western
United States. This compound inhibits the growth of compet-
ing species and is important in plant-plant interactions
known as "allelopathy," a phenomenon which will be dis-
cussed more fully (see Chapters 7, 8, and 19).
The wood of Dalbergia species (a tropicallegnme) con-
tains quinones with microbiocidal and algicidal activity, is
resistant to marine borers, and causes allergic reactions. The
intensely orange heartwood of Dalbergia retusa contains
two major pigments: obtnsaquinone (32) (3% of the weight
of the undried wood) and a black pigment, 4-methoxydalber-
 8en::.vquinones, Naphr/lOquinones. and Anrhraquinones 79

()I~
Q$d
o

~:O-<
yu
'" 0

C~';
yqy
(19) (4) (20)
o

cordiachrome A (21) (22) (23)

~
Ytb=
il-Mil
cordiachrome 6 (24) maturinone (26) decompositin (27)

M
R OH

~ ~ ~ ~

OH OH

(25)

Fig. 6.3. Some terpenoid quinones.

gione (33) (Fig. 6.6). Obtusaquinone is highly toxic to fish

(Leistner, 1985).
OH
Other quinones from Australian blackwood, Acacia mela-
OH noxylon (Fabaceae), are also capable of inducing allergenic
reactions. Among these are 2,6-dimethoxybenzoquinone
CH30 (see section above on plant-plant interactions) and 2-
OH methyl-6-methoxyfuranobenzoquinone (34) (Fig. 6.6). 2,6-
Dimethoxybenzoquinone (30) also is found in the wood of
(28)
Bowdichia nitida (Fabaceae) (Leistner, 1985) and in Ama-
ranthus palmeri (Amaranthaceae), where it is responsible
for allelopathic effects (Fischer and Quijano, 1985).
Simple phenols that can be converted readily to quinones
0 by enzymatic oxidation are used by arthropods as defensive
OH secretions. The biosynthetic origin of the phenolic substrates
is not known. Probably the most remarkable of these is the
CH3
defense of bombardier beetles, of the genus Brachynus. A
secretion as hot as IOO'C is produced by a reaction among
0
(29) hydroquinone, a phenolic substrate, H20 2 and the enzyme
Fig. 6.4.A gennination stimulant for Striga asiatica seeds from catalase. A highly exothermic reaction occurs as hydroqui-
Sorghum hie%r and a possible precursor. none is oxidized to benzoquinone, the major product of de-
fense. The beetle, when endangered, discharges a hot explo-
80 Benzoquinones, Naphthoquinones. and Anthraqu;nones

2) -- ¢
CO,H CO,H
I

000. -- OH
I

shikimic acid
:'
LaphenylalBRine
OH
E.4.hydroxycoumaric acid

/
\
HO
4 ~ OH
/"

4
OH

/ galJicacid
0

CH3 "'"'

OH
OCH,
- rnp~_ 0

syringlc acid (31) 2,6-dimethoxy-p-benzoquinone

(30)

Fig. 6.S. Proposed biosynthesis of 2,6-dimethoxy-p-benzophenone.

sive cloud of toxin in the direction of the attacker (Harborne,
1982).
The spider, Vonones sayi, produces a mixture of quinones
that presumably serve as defensive compounds. These com-
pounds are both crystalline at ambient temperatures but exist
as a liquid in the proportions found in the spider. This ap-
pears to be necessary to permit secretion of the compounds
(Mann, 1987).
l'IAPIITIIOQUIl'IOI'IES
Phylloquinones, such as vitamin K J (37) (Fig. 6.2) are found
in all green plant tissues; menaquinones and other naphtho-
quinones are found in bacteria, fungi, and a number of plant
families. Naphthoquinones occur free or as glycosides within
the plants. They are usually colored and may serve as a
source of pigmentation in some plants.
Biosynthesis of l'Iapbthoquinones
Notably, many types of naphthoquinones and anthraqui-
nones are synthesized and accumulated in plant tissue cul-
tures. This fortuitous situation has facilitated much recent
work on the biosynthesis of naphthoquinones and anthraqui-
nones (Ellis, 1988; Leistoer, 1981, 1986; Simpson, 1986).
Plant tissue cultures often do not accumulate other types
of secondary metabolites. Although naphthoquinones and
anthraquinones often have similar structures, the biosyn-
thetic paths leading to individual compounds are sometimes
different (Inouye and Leistner, 1988).
As is true for benzoquinones and anthraquinones, naph-
thoquinones are derived both by acetate-malonate and by
shikimic acid pathways.
Plumbagin (2-methyljuglone) (6) (and probably 7-meth-
yljuglone) in Plumbago (Plumbaginaceae) and Drosera
(Droseraceae) species is derived from acetate. However, at
least in the family Droseraceae, the acetate is derived from
L-tyrosine (Haslam, 1986).
The biosynthesis of compounds derived from shikimic
acid is closely linked to that of isomers of vitamin K (35)
(Fig. 6.7). In plants and in microorganisms, the aromatic
ring is formed via the shikirnate pathway, which does not
exist in animals. Only recently has it been established that
vitamin K synthesis branches from iso-chorismic acid (36)
and not from chorismic acid (37). iso-Chorismic acid (36) is
derived from shikimic acid (see Chapter 7) (Leistner, 1986).
Both of the cyclization steps leading to naphthoquinones and
vitamin K are unusual in plants.
The key intermediate in the formation of these com-
pounds is o-succinylbenzoic acid (OSB) (38) which is
formed from iso-chorismic acid and a-ketoglutararic acid
(39), a tricarboxylic acid cycle intermediate (Fig. 6.7) (Si-
mantiras and Leistoer, 1989). a-Ketoglutaric acid can be
converted to glutamic acid, which previously was proposed
 Benzoquinones, Naphthoquinones, and Anthraquinones 81

as a precursor to OSB by transamination. In a cell-free sys-
tem prepared from Escherichia coli, iso-chorismic acid and
a-ketoglutarate were converted to o-succinylbenzoic acid in
an almost 90% yield (Leistner, 1986). A subunit of the en-
zyme system, OSB synthase, is responsible for decarboxyl-
ation of a-ketoglutaric acid, and a thiamine pyrophosphate
(TPP) adduct of succinic semialdehyde, the direct product
of decarboxylation, has been isolated (Leistner, 1986).
Formation of the coenzyme A ester of the aliphatic car-
boxyl group of o-succinylbenzoic acid (38) appears to acti-
vate the methylene proton sufficiently to permit attack at the
aromatic carboxyl group (Fig. 6.7). 2-Carboxy-4-oxotetra-
lone (COT) (43) andlor 1,4-dihydroxy-2-naphthoic acid
(DHNA) (40) are likely intermediates for later stages of syn-
thesis. The enzymatic conversion to DHNA with naphthoate
synthase (which consists ofOSB CoA synthetase and DHNA
synthetase) requires ATP, Mg2+, and coenzyme A. 1,4-Dihy-
droxy-2-naphthoic acid (40) is a precursor of vitamin K2
(35) and menaquinones (such as 44) (Inouye and Leistner,
1988; Kolkmann and Leistner, 1987; Leistner, 1986). The
final steps of formation of vitamin K2 (35) involve the addi-
tion of a mevalonate-derived unit (Fig. 6.7) (see Chapter
18), and methylation.
Juglone (7) (from Juglans regia) and lawsone (41) (from
Impatiens balsamina) both come from shikimic acid (Fig.
6.8) (packter, 1980). The initial steps of biosynthesis are
identical to those of vitamin K2 (Inouye and Leistner, 1988;
Kolkmann and Leistner, 1987). Either 1,4-dihydroxy-2-
naphthoic acid (40) or 2-carboxy-4-oxotetralone (COT) (43)
is incorporated efficiently into both juglone and lawsone
(Leistner, 1981). Biosynthesis of juglone proceeds through
a symmetrical intermediate; 1,4-naphthoquinone (42) is an
efficient precursor (Leistner, 1981). In contrast, the biosyn-
thesis oflawsone (41) does not appear to involve a symmetri-
cal intermediate (Haslam, 1974; Inouye and Leistner, 1988).
Phylloquinone (37), vitamin K J (Fig. 6.2), closely related
to vitamin K2 (35) (Fig. 6.7) in biosynthesis, has a "menadi-
one" nucleus and a phytyl side chain (Fig. 6.9) and occurs

Dalbergia retusa
4-methoxydalbergione (33)
OCR,

o
CR3 o A , 0 , - - CR,-O
oR I I%
: O 0
~. RO
o I I
o OCR,
acmelin (34)
o
Acacia melanoxylon
Dalbergia Ian/oUa bowdichione
OR 0 latinone

0 OCR,
diospyrin diosindigo A (53)

CR,O OR 0 OR 0 OR 0
OR

Ro~R ~ '" OR
0 0
OR OCR,
alternin 2-methoxystypandron
diosindigo B

Fig. 6.6. Quinones from Dalbergia and Acacia species (modified from Leistner, 1985; used with pennission of the copyright owner, Academic Press,
Orlando. FL),
82 Benzoquinones, Naphthoquinones, and Anthraquinones
--
chorismie acid (37)
OC1
;:?'
""- I
oa °
SCoA
-
!°
benzoic acid (38)
~~~~
~COd_~
° OH
1,4-dihydroxy-2-naphthoie acid
Fig. 6.7. Biosynthesis of the naphthoquinone skeleton from o-succinylbenzoate (modified from Inouye and Leistner, 1988; used with pennission of the
copyright owner, John Wiley & Sons, Ltd., Chichester).
in the chloroplasts of all green plants. Under certain environ-
mental, hormonal, and cultural conditions, photosyntheti-
cally active cell cultures of Morinda lucida cease synthesis
of phylloquinone and accumulate anthraquinone pigments
(see Section 6.4.1).
When [1-carboxy-14C]o-succinyl benzoate is adminis-
tered to plants of Catalpa ovata (Bignoniaceae), it is incor-
porated into a-Iapachones (such as 45), catalponol (46), and
catalpalactone (47). Examination of the 3H/14C ratio in catal-
ponol (46) after administration of [1-carboxy- 14C,2'-3H2 ]o-
succinylbenzoate reveals that the two protons at the 2'-posi-
tion are both retained in the 3-position of catalponol (Fig.
6.9). Thus, prenylation occurs at the 2-position and does
not involve an aromatic compound such as 1,4-dihydroxy-
2-naphthoic acid (DHNA) (40) (Inouye and Leistner, 1988).
2-Carboxy-4-oxotetralone (COT) (43) or 2-carboxy-4-hy-
droxy-l-tetralone (48) are possible acceptors for the prenyl
unit. When 2-carboxy-4-hydroxy-l-tetraione (48), or its
methyl ester, was introduced into the plant, the prenyl deriva-
tives of 2-carboxy-4-oxotetralone (COT) (43) and 2-car-
boxy-4-hydroxy-l-tetralone (50) were isolated as intermedi-
ates (Inouye and Leistner, 1988).
Chimaphilin (51), a naphthoquinone found in members
of the Ericaceae, is derived from shikimic acid, but by a
quite different route. In this case, the precursors appear to be
0/"0
coo
w-
iso-ehorismie acid (36)
a-ketoglutarate (39)
TPP = thiamine pyrophosphate
°
°
ortho-succlnyl-
2-carboxy-4-oxotetralone
(COT) (43)
~COOH
-
vitamin K2 (menaquinone)
(40) (35)
homogentisic acid (52) and mevalonate (Fig. 6.10) (Haslam,
1974).
Naphthoquinones such as alkannin (52) seem to be de-
rived from p-hydroxybenzoic acid by the addition of geranyl
pyrophosphate (Fig. 6.3). These naphthoquinones are espe-
cially common in the family Boraginaceae (Leistner, 1981).
Dimers of naphthoquinones [such as diosindigo A (53),
(Fig. 6.6)] are formed by free-radical coupling of monomeric
units. These compounds are widespread in plants and usually
co-occur with the corresponding monomeric compounds
(Scott, 1967).
Disbibution of l'Iaphthoquinones Among
Higher Plants
The distribution of naphthoquinones and anthraquinones
among higher plants is closely linked. In some instances,
however, naphthoquinones are accumulated in families that
normally do not accumulate anthraquinones. Among these
are the Balsaminaceae, Boraginaceae (Mathis, 1966), Dros-
eraceae, Ebenaceae, Ericaceae, Iridaceae, Juglandaceae,
Plumbaginaceae, and Proteaceae (Zenk and Leistner, 1968).
Juglone and related compounds occur in the family Juglan-
daceae (Carva and Juglans) and the Proteaceae (Conosper-
mum, Lomatia, and Stenocarpus) (Leistner, 1985).
 Benzoquinones, Naphthoquinones. and Anthraquinones 83

Biological Functions of l'Iaphthoquinones
A number of naphthoquinones are known to have pro-
nounced physiological effects. One well-known example in-
volves the compounds juglone (7) and the [3-g1ucoside of the
corresponding hydroquinone (54) found in walnut, Juglans
regia (Juglandaceae) and in related species such as Jug/ans
nigra (Leistner, 1985). Juglone is a water-soluble yellow
pigment which causes the characteristic brown staining of
the hands caused by handling walnuts. It has long been rec-
ognized that many garden plants such as tomatoes and lettuce
do not grow well when planted near walnut trees. Juglone
is toxic and an effective inhibitor of seed germination for
many plants. At a concentration of 0.002%, it completely
prevents germination of lettuce seed.
When tomato and alfalfa plants were planted different dis-
tances from walnut trees, plants close to the tree did not sur-
vive. The position at which the tomato plants were unaffected
by the "allelopathy" coincided with the extent of the root
growth of the tree and it was assumed that the plants were
killed by the exudation of toxin from the roots. Later work
suggested that the effect might actually be caused by leaching
of a bound form ofjuglone from the leaves and stems followed
by hydrolysis and oxidation in the soil to release the actual
toxin, juglone. The bound form has been identified as the 4-
glucoside of 1,4,5-trihydroxynaphthalene (54) (Harborne,
1982). (Fig. 6.11). In practice, both root exudation and leaf
leachates may be involved in the resulting allelopathic effects
(Harborne, 1982). Juglone strongly inhibits growth and nitro-
gen fixation by Frankia species in European black alder trees
(Alnus g/utinosa) (Neave and Dawson, 1989).
In order to determine if juglone is effective in "chemical
warfare" (or allelopathy) among plants, a number of other
effects, such as shading and mineral and water depletion
should be considered. Further, if juglone is to be effective,
it must persist in the soil. Bacteria that degrade juglone have
been isolated from soil and from beneath walnut trees (In-
ouye and Leistner, 1988). Some Pseudomonas species are
able to use juglone as their sale carbon source (Inouye and
Leistner, 1988; Schmidt, 1988). In the field, a number of
presumably coadapted plants grow well near walnut trees
and appear able to tolerate the effects of juglone.
Juglone also has been shown to be inhibitory to many
insects. Differences in sensitivity exist, and, often, related
insect species are not all equally sensitive to a particular
allomone. For example, juglone is a feeding deterrent to the
smaller European elm bark beetle (Scolytus multistriatus)

«r :?' . . o)oH
o o
ricOOrCOOH
0y- o
:,..,
I
o
Impatiens
C02H
balsamina
o

/
(38) (43) lawsone (41)

W - oQ.
OH OH
r
:,..,
I I luglans regia
C02H
:,..,
l';
h
~
vy
OH OH o
(40) ~ (42) ~

~ ~ ~
~- yy
~ ~ OH 0
"" H ?I O-glucose ? / jugJone (7)

"" I I n 't /

yQ:?' y:):?'
OH OH

o (44)
menaquinone ~ ~! --. : :. . . ~ I
(vitamin K 2)
OH OR OH O-glucose

Fig. 6.8. Biosynthesis of juglone and lawsone (modified from Inouye and Leistner, 1988; used with permission of the copyright owner, John Wiley &
Sons, Ltd., Chichester).
84 Benzoquinones. Naphlhoquinones, and Anlhraquinones

(YCOO(COOH ~COOH ~IC~.:~ ~ 0

0y-Vy o 0
-~-Vy
0 0

:
(38) (43) (49)

wro~
" ~
I • I

c¢Y
''''\': OR ? '0 0

I I (48) ~ r (2R,4S).::'ponol (46) ::,... 0

~

¢¢X
....... // catalpalactone (47)

~
?I
R,
00

0
IVY·
R, ~

OH
(2R,4S). (50)
#
Wok-
0

a·lapochones (45)
R,

Fig. 6.9. Biosynthesis of modified naphthoquinones in Catalpa ovata (modified from Inouye and Leistner, 1988; used with permission of the copyright
owner, John Wiley & Sons, Ltd., Chichester),

but not to the closely related hickory bark beetle (Scolytus
quadrispinosus) (Seigler, 1983). It is probable that the host
(Carya spp., Juglandaceae) of the hickory bark beetle con·
tains juglone or related compounds and that the insect is
probably coadapted to the presence of this naphthoquinone.
The larvae of the chrysomeJid beetle GastroUna depressa
accumulate juglone, presumably from the leaves of the host
plant Juglans, on which they feed (Pasteels et aI., 1988).
A number of fungal naphthoquinones, including juglone,
have been shown to act as phytotoxins (Stoessl, 1981). Jug·
lone is highly toxic to the fungus Fusicladium effusum, a
pathogen of pecans (Carya illinoensis, Juglandaceae) in the
southeastern United States (Leistner, 1985).
Plumbagin (6) is as inhibitory to seed germination as jug·
lone (7); the effect of a number of naphthoquinones on seed
germination of Abutilon theophrastii have been evaluated

6 CO~::, HX
OH

yIy,
I
¢ r o H COOH
y opp _ _

::?
I
--- """ -. ~ COOH CH,OH

"'" OH OH ""- /

(52) ~\

W-W-'C¢r
o 0 OH

o 0 OH
chimaphilin (51)

Fig. 6.10. Biosynthesis of chimiphilin (Haslam, 1974),


«>
OR
~ Anthraquinones are among the most common quinones
W
1) hydrolysis
2) oxidation
OR O.glucose
4·glucoside of
l,4.5-trihydro"ynapbtbalene
(54)
Fig. 6.11. Hydrolysis of the 4-glucoside of 1.4,5-trihydroxynaphthalene
to produce juglone (modified from Harbome, 1982).
(Powell and Spencer, 1988). To date, only juglone has been
demonstrated to produce allelopathic effects in the field.
Prenylated naphthoquinones occur in the roots of several
genera of the Boraginaceae (Leistner, 1985). The shikonins
(55), an important group of prenylated naphthoquinones
used in Japan for their anti-inflammatory properties, antibac-
terial activity, and. as dyestnffs, have become one of the
most important groups of secondary compounds produced
in tissue cultnre (Ellis, 1988; Flores et al., 1987). These com-
pounds come from the roots of Lithospermum erythrorhizon
(Boraginaceae). Although the roots accumulate up to 2%
naphthoquinones, several years are required for the plant to
reach commercial size. In a 23-day fementation period, cells
in a 750-L tank accumulated 23% of their dry weight as
shikonins (Flores et al., 1987).
A number of bisnaphthoquinones from the genera Euclea
and Diospyros (Ebenaceae) (Fig. 6.6) have antifungal, anti-
bacterial, and temite-resistant properties. Scrapings of wood
are used in African folk medicine for the treatment of lep-
rosy, and the ichthyotoxic properties of the bark of some
species are used for captnre of fish. One of these compounds,
diosindigo A (53), is blue and responsible for the blue color
of the heartwood of some Diospyros species (Fig. 6.6) (Leis-
tner, 1985).
Several woods that contain naphthoquinones, anthraqui-
nones, and related compounds are highly resistant to attack
by marine borers (Southwell and Bultman, 1971). The wood
of Tabebuia guayacan (Bignoniacae) was shown to contain
lapachol (56) and several related compounds (Manners et
al., 1975) and it is thought that these compounds are respon-
sible for the observed resistance (Fig. 6.12).
«roo ~ @
: I
0
0
lawsone (41)
I
Fig. 6.12.
Benzoquinones, Naphthoquinones, and Anthraquinones 85
o AI'lTHRAQUIl'IONES
found in natnre. Over 200 of these compounds are known
from flowering plants, and many others are produced by
OR 0 lichens and fungi (see also Chapter 5). Many anthraquinones
occur as glycosides within the plant, but are converted into
JUglone(')
the aglycones by (3-glucosidases or oxidative processes. An-
thraquinones are especially common in the families Faba-
ceae (Cassia), Liliaceae (Aloe), Polygonaceae (Rheum,
Rumex), Rhamnaceae (Rhamnus), Rubiaceae (Asperula,
Coelospermum, Coprosma, Galium, Morinda, and Rubia),
andScrophulariaceae (Digitalis). Members of the Rubiaceae
(e.g., madder, Rubia tinctorial are characterized by brightly
colored anthraquinone pigments that have been used in the
past for dyeing. These compounds are partly responsible for
the colors of several tropical woods. In basic solution, most
anthraquinones produce a deep red or blue color.
Anthraquinones derived from shikimic acid are usually
accompanied by substitnted naphthoquinones. A knowledge
of the structures of these compounds has been useful in es-
tablishing several portions of the biosynthetic pathways for
anthraquinones.
Biosynthesis of Antbraquinones
As is true for the naphthoquinones, anthraquinones are
synthesized by a variety of routes in plants and fungi (Pack-
ter, 1980). Most are derived from either acetate-malonate
or isochorismate-cx-ketoglutaric acid-mevalonate path-
ways. Anthraquinones also are produced frequently in plant
tissue cultnres (Ellis, 1988). Tissue cultures of Cinchona
species (Rubiaceae) produce at least 30 different anthraqui-
nones.
Emodin (11) and helminthosporin (9) (Fig. 6.1) (see also
Chapter 5) are derived from acetate-malonate precursors.
An enzyme that provides strict substrate contrul, emodin 1-
O-methyltransferase, was purified 89-fold (Hutchinson,
1986). Chrysophanol (57), found in Rumex (polygonaceae)
and Rhamnus (Rhamnaceae) species, appears to result from
folding of the polyketide chain in one arrangement (58),
whereas aloesaponarin (59) seems to involve a second form
(60) (Fig. 6.13). Both chrysophanol and aloesaponarin occur
in the roots of Aloe saponaria (Liliaceae) (Leistner, 1981).
Under special conditions, callus cultures of Rhamnus species
0
0
::,..,
OR 0
,&
lapachol (56) shikonin (55)
Shikonin from Lithospermum erythrorhizon.
86 Ben:oqu;nones. Naphrlwqu;IIolles. ({lid Amlwaquillones

O~
o ~
~
0 0 _

CO,H
000 OH 0 OH

""
(58)
chrysophanol (57)

°fuC o
o

0
0

o COOH
_
c;.¢yc;
""" I
OH
°

0
I ~
OH

0
OCH,

(60)
aloesaponarin (59)

Fig. 6.13. Different folding mechanisms involved in the synthesis of chrysophanol and aloesaponarin (Leistner, 1981; modified and used with
pennission of the copyright owner, Academic Press, New York).

produce labile anthrone and dianthrone derivatives. Bark of
these same plants contains similar, but distinct, compounds
(Ellis, 1988).
Certain other anthraquinones of this pathway begin with
more complex starter units. The CoA derivative of hexanoic
acid (n-C,HllCO-SCoA) is utilized to produce the some-
what unusual anthraquinone solorinic acid (61) (Fig. 6.14).
Anthraquinones derived from acetate-malonate path-
ways are particularly common in fungi and lichens, but are
often found in higher plants as well. Acetate-malonate-de-
rived anthraquinones usually can be distinguished by their
structures because they possess substituents in both benze-
noid rings of the anthraquinone nucleus (also see Chapter
5), although there are some exceptions to this generalization.
Anthraquinones in which only one ring is substituted are
particularly common in the Biguoniaceae, Rubiaceae, and
Verbenaceae, but do not appear to occur in fungi, the Poly-
gonaceae, Rhamnaceae, Fabaceae, CaesaIpinioideae, or the
Liliaceae (Aloe). These compounds are derived from a path-
way similar to that previously discussed for naphthoqui-
nones, but with subsequent addition of mevalonate-derived
units (Fig. 6.8).
As indicated under the biosynthesis of naphthoquinones
above, prenylation can occur at either the 2- or 3-position in
intermediate compounds such as 2-carboxy-4-oxotetralone
(COT) (43) and/or 1,4-dihydroxy-2-naphthoic acid (DHNA)
(40) (Fig. 6.8) or 2-carboxy-4-hydroxy-l-tetralone (48) (Fig.
6.9). Attack at both positions is observed in the biosynthesis
of anthraquinones. Clues as to the site of prenylation in bio-
synthesis of anthraquinones can be found not only by label-
ing studies or by examination of prenylated but uncyclized
naphthoquinones that co-occur with anthraquinones in sev-
eral plants and in plant tissue cultures.
Phylloquinone (37), plastoquinone, a-tocopherol, and
ubiquinone (13) (Fig. 6.2) are produced by a cell suspension
culture from Morinda lucida (Rubiaceae). Changes in envi-
ronmental, hormonal, and other cultural conditions result
in accumulation of anthraquinones in cultures of Galium,
Morinda, and Rubia (all Rubiaceae). The addition of o-succi-
nylbenzoic acid (38) causes an increase in the amount of
anthraquinones produced. 2-Carboxy-4-oxotetralone (43) or
1,4-dihydroxy-2-naphthoic acid (40) appear to be intermedi-
ates in the synthesis of both anthraquinones and phylloqui-
nones.
In robiaceous plants, anthraquinones are related closely to
prenylnaphthoquinones with which they co-occur. Specific
incorporation of 14C from [7-14C]shikimic acid into the 9-
position of anthraquinone provides evidence that prenylation

OHO OHO

-
o 000 0
~n'C5HIl
o~
n'C5HIl __
"
"C5H11 CSCoA
+ malonyl.eoA
o 0
CO,H HO~OH
o
solorinic acid (61)

Fig. 6.14. Biogenesis of solorinic acid (Geissman and Crout. 1969).


07
OH
'CO'H CO,H
I --
""
1 /
o OH
(38) (40)
OH
oq
(65) OH
1
OH 0 OH
CO'CH'c¢Cc
"'" I "'" "'" "'"
~ .&- I ~ I I.&-
o 0
lucidin primeveroside
mollugin (64)
Fig. 6.15. Proposed biosynthesis of antbraquinones in species of Rubiaceae (modified from Inouye and Leistner, 1988; used with pennission of the
copyright owner, John Wiley & Sons, Ltd., Chichester).
occurs at the position corresponding to C(3') of o-succinyl-
benzoate (38) in the biosynthesis ofthe anthraquinones aliza-
rin (62) and morindone (63) in Rubia tinctoria and Morinda
citrifolia. This and the co-occurrence of mollugin (64) and
2-methoxycarbonyl-3-prenyl-I,4-naphthoquinone (65) in
Galium mollugo support the idea that prenylation in these
plants occurs at the 3-position of 1,4-dihydroxy-2-naphthoic
acid (DHNA) (40) (Fig. 6.15) (Inouye and Leistner, 1988).
Intact plants and cell cultures of Streptocarpus dunnii
(Gesneriaceae) contain several 1,2-naphthoquinones with a
reversed prenyl side chain, such as that in dunnione (66)
(Fig. 6.16). I-Hydroxy-2-methylanthraquinone (67) and 1-
hydroxy-2-(hydroxymethyl)anthraquinone (68) were also
isolated from this culture. Administration of [I-carboxy-
l3C]o-succinylbenzoate revealed that l3C was incorporated
into the I-position of dunnione and the lO-position of anthra-
quinones. These results, together with those of feeding ex-
periments in which lawsone (41) and its 2-prenyl ether (69)
were applied, suggested that dunnione (66) was formed by
a Claisen-type rearrangement at the 2-position of 2-carboxy-
4-oxotetralone (COT) (43), whereas anthraquinones were
formed by prenylation at the 2-position of 2-carboxy-4-oxo-
tetralone (COT) (43) or 1,4-dihydroxy-2-naphthoic acid (40)
(Inouye and Leistner, 1988).
The anthraquinones of madder, Rubia tinctoria (Rubia-
ceae), are well known. Most of the anthraquinones occur as
glycosides within the plant. One of these, ruberythric acid
(67), a diglucoside, can be converted to alizarin (62) by hy-
drolysis. Many biosynthetic studies have been carried out
Benzoquinones, Naphthoquinones, and Anthraquinones 87
o OH
CO,H OH
. "'
o alizarin (62)
«tr
o OH
- -HO I I .&-
~
OH 0
morindone (63)
o OH
OH
OH
O-primereverosyl OH
o
lucidin
with madder (Haslam, 1974). 1,4-Dihydroxy-2-naphthoate
(DHNA) (40) and 2-carboxy-4-tetralone (COT) (43), formed
from o-succinylbenzoic acid (OSH) (38), undergo prenyla-
tion, decarboxylation, and hydroxylation. Labeled meva-
lonic acid labels the C ring of Rubia tinctoria anthraquinones
(Fig. 6.17) (Leistner, 1981).
Administration of [5_ l4C]_ and [2-14C]-MVA (mevalonic
acid) to the two plants resulted in incorporation of C-5 of
MVA into C-4 of alizarin (62) and C-2 of MVA into C-lI
of pseudopurpurin (70) (Inoue et aI., 1984).
In order to establish unambiguously the biosynthetic ori-
gin of a particular anthraquinone, feeding experiments with
labeled precursors must be done, although other evidence is
helpful in the determination of the biogenetic origin. For
example, a number of species of the Rubiaceae and Verbena-
ceae that synthesize anthraquinones also contain a series of
nonquinonoid compounds that are structurally related to in-
termediates in the biosynthesis of the anthraquinones (Fig.
6.18) (Geissman and Crout, 1969).
Distribution of Antbraquinones
Anthraquinones derived from acetate-malonate (polyke-
tide) pathways are widespread in fungi and lichens, but less
common in higher plants. Emodin (11) is among the com-
pounds frequently found in all of these groups.
Polyketide-derived anthraquinones have a wide and scat-
tered occurrence in the following families: Monocotyle-
dons-Iridaceae, Liliaceae (Asphodelaceae) (Aloe), Zingib-
88 B('II;/J'Iuill(Jf1I'.\". Nat'hrIIlJCffliIlOIlf'S. dlld Anrhra'l"illOIl('.\·

. o 0

r-yCO',(CO,H

~~
~oo~
l
1 0

W
(40) (68) 0 HO '" 0 HO
(38)

~ .
o
eo'H o ~$~:
I I
I -- .Q

l
~ ~

(43) 0 o

C\f
(40) ? 0 (57)

!~ I
OHeo,H ~~
I
~- - w·~·:
I
~

«r\-of)-
~ ::::,.. ::::,.. .Q

!
o 0 OH

0 0 0

c¢'~ o
dunnione (66)
Iawsone (41) (69)

Fig. 6.16. Proposed biosynthesis of anthraquinones and prenylated naphthoquinones in species of the Gesneriaceae (modified from Inouye and Leistner,
1988; used with permission of the copyright owner, Jolm Wiley & Sons, Ltd., Chichester).

eraceae; Dicotyledons-Anacardiaceae, Asteraceae, Biological Functions of Antbraquinones

CaryophylJaceae, Chenopodiaceae, Clusiaceae, Combreta-
ceae, Ericaceae, Euphorbiaceae, Fabaceae, Lythraceae, Po-
lygonaceae, Rhamnaceae, Rhizophoraceae, Saxifragaceae,
Scrophulariaceae (?), Simaroubaceae, Sonneratiaceae, Sola-
naceae, Urticaceae, and Xanthorrheaceae. In the Fabaceae,
anthraquinones are almost exclusively found in the genus
Cassia (Senna) (Dahlgren et al., 1981; Zenk and Leistner,
1968).
The fresh bark of Rhamnus frangula and most Cassia
species contains anthrones and not anthraquinones (Leistner,
1985). After storage and extraction, anthraquinones and di-
anthrones are isolated but are probably artifacts. Except for
.a dubious record of acetate-derived anthraquinones in the
Scrophulariaceae, these compounds are not yet recorded
from orders of plants that produce iridoid monoterpenes (see
Chapter 20).
Anthraquinones derived from shikimic and isochorismic
acid are known to occur only in certain dicotyledonous fami-
lies: Bignoniaceae, Gesneriaceae, Rubiaceae, Scrophularia-
ceae, and Verbenaceae (Gentianales, Larniales, and Scro-
phulariales). These families also characteristically
accumulate iridoid monoterpenes (Dahlgren et al., 1981).
Anthraquinones are involved frequently in plant-insect
interactions. For example, two anthraquinones (72) and (73)
(Fig. 6.19) and the related anthrones have been found in
the larvae of the elm leaf chrysomelid, Pyrrhallta luteola.
Because these compounds do not occur in elm leaves, it is
probable that they are synthesized by the insect or its sym-
biotic microorganisms (Harborne, 1986).
The chrysomelid beetle, Galeruca tanaceti, feeds on Ta-
necetum vulgaris or Achillea millefolium (Asteraceae), nei-
ther of which produce anthraquinones. However, the beetles
or their microbial associates produce two anthraquinones,
chrysophanol (57) and chrysazin (74). The eggs of this insect
contain these two compounds and are protected against the
ant, Myrmeca ruginodus. Both compounds are potent micro-
bial growth inhibitors (Cudlin et al., 1976; Hilker and
Schulz, 1991).
Several types of woods that contain anthraquinones and
related compounds are highly resistant to attack by marine
borers (Southwell and Bultman, 1971). 2-Methyl- (57), 2-
hydroxymethyl- (75) and 2-formylanthraquinones in the
heartwood of teak (Tectono grandis, Verbenaceae) are effec-
 X
Benzoquinones, Naphthoquinones, and Anthraquinones 89

HO
cq~" '(~ +--
COOH CH,OH
•

0,,/
$0
(38)

$0
""'" $.0
0: OH
I I I -- I IC I I
.
-+--
~ ~.d' ~ .d'

o 0(57) 0

! alizarin (62)

#-'
o O.p.primeverosyl

purpurin (71) pseudopurpurin (70) ruberythric acid (67)

Fig. 6.17. Localization of label from shikimic acid in anthraquinones and naphthoquinones of Rubia tinctoria (modified from Haslam, 1974).

tive in inhibiting tennite activity (Rudman and Gay, 1961;
Seigler, 1983).
Economic Importance and Uses
Dyestuffs from Rubia tinctoria (madder, Rubiaceae),
sometimes known as turkey red, have been used extensively
in the past. Although the importance of vegetable dyestuffs
has diminished greatly, madder is still used in certain Near
Eastern countries. Alizarin (62), derived by enzymatic hy-
drolysis ofruberythric acid (67) (Fig. 6.17), is the most im-
portant compound. An aluminum lake prepared from alizarin
is utilized to effect binding of the dye to the fabric. Both
the lake and various mordants are used to adjust the colors
obtained.
A red carbon-carbon-bonded anthraquinone glycoside,
carminic acid (76), from the scale insect Coccus cacti (Ho-
moptera, cochineal), has also been used as a dyestuff. This
compound was first isolated and utilized by the Indians of

«»-
o OH
~
o
~OCH,

Fig. 6.18. Compounds that accompany anthraquinones in the Rubiaceae and Verbenaceae (Geissman and Crout. 1969).
90 Benzoqltinones, Naphthoquinones, and Anthraquinones

OH 0 OH OH 0 OH

6¢6 o ~ o
(72) (73)

t¢5 o
chrysophanol
OH chrysazin (74)

~
"
c¢u HO~
I
o

I
~
OH HO o~HOH
0 COH
r
~ I I
",'
h
HO OH
o OH 0
2-hydroxymethylanthraquinone (75) carminic acid (76)

Fig. 6.19. Biologically active anthraquinones.

0 OH OH 0 OH

OH 0 OH

~$
CO,H CH,OH

CH,OH HO

H H

O-glc 0 OH OH 0 OH
emodin anthrone (12)
sennoside B palmidinA

OH 0 OH
OH 0 OH

HO

HO

hypericin (77) fagopyrin (78)

Fig. 6.20. Anthones and anthrone dimers.

 Benzoquinones. Naphthoquinones. and Anthraquinones 91

08 0 08 08 0 08
08 0 08

~
.0$-00
80 "'" 8 h
80 80
-+
80
<7 '<:::

i.
::,.. I I h

08 0 08 08 0 08 OH 0 OH
bv
(79) byperico-dehydroanthrone

08 0 OH 08 0 08 08 0 OH

bv 80
80
-80
HO

08 0 08
08 0 08 08 0 OH

penilliopsin protohypericin (80) hypericin (17)

Fig. 6.:Z1. Proposed biosynthesis of hypericin (Scott. 1967; modified and used with pennission of the copyright owner, Marcel Dekker, Inc., New
York).

Mexico (Fig. 6.19). When prepared as an aluminum-cal-
cium lake, the compound is known as "carmine."
Anthraquinone glycosides have long been used medici-
nally as cathartics and laxatives. Plant-derived drugs of this
type include aloes (Aloe species), cascara sagrada (Rhamnus
purshianus), frangula (Rhamnusfrangula), rhubarb (Rheum
officinale), rumex or yellow dock (Rumex crisp us) and
senna (Cassia spp.). Many of the commercial preparations
(patent medicines) based on these plants are readily avail-
able.
Antbrones and Antbrone Dimers
Anthrones e.g., emodin anthrone (12) are probable inter-
mediates in the biosynthesis of anthraquinones such as em-
odin from polyketide pathways (Fig. 6.22) and occur widely
in nature. The position para to the carbonyl oxygen of the
center (B) ring is sensitive to oxidation and, in many in-
stances, oxidation products may be the major or only com-
pounds isolated from plants which contain anthraquinones
after storage (Leistner, 1985).
In addition to conversion to anthraquinones, compounds
such as emodin anthrone can be coupled by free-radical pro-
cesses to produce a series of complex dimers such as hyperi-
cin (77) and fagopyrin (78) (Fig. 6.20) (Brockman and Lack-
ner, 1979; Scott, 1967).
Hypericin and Anthrone Dimers
Hypericin (77), a complex anthrone dimer, is found in
approximately half of the nearly 200 species of the genus
HypericUm (Clusiaceae) (the names Hypericaceae and Gut-
tiferae which have formerly been used for this family are
incorrect). Hypericin and related compounds serve as pig-
ments in certain fungi, for example, Polys/ictus versicolor
and Dermocype austrovena/a (Gill and Gimenez, 1991). In
Hypericum species, the compolJ!ld is found in small, opaque
glands on the leaves, sepals, and petals. This substance co-
occurs with a related compound, pseudohypericin. Both
compounds are a brilliant red color. In alkaline solution,
hypericin appears to be dark green and can be distinguished
from anthraquinones, which are red (Knox et al., 1987).
Structurally related compounds occur in other plants such
as Cassia (Fabaceae) (Scott, 1967).
Emodin (11) also has been found in most of the plants
and fungi that produce hypericin. The first intermediate (79)
in the biogenesis of hypericin probably is joined by a single
bond between the two anthrone molecules. This compound
is then converted to the corresponding dehydru compound
and by light into protohypericin (80) (Fig. 6.21). Protohyper-
icin is converted by light to hypericin.
Hypericin and pseudohypericin have been shown to in-
hibit the retroviral infection and replication cycle of mV-I
at two or more points (Kinghorn, 1992).
st. John's wort (or Klamath weed as it is called in the
western United States), Hypericum perjoratum, was intro-
duced quite early into the United States from Europe and
became a major weed problem. By the early 1950s, this plant
caused considerable mortality among livestock in the west
92 Benzoqu;nones, Napluhoqu;nones, and Anthraqu;nones
and was a major weed on about two million acres of range
land. When animals, chiefly cattie, graze on Klamath weed
and are subsequently exposed to sunlight, they become sus-
ceptible to sunburn and other tissue damage. This photody-
namic activity is caused by the presence of hypericin which
is absorbed by the animals and enters peripheral circulation.
Serious necrosis of the skin and infection often occurs (Dow-
num, 1992; Knox et aI., 1987).
In Europe, where the plant is native, several species of
the genus Chrysolina feed on species of the genus Hyperi-
cum. One of these beetles, Chrysolina brunsvicensis, appar-
ently requires the presence of hypericin as a feeding stimu-
lant and will eat only species of Hypericum that contain
the compound. Plants of H. androsaemum (which lack the
compound) are untouched even though plants of H. perfora-
tum growing near them are eaten. A similar species of beetle,
Chrysolina quadrigemina, from Europe was introduced into
the United States in an effort to control Klamath weed. By
the late 1950s, this noxious weed had been reduced to about
I % of its former level. Interestingly, the plant was untouched
when it grew in shady areas; apparently, the insect was not
able to locate the plant host under those conditions. Although
it has been reported that some Chrysolina species accumu-
late hypericin in their bodies, this has not been confirmed
(Pasteels et al., 1988).
Hypericin is phototoxic to generalist feeding lepidopteran
larvae such as Helicoverpa zea and Planynotaflavedana on
artificial diets in the presence of light. In nature, Planynota
flavedana survives by tying together leaves and feeding in-
side the ties where the larvae are protected from light (Sand-
berg and Berenbaum, 1989).
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CHANG, M. and D. G. LYNN, The haustorium and the chemistry of
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CHANG, M. and D. G. LYNN, Phmt-plant recognition: Chemistry-
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CHANG, M., D. H. NETZLY, L. G. BUTLER, and D. G. LYNN, Chemi-
cal regulation of distance: Characterization of the rrrst natural
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Soc., J08, 7858-7860 (1986).
CUDLIN, J., M. BLUMAUEROVA, N. STEINBROVA, J. MATEJU, and
V. ZALABAK, Biological activity ofhydroxyanthraquinones and
their glucosides toward microorganisms, Folia Microbiol., 21.
54-57 (1976).
DAHLGREN, R. M. T., S. ROSENDAL-JENSBN, and B. J. NIELSEN, A
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chemistry and Angiosperm Phylogeny (D. A. Young and D. S.
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DOWNUM, K. R., Light-activated phmt defence, New Phytol., 122,
401-420 (1992).
ELLIS, B. E., Natural products from plant tissue culture, Nat. Prod.
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FiSCHER, N. H. and L. QUUANO, AI1elopathic agents from common
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FLORES, H. E., M. W. Hoy, and J. J. PICKARD, Secondary metabo-
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GEISSMAN, T. A. and D. H. G. CROUT, Organic Chemistry of Sec-
ondary Plant Metabolism, Freeman Cooper, San Francisco,
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Gn.r., M. and A. GIMENEz, Austrovenetin, the principal pigment
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HAREORNE, J. B., Recent advances in chemical ecology, Nat. Prod.
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HASLAM, E., The Shikimate Pathway, Wiley, New York, 1974.
HASLAM, E., Secondary metabolism-Fact or fiction, Nat. Prod.
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lIn.KER, M. and S. SCHUlZ, Anthraquinones in different develop-
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HUTCHINSON, C. R., Biological methods for studying the biosyn-
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INOUYE, H. and E. LEISTNER, Biochemistry of quinones, in The
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KALIDHAR, S. B.o Location of glycosylation and alkylation sites in
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KINGHORN, A. D., Plants as sources of medicinally and pharmaceut-
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KOLKMANN, R and E. LEISTNER, 4-(2'-Carboxyphenyl)4-oxobu-
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KUBITZKI, K. and O. R. GOTILIEB, Phytochemical aspects of angio-
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LEISTNER. E., Occurrence and biosynthesis of quinones in woody
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7
Shikimic Acid Pathway
Introduction
Biosynthesis
Use of Mutants in Biosynthetic Studies
Fonnation of Chorismic Acid
Derivatives of Chorismic Acid
Biosynthesis of Tryptophan
Indole 3-Acetic Acid
Avenalumins from Oats
DIMBOA and Related Compounds
Biosynthesis of Phenylalanine and Tyrosine
Compounds Derived from Shikimic Pathway
Intermediates
Derivatives of iso-Chorismic Acid
Arbutin and Hydroquinones
References
Il'fI'KODVCTlOI'l
Most aromatic compounds in plants are derived from shiki-
mic acid metabolism; many of these substances are phenols.
Compounds derived from this pathway are extensively mod-
ified and considered under other classes of plant secondary
metabolites. Although many types of secondary compounds
are produced from intermediates of the shikimic acid path-
way (e.g., certain naphthoquinones and anthraquinones dis-
cussed in Chapter 6), most are derived from four aromatic
amino acids: phenylalanine, tyrosine, anthranilic acid, and
tryptophan. Aromatic compounds that arise from the shiki-
mic acid pathway usually can be distinguished from those
of other origins by their substitution patterns and by a knowl-
edge of the compounds with which they co-occur.
Shikimic acid, for which the pathway is named, was fIrst
discovered in the plant Illicium religiosum in 1885 and was
named after the Japanese name for the plant, shikimi-no-ki.
The compound makes up 20% of the dry weight of the fruits
of this plant. For many years, chemists considered this com-
94
pound an oddity of plant metabolism and failed to recognize
its importance in primary metabolism. Several of the inter-
mediates of the shikimate pathway [e.g., (- )-shikimic and
( - )-quinic acids1 are now known to occur free in plants.
Most of these compounds are actively metabolized during
growth.
Plants and microorganisms are capable of making aro-
matic amino acids, but most animals cannot. In particular,
animals cannot synthesize L-phenylalanine and L-tryptophan
and are dependent on bacterial or plant sources of these es-
sential compounds. Many animals can make L-tyrosine from
L-phenylalanine.
BIOSl'1'ITHESIS
The shikimic acid (or shikimate) pathway can be divided
into three parts: condensation of erythrose-4-phosphate and
phosphoenolpyruvate and the subsequent cyclization and
production of shikimic acid (Fig. 7.1), alteration of shiki-
mate-3-phosphate to chorismic acid (Fig. 7.1), and the con-
version of charismate into other products (Fig. 7.2). The
shikimic acid pathway might more appropriately be called
the chorismic acid pathway, as that compound is the key
intermediate and branching point for most plant secondary
compounds produced.
Most of the enzymes of this pathway have now been
isolated and studied (Floss, 1986; Jensen, 1986). The shiki-
mic acid pathway is predominately found in plastids in
higher plants; isolated spinach chloroplasts can assimilate
CO2 or shikimate and produce aromatic amino acids. The
controls for this pathway have been reviewed (Jensen, 1986).
The following discussion will consider the reactions re-
sponsible for the production of chorismic acid and then reac-
tions leading to other metabolites.
 Shikimic Acid Pathway 9S

HO

HO,OH
xS pp:u °
H

O--+HO!
OH
H

;
po~ ·4°o
_D_A_H_P_S_YD_th_e_tase
__

(1M
erythrose phospboenolpyruvate OH

D
4·phosphate (1) (2) DAHP(3)

3·dehydroquinate
synthetase

NAD+,Co++ o
D
BO

i
COr 3-dehydroquinate
debydratase

o~~======' 0
~
eOl

i
-

OH

OH OH
3-debydroquinate 3·dehydroshikimate

I
(4)
NADPHf?;': (5)
V/
3-dehydroshikimate
reductase

ooD~ ~H
ooh~ ~ oo~~ ;
OH OH
(a)
quinate shikimate (6) gallic acid

HO I
OH
OH ATP PO
h i
OH
)1,",
OH EPSP synthase
hol~
e OH
shikimate (6) shikimBte 3-phosphate
(7)

PO = phosphate
glyphosate
inhibits here

~
co,. o 0

II II
~)l,""
chorismate
~oJlCO" __8yn=-th_e_IB_se_.
/
C.CH,.NH·CHrP.OH
I
, HO OH
OH
tm glyphosate (10)
5-enolpyruvylshikimate-3-phosphate N-(phosphonomethyl)glycine
chorismate (9)
(b) (8)

Fig. 7.1. (a & b) The biosynthesis of chorismate in microorganisms 1995; (modified and reprinted from Phytochemistry, Vol. 39, J. Schmid and N.
Amrhein. The pathway from erythose 4-phosphate to chlorismate. pp. 737-749. Copyright 1995 with kind pennission from Elsevier Science Ltd.• The
Boulevard, Langford Lane, Kidiingto. OXS 1GB, UK.)
96 Shikimic Acid Pathway

U5 OO~H
HO"" , PPo
u HO~
~CO,-
NU,+ --

HO , ~ HO"''', 0 CO,- / L-tyrosine L.phenylalanine

NH,
D-glu::e erythrose 4-Ph~s:hate ~ Jl --------- UN)
(; ~CO'H
..
~ )l.-/ fm 0 CO,- ¢H'N L·tryptophan

PO COr chorismate r
PhOSPhoenOIPyruvate~
/ "" I

6:. Jl -
/ CO,H
COzH $~aminObenzoate
,OH I I ""
""
?'

"'- 0 COH
~
, 0
isochorismate isoprenoid quinones

Fig. 7.2. An outline of the products derived from chorismate (modified from Haslam, 1974).

Use of Mutants in Biosynthetic Studies is not used by the organism into a compound capable of
sustaining growth. Although not normally an intermediate
Most steps of the shikimic acid pathway have been stud-
in the shikimic acid pathway, quinic acid may be used in-
ied by means of mutants, isotopically labeled precursors,
stead of 3-dehydroquinic acid when present. It is sometimes
and studies of the specific enzymes from cell-free systems.
difficult to distinguish between "precursors" and "interme-
The use of mutants for examination of various steps of the
diates" (Weiss and Edwards, 1981).
shikimic acid pathway has been of great value for the study
In some instances, an established intennediate may not
of the enzymes and intermediates involved. Use of mutants
be utilized by intact cells of mutants. Several obligatory in-
permits interruption of the pathway at a stage that normally
termediates of the shikimic acid pathway are not utilized
would not be seen. Mutants that involve one step of the
when introduced exogenously. This phenomenon usually has
pathway are especially usefuL In some situations, intermedi-
been attributed to failure of the intermediate to reach the site
ates are accumulated in large quantities, facilitating analysis
of synthesis or utilization, a problem which sometimes can
of the sequence of steps in the pathways. Sometimes, how-
be averted with cell-free systems. The amount of a particular
ever, the accumulation of intennediates exerts control over
precursor introduced is also important. The presence of
earlier stages of the biosynthetic process and inhibits the
larger than normal amounts of an intermediate may also
activity or represses fonnation of enzymes at a previous
cause deviation from the usual sequence of events (Weiss
point in the pathway. In these circumstances, the biosyn-
and Edwards, 1981).
thetic intermediate before the break in the pathway often
In early examinations of the shikimate pathway leading
will be unable to serve as a precursor. Mutants of this type
to aromatic compounds, a number of possible precursor
normally do not survive unless provided with an outside
compounds were evaluated. Surprisingly, out of about 50
source of an intermediate or product that occurs after the
compounds tested in mutant systems, only shikimic acid was
point at which the pathway is blocked.
found to be utilized. This compound could replace all three
Employment of mutants for the study of biosynthetic
common aromatic amino acids and p-aminobenzoic acid
pathways is often complicated and is usually feasible only
(Weiss and Edwards, 1981).
for microorganisms or plants in tissue culture. The mutant
must be unable to grow in the absence of the products of
Formation of Chorismic Acid
the pathway of interest (Weiss and Edwards, 1981).
The products accumulated and isolated from the cultures The starting materials for the shikimic acid pathway,
of mutants are sometimes not those of the actual pathway, erythrose-4-phosphate (1) and phosphoenolpyruvate (2) are
but modified products derived from intermediates involved. both involved in the primary metabolism of sugars and have
For example, in Neurospora mutants blocked after the for- key roles in the carbon assimilation cycle of photosynthesis,
mation of dehydroshikimic acid, only protocatechuic and a process principally found in higher plants and algae
vanillic acids (derived from dehydroshikimic acid) accumu- (Bonner and Varner, 1976).
late. In other instances, an intennediate or a derivative of The first step of the pathway is a condensation reaction
an intermediate may be converted by a pathway that usually involving phosphoenolpyruvate (1) and D-erythrose-4-phos-
 Shikimic Acid Pathway 97

phate (2) (Fig. 7.1). This initial condensation is catalyzed

by 3-deoxY-D-arahino-heptulosonate 7-phosphate (DAHP)
synthase, an enzyme system specific for these precursors.

--
Recent evidence indicates that this is actually a complex of
several related enzymes that are sensitive to end-product
control by tyrosine and tryptophan (in E. coli). The isozymes anti

responsible for the fonnation of tryptophan and tyrosine B:

H
seem to differ somewhat from those that are involved in the B:H
fonnation of phenylalanine (Dewick, 1989; Jensen, 1986;
Floss, 1986). '"yXCO'H P~CO'H
The first acyclic intennediate, 3-deoxY-D-arabino-heptu-
losonic acid 7 -phosphate (DAHP) (3), is then cyclized by p~3H '~3H
3-dehydroquinate synthase to 3-dehydroquinate (4), the first
cyclic intennediate in the pathway (Dewick, 1989; Knowles, HO·R OR
1989). ~ anti
In the next step of the sequence, 3-dehydroquinate (4) is
dehydrated via a Z-elimination to produce 3-dehydroshiki-
B,
mate (5). This reaction is catalyzed by 3-dehydroquinate de-
hydratase. 3-Dehydroshikimate (5) is, in tum, reduced to
shikimate (6) by 3-dehydroshikimate reductase, an enzyme
that requires NADPH as a cofactor. Shikimate (6) is then
POSfCO'H 3H

converted to the 3-phosphate (7) by the action of shikimate

kinase and ATP.
The conversion of shikimate-3-phosphate (7) to 5-enolp- 2 OR
yruvylshikimate (EPSP) (8) by 5-enolpyruvylshikimate-3-
phosphate synthase represents a rare type of reaction in
which the enolpyruvate fragment of phosphoenolpyruvate
l·PO
(2) is transferred to a molecule of (- )-shikimate-3-phos- H,B

phate (7) (Figure 7.1). The herbicide glyphosate (10) blocks

the enzyme that catalyzed this reaction (Fig. 7.3). In 1984,
sales of this herbicide totalled $480 million (Amrhein, 1986;
Floss, 1986).
By means of phosphoenolpyruvate labeled with both tri-
tium and deuterium (E-[3-2H,,3Hdphosphoenolpyruvate), it
is possible to detennine the stereochemistry of both the addi-
tion and the elimination step involved in the fonnation of 5-
enolpyruvylshikimate-3-phosphate (EPSP) (8) (Floss, 1986)
(Fig. 7.3). The EPSP synthase reaction involves addition and
elimination at the 2,3 double bond with opposite stereochem-
istry (i.e., either syn addition and anti elimination or anti
addition followed by syn elimination) (Floss, 1986).
A 1,4-conjugate elimination of phosphoric acid then
transfonns 5-enolpyruvylshikimate-3-phosphate (8) into
chorismate (9) (Fig. 7.1). The 6-pro-R hydrogen atom is
labile in the chorismate synthetase reaction; hence, the reac-
tion occurs with overall trans-geometry.
Many aspects of the shikimic acid pathway have been
reviewed in detail (Conn, 1986; Weiss and Edwards, 1981).
5-enolpyruvylskikimate-3-phosphate (8)
Fig. 7.3. Stereochemical course of the 5-enolpyruvylshikimate 3-
phosphate synthase reaction (adapted with permission from Asano et a1.,
1985, copyright 1985, American Chemical Society).
Although the fonnation ofp-aminobenzoic acid (36) (Fig.
7.12) can be explained by amination and loss of pyruvate
from iso-chorismic acid, enzyme extracts from Enterobacter
aerogenes and two Streptomyces species contain p-amino-
benzoate synthase and iso-chorismate synthase activity. Ki-
netic data suggest that synthesis of p-aminobenzoic acid oc·
curs from chorismic acid (Johanni et aI., 1989). p-
Aminobenzoic acid is important in the fonnation of folic
acid in fungi and bacteria (Haslam, 1974).

Derivatives of Chorismic Acid

From chorismic acid, four major pathways lead to essen-
tial metabolites: tryptophan, phenylalanine and tyrosine, p-
aminobenzoic acid and the folate group of coenzymes, and
the isoprenoid quinones (Fig. 7.2). Numerous secondary
compounds in plants and other organisms are fonned from
products and intennediates of these pathways.
BIOSYl'ITIIESIS OF TRYPTOPHAN
Tryptophan is an essential amino acid for most organisms. In
plants and bacteria, this compound is derived from chorismic
acid. Many groups of secondary compounds are fonned from
tryptophan; among these are several simple amine deriva-
tives and a number of alkaloids.
98 Shikimic Acid Pathway
l:l Hx'H
) : 2
+ glutamate
3nthron;}at.
synthase
chormismate (9)
Fig. 7.4. Steric course of the anthranilic synthase reaction (adapted with pennission from Asano et al., copyright 1985 American Chemical Society).
The fIrst step in the formation of tryptophan involves
conversion of chorismate (9) to anthranilate (11) (Fig. 7.4).
Although the reaction is not well understood, it is catalyzed
by the enzyme anthranilate synthase and utilizes L-gluta-
mine. By means of specifically labeled chorismic acid, it was
determined that the protonation involved in the formation of
anthranilic acid had occurred from the re face (Figure 4)
(Floss, 1986). Anthranilic acid (11) also serves as an inter-
mediate for the synthesis of a number of secondary com-
pounds and occurs free and as various derivatives in many
plants and other organisms (Dewick, 1989).
The second enzyme of the pathway leading to tryptophan,
5-phosphoribosy1-pyrophosphate transferase (PR transfer-
ase), causes addition of a phosphoribosyl unit (12) to anthra-
nilic acid. An additional series of enzymes then brings about
a rearrangement and the ultimate formation of indoleglycerol
3-phosphate (13).
Indoleglycerol 3-phosphate (13) is converted into trypto-
phan (14) by the action ofL-tryptophan synthase. The mech-
anism of this enzymatic reaction involves formation of a
Schiff base with an enzyme-bound pyridoxal phosphate. The
a-aminoacrylate Schiff base formed undergoes the addition
of a j3-substituent to produce tryptophan (Floss, 1986) (Fig.
7.5).
Indole 3·Acetic Acid
Indoleacetic acid (IAA) (17) is involved in many aspects
of plant growth and development (Bonner and Varner, 1976;
Kosuge and Sanger, 1986). This hormonal substance is de-
rived in most plants by conversion of tryptophan to indole
3-pyruvic acid (15) (tryptophan amino transferase), decar-
boxylation to the indole 3-acetaldehyde (16) (indole pyru-
vate decarboxylase), and oxidation to indole 3-acetic acid
(17) (indole acetaldehyde oxidase) (Fig. 7.6) (Goodwin and
Mercer, 1983).
Indole 3-acetic acid (IAA) (17) also is found in certain
bacteria. IAA is a virulence factor in the relationships of
one bacterium, Pseudomonas syringae pv savastanoi, and
its plant hosts, Nerium oleander (oleander, Apocynaceae)
and Olea europaea (olive, Oleaceae). Virulence is assessed
by the production of tumor-like outgrowths by the plants
in response to secretion of phytohormones by the pathogen
(Kosuge and Sanger, 1986). The bacterium produces IAA
by conversion of L-tryptophan to indoleacetamide (18) and
anthranilic acid
(11)
then to indoleacetic acid (17) (Fig. 7.6). Two enzymes are
involved: tryptophan 2-monooxygenase and indoleacetam-
ide hydrolase (Kosuge and Sanger, 1986).
AVBI'IALUJIIINS FROM OATS
Three compounds, avenalumin I, II, and III (19-21), are
formed in resistant lines of oats (Avena sativa, Poaceae) in
response to attack by crown rust, Puccinia coronata f. sp.
avenae (Fig. 7.7) (Mayama, 1983). The structures of these
compounds suggest that they are derived from anthranilic
acid.
DllImOA AND RELATED COJIfPOUNDS
A series of hydroxamic acid derivatives with 4-hydroxy-
1,4-benzoxazin-3-one structures occur in a number of cereal
grain species (Poaceae or Gramineae) (Fig. 7.8) (Niemeyer,
1988). These compounds usually occur in plants as the
2-j3-0-o-glucosides; enzymes that hydrolyze the com-
pounds usually co-occur. DIBOA [2,4-dihydroxy-I,4(2H)-
benzoxazin-3-onel (22) is the major compound in rye and
DIMBOA [2,4-dihydroxy-7 -methoxy-I ,4(2H)-benzoaxa-
zin-3-one1 (23) in wheat and maize. Although these com-
pounds are found in most plant patts, hydroxamic acids typi-
cally occur in highest concentration in young seedlings and
roots. Young leaves usually contain higher levels than old
leaves. Higher concentrations of hydroxamic acids are found
in the vascular bundles (Niemeyer, 1988), DIMBOA gluco-
side is found in the honeydew of the aphid Rhopalosiphum
padi feeding on wheat (Givovich et aI., 1992). DIMBOA
tastes sweet to humans (Hamilton et aI., 1962).
Benzoxazinones share a major patt of the biosynthetic
pathway of tryptophan. Label from quinic acid and anthra-
nilic acid is incorporated into the aromatic ring of benzoxazi-
nones. The carbon atoms of the heterocyclic ring stem from
ribose. C-2 comes from C-2 of ribose, whereas C-3 comes
from C-I of ribose (Niemeyer, 1988). A number of questions
concerning the nature of the biosynthetic reaction sequence
remain to be answered. Heating these compounds produces
benzoxazolin-2-ones and fonnic acid. Benzoxazinones de-
compose readily at higher pH (Niemeyer, 1988).
 Shikimic Acid Pathway 99

Both OIMBOA and OIMBOA glucoside inhibit photo·
phosphorylation by spinach chloroplasts (Queirolo et al.,
1981). OIMBOA is a potent inhibitor of cyanide-insensitive
respiration in potato mitochondtia (Hediger and Seigler, un-
published data).
Both hydroxamic acids and benzoxazolinones have been
linked to resistance to insect pests and fungal and bacterial
diseases (Niemeyer, 1988). Although many of these com-
pounds are toxic or deterrent to a variety of organisms, hy-
droxamic acids of this type are not stable in culture media
at pH 7; the results of many previous feeding studies should
be reexamined. In other instances, concentrations of the
compounds thought to be active are not sufficiently high in
the appropriate tissues to explain the levels of resistance
observed. More recent studies, however, demonstrate that
OIMBOA in the diet of the European com ear worm, Os·
trinia nubilalis, increases the mean time to pupation and
adult emergence. Both pupal and adult weights decreased
(Campos et aI., 1989). Other reports have shed doubt on the
role of these compounds in disease resistance (Lyons and
Nicholson, 1989; NyhUS et al., 1989).
Compounds of these classes also are thought to be respon-
sible for the allelopathic effects of some cereal grains. In
most instances, the hydroxamic acids rather than the corre-
sponding benzoxazolinones are thought to be active. OIBOA
glucoside inhibits germination and seedling growth of Abuti-
Ion theophrastii, a common field weed in many parts of the
world (Niemeyer, 1988). OIBOA has been shown to be an
allelopathic agent from winter rye, Secale cerale. This com-
pound is released from the corresponding glycoside, and
although it does not inhibit seed germination, it inhibits root
growth at concentrations of 0.37 mmoVthn (Harbome,
1989). The synthetic herbicide Bentazon (25) (Fig. 7.8) has
a structure reminiscent of OIBOA.
6·Methoxybenzoxazolinone (MBOA) (24), the decompo-
sition product of OIMBOA, stimulates reproduction in the

O1
E: ...... 0
CO'_HN~CO,.

I~ X
~
J H H NH,+

anthranilate
CO
'. ~'Hy'y'
Jf"~-
c!H 0
",
CO,·
synthase
~ 0 CO,.

chorlsmate (9)

(XI CO,H
phosphoribosyl
(XI ~H
:
CO,.

H PRA isomerase
'-~--+-. NH CH,OP •
~ NH, transferase OH o.R
anthranilic acid H H H O~~
(11) ~,A----h CH,OP

~-~
OPP O/H

(X
(12)
cor
: I IGP .yntbetase
NHHO H
~CH'OP
o H OH
1·(o·carboxyphenyJamlno)-
I-deoxyribulose pbosphate Indoleglycerol phosphate
(CRDP) (lGP) (13)
NH,

tryptophan ~CO'H
l0l ) ••
synthetase N

L·tryptophan (14)

Fig. 7.5. Biosynthesis of tryptophso (modified from Luckner, 1990).

100 Shikimic Add Pathway

cc"'
NH,

--+
h
CO'H_
NH,
~
I I
P"
CO'H
:::,... NH
H

IRPlaY
chorismate (9) anthranilic acid (11) IAryptophnn (14)

1 in bacteria

°
~CO'H
° ~NH'
UN) UJ
indole-3-acetamide (IS)
(15)

°
~OH
UJ
indole-3-acetic add

~ ~ .
Fig. 7.6. . (modi'fled from Smith. 1980; used with pemnSSlon
.aCId
Biosynthesis of indole aceUc . . 0f the cop yright owner, Springer-Verlag, BerlIn),

avenalumin I (19) avenalulDin II (20) avenalumin m (21)

Fig. 7.7. Avenalumin It II, and m.

CH,-0yY° X O-glucosyl
CH'-°yY°XOH
~NI ° ~NI °
OH OH

a:x:H
DIMBOA glucoside DIMBOA(23) BentazoD (25)

CH,'°yY>=O
I
OH ~NH
DmOA(22) MBOA(24)

Fig. 7.8. l,4-Benzoxazin-3-ones and benzoxazolin-2-ones from the Poaceae.

 Shikimic Acid Pathway 101

montaine meadow vole (Microtus montanus) and may serve
as an environmental cue affecting reproductive cycles in
many mammals (Berger et aI., 1981; Sanders et aI., 1981).
Although benzoxazinones mostly have been reported
from grasses (Aegilops, Arundo, Chusquea, Coix, Elymus,
Secale, Sorghum, Tripsacum, Triticale, Triticum, and Zeal,
DIBOA glucoside has been reported from Acanthus moWs
(Acanthaceae) (Powell and Spencer, 1988; Wolf et aI., 1985)
and MBOA bas been found in Scoparia dulcis (Scrophularia-
ceae) (Chen and Chen, 1976).
Methods for the analysis of DIMBOA and related com-
pounds have been reviewed (Lyons et aI., 1988; Niemeyer,
1988).
BIOSYl'lTHESIS 01' PHENYLALANINE
ANDTYKOSIl'IIl
In both bacteria and plants, two additional amino acids, phe-
nylalanine and tyrosine, are fonned from chorismic acid.
From chorismate, two separate routes diverge and lead to
the amino acids L-phenylalanine and L-tyrosine. However,
the pathways in bacteria and plants are distinct and involve
different intennediates. Both of these pathways pass through
the same intennediate, prephenic acid (26) (Fig. 7.9) (Floss,
1986; Jensen, 1986). These essential amino acids serve as
precursors to a large number of other types of secondary
compounds.
In bacteria, two soluble, multiactivity enzymes or enzyme
complexes function in the utilization of chorismate for L-
phenylalanine and L-tyrosine synthesis. A complex contain-
ing chorismate mutase and prephenate dehydratase activities
has been observed. Although the reaction proceeds by what
appears to be a Claisen rearrangement, the rate-limiting tran-
sition state appears to be different in the enzymatically con-
trolled process. It is not known if fonnation of the higher-
energy diaxial confonner (27) occurs after binding to the
enzyme or is from an equilibrium mixture (Dewick, 1984;
Floss, 1986; Jensen, 1986).
Stereochemical studies indicate that the branch for the
pathway leading to tyrosine and that leading to phenylala-
nine of the chorismate mutase enzyme systems function with
the same stereochemistry (Floss, 1986) (Fig. 7.10).
Prephenate (26) is converted to phenylpyruvate (28) in
many bacterial systems. In some organisms, such as Esche-
richia coli, prephenic acid also is oxidatively aromatized to
p-hydroxypbenylpyruvic acid (29) by a soluble, NAD+-de-
pendent enzyme, prephenate dehydrogenase. p-Hydroxy-
phenylpyruvic acid is then transaminated by the addition of
L-glutamate and pyridoxal phosphate to yield L-tyrosine (30).

***phenyIpyruvate aminotransferase

chorismate mutase-
6~
CH'COCO" PLP

I~
***
L-phenylalanine
prephenate dehy~~;ta/
(28) / (31)
(bifunction/ (enzyme bound)
(27) /arogenate dehydratase
CO2-

OoJlco,_ -- .. ·0 ( J " C O ' . _o,~.. CO,·

2 "~. 0 PLP ~'" NH3+

II ~II
****

arog~:te ~at~:;drogenase
i
OH
prePhe:: (26) (32)
chorismate (9)

** chorismate mutase
prePhenat~
dehydrogenase ;;COCO,.~ ~C02"
PLP = pyridoxal 5 -phosphate
**** prephenate aminotransferase
V HO~-NH3+
OH L-tyrosine (30)
"* p-hydroxyphenylpyruvate aminotransferase
p-hydroxyphenylpyruvate
(29)

Fig. 7.9. Formation of prephenic acid from chorismic acid (modified from Dewick, 1984; used with permission of the copyright owner, the Royal
Society of Chemistry, London),
102 Shikimic Add Pathway

&I
C:. 'HR'IEH r HOC @j-
2
o,:O'Hl
R
28 E.coU
'gHCO~:,
'H R

l
o
E.•oU.
CO. cborismate 1,1
P'I
j
OH
2 mutase ~
OH OH
I

HOD-CO"
~1b-
H j CO,.
~.
~

H OH
diequatoriaJ dimal

m-
OH
°it~(
enzyme-bound
diaxial chorismate
oo
'
- d:
=
HO
prepbenate (26)
co:.

Fig. 7.10. Stereocbemistry of the formation of prephenic acid from chorismic acid (modified from Baldwin and Davidson, 1983; used with pennission
of the copyright owner, Elsevier Science, Amsterdam),

Phenylalanine (31) may be fonned by conversion of choris·
mate (9) to prephenate (as an enzyme·bound intennediate)
and subsequent fonnation of phenylpyruvate (28). Transami·
nation of this intennediate produces phenylalanine (31).
In higher plants, phenylalanine seems to be fonned in
an alternative manner by fonnation of prephenate (26) and
conversion of this intennediate into arogenic acid (32).
Chorismate mutase occurs as two isozymes which have been
purified to homogeneity from mung bean and sorghum. All
chorismate mutase isozymes show allosteric activation by
chorismate (Poulsen and Verpoorte, 1991). One chorismate
mutase isozyme is inhibited by phenylalanine or tyrosine
and activated by tryprophan, whereas the second is not af·
fected by any of the aromatic amino acids.
Arngenic acid is converted into phenylalanine by the ac·
tion of arogenate dehydratase. Although plants nonnaIIy do
not appear to make phenylpyruvic acid (28) and p·hydroxy·
phenylpyruvic acid (29), there is some evidence that these
compounds can serve as precursors for phenylalanine and
tyrosine, respectively (Jensen, 1986; Widholrn, 1974).
Fonnation of tyrosine in plants involves a similar hut
distinct series of enzymes and reactions to that discussed for
phenylalanine above. Although both prephenic and arogenic
acids are intennediates, they are part of a different' 'branch"
leading to tyrosine. In higher plants, arogenic acid (32) is a
direct precursor to tyrosine. L·Phenylalanine does not appear
to be a precursor of L·tyrosine in either plants or bacteria;
they lack phenylalanine hydroxylase, which is an important
enzyme in animals.
In plants, cinnamic and p-coumaric acids and their deriva-
tives are ubiqnitous. These compounds, in torn, give rise to
phenylpropanoids, lignans, lignin, flavonoids, and tannins.
Both phenylalanine and tyrosine are precursors to numerous
alkaloids.
COJllPOlJI'IDS DERIVED fROM SHIKIJIIlC
PAntWAY IN1ERJIIEDlATES
Several secondary metabolites derived from intennediates
in the shikirnate pathway are widely distributed in higher
plants. As previously mentioned, shikimic acid and quinic
 Shikimic Acid Pathway 103

6
OH

HO COzH 0 ~OH
~ ~
o H
HO i OH H o z c f fOH
OH OH OH

sbikimic acid (6) quinic acid (33) chlorogenic acid (34)

Fig. 7.11. Chlorogenic acid. shikimic acid. and quinic acid.

COZHr;:-
~H
0:)00:-
..
RNHz
z
~:XCOZH
+
•
isochorismic acid (35)

(yCOzH

V1--0H
!

salicylic acid
¢ NHz
p-aminobenzoic acid
(36)

FIg. 7.12. Origin of salicylic acid from iso-chorismic acid (modified from Luckner. 1990).

troy
0 0 0

t:c
O)lPh o O)lPh OApb

troy
o 0 ::,.. 0 0 ::,.. 0

o O~ O~ O~Ph
crotepoxide (36) senepoxide (37) pipoxide (38)

Croton macrostachys Uvarla catocarpa Piper hoo"ri

Euphorbiaceae Annonaceae Piperaceae

Fig. 7.13. Crotepoxide, senepoxide, and pipoxide.

104 Shikimic Acid Pathway

¢ -- ¢ -- ¢ --
COO COO COO

~CO'-
::7 I H Fe"
02 or
""- NH,+- HOO·
HO

0- O· 0
L~tyrosine

H'

"-~O
6~Q -- ¢
OH
---.... OOH

I~ 1--
0") OH Oglucosyl
0
H' hydroquinone (39) arbutin (40)

Fig. 7.14. Biosynthesis of hydroquinone and arbutin (modified from Torssell, 1983; used with pennission of the copyright owner, John Wiley & Sons.
Ltd" Cbichester).

acid are found free in many plants. They also occur as esters
and in other forms. For example, quinic acid (33) occurs
frequently as the caffeoyl acid ester, chlorogenic acid (34)
(Fig. 7.11). Up to 10% of the dry weight of a cup of coffee
is comprised of this compound. Chlorogenic acid is pro-
duced as a response to wounding in many plants_ Other iso-
mers, such as isochlorogenic acid, also occur. The physio-
logical importance of chlorogenic acid will be discussed later
(see Chapter 8).
In some plants, these compounds appear to arise by oxida-
tive decarboxylation of p-hydroxybenzoic acid. p-Hydrox-
ybenzoic acid (36) has vitamin-like activity in some organ-
isms_ This growth factor requirement is associated with the
formation of ubiqninone (coenzyme Q) and serves as an
effective precursor for the benzoquinone ring of ubiquinone
in mammals, bacteria, fungi, and plants (Haslam, 1974; also
see Chapter 6).

Derivatives of iso-Chorismic Acid

iso-Chorismic acid (35) is derived from chorismic acid
in plants. This compound gives rise to a number of primary
and secondary metabolites. In some organisms, salicylic acid
is known to arise from iso-chorismic acid (Fig. 7.12).
However, salicylic acid may be synthesized directly from
benzoic acid by means of a benzoate hydroxylase enzyme
system (LeOn et al., 1993; Yalpani et al., 1993) (see Chapter
8). The relative importance of these systems in higher plants
is not known.
As discussed in Chapter 6, iso-chorismic acid is involved
in the biosynthesis of naphthoquinones and anthraquinones
in a number of plants and possibly other organisms (Leistner,
1986; see Chapter 6).
Another series of compounds that appear to be derived
from iso-chorismic acid are cyclohexene oxides such as ero-
tepoxide (36), senepoxide (37), and pipoxide (38) from Cro-
ton macrostackys (Euphorbiacee), Uvaria zeylanica (An-
nonaceae), and Piper kookeri (Piperaceae), respectively
(Fig. 7_13). These compounds have demonstrated antitumor
activity (Jolad et al., 1981).
Arbutin and Hydroquinone
Hydroquinone (39) and the glucoside arbutin (40) are
derived variously from acetate-malonate, shikimic acid, or
from tyrosine (Fig. 7.14).
REFERENCES
AMRHEIN, N., Specific inhibitors as probes into the biosynthesis
and metabolism of aromatic amino acids. in The Shikimic Acid
Pathway (E. E. Conn, ed.), Recent Advances io Phytochemistry
Vol. 20, 83-117, Plenum Press, New York, 1986.
ASANO, Y., J. J. LEE, T. L. SHIEH, F. SPRBAFlCO, C. KOWAL, and
H. G. FLOSS, Stereochemical course of the enol pyruvylsbimi-
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BONNER, J. and J. E. VARNER, Plant Biochemistry, 3rd ed., Aca-
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CAMPOS, F., J. ATKlNSON, J. T. ARNASON, B. J. R. PHlLOOENE, P.
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8
Phenylpropanoids

Introduction In this chapter, the origin of cinnamic and p-coumaric acids

Cinnamic Acid, p-Coumaric acid, and Related and their simple derivatives will be discussed initially, as
Compounds these intermediate substances are precursors to most other
Biosynthesis groups of related compounds. Various other modified C6 -C,
Physiological Roles compounds, such as simple phenylpropanoids, lignans, neo-
Volatile Phenylpropanoid (C6 -C,) Compounds lignans, lignin, and hydroxybenzoic acids, will then be cov-
Biosynthesis ered.
Some Important Phenylpropanoids Two separate routes of biosynthesis diverge from choris-
Biological Activity mic acid (3); one leads to L-phenylalanine (4) and another
Lignin to L-tyrosine (5) (see Fig. 7.9) compounds 3, 6, 7, and 10
Composition of Lignin are illustrated therein; Jensen, 1986). Both pathways involve
Origin of the Monomeric Units the common intermediate prephenate (6) that is derived from
Polymerization of Lignin chorismate by a Claisen rearrangement. There are two
Lignans chorismate mutases: one is plastidic and extensively regu-
Biosynthesis lated by phenylalanine and tyrosine, and the other is a cyto-
Biological Activity solic form that is unregulated. Prephenate is then converted
Neolignans into arogenate (7) via the action of prephenate aminotrans-
Hydroxybenzoic Acids (C6-C I ) Compounds ferase. Subsequently, arogenate is converted into phenylala-
Biosynthesis
nine by the enzyme arogenate dehydratase and into tyrosine
Distribution of Hydroxybenzoic Acids and Their
by arogenate dehydrogenase (Dewick, 1984; Jensen, 1986).
Derivatives
Although plantS and bacteria do not have the ability to
Biological Activity
do so, most animals can convert phenylalanine to tyrosine
Allelopathy
(Haslam, 1974). C6 -C2 compounds are probably formed by
References
a-oxidation of ketoacids such as phenylpyruvic (10) and p-
hydroxypyruvic acid (11). One well-known example, phen-
INTRODUCTION ylacetic acid (8), is common in plants (Gross, 1981). Mam-
Compounds derived from phenylalanine and/or tyrosine are mals and some microorganisms convert phenylalanine and
among the most common of all secondary metabolites in tyrosine to another C6-C2 compound, homogentisic acid (9)
plants, bacteria, and fungi. These include phenylpropanoid (Fig. 8.3).
compounds as well as many C6 -C I compounds (Fig. 8.1) Although both phenylpyruvic acid (10) and p-hydroxy-
(Gross, 1981). Relatively simple C6 -C3 compounds, such phenylpyruvic acid (11) can serve as precursors for phenylal-
as cinnamic (1) and p-coumaric acids (2), are modified to anine and tyrosine, respectively, it does not appear that plants
produce more complex derivatives (Fig. 8.2) (Conn, 1981, synthesize either compound. In E. coli, however, these two
1986). The term "phenylpropanoid" is sometimes used to intermediates are involved in the synthesis of phenylalanine
refer to any compound bearing a 3-carbon chain attached to and tyrosine. Both phenylpyruvic acid and p-hydroxyphen-
6-carbon aromatic ring (C6 -C, compounds). Most phenyl- ylpyruvic acid have been postulated to serve as precursors
propanoids are formed from cinnamic or p-coumaric acids. for a number of other compounds in plants-in particular,

106
 Phenylpropanoids 107

HO

HO~O HO-P-'Ll

L-phenylalanine (4) J' HO caffeic acid (12) OH CH3-0 OH

I via quinate Intermediate /' S·hydroxyferulic acid

~ Ho~:aq/:einterm~~~_o
t
OH CH3 -r ~H HO ~_ ~ ~ 0

! !
E·cinnamlc acid (1) ferullc acid (13) CH]" 0 OK
slnapic acid (14)

HO~O HO~O CH3~OH

OHCH3-O H HO~O
E-4-hydroxycinnamic acid (2) coniferaldehyde CH3" 0 H
sinapaldebyde

~
(p-coumaric acid)

+ HO~~
HO~~
- ~
0)=/
CH -O
~OH 3
H coniferyl alcohol

-
t lignans
sinapyl alcohol (43)

HO~ OH
neolignans

"=T'L.I lignin

p-coumaryl alcohol (44)

Fig. 8.1. Phenylpropanoid compounds and their derivatives.

alkaloids_ The role of these compounds will be discussed in
more detail in Chapters 32, 33 and 37_
CII'II'IAMIC ACID. p·COlJMARlC ACID.
Al'ID RELATED COlllPOUl'IDS
Cinnamic acid and p-coumaric acid, derived from L-phenyl-
alanine, probably occur in all plants and fungi_ Their biosyn-
thesis was discussed in Chapter 7_
Biosynthesis
Phenylalanine is converted to cinnamic acid by the action
of the Ubiquitous enzyme L-phenylalanine ammonia lyase
(PAL) (EC 4.3_11.5) (Davin et al_, 1992; Hanson and Havir,
1981)_ This enzyme, which catalyzes loss of ammonia and
production of E-cinnamic acid (I), has been detected in a
large number of vascular plants and several genera of basidi-
omycetes_ PAL occurs mainly in the cytoplasm, but some
plants contain low levels of PAL in plastids, mitochondria,
and microbodies (Hanson and Havir, 1981)_ Cinnamate is
produced by the action of PAL in an elimination reaction
(E2) and remains attached to the enzyme until the elimina-
tion step. At that point, the "amino enzyme complex" either
releases ammonia and cinnamate or reacts again with cinna-
mate to regenerate L-phenylalanine (Fig. 8.4). PAL operates
in a clearly defined stereochemical manner. Exclusive loss
of the pro-3S-hydrogen of phenylalanine is observed (Fig.
8.4) (Davin et al., 1992).
Some grasses (poaceae or Gramineae) have the corre-
sponding enzyme, L-tyrosine ammonia lyase (TAL), capable
of converting L-tyrosine (5) into p-coumarate (2), but this
enzyme is not widely distributed. TAL also acts in a highly
stereospecific manner. The reaction also proceeds with re-
moval of the pro-3S-hydrogen from the j3-methylene atom
of L-tyrosine. It is not completely resolved that this enzyme
is distinct from PAL (Hanson and Havir, 1981).
E-Cinnamic acid (1) is the precursor of E-p-coumaric
acid (2) in plants, and the presence of enzymes that catalyze
the hydroxylation of cinnamic acid to p-coumaric acid has
been demonstrated (Butt and Lamb, 1981). These mixed-
function oxidases (in peas) are associated with the microso-
mal fraction and require molecular oxygen, NADPH, and
mercaptoethanol for the production of E-p-coumaric acid.
p-Coumaric acid has a strong regulatory effect on the en-
108 Phenylpropanoids

go
~
o OH SCoA ~OOH ~ umbelliferone
Q QQ.... ~nA a coumarin
,:? __ ...... ~,:? O~··· HO % 0 0

I ,:? I I { alkaloids
~ ~ ~ cyanogenic glycosides

OH OR OH .. ". ~;:;:;~~::smino adds

p·coumaric acid (2) OH

....
HO~OO'Q"O HO~O
OH
OH
OH"
~ I I
OH I o
gallic acid ~ OH: I a flavonoid
OH
hydroxyacetophenones neoflavonoids stilbenes OH

gallotannins
eUagitannios

Fig. 8.2. Other major groups of secondary metabolites derived from phenylpropanoid metabolism (modified from Haslam, 1974).

zyme at 3 X 10-7 to 10-6 M concentration. When cinnamic
acid is fed to plants, it is recovered as p-coumaric acid (2)
(usually) glucosylated at the carboxyl group. Cinnamic acid
is a precursor of caffeic (12), ferulic (13), and sinapic (14)
acids in most plants; quinate or shikimate esters appear to be
involved as intermediates (see below) (Gross, 1981; Haslam,
1974) (Fig. 8.5). Cinnamic and related acids often occur in
plants as esters. A number of methyltransferases (EC 2.1.1.6)
can convert the hydroxycinnamates to methyl ethers (Davin
et al., 1992; Poulton, 1981). Cinnamic acid and its derivative
acids, their ethers, and their esters are the principal constitu-
ents of the phenylpropanoid pool in plants (Haslam, I 974).
Some relatively nonspecific enzymatic formation of caf-
feic (12), ferulic (13), and synapic (14) acids has been noted
(Davin et w..,
1992). Monooxygenases of microsomal frac-
tions appear to be involved. For example, a specific p-coum-
arate-3-hydroxylase has been isolated from mung beans.
However, other work suggests that the carboxyl group of p-
coumaric acid must be esterified as aquinic acid ester before
OH
the second OH group is introduced (Grand, 1984; Kiihnl
et al., 1987). The reaction requires NADPH and molecular
oxygen (Heller and Kiihul, 1985). Although shikimate and
other esters may be involved, quinates appear to represent
the major route of synthesis of hydroxybenzoic acids (Kiihul
et al., 1987).
Once formed, these phenolic acids playa central role in
the synthesis of lignin, flavonoids, and a wide range of other
phenolic secondary constituents.
In plants, phenylpropanoic acids generally are bound to
various alcohols, especially sugars; mono-, di-, and trisac-
charide esters are common (Mf/llgaard and Ravn, 1988). Mo-
noglycosides are common in all dicotyledonous plants,
whereas di- and triglycosides are most common in sympetal-
ous plants. Quinic acid esters, such as chlorogenic acid (15),
are widespread in the Asteraceae, Solanaceae, and Rubia-
ceae, whereas rosmarinic acid (16) and related compounds
are restricted to the Lamiaceae and Boraginaceae. Disaccha-
ride esters are found primarily in the Scrophulariaceae and
Brassicaceae (Mf/llgaard and Ravn, 1988). Complex glyco-
sides are known (Calis et al., 1990; Klick and Herrmann,
1988); for example, 3,4-dihYdroxY-13-phenethyl-O-13-D-glu-

~-
OH
phenylacetic acid (8)
homogentisic acid (9)
Fig. 8.3. Phenylacetic and homogentisic acid.
copyranosyl- (1- 3}-4-0-caffeoyl- 13- D-glucopyranoside,
plantamajoside (17), has been isolated from callus of Reh-
mannia glutinosa (Scrophulariaceae) (Fig. 8.6) (Ravn and
Brimer, 1988).
Physiological Roles
Cinnamic acid, p-coumaric acid (2), and several related
compounds modify growth in plants (also see Section 8.8).
 PhenyJpropanoids 109

!1=
•
. ' \.
q-NH
°
CH~ .' \.
UN .;
° B:,~~
~ c::.J~~+Jl _
~
H,N ''''''H
CO,-
"..
HO '.
k-NH
....

H H
H~~
>-;0'H~+ · "·"H - CO,.

° HO'.l L-phenylalanine(4) ...• ~ 'H

'.~O"'\
HO
....

/"\,;-NH
NH
-
P<~~
H
-O,C I ---

d
E-cinnamic acid (1)

H1CO'-

0-:~~+
HoN ~~ HO
17

"""-
I HB

L-tyrosine (5) p.coumaric acid(l1)

Fig. 8.4. Stereochemistry of PAL action (modified from Havir and Hanson, 1970; published with pennission of copyright owner, Academic Press,
Orlando, FL.)

For example, E-cinnamic acid (1) was shown by Bonner
and Galston (1944) to be strongly inhibitory to seedlings of
Partheniurn argentaturn, guayule (Asteraceae). In attempts
to cultivate this plant, plants in the center of fields were
stonted in appearance. Presumably, those at the periphery
were exposed to lower concentrations of the active com-
pound. In later work, it was shown that E-cinnamic acid is
liberated from the roots of adult plants; the leachate from
20,000 roots yielded 1.6 g of E-cinnamic acid. In the labora-
tory, this compound proved to be inhibitory to Partheniurn
growth at a concentration of 0.0001 %, whereas tomato seed-
lings were affected only if treated with a solution containing
100 times this concentration (Harborne, 1982).
A series of phenylpropanoid compounds from Pirnpinella
spp. (Apiaceae) that contained epoxide rings were powerful
seed germination inhibitors (Cutler, 1992).
VOLATILE PHBNYLPROPAl'IOm (c,,-C3 )
COlllPOlll'IDS
The term phenylpropanoid also is used in a more restricted
sense to indicate a number of relatively volatile compounds
in which the carbonyl function has either been removed,
reduced, or otherwise modified. A number of volatile phen-
ylpropanoid compounds found in essential oils have pro-
nounced biological properties. These compounds are fre-
quently found in essential oils from plants and some are
quite important as flavorings and perfumery ingredients.
Pltenylpropanoids are especially common in plants of the
Magnoliales and the Apiaceae.
Biosynthesis
Cinnamic (I), p-coumaric (2), and related acids may be
activated by conversion to CoA esters by CoA ligases [e.g.,
4-coumarate:CoA ligase (BC 6.2.1.12)] in much the same
way that fatty acids are activated. The reduction of the CoA
esters of cinnamic acids to cinnamyl alcohols involves two
enzymes: cinnamoyl-CoA oxidoreductase (which forms the
aldehydes) and cinnamyl alcohol dehydrogenase (Grisebach,
1981). Phenylpropanoids appear to be syuthesized from the
CoA esters of this series of acids by conversion to the corre-
sponding aldehydes, then to the alcohols, and finally, by
elimination of a phosphate group, to allyl and propenyl com-
pounds. In many plants. mixtures of all types co-occur (Fig.
8.7) (Gross. 1981; Mann, 1987). Reduction of the side chain
to produce dihydrocinnamic acids and related compounds is
also known to occur in nature.
Some Important Phenylpropanoids
Many phenylpropanoids are of ecological and economic
importance. These compounds are the principal volatile con-
110 Pllenylpropanoids
~O-
cionamic acid (1)
L-phenylalanioe (4)
HO~"", CH'-O~""'- CH'-O~,<::::
""'- 0 0-
~ --
HO HO
caffeic acid (12)
E-S-O-(4-coumaroyI)-D-qulnate
•• These oxidations probably occur as quinic and shikimic esters, not as the free acids
Fig. 8.5. Biosynthesic steps of the hydroxycinnamic acids.
stituents of several of the most important spices and herbs.
Others are involved in plant-animal interactions as allo-
mones, kairomones, and synomones.
Among those from spices are eugenol (18), the major
component (85%) of oil of cloves (Fig. 8.8), and cinnamalde-
hyde (19), the principal flavor constituent of oil of cinnamon.
However, the latter compound occurs in a bound form as
cinnamyl acetate in the plant and fresh bark. During the
fermentative processing of the bark, this ester almost com-
pletely disappears and is not found in any quantity in com-
mercial cinnamon. Studies with radioactively labeled materi-
als confirm that the ester is converted into cinnamaldehyde.
A number of phenylpropanoids are perceived as pungent
by humans and presumably by other organisms. Among
these are capsaicin (20), the pungent principle of peppers
(Capsicum species, Solanaceae) and piperine (21), the pun-
gent principle of black pepper (Piper nigrum, Piperaceae)
(Fig. 8.9) (Harborne, 1982).
E-3'-Methylsulfonylallyl E-cinnamate (22) has been iso-
lated from the bark of Phoebe brenesii (Lauraceae) (Castro
et al., 1985).
The precursors of some phenylpropanoid odorlflavor
components of raspberry fruit occur as the 4'-O-~-D-gluco­
pyranoside of 4-(4'-hydroxyphenyl)butan-2-one (raspberry
ketone) and the 3'-O-~-D-glucopyranoside of 4-(3',4'-dihy-
droxyphenyl)butan-2-one (Pabst et aI., 1990).
p-coumarate (2)
* clnnamic 4-hydroxylase
o
0 0- ""'- 0-
I __ HO~
~
OCH,
ferulic acid (13) sinapic acid (14)
E-5-0-(4-caff.oyl)-D-quinale
Biological Activity
An epimeric pair of dehydrodiconiferyl alcohol ~-D-gly­
cosides (23, 24) from crown gall (Agrobacterium tumefa-
ciens) tumors in transformed Catharanthus roseus cultures
has been shown to promote cell division and replace the
cytokinin requirement in tobacco cells (Fig. 8.10) (Binns et
al., 1987; Lynn et al., 1987).
Methyl Z-ferulate is a powerful inhibitor of uredospore
germination in a range of rust fungi (Friend, 1979). This and
related- compounds occur in the fungi themselves. They are
gradually leached from the spores on the host surface. This
process must take place before germination of the spores
occurs.
Safrole (25) and isosafrole were once important as the
flavoring for root beer. These compounds are present in the
plant extracts used to make this beverage. By the 1950s,
however, most root beer was flavored with synthetically de-
rived safrole. Both safrole and isosafrole were shown to be
weakly carcinogenic and now have been banned for this
purpose (Fishbein et aI., 1967). These compounds have a
methylenedioxy strocture and are known to inhibit mixed-
function oxidase enzymes. Two compounds of similar stroc-
ture, piperonal (26) (naturally occurring) and piperonyl bu-
toxide (27) (synthetic) are mixed function oxidase inhibitors
and are used as synergists for insecticides such as pyrethrins,
rotenoids, and Sevin (a carbamate insecticide) (Fishbein et
al., 1967).
 Plienylpropanoids 111

Myristicin (28), which occurs in oil of nutmeg as well as
in essential oils of many members of the Apiaceae (Umbelli-
ferae), is a hallucinogenic compound. This, and a related
compound, elemicin (29) (Fig. 8.8), are largely responsible
for the hallucinogenic effects of nutmeg. The synthesis of
myristicin in carrots is increased by exposure of carrot roots
to light (Yates, 1987). Myristicin has also been shown to
have antifeedant properties for certain insects (Seigler,
1983), to be insecticidal, and to serve as a synergist for a
number of natoral and synthetic pesticides. Such synergists
in leaf tissue can significantly increase the toxicity of an
insecticide (Berenbaum and Neal, 1985, 1987; Lichtenstein
and Casida, 1963; Neal, 1989).
The essential oil of Acorus calamus (Araceae) contains
f3-asarone (30) that causes depression of development of
the gonads and ovaries of the insect Dysdercus koenigii.
Although third and fourth instar larvae molted normally to
the next instars, fifth instar larvae molted normally to adults
but the ovaries were irreversibly affected. In such adults,
the ovaries remained permanently immature (Saxena et ai.,
1977).
One of the most interesting examples of the biological
activity of phenylpropanoids in plant-insect interactions is
that of the oriental fruit fly and methyleugenol (31). This
insect, Dacus dorsalis, uses methyleugenol as an aggrega-
tion pheromone. Pheromonal activity is exhibited both in
feeding and male aggregation. The same compound is pro-
duced by the flowers of several plant species, including Cas-
sia flstulosa (Fabaceae: Caesalpinoideae). As a result, male
fruit flies congregate on Cassia trees and perceive the pres-
ence of methyleugenol as a sign to eat the leaves. If there
is enough methyleugenol in the air, the flies will continue
to eat until they die. As little as 0.01 fLg of methyleugenol
will produce a response in a single fly in a cage. Other ana-

o
o
HO~0-60
fiOH
~ \d OH
o H HO~ HO........... _

HO'c#0H o ~ b OH

OR OR cblorogenic acid (15) rosmarinic acid (16)

0.1:
fO,H OH

:~OH
HCOH

0' -
I HO

HC~
I ~ o
CO,H ~ h OH 0
g1u<osyJ-O HO monardein
H OH

t;
OH
p-coumaroyl m-tartrate
0H OHOH

~/7 OH

~ ~OLQ OH
o
benzyl clnnamate
~O
HO~ .
HO
4-p--coumaroyl myoinositol

HO~
~~ ~ O~OH
~
HOHO
OH
H
00
0

OH
H
0
Y"--Q-OH
_
OH

plantamajoside (17)

Fig. 8.6. Naturally occurring phenylpropanoid acid esters.

III Phenylpropanoids

o o o

HO
~ "":::'"
,& --
OH CH'.O~:::'"
I"
HO
OH
..& coenzyme A t
CH'.O~:::'"
1 "
HO'&
SCoA
NADPjf
~umaric acid (2) ferulic acid (13)

CH'.O~O
1 "" ~
CH'.O~:::'"
I" ~
CH,.o~:::,..?H
1 O-~=O
HO ,& NADPH HO b HO'& OH

coniferYI~/

eugenol (18) isoeugenol (83)

Fig. 8.7. Biosynthetic pathways for volatile phenylpropanoids in plants.

CH'.O~"
" ~ CH'.O~ CH'.O~:::'"
1 OH
HO'& HO~ HO ,&

eugenol (18) isoeugenol (83) coniferyl alcohol (42)

0
~H
1,,9 <0O~
I .# <0 ° v 1,,9
OCH,
cinnamaldehyde (19) safrole (25) myristicin (28)

CH'O~
1 .
~
CH'O~
CH,·O
Ib CH,·O ,& CH,.O 1 ,&

methylisoeugenol (32) metbyleugenol (31) anethole (36)

0""""0

~~
°OCHO
<0 1 .& CH,·O ~
1,&

methylchavicol
piperonal (26)
O(CH,),O(CH),OC,H, or estragole (35)

(a) piperonyl butoxide (27)

Fig. 8.8. (a & b) Some common phenylpropanoids.

 Phenylpropanoids 113

isoasarone (37) p-asarone (30) elemicin (29)

OCH,
CH,O

~
HOV

chavicol (34) veratrole (33)

3' d:C
r"

4' "'"
,pOl'
I l' "'"fl 0 ~2 S02CH3

E-3'-methylsulfonyl-E-cinnamate (22) piperenone (38)

~ OH

~ \~O O~O-CH'-CH'{}-OH
O~ H
H~~~\.-
IU~ 'ci\(
0 OH

(b) H mussatioside I (41)

Fig.8.8 (continued)

logs generally have reduced or no activity (Metcalf et ai.,
1975),
E-Methyl isoeugenol (32), E-asarone (2,4,5-trimethoxy-
I-propenylbenzene), and, to a lesser extent, the leaf alde-
hydes hexanal, E-2-hexenal, and heptanal (see Chapter 2)
gave strong electroantennogram responses for the female
carrot rust fly Psila rosae (Guerin et ai., 1983). A mixture
of E-asarone and hexanal is more attractive than either com-
pound alone and probably serves as an oviposition stimulant
for the female fly. A synthetic mixture of E-methylisoeu-
genol, E-asarone, osthol (a coumarin), bergapten (a furano-
coumarin), xanthotoxin (a furanocoumarin), and falcarindiol
(an acetylenic compound) was equally attractive as raw car-
rot extract and the components exhibited synergistic action
(Stadler and Buser, 1984).
Southern corn rootworm (Diabrotica undecimpunctata
howardii) adults are attracted late in the season to many
aromatic compounds: phenylacetaldehyde, benzyl acetone,
phenethyl alcohol, phenyl acetate, indole, veratrole (33),
methyleugenol (31), methylisoeugenol (32), eugenol (18),
and isoeugenol. Only veratrole (33), phenylacetaldehyde,
and chavicol (34) were active in early and middle August
however. Western corn rootworrn (Diabrotica virgifera vir-
gifera) adults were attracted to a different set of compounds:
estragole (4-methoxy-l-allylbenzene) (35), E-anethole (36),
and indole. Estragole (35) was an effective attractant from
early August (corn tasseling) until early October. 4-Me-
thoxycinnamaldehyde and 4-methoxy-1-propylbenzene also
are potent attractants (Metcalf and Lampman, 1989). Euge-
nol (18), isoeugenol, and cinnamyl alcohol significantly at-
tracted northern corn root worm (Diabrotica barberi) adults
(Lampman et ai., 1987; Metcalf and Lampman, 1989).
The effects of a series of phenolic compounds in artificial
diets on biotype B greenbugs (Schizaphis graminum) has
been evaluated (Levin, 1976, Todd et ai., 1971). Z-Caffeic
acid (but not E-caffeic acid) caused a drastic reduction in
growth and inhibited reproduction. Less than 20% of the
greenhugs survived on diets that contained vanillic, sinapic,
gentisic, or ferulic acids (Todd et ai., 1971).
Isoasarone (37) (from Piper Jutokadzura, Piperaceae) and
piperenone (38) are highly active as antifeedants against
Spodoptera litura (Seigler. 1983).
114 Phenylpropanoids

zingerone gingerol (40) paradol

Zingiber officinak

CH,NHCO(CH,),CII=CHCH(CH,), CH=CHCII=CHCQ---NQ

¢loc~
OH
~, 0---.1
ar-turmerine capsaicin (20) piperine (21)
Curcuma /onga Capsicum annuum Piper nigrum

Fig. 8.9. Pungent principles from plants (modified from Harhorne. 1982).

A series of structurally similar compounds derived by LlGl'IIl'I

acetate extension of phenylpropanoid precursors is also
found in the Piperaceae. Pipercide (39) from Piper nigrum
was insecticidal, but the mixture of amides from this plant
was significantly more toxic and it appears that co-occurring
compounds exert synergistic effects (Fig. 8.11) (Berenbaum,
1985).
Gingerol (40) (Fig. 8.9), a pungent principle of Zingiber
officinale (Zingiberaceae), ginger, has cardiotonic activity
(Shoji et aI., 1982).
Phenylpropanoid glycosides such as mussatioside I (41)
(Fig. 8.9) from a Mussatia species (Bignoniaceae) are re-
ported to have medicinal properties. Some species are
chewed with coca or alone in Peru and Bolivia (Jimenez et
al.,1987).
Lignin is the most abundant and most widely distributed
phenolic natural product in higher plants. This material,
which is associated with the advent of land plants, is not
found in algae, nor is true lignin found in bryophytes (Lewis
and Yamamoto, 1990; Zinsmeister and Mues, 1987). Only
with lignified walls was it possible to build the rigid stems
of woody plants and trees and the conducting elements for
water transport (Grisebach, 1981).
It is not possible to designate a definitive structure for
this amorphous polymeric material. Lignin is difficult to iso-
late in its natural state and is difficult to degrade chemically.
Nonetheless, there is general agreement concerning the prin-

OH OH
12

OCH, OCH,

OH

~
"OH "
HO~< _''''''0, 0
HO
HO
.0 ,• 0 ,. HO~
OH OCH,
OHI" OCH,

A(+)(23) 8(.)(24)

Fig. 8.10. Dehydrodiconiferyl alcoholj3-D-glycosides.

 Phenylpropanoids 115

o
<o NH~
o
plpercide (39)
o
<o NH~
dihydroplpercide

o
<o
o
guineensine
o

~ NH~
o
piperstachine

piperine (11) pellitorlne

Fig. 8.11. Extended phenylpropanoids from Piper species.

cipal Structural features and the manner in which it is formed
in the plant.
Analytical methods for the detection and study of lignin
have been reviewed (Lewis and Yamamotu, 1990).
Composition of Lignin
Plant lignins can be divided into three broad classes that
are usually referred to as softwood (gymnosperm), hardwood
(dicotyledonous angiosperms), and grass or annual plant
(monocotyledonous angiosperm) lignins. All are polymers
formed largely, ifnot entirely, from C.-C3 monomeric units.
Coniferous or softwood lignins often are derived from coni-
feryl alcohol (42) (Fig. 8.8), but more variety exists than has
heen recognized in the past (Lewis and Yamamoto, 1990).
Syringyl-hased lignins also are found in many gymno-
sperms. Hardwood lignins are formed mostly from coniferyl
and sinapyl (43) alcohols [e.g., in beech lignin the ratio is
about I: I (Fig. 8.12)], but, again, many exceptions exist.
Finally, lignins from grasses and from such plants as bamboo
and palms involve p-coumaryl alcohol (44) in addition to
the coniferyl and sinapyl monomers.
Origin of tbe Monomeric Units
The formation of the monomeric units has been described
in Section 8.3. The mechanism and regulation of transport
of monomers from the cytoplasm into the cell wall and the
subsequent polymerization are not well understood (Davin
et aI., 1992; Lewis and Yamamoto, 1990). Only p-coumaric,
ferulic, and sinapic acids are viewed as bona fide lignin
precursors; they are converted into the corresponding mono-
mers without modification of the aromatic ring (Lewis and
Yamamoto, 1990). The principal monomeric units (monolig-
nols) are p-coumaryl alcohol (44), coniferyl alcohol (42),
and sinapyl alcohol (43), although other compounds also
may be involved. Most of the enzymes required for monomer
formation have heen purified and reasonably well character-
ized (Davin et aI., 1992; Lewis and Yamamoto, 1990). An
oxidoreductase, cinoamyl alcohol dehydrogenase (EC
1.1.1.195), catalyzes the fmal reductive step of monolignol
synthesis. This enzyme has been detected in various gymno-
sperm and angiosperm species (Davin et aI., 1992). Ferulic
acid is incorporated into coniferyl alcohol and the lignin of
wheat without degradation.
In general, the levels of monomeric compounds in plants
is small. Coniferyl alcohol occurs in the sap of gymnosperms
as the glucoside, coniferin (45) and sinapyl alcohol as the
glycoside, syringin (46) (Fig. 8.13). These compounds are
accumulated only rarely in angiosperms. In has heen sug-
gested by some that the corresponding f3-glucosides are in-
volved in transport of the precursors through the plasma
116 Phenylpropanoids

9'
~H,OH CH,OH
CH I 'fL
A
OHCCH, CH

0
- , HOCH, CH· CH CJr"" - ---..CH, C
co *CH_~H ~:,OH

0 :(
I : CH,O"f' I ..., CH- CH,o O---CH
~H, CH,·O

*
OCH, 0-
"OCH,
CH~~CH' CH----O CH,OYOCH,
CH· Q
0 - CH OH CH9
1-<

°---CH - OCH ~ CH~HOCH, CH,OH

CH,O~ I h ~' 'I ~ o----~H / 0
I ~ OCH, I - IH"
CHP ~CH~:::-O *C~OH OCH, ~c'"
• ______CH,OH CH,OH I I ~
~H,OH C~H,O-y

M" I
CH OCH OCH,
~~O--CH co ~ ,
- CH "=(OCH, I I HOCH,·CH·C~
~
~
'" I
CH 0
'0
'" "" CH,OH
O-CH
CH,OH
~H OCH,
0
·CH,
OCH, II~

*
I , I

~ HOCH,.CH.CHO ;OCO ~CH~O~:_

~H-CHO '" I I '" OCH',¢-
- CH CH,O CH,O.& I
~H*OH
~ O~H OCH, CH,.O ~
CH",I c~ «;I

*
C"--
.. - - 0 OCH, I I
HOCH, CH

~
'"
I
OCH3
CH,OHcH.O
"
CHOH
CII
""

0
OCH
'0
OCH~
3 ~
I
CH

?
CH-CHO
,
CH,OH CH,o '"
I
OCH,
CH,·O I .&
OH
0-

Fig. 8.12. Structure of beechwood lignin (modified from Grisebach, 1981; used with permission of the copyright owner, Academic Press, Orlando, FL).

o o
~O.gIUCOSYI
SCoA ~SCOA
HO
via quinate
intermediate• HOY ----....~ RO~
OCH,
OH
coniferin (p·D-glueosyl) (45)

via quinate intermediate

+
+ + 0
~OI~HrO~S~:~·O~O.g1UCOSYI
HO
~ HOY -- OCH,
RO~
OCH,
p.coumaryl alcohol (44) syringin (R = ~·D·g1ucosyl) (46)

Fig. 8.13. Fonnation of coniferin and syringin.


membrane and to the cell wall where lignification occurs;
the corresponding l3-glucosidases are present (Davin et aI.,
1992). Alternatively, these glucosides may serve only as
storage products.
Coniferin can be incorporated into lignin in a variety of
species (Grisebach, 1981) and, because a l3-glucosidase has
been located in the xylem of some plants, it is possible that
this enzyme controls the rate and location of lignification.
Although coniferin is incorporated into lignin, there is little
evidence that it is an obligatory precursor. Compounds of
this type may be involved in transport of the monomers
(Lewis and Yamamoto, 1990).
Although Z-monolignols occur in many plants (e.g., in
the bark of Fagus grandifolia), these appear to arise from
E-monolignols by enzymatic reactions (Davin et a1., 1992).
Polymerization of Lignin
The phenylpropanoid monomeric units responsible for
the formation of lignin are polymerized by the action of
peroxidase enzymes (Grisebach, 1981; Lewis and Yama-
moto, 1990). Coupling of phenoxy radicals leads to dilignols
and, afler reoxidation and radical coupling, to oligomeric
units, and, finally, to the lignin macromolecule (Grisebach,
1981). The half-life of the typical flee-radical intermediate
is about 45 s.
Lignin is deposited initially at the outer layers of the cell
wall, and the enzymes which control the oxidative process
must be located near these sites. A carbohydrate matrix may
be required for polymerization of Iignins (Haslam, 1974).
The molecular architecture of lignin is complex but not
completely random, with a methodical distribution of certain
types of linkage and certain building units throughout the
structure (Haslam, 1974; Lewis and Yamamoto, 1990).
There is much need for additional study of lignin (United
States Department of Energy, 1988). However, new ap-
proaches such as the use of enzymes from Iiguin-degrading
fungi and solid-state 13C-NMR spectroscopy promise to pro-
vide resolution of problems long considered intractable
(Lewis and Yamamoto, 1990).
L101'1A1'1S
Dimeric compounds derived from precursors related to those
involved in the formation of lignin are distributed widely
among higher plants (Davin et a1., 1992; MacRae and Tow-
ers, 1984; Pelter, 1986; Weinges and Spiinig, 1967). About
450 Iignans from at least 55 families are known (Ayres and
Loike, 1990), especially from the Asteraceae, Pinaceae, and
Rutaceae. Four major subtypes occur: dibenzylbutane deriv-
atives (47), dibenzylbutryolactones (lignanolides or deriva-
tives of butanolide) (49), monoepoxy Iignans ·or derivatives
of tetrahydrofuran (49), and bisepoxylignans or derivatives
of 3,7-dioxabicyclo(3.3.0)-octane (50) (Fig. 8.14) (MacRae
and Towers, 1984). The use of spectroscopic methods for
characterization of this group of compounds has been re-
Phenylpropanoids 117
viewed (Ayres and Loike, 1990). Lignans are related closely
to intermediates in the biosynthesis of lignin and probably
are formed from analogous pathways. It should be noted,
however, that the majority of Iignans occur in distinctive
chiral forms, whereas most Iignins do not; no optically active
degradation product of lignin has yet been isolated. Calli of
Podophyllum peltatum produce the same array of Iignans
[podophyllotoxin (51) (Fig. 8.15), a-peltatin (52), and 13-
peltatin (53) (Fig. 8.17) as the plant rhizome. Lignans also
have been found in cell cultures of plants for which no previ-
ous record of Iignans occurs. For example, root organ cul-
tures of Unum flavum yield very toxic extracts. This toxicity
is caused by the presence of 5-methoxypodophyllotoxin, ap-
parently as the 4-0-glucoside in the culture (Ellis, 1988).
Biosynthesis
Many Iignans occur in optically active forms, suggesting
that the coupling process is stereoselective. In other in-
stances, however, enantiomeric mixtures are encountered
(Davin et a1., 1992). This may require the presence of two
stereoselective enzymes with different activities. Alterna-
tively, optically active compounds may be racemized in later
steps in some instances.
Coniferyl alcohol (42) is the specific precursor of (-)-
secoisolariciresinol (54) in the presence of NADH, H2 0 2 ,
and a crude cell extract from Forsythia intermedia (Ume-
zawa et a1., 1990a). A specific dehydrogenation then occurs
to afford (- )-matairesinol (55). In Forsythia suspensa, coni-
feryl alcohol is the precursor of ( + )-pinoresinol (56). For-
mation of these compounds involves a direct stereochemi-
cally controlled coupling of couiferyl-alcohol-derived
moieties. This conversion has been demonstrated both in
vivo and in vitro with a crude enzyme preparation (Davin
et a1., 1992; Umezawa et a1., 1990b). Nonspecific coupling
occurs in the presence of H 20 2 and horseradish peroxidase.
Subsequent processes are dependent on the regiochemistry
and stereochemistry of the initial linkage (Fig. 8.16) (Davin
et a1., 1992; Weinges and Spiinig, 1967).
The results of these studies have been explained tenta-
tively in the following manner (Davin et a1., 1992). IriFor-
sythia suspensa stems, couiferyl alcohol undergoes stereose-
lective condensation to form the putative (-) (8R,8R,)-
quinone methide (Fig. 8.16), and not the corresponding ( + )-
enantiomer. Subsequent intramolecular cyclization of the
( - )-form yields ( + )-pinoresinol (56). In contrast, coniferyl
alcohol in cell-free extracts of Forsythia suspensa is not
properly compartmentalized and is in contact with nonspe-
cific peroxidases as well as the stereospecific coupling sys-
tem producing both ( + )- and ( - )-pinoresinol. When F or-
sythia . intermedia cell'free extracts are incubated with
coniferyl alcohol, both ( + )- and ( - )-quinone methides are
produced when H 20 2 is present as a cofactor. The (-)-
antipode is reduced by a stereoselective NAD(P)H requiring
reductase to form (- )-secoisolariciresinol (54); the (+)-
form is not reduced. Lastly, in a stereoselective enzymatic
NAD(P)-requiring dehydrogenation, only (- )-secoisolar·
118 Phenylpropanoids

x ~x
~1'1 - -
OCH,
I
I
I
OCH,
o 0

l o HO
H

X HO
CH,O H".. H
x
o

~
\

{~ )
Ho?cfCJ H""'"

h, , , , 0
"" H
::::::...
\

(. )-dihydrosesamin
OCH, OH
dibenzylbulane type (47)
OH nordihydroguaiuretic acid

CH,- 0 "" monoepoKy or tetrahydrofuran type (49)

OCOC~,CH' ~ 0

CH,O
o
CH,'O
o
asarinin
justicidin-A
o
' - - 0 3,7-dioxabicyclo(3.3.0)·octane type (50)

lignanolide or butenolide type (48)

Fig. 8.14. Types of lignans and their (probable) biosynthetic relationships (modified from Whiting, 1985; used with permission of the copyright owner,
the Royal Society of Chemistry).

iresinol is converted to ( - )-matairesinol (Davin et aI., 1992;
Umezawa et aI., 1990a,b),
Phenylalanine and p-coumaric acid, but not 3,4-dihydrox-
ycinnamic (caffeic) acid or acetate, were incorporated into
podophyllotoxin (51). In Podophyllum hexandrum (Berberi-
daceae), both cinnamic and ferulic acids are incorporated
into both halves of the molecule. The carbon of the O-methyl
group of ferulic acid is distributed into both rings A and C.
Sinapic and 3,4,5-trimethoxycinnamic acids are not incorpo-
rated. This suggests that other oxidation and methylation
occurs after the initial dimerization reaction (Jackson and
Dewick, 1984; Pelter, 1986; Poulton, 1981).
Biological Activity
Many of the biological activities of lignans have been
reviewed (Davin et aI., 1992). These compounds may be
antimicrobial, antifungal, or antifeedant in a number of in-
stances. They may also be active in plants. A lignan (34)
isolated from the seed hulls of Aegi/ops ovata (Poaceae) is
a potent germination inhibitor for lettuce seeds (Lavie et aI.,
1974).
Lignans are known to be active in plant-insect relation-
ships. Sesarnin (58) (Fig. 8.17) occurs in Sesamum indicum
(Pedaliaceae) seed oil, as well as in a number of other plants.
This compound was isolated from Magnolia kobus (Magno-
liaceae) and demonstrated to be a growth-inhibiting sub-
stance for Bombyx mori (Karnikado et aI., 1975). Lignans,
for example, those of Piper Jutokadzura and Libocedrus va-
teensis, have antifeedant propereties as well (Davin et aI.,
1992).
Sesarnin (58) and asirinin (59) are effective in synergizing
the activity of insecticides (MacRae and Towers, 1984). The
methylenedioxy groups deactivate mixed-function oxidases
needed to detoxify the insecticides.
 Phenylpropanoids 119

~ ~:~o 1');0.:
~
<O~o
o~....{
() ._ oo~, ~
~OCH' / HO
I
00

¥ i,~,
OH
LOH

CH,-O""'-
OCH,
OCH, CH,-0 ~O
2''':::'''''- OH

podophylloloxln (51) HO """ HO

ferulicadd OCH, pinoresinol (56)

Fig. 8.15. Proposed precursors of some lignans.

ooq -
OH HO

OCH,
CH,O OCH,
coniferyl alcohol
o
NADPH!
H 0
2 2

HO
! ome:O:oH
(-)-(8R,8 R)-quinone

::?" H 8H """ OCH,

O
HOV'
CH,o OCH, OCH, (+)'pinoresinol (56)

CH,O

HO

OH
OH

(.)-.e<o·ISOIBrlclresinol
.. (54)
ynlheSls of (_)-mataIresinol
. and related r (.)-mataireSlnol
. (55)
Fig. 8.16. Bios . Ignans (based on data fro m Umezawa et aI., 1990 a,b).
120 Phenylpropanoids
sesamio (58)
OR
OCH,
o
OCH,
justicidin A (R=CH,) (85)
justicidin B (R=H) (86)
CH,.O
HO
a-(-)-peltatin (R=OH) (52)
~-peltatin (R=OCH,J (53)
(a)
Fig. 8.17. (a & b) Some biologically active lignans.
Justicidin A and B (85, 86) (Fig_ 8_17), from Justicia
hayatai, have piscicidal activity as powerful as that of rote-
none (Davin et al_, 1992).
Nordihydtoguaiaretic acid (NOGA) (60) is found in latge
quantities in Larrea divaricata (creosote bush, Zygophylla-
ceae), a plant that is extremely abundant in the Chihuahuan,
Sonoran, and Mojave deserts, as well as in southern South
America. This compound was widely used in the food indus-
try for several yeats as an antioxidant, but its use has recently
been restricted. NOGA possesses light-activated toxicity
(Downum, 1992).
At least 40 lignans ate known to have antitumor and anti-
viral activity and many ate cytotoxic (Ayres and Loike,
1990; Davin et al., 1992; MacRae and Towers, 1984; Mac-
Rae et al., 1989), although there ate no common structural
features to explain this activity. Podophyllotoxin (51) (Fig.
8.15), which has been isolated from a number of plant spe-
cies, is a potent antineoplastic (i.e., tumor destructive) com-
pound. Although too toxic for practical value, synthetically
OH
OH
OCH,
guaiaretic acid
OCH,
OH
(57)
modified derivatives with reduced toxicity may be useful in
this regatd (Kinghorn, 1992). Podophyllum resin has long
been used for treating venereal watts; podophyllotoxin, 13-
peltatin (53), deoxypodophyllotuxin, picropodophyllotoxin,
and a-peltatin (52) all have activity against measles and
herpes simplex type I viruses. A variety of lignans inhibit
activity of certain enzymes. Among these ate the enzymes
of respiration and cAMP phosphodiesterase (MacRae and
Towers, 1984).
Compounds structurally related to podophyllotoxin often
have antimitotic activity. They arrest cultured cells at meta-
phase and bind to purified tubulin prepatations. The lactone
ring of podophyllotoxin is involved in this binding (MacRae
and Towers, 1984).
A phenolic compound that resembles lignans in structure,
platyphylloside (61), from Betula pendula, the Scandinavian
birch, has been shown to account for 80% of the observed
depression of in vitro organic matter digestibility in ruminant
test systems (Sunnerheim et al., 1988). This observation cor-
 Phenylpropanoids 121

relates with seasonal variation of phenolic compounds in the
plant and with observed resistance to herbivores. Platyphyl-
loside also occurs in B. platyphylla, the Japanese birch.
A number of other types of biological activity have been
reviewed (MacRae and Towers, 1984).
1'IEOLiGNAi'lS
Related dimers in which the two C.-C, units are joined by
dimerization of the aromatic rings instead of by the propa-
noid "tail" are called neolignans (Davin et aI., 1992; Got-
tlieb, 1978). Eusiderin (62) is an example of this type of
compound (Fig. 8.17). Neolignans occur commonly in the
heartwood of species of the families Lauraceae, Magno-
liaceae, and Piperaceae. Neolignans also occur in the fruit
and seed of Ocotea veraguensis (Lauraceae). These fruits
are involved in a number of biological interactions (Dodson
et aI., 1987).
HYDROXYBENZOIC ACID CCs-C,) CO!IIPOUl'lDS
A family of hydroxybenzoic acids (C.-C l ) and structurally
related compounds in plants is derived from cinnamic acid
and p-coumaric acid. These are sometimes similar in struc-
ture to compounds derived from acetate-malonate pathways
(e.g., 6-methylsalicylic acid) and to those derived from early
intermediates in the shikimic acid pathway (often from shiki-
mic or quinic acid) (see Cbapters 6 and 7). Hydroxybenzoic
acids usually occur in plants as esters or as glucosides that
are widely distributed among higher plants. Salicin (63) was
the first glucoside to be found in nature; it is widely distrib-
uted in the Salicaceae, the willow family.
Biosynthesis
Hydroxybenzoic acids may arise by polyketide pathways
(primarily in bacteria and fungi), from shikimate and possi-
bly other intermediates of the sbikimate pathway, by l3-oxi-
dation of cinnamic acid and related compounds, and by hy-
droxylation of benzoic acid and other C6-C l compounds
(Leon et aI., 1993; Yalpani et aI., 1993).
In virus-inoculated tobacco, benzoic acid is converted by
the monooxygenase enzyme, benzoic acid 2-hydroylase, into
salicylic acid. NADPH was required. Feeding of phenylala-
nine, cinnamic acid, or o-coumaric acid (all potential precur-
sors) failed to induce the enzyme (Leon et aI., 1993).
L-Phenylalanine and cinnarnic acid serve as efficient pre-
cursors for salicin (63) (Fig. 8.18) (Pridliam and Saltmarsh
1963; Zenk 1967). The initial steps of this process involve
l3-oxidation and removal of acetyl-CoA from the side chain

voJ:'
OCH,

OCH,
kobusin

: ,.
monoepoxylignanolide
0\

o
oE},
(I#HO
""'"
H·
OH~O
,H
CH,-O?,

CH,.O :::,...
OCH,
I 0
~

o asirinin (59) eusiderin (62)

OH

HO HO-Q--lYY'-O-OH

OCH, O-~.D.g1u<osyl

I
plalyphylloside (61)
OH
silycbristin
(a) a navono-lignan
Fig. 8.17. (continued)
122 Phenyipropanoids
C02-
~
I
~
H''''''
NH,+
- I"""
JOI --- ~ VI
phenylalanine (4)
HO~O~
OH
HO
OH CHO
H H
helicin
(b) (64)
Fig. 8.18. Proposed biosynthesis of salicin (modified from Zenk, 1967).
of the phenylpropanoid substrate. A related compound, 0-
hydroxybenzyl-[3-D-glucoside (64), was formed from sali-
genin (83), but not salicin (63). It has been suggested that
vanillin (84) (Fig. 8.18) results from the breakdown offerulic
acid in a similar manner (Gross, 1981; Haslam, 1974). This
general process has been proposed by Zenk (1979) as a way
to explain the origin of many types of C 6 -C, compounds
(Fig. 8.19).
Ferulic, caffeic, and related acids, derived from cinnamic
and p-coumaric acid, give rise to a family of C6 -C, deriva-
tives.
Distribution of Hydroxybenzoic Acids and
Their Derivatives
Many hydroxybenzoic-acid-derived (C6 -C,) compounds
(acids, esters, aldehydes, alcohols, etc.) are found in the es-
sential oils of plants. Several essential oils have commercial
importance, although many important components are read-
ily synthesized. In many cases, the synthetic products have
eclipsed the naturally occurring ones in importance. For ex-
ample, vanilla extract contains vanillin (Fig. 8.18). As the
user of synthetic vanilla will realize, however, synthetic sub-
stitutes often lack minor components that make natural va-
nilla preferable.
In some fungi, salicylic acid (65) and related compounds,
such as 6-methylsalicylic acid, are derived from acetate-ma-
lonate pathways. In bacterial systems, similar compounds
are derived from chorismic acid via isochorismic acid (see
Chapter 7). Salicylic acid often is found in species of Salix
(X1---+
o
~
CHO
OH_
# ~ OH
E-cinnamic acid (1) salicylaldehyde
~
OH
HOHO 0
OH CH,OH
salicin (63)
CHO
H"~ CH,OH
~~, OH
saligenin (83) vanillin (84)
and Populus (Salicaceae) and in a number of other higher
plants.
The methyl ester of salicylic acid is encountered com-
monly in essential oils and is especially abundant in the oil
of wintergreen (Gaultheria procumbens, Ericaceae). Methyl
salicylate occurs as a glycoside but is hydrolyzed upon injury
to the plant. This ester is widely used as a flavoring in can-
dies and as a perfumery ingredient. It is a major component
of liniments and is reputed to have antirheumatic properties.
Anisaldehyde (66) (Fig. 8.19), a major component of the
seed oil of anise (Pimpinella anisum, Apiaceae), also is used
widely as a flavoring.
Biological Activity
C6 C,-Phenolics and their derivatives have a range of bio-
logical activities. One such compound, salicylic acid (65),
has extensive functions in plants (Leon et aI., 1993; Raskin,
1992a, 1992b; Yalpani et aI., 1993). Others are involved in
plant movements, play developmental roles, are participants
in plant-insect interactions and plant-plant interactions (al-
lelopathy), or play defensive or pheromonal roles in insects.
Salicylic acid has long been known to be an analgesic,
antipyretic, and anti-inflammatory compound. Willow bark
has been used for thousands of years by peoples from various
parts of the worlds as a pain reliever. Aspirin, the sodium
salt of acetylsalicylic acid, was introduced in 1898 by the
German chemical company Bayer as a medicinal. This com-
pound has become one of the world's leading drugs. Ameri-
cans consume over 16,000 tons annually at a cost of $2
 Phenyipropanoids 123

billion (Raskin, 1992a, 1992b). In humans, aspirin blocks
the synthesis of prostaglandins involved in pain and bleeding
responses (see Chapter 2), as well as a variety of other ac-
tions. Surprisingly, salicyclic acid has been found to be an
important endogenous substance in plants as well (Yalpani
et a!., 1993). Salicylic acid induces flowering in many plants.
In addition, this phenolic compound initiates a series of
events in thermogenic plants, notably those of the family
Araceae, that lead to a rise in temperature of the reproductive
parts as well as formation of amines involved in pollination
of the plants (Raskin, 1992a, 1992b). Salicylic acid also is
involved in disease resistance of plants. This compound is
exported from the site of infection to uninfected tissues; the
highest concentrations are observed in and around hypersen·
sitive lesions (Raskin, 1992a, 1992b). Salicylic acid also
has been found to occur in allelopathically active phenolic
fractions and inhibits growth of surrounding vegetation.
Certain gallic acid glycosides such as K-PLMF 1 (67)
(turgorins) are involved in turgor movement in plants and
folding of leaves of plants such as Mimosa pudica (Faba-
ceae) (Schildknecht, 1983).
Acetosyringone (68) and a-hydroxyacetosyringone (69)
activate the virulence (Vir) gene in Agrobacterium tumefa·
ciens. These molecules induce the entire vir regulon as well
as the formation of T·DNA intermediate molecules (Fig.
8.20) (Stachel et a!., 1985). However, these compounds do
not appear to be common in plants. The lignin precursors,
sinapyl (43) (Fig. 8.1) and coniferyl alcohol (42) (Fig. 8.7)
have activity in the range of that of acetosyringone (Spencer
and Towers, 1988).
Larvae of the butterfly Papilio glaucus glaucus feed
mainly on members of the Magnoliaceae, but rarely survive
past the first instar when fed plant material of the genus
Populus (Salicaceae). In contrast, larvae of Papilio glaucus
canadensis perform well on aspen and other Populus spe-
cies, but die when fed members of the Magnoliaceae (Lin·
droth et a!., 1988). The major compounds responsible for the
lack of acceptability of Populus species to larvae of Papilio

o 0

~~~OH
~CO,.

H'''~H'+
V
() __
HO~ ...

j
~ p.coumaric acid (2)
phenylalanine (4)

~
(yCO,H

~OH -- V I ....::::-
COlH

HO~
(Y COH
1

salicylic acid (65) benzoic acid p-hydroxybenzoic acid (78)

o
Ho)(yCOlH HO~
I -- I ~ OH
HO""::::- HO""::::-

protocatechuic acid caffeic acid (12)

! o
CH3'O~
I "" OH
HO #
vanillic acid (77) ferulie acid (13)

Q CHO
CH"OXlCOlH

HO
I ""
#
OCH,

syringic acid (80)

--
CHjO~"'" CO,H
HO
I h
OCH,

sinapic acid (14)

anisaldehyde (66)

Fig. 8.19. Suggested route of biosynthesis for some C6 -C, compounds (modified from Haslam, 1974),
124 Phenylpropanoids
glaucus glaucus are four phenolic glycosides, salicin (63),
salicortin (70), tremuloidin (71), and tremulacin (72) (Lin-
droth et aI., 1987a). All four compounds occurred in P. trem-
ulaides and P. grandidentata, but tremulacin was lacking
from P. deltaides (Lindroth et aI., 1987b). Special care must
be used in studies of these compounds in Populus and Salix
tissues, however, because the amounts varied dramatically
when leaves were freeze-dried or oven-dried. These changes
in composition were avoided only by working with fresh
plant tissue (Lindroth and Pajutee, 1987).
Several simple phenols are found as defensive com-
pounds in insects (Fig. 8.21).
Although many chrysomelid beetles synthesize and accu-
mulate iridoid monoterpenes (see Chapter 20), which ap-
pears to be a primitive defensive system within the family,
several species of the genera Chrysamela (subttibe
Chrysomelina) and Phratora (subttibe Phyllodectina) have
shifted onto plants of the genus Salix (Pasteels et aI., 1988;
Rowell-Rabier and Pasteels, 1986). In this instance, the in-
sect larvae convert salicin (63) from the plant into salicylal-
dehyde (73). Laboratory tests with a generalist predator ant
acetosyringone (68) a;·hydroxyacetosyringone (69)
HO~O, -0
HO~O ~
OHH CH,OH
salicin (63)
tremuloidin (71)
Fig. 8.20. Some biologically active
Myrmica rubra show that salicylaldehyde is a more potent
deterrent that salicin (63) or its aglycone saligenin (83). The
eggs of some of the beetles that feed on members of the
Salicaceae contain salicin. Salicylaldehyde is detected in ne-
onate larvae, suggesting that salicin is quickly converted to
the aldehyde (Pasteels et aI., 1986; Rowell-Rabier and Pas-
teels, 1986). This shift to members of the willow family
appears to have occurred at least three times independently.
The species that shifted are able to exploit a food source,
yet are well protected. The larvae are provided with an addi-
tional method of defense; the adults are able to sequester
sufficient salicin in the eggs to make them potentially lethal
to ants and to provide protection for the neonate larvae (Pas-
teels et aI., 1986, 1988, 1989; Rowell-Rabier and Pasteels,
1986).
The simple phenolic compounds 5-ethyl-2-methoxy-
phenol, phenol (74), guaiacol, and veralrole (33) (Fig. 8.8)
have been proposed as sex pheromones for grasshoppers;
phenol (73), a-cresol, p-cresol (75), guaiacol, hydroquinone
(76), catechol, p-benzoquinone, 4-methoxybenzaldehyde,
2,6,6-trimethylcyclohex-2-ene-1,4-dione, isophorone, and
K-PLMF 1 (67)
j
HOH4o-o
~
O~o
salicortin (70) lJ
tremulacin (72)
C6~Cl compounds.

¢ A
OH
p-cresol (75) hydroquinone
ground-beetle
Calasoma
protocatechuic acid
methyl ester
water-beetle
Dytiscus
Fig. 8.21. Some simple phenols used as defensive agents by arthropods (modified from Harhorne, 1982).
2,5-dichlorophenol have been isolated from grasshopper de-
fensive secretions (Whitman, 1990). The sex pheromone of
the soybean cyst nematode, Heterodera glycines, has been
identified as vanillic acid (77) (Jaffe et aI., 1989).
p-Hydroxybenzoic acid (78) (Fig. 8.20) has vitamin-like
activity in some organisms. This growth factor requirement
is associated with the formation of ubiquinone (coenzyme
Q). The compound serves as an effective precursor for the
benzoquinone ring of ubiquinone in mammals, bacteria,
fungi, and plants (Haslam, 1974; also see preceding chapter).
ALLELOPATHY
Compounds derived from shikimic acid pathways and espe-
cially phenolic substances have been encountered in a num-
ber of studies of chemical interactions between plants. This
"chemical warfare" is often called allelopathy. Although
much controversy surrounds the importance of this phenom-
enon, allelopathy seems to be most important in seasonally
dry habitats.
A number of phenylpropanoid-derived compounds are
capable of inhibition of seed germination and seedling
growth of other plants. Dihydrocinnamic acid (79), from
Ceratiola ericoides (Empetraceae), a common plant in the
Florida scrub, was shown to inhibit both germination and
growth of Schizachyrium scoparium (little blue stem,
Poaceae), Leptochloa dubia (Poaceae), Rudbeckia hirta (As-
Phenylpropanoids 125
A
y OH
Y CO,H
(76) p-hydroxybenzoic acid (78)
water-beetle
Dytiscus
6
OH
~
cx
CHO
#' OH
phenol (74) salicylaldehyde (73)
grass grub beetle water-boatman
Notonecta
teraceae), and Heterotheca subaxillaris (Asteraceae). This
compound had little effect on big blue stem (Andropogon
gerardii, Poaceae) (Fischer, et aI., 1988; Weidenhamer et
aI., 1988).
In the Mojave desert of California, the well-known plant
physiologist Fritz Went observed that the soil was usually
bare around the shrub EnceliaJarinosa (Asteraceae) (Went,
1970). He suggested that this situation was produced by the
toxic effects of the root exudates. Exudates of the plant are
apparently not self-inhibitory, but they inhibit growth of
most annual plants. An active substance was later identified
as 3-acetyl-6-methoxybenzaldehyde (82) (Fig. 8.22). Al-
though primarily produced in the leaves, this toxin is re-
leased when the leaves fall to the ground and decompose.
It is persistent and is not removed, except by very heavy
rains (Muller, 1953; Harborne, 1982).
The Californian chaparral is a vegetational area of rela-
tively low Mediterranean rainfall (i.e., wet cool winters and
hot dry summers) along the coastal strip of southern Califor-
nia. Many areas of chaparral are adjacent to areas of natural,
uncultivated grassland. One of the most striking natural phe-
nomena of this shrubby grassland area is the zonation of
herbs around the thickets of shrubs which dominate this
flora. Two of the dominant shrubs in the chaparral are cham-
ise, AdenostomaJasiculatum (Rosaceae) and Arctostaphylos
glandulosa (Ericacae). Both are widespread and reported to
exert allelopathic effects on herbs. Adenostoma grows in
pure stands on dry exposed slopes. Even though the soil is
fully exposed to the sun and receives ample rain, no herbs
 cc"'
126 PhenyJpropanoids

o o

~OH ~OH
CO,H

b OH
l(AOH HO~
salicylic acid (6S) o-coumaric acid (81) p-coumaric acid (2)

o
CH'.O~OH
(yCO,H CH,·0 r(YCO,H

HO~
HO~ HO~
ferotic acid (13) p-hydroxybenzoic acid (78) vanillic acid (77)

))H'
YCHO
OCH,

dihydrocinnamic acid (79) syringic acid (SO) 3-acetyl-6-methoxybenza1dehyde

Enceliafarinosa (82)

Fig. 8.22. Phenylpropanoid-derived compounds with allelopathic activity.

grow in the vicinity of the lower slopes. Adjacent roadsides
produce a heavy crop of anouals.
Experiments of McPherson and Muller (1969), McPher-
son et al. (1971), and Muller and Chou (1972) have shown
that substances responsible for the observed allelopathic ef-
fects are water soluble and waterborne with both species.
One of the major climatic features of this vegetation is
coastal fog; even in the summer months and although rainfall
is only moderate, there is a constant drip of moisture on to
the leaves of these shrubs and, hence, onto the surrounding
soil. This dripping is sufficient to carry a regular supply of
water-soluble inhibitors from leaves to the soil where they
remain in sufficient concentration to prevent growth or seed
germination of any anoual species near these shrubs (Mc-
Pherson and Muller, 1969).
The leaves of both Adenostoma and Arctostaphylos spe-
cies are relatively rich in water-soluble compounds and it is
not surprising that the inhibitors turned out to be varying
mixtures of phenols and phenolic derivatives (Fig. 8.22). A
similar, but not identical range of compounds, was isolated
by leaching the foliage and by extracting the surrounding
soil. Differences between leachate and soil probably occur
because some leachate compounds are irreversibly bound to
the soil or metabolized rapidly by microorganisms (Bar-
borne, 1982; McPherson et aI., 1971; Muller and Chou,
1972). All of the compounds involved were simple, wide-
spread phenolics derived from shikimic acid. Among the
active compounds were hydroquinone (76) and p-hydrox-
ybenzoic (78), and vanillic (77), syringic (80), o-coumarlc
(81), cinnamic (1), salicylic (65), and ferulic acids (13) (Fig.
8.22). The effects of several of these compounds have been
examined in other systems. Ferulic acid (13) is especially
toxic to several test species (Blum and Dalton, 1985a,b;
Blum et al., 1987; Toro et al., 1988).
Periodic occurrence of fire removes the litter from the
ground. During the following rainy season, growth of herbs
is again observed in the area around the shrubby plants. Most
of the shrubs survive the fires as crowns. Over a period of
years, the shrubs again "poison" the ground around them
and the herbs gradually disappear.
As is true for most allelopathy problems, one must con-
sider many factors. Among these are nutrition, water, min-
erals, soil oxygen, shading versus light, grazing effects, and
all of the above combined.
Several plants that normally grow in chaparral areas (Bro-
mus rigidus (introduced), Oenothera micrantha, Helian-
themum scoparium, Lotus scoparius, and Calindrinia cil-
iata) were tested (in addition to tomato and other cultivated
plants). Seed germination was markedly decreased and plant
growth strongly inhibited (McPherson and Muller, 1969).
The allelopathic effects are cyclic and seem to involve
the following series of events: Materials accumulate in the
soil in the dry season. Rain carries the toxins into the soil
where they are absorbed into the top 3 cm of soil. The effec-
tiveness of procedures for isolation of phenolic acids from
soil have been evaluated (Dalton et al., 1987). These biologi-

cally active compounds inhibit germination of virtually all
seeds, and when the seeds do germinate, they fail to develop.
Root growth is suppressed. Fire interrupts the cycle by re-
moving the source of the phytotoxins and destroying some
of the accumulated compounds near the soil surface. The
soil microorganisms decompose the compounds also, but
can work effectively only when the soil is wet (Harborne,
1982; McPherson and Muller, 1969; McPherson et aI.,
1971).
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9
Coumarins
Introduction
Biosynthesis
Biosynthesis of Cownarins
Biosynthesis of Cownarins derived from p-coumaric
acid
Biological Activity
Furanocoumarins
Biosyothesis of Furanocoumarins
Systematic and Phylogenetic Importance of
Furanocoumarins
Biological Properties of Furanocownarins
Effects of Furanocoumarins on Plants
Furanocoumarins as Phytoalexins
Furanocoumarins and Insects
Toxicity of Furanocoumarins to Mammals
Furanocoumarins in Foods
Medicinal Uses of Furanocownarins
References
Il'ITKODVCTlOI'l
Simple cownarins (iactones of phenylpropanoic acids with
a 2H-l-benwpyran-2-one nucleus) are widespread in plants;
the four most widely distributed coumarins are coumarin
(I), wnbelliferone (2), esculetin (aesculetin) (3), and scopo-
letin (4) (Fig. 9.1) (Brown, 1979). Coumarins have not been
reported from algae or mosses, although umbelliferone has
been reported from a liverwort (Berenbaum, 1991). Cou-
marin is both the name of a specific compound and the name
of a group of structurally related compounds. Variations of
these basic coumarin structures are encountered commonly
(especially in the Apiaceae) and at least 300 simple coumar-
ins and a total of at least 1000 naturally occurring cownarins
are known (Berenbaum, 1991; Brown, 1986, personal com-
munication). Many coumarins, such as xanthyletin (5) and
seselin (6), are prenylated.
130
Cownarin (I), fIrst isolated from Dipteryx (Coumarouna)
odorata (tonka bean, Fabaceae) and a component of a num-
ber of spices and herbs, is found in essential oils from many
plants. Cownarin from plant sources is still used to a certain
extent as a flavoring, but most coumarin comes from syn-
thetic sources. The use of syothetic coumarin as a flavoring
in food products is restricted in the United States.
Although free cownarins are known to occur in plants,
most simple cownarins occur as glucosides. The involve-
ment of such glucosides in the biosynthetic sequence is a
unique feature among higher plants. The ~-D-glucoside of
o-coumarinic acid (7) (Fig. 9.2) is found in plants such as
sweet clover (Melilotus alba) and lavender (Lavandula offi-
cinalis). Usually, free cownarin (1) is formed by hydrolysis
of the glucoside and subsequent lactonization of the Z-o-
coumarinic acid (8). A similar situation probably is true for
umbelliferone and scopoletin (Haslam, 1974).
Coumarins have been found in all plant parts; most have
been reported from seeds and roots. Concentrations as great
as 9% by weight have been observed. Generally, cownarins
are located within specialized structures such as secretory
ducts called vittae (Berenbaum, 1991).
BIOSYl'lTHESIS
Biosynthesis of Coumarin
L-Phenylalanine, a precursor for coumarin (1) in Melilo-
tus alba, is first converted to E-cinnamic acid by the action
of phenylalanine ammonia lyase (PAL) and then to ortho-
coumaric acid (9) by the action of cinnamic acid o-hydroxyl-
ase (Fig. 9.2). Although this step of the pathway was initially
reported to occur in the chloroplast, at present none of the
steps of the reaction sequence appear to occur there. Coum-
aric acid (9) is converted into the corresponding ~-glucoside
(10) by UDP-glucose and an O-glucosyltransferase. This
 rrx
Coumarins 131

5 4

~ <?'
I
""", HO~ CH3-0~

~oAo HO 7"'"
8
0
2

0 Ho~oAo Ho~oAo
coumarin (1) umbelliferone (2) esculetin (3) scopoletin (4)

HO~"""
I gIUCOSYI-O~

HO""'OO
HO HO
~"A
0 0

our"
dicoumarol (13)
daphnetin esculin

OH
xanthyletin (5) warfarin (14) sesilin (6) columbianetin (28)

Fig. 9.1. Some important coumarin structures.

glucoside (10) undergoes a UV-light-mediated E-Z Biosynthesis of Coumarlns from P'

(trans-cis) rearrangement to produce the isomeric J3-gluco-
side (7) that is accumulated in the plant. Examination of
Melilotus cells indicated that a mixture of the two isomers
is present (Oba et aI., 1981). Under various conditions, espe-
cially injury, a co-occurring J3-glucosidase cleaves the gluco-
side (7) to yield glucose and coumarinic acid (8), which is
spontaneously cyclized to coumarin (1). In this plant, the
glucosides were shown to occur in the vacuoles. The 13-
glucosidase occurs in the sarne cells, but outside the vacuole,
perhaps in the intercellular spaces or attached to the cell wall
(Brown, 1986; Oba et aI., 1981; Poulton et aI., 1980).
Coumarlc Acid
Although cinnamic acid does serve as a direct precursor
for coumarin (1) itself, most other coumarins are derived
tromp-coumaric acid and umbelliferone (2) (Fig. 9.3). Addi-
tional hydroxyl functions usually are added after the cou-
marin nucleus is constructed. There is some evidence for the
conversion of ferulic acid to scopoletin in tobacco, but this
appears to be an exceptional case (Brown, 1986).
As in coumarin biosynthesis involving phenylalanine ox-
ygenation of p-coumaric acid in the ortho position is the key

o-coumaric acid (9)

O-glucosyl

o-coumaric acid
OH

--
poD-glucoside (10)

~C02H
~O.gIUCOSYI
o-coumarinic acid
- ~CO~
~OH
Z-o-coumarinic acid (8)
~
~oAo
coumarin (1)
P-D-glucoside (7)

Fig. 9.2. Biosynthesis of coumarin in plants (Luckner, 1972; used with pennission of the author).
132 Coumarins
reaction in this series. A number of feeding studies indicate
that umbelliferone (2) is an efficient precursor for many cou-
marins of this type. The 2' -hydroxylase responsible differs
from the one involved in the biosynthesis of coumarin itself
(see above) in its site specificity and the requirement for a
tetrahydropteridine cofactor (Berenbaum, 1991). Glycosyla-
tion, followed by a light-mediated E-Z isomerization of the
side-chain double bond, occurs. Removal of glucose by a
i3-g1ucosidase leads to the acid (11) which immediately cy-
clizes. Umbelliferone (2) then is formed by removal of the
remaining sugar from umbelliferone glucoside (12).
In tobacco cell cultures, a UDP-glucose o-dihydroxycou-
marin 7-0-glucosyltransferase mediates glucosylation of es-
culetin (3) with strict positional specificity (Brown, 1986).
Coumarins may be formed at various sites in plants. In
Melitotus alba, sweet clover, young actively growing leaves
seem to be the principal site of synthesis (Brown, 1981).
BIOLOOICAL ACTIVITY
A large number of experiments involving simple coumarins
and growth of plants have been conducted (Brown, 1981).
Observed effects include growth inhibition or stimulation,
inhibition of pollen tube formation, modification of stomatal
action, rhizoid fonnation, inhibition of seed germination, and
petiole abscission. Scopcietin (4) (Fig. 9.1) is a potent germi-
nation stimulant (active at concentrations of 2-20 ppm).
Growth of Chinese cabbage seedlings is strongly inhibited
by both umbelliferone (2) and scopoletin (4) (Brown, 1986).
Many effects on specific enzymes also have been observed
(Brown, 1981). For instance, both scopoletin and esculetin
have inhibitory effects in tobacco cultures. The glycosides
o ~O
~OR
~ __
RO~ RO
-:OSYI-O cc:
I ""
# O-glucosyl
CO,R
'"_~O~O - umbelliferone glycoside (12)
Fig. 9.3. Biosynthesis of simple coumarins derived from p-Coumaric acid in plants (Luckner, 1972; used with permission of the author),
actively inhibited 6-phosphogluconate dehydrogenase, an
enzyme of the pentose phosphate pathway. Coumarin is
known to enhance IAA (Indole Acetic Acid) oxidase activity
in some plants and lAA synthetase in other systems. Effects
on gibberellin and abscisic acid also have been observed
(Brown, 1981, 1986).
Most coumarins also have pronounced physiological ef-
fects in mammals and insects. Coumarin (0.1 %), ferulic acid
(0.1 %), and p-coumaric acid (5%) were shown to be toxic to
the larvae of the bruchid beetle, Callosobruchus maculatus
(Janzen et al., 1977).
In fermenting hay, o-coumaric acid (8) is converted into
dicoumarol [3,3'-methylenebis(4-hydroxycoumarin)] (13), a
compound with marked anticoagulant properties (Bellis et
a!., 1967; Davies and Ashton, 1964), that occasionally has
been responsible for the death of livestock (Sneader, 1985).
The synthesis of warfarin (14), a powerful rodenticide, was
based on these properties, and for a time, this compound
was effective in controlling populations of rats. Recently,
however, a strain of "super rats" has emerged which have
developed an enzyme system that allows them to cope with
this warfarin (Marm, 1987; Sneader, 1985). Regular low
doses of warfarin can prevent strokes in humans (Singer,
1990).
FURANOCOUMARll'lS
In addition to relatively simple coumarins, a second group
of more complex coumarins is known in which the coumarin
structure is prenylated (i.e., a five-carbon unit derived from
mevalonic acid metabolism is attached). The five-carbon
mevalonate-derived unit of these compounds usually is re-
I "'" ~
0
14 ~ "'"
-- ~
OR
OR
OR
glucosyl-- 0
#
O~glucosyl
--- glucosyl- 0 cc --
I ""
#
(11)
OR
CO,R
""~O
umbelliferone (2)

umbelliferooe (2) demethylsuberosin (20)
HO~
0:0
9'
"'"
I
0
""
--
0
HO
~O
I 9'
(+)-(S)-marmesin (21)
Fig. 9.4. Proposed biosynthetic pathway to linear furanocoumarins.
duced to two carbons which are part of a furan ring. At least
200 structures of these furocoumarins or furanocoumarins
occur in plants (Ivie, 1987, Ivie et aI .. 1987). Two principal
types, linear and angular furanocoumarins, arise by prenyla-
tion at position C-6 or C-8, respectively, followed by cycliza-
tion and modification of the ring (Fig. 9.4). In contrast to
simple coumarins, furanocoumarins are restricted in distri-
bution. A substantial proportion of the furanocoumarins of
many plants is found on the leaf surface (Zobel and Brown,
1989).
Most common furanocoumarins have characteristic reten-
tion properties on HPLC (High Performance Liquid Chro-
matography) with both reversed-phase and conventional-
phase columns (Spencer et aI., 1987). The assigument of
ring-substitution patterns of plant-derived furanocoumarins
can be made by negative-ion mass spectrometry (plattner
and Spencer, 1988).
BIOSl'l'lTHESlS OF FURANOCOUJllARll'lS
Cinnamic acid is a precursor of p-coumaric acid and of most
furanocoumarins, just as it is for ordinary coumarins (Floss
and Mothes, 1964). Umbelliferone (7-hydroxycoumarin) (2)
also is incorporated into most furanocoumarins. Coumarin
(I) and scopoletin (6-methoxy-7-hydroxycoumarin) (4) are
much poorer precursors than umbelliferone for both angular
furanocoumarins [such as sphondin (IS) and pimpinellin
(16) (Fig. 9.6)] and linear furanocoumarins, suggesting that
any additional oxygenation occurs after formation of the
coumarin nucleus (Brown, 1986). In intact plants, this bio-
synthetic system may represent a channeled process; incor-
poration of probable intermediates is low. Suspension cul-
tures of PetroseUnum hortense (syn. P. hortense) contain
only traces of furanocoumarins until challenged by prepara-
tions of fungal elicitors. Regulation of coumarin biosyn-
thesis at the molecular level has been studied (Berenbaum,
1991; Hahlbrock and Ragg, 1975; Hahlbrock et aI., 1981).
Coumarins 133
o ~
__
HO"'"
9'
I ""
0 0
-
""
--5'
ccexo
4'54
f 9'
•
I
psoraleo (17)
"'"
Coumarin biosynthesis involves formation of PAL and 4-
coumarate CoA ligase which is light and elicitor inducible.
Cells of P. crispum respond by producing the linear furano-
coumarins psoralen (17), bergapten (18), and xanthotoxin
(19) (Fig. 9.6), as well as other furanocoumarins (Ellis,
1988). The relative amounts offuranocoumarins in the mix-
ture was changed by use of different fungal elicitor sources.
Floss and Mothes (1964) established that two carbons of
the furan ring are derived from mevalonate. Experimentally,
the overall incorporation of mevalonate is low, a phenome-
non observed in many other studies (see Chapter 19). In
Ruta graveolens (Rutaceae), the first step in linear furano-
coumarin formation is the prenylation of the C-6 position
of umbelliferone (2) to yield demethylsuberosin (20) (Fig.
9.4). In this case, no intermediate that leads to the formation
of angular furanocoumarins is formed. In elicitor-treated
Ammi majus cell cultures two dimethylaIIyl diphosphate:
umbelliferone dimethylallyltransferase activities, one cata-
lyzing 6-prenylation and the other 7-0-prenylation were in-
duced (Hamerski et aI., 19900). Demethylsuberosin (20) was
rapidly metabolized. In a separate work, Brown and Steck
(1973) demonstrated that (l-hydroxyisopropyldihydrofura-
nocoumarins, such as ( + }-(S}-marmesin (21), are interme-
diates in the biosynthesis of furanocoumarins. An as-yet un-
identified "psoralen synthase," that appears to be a
cytochrome P-450 monooxygenase, may be involved in the
formation of psoralen (17) from marmesin (21) (Berenbaum,
1991). Psoralen (17) then can be modified further to produce
a series of oxygenated furanocoumarins (Brown, 1986;
Grundon, 1983).
In Ruta graveolens, two different methyltransferases, S-
adenosylmethionine:xanthotoxol O-methyltransferase and
S-adenosylmethionine:bergaptol O-methyltransferase, are
involved in the formation of 8-hydroxybergapten (22) and 5-
hydroxyxanthoxin (23) from bergaptol (24) and xanthotoxol
(25), respectively (Berenbaum, 1991). 5,8-Dihydroxypso-
ralen (26) is a much more efficient precursor for the biosyn-
thesis of isopimpinellin (27) than are the monomethylated
134 Coumarins

OCH,

~
\VoAo
OH
bergaptol (24)
S·bydroxybergapten (22)

i
$0-+--
OH OCH,

~
'o~OAo
~
\VoAo
OCH,

/~"'
psoralen (17)
isopimpinellin (27)

! t
OH

~
'o~oAo
~
\VoAo
OH OCH,

xanthotoxol (25) 5·bydroxyxanthotoxln (23)

Fig. 9.5. Proposed pathways from psoralen to isopimpineilin.

furanocoumarins bergapten (18) or xanthotoxin (19) (Fig.
9.5) (Brown, 1986; Dewick, 1984).
Angular furanocoumarins are derived by prenylation at
the 8·position of umbelliferone followed by cyclization via
similar intermediates, although experimental evidence is not
as good as for linear furanocoumarin biosynthesis. Columbi·
anetin (28) (derived by 8·prenylation) is involved in the bio·
synthesis of angelicin and derived angular furanocoumarins
(Fig. 9.3).
The mRNAs induced by fungal elicitors and by light in
parsley proved to be similar or identical, suggesting a •• com·
mon" defense response to different sources of plant stress
(Berenbaum, 1991).
SYSTEJllADC Al'ID PHYLOGEl'IEDC
IJI1POKTANCE OF FURAl'IOCOlJlllAKll'lS
Although simple coumarins are found in many plant fami·
lies, the distribution of furanocoumarins is restricted. Furan·
ocoumarins have been reported from the Apiaceae (Umbelli·
ferae), Asteraceae (Compositae), Moraceae (Brosimum,
Dorstenia, Fatoua, and Ficus), Pittosporaceae, Rosaceae,
Rutaceae, Solanaceae, and Tbymelaeaceae (Bilia et al.,
1992,1993; Murrayetal., 1982; Swain and Downum, 1990).
Certain precursors to this group of compounds are found in
the Cneoraceae (Murray, 1978).
Although linear furanocoumarins occur in at least 19
plant families, they are common only in two, the Rutaceae
and the Apiaceae (Berenbaum, 1991). Within the Apiaceae,
coumarins are only found in subfamily Apioideae (not in
the Hydrocotyloideae or Saniculoideae). Further, these com·
pounds are not found in the closely related family Araliaceae
(Berenbaum, 1991). 1n contrast to linear furanocoumarins,
angular furanocoumarins are restricted primarily to two, the
Apiaceae and Fabaceae. 1n the Apiaceae, angular furano·
coumarins are found in two advanced trihes, the Apieae and
the Peucedaneae. Although many plants synthesize linear
furanocoumarins in the absence of angular furanocoumarins,
few, if any, produce angular furanocoumarins in the ahsence
of linear furanocoumarins suggesting that the biosynthesis
of angular furanocoumarins evolved more recently. Angular
furanocoumarins appear to he less toxic to most organisms
than linear furanocoumarins (Berenbaum and Feeny, 1981;
Ivie, 1987; Ivie et al., 1987).
BIOLOGICAL PKOPEKnES
OF FURAl'IOCOlJMARll'lS
Linear furanocoumarins are potent phototoxins capable of
killing or inhihiting the growth of viruses, bacteria, and fungi
as well as affecting many higher organisms including both

insects and nematodes. Photoactive furanocoumarins require
activation at UV-A wavelengths (320-400 nm). Under these
conditions, linear furanocoumarins can form cross-linkages
between the two strands of the DNA double helix by joining
pyrimidine bases, resulting in a partial loss of template activ-
ity for RNA synthesis as well as inhibition of DNA replica-
tion (Berenbaum, 1991; Downum, 1992; Downum and
Nemec, 1987).
Effects of Furanocoumarins on Plants
As is true for simple coumarins, many furanocoumarins
affect various growth and developmental processes in plants
and specific enzymes (see above) (Brown, 1981). For exam-
ple, a number of furanocoumarins such as bergapten (18) and
sphondin (15), vaginidiol, isopimpinellin (27), pimpinellin
(17), and isobergapten (Fig. 9.6) are known to either stimu-
late or inhibit growth of Chinese cabbage seedlings (Brown,
1986). Psoralen (17) is a powerful germination inhibitor and
can inhibit growth of plants (Downum, 1992). There is some
evidence that coumarins interact with other growth regula-
tors.
Furanocoumarins as Phytoalexins
Cell suspension cultures of Ammi majus propagated con-
tinuously in the dark produced only the coumarin umbelli-
ferone (2). The addition of fungal cell wall fractions induced
CH30~
p- I "'"
o ~
angelicin (30) spbondin (15)
bergapten (18)
~
\yoA
OCH3
khellin (33)
Fig. 9.6. Some important furanocoumarins.
Coumarins 135
formation of large amounts of umbelliferone in addition to
isopimpinellin (27), (S)-marmesin (21), (R)-ammirin, as
well as other furanocoumarins (Harnerski et a!., 1990b).
Xanthotoxin (19) has been identified as a phytoalexin in
parsnip. The ED,o for xanthotoxin against Ceratoeystis fim-
briatum is 21.6 flog/ml (KuG, 1992).
However, strains of the fungus Gibberefla pulicaris (Fu-
sarium sambucinum) isolated from both furanocoumarins
and non-furanocoumarin-containing plants were tolerant to
and able to metabolize 16 furanocoumarins and furanocoum-
arin precursors (Desjardins et a!., 1989).
Furanocoumarins and Insects
Insect herbivory is an important selective force in the
ecology and evolution of plants. The linear furanocoumarin,
xanthotoxin (19), found in many plants of the Apiaceae and
Rutaceae is toxic to the larvae of Spodoptera eridania, a
generalist insect herbivore. This toxicity was shown to be
increased in the presence of UV light.
Photons can alter the electronic configuration and form
a highly reactive excited state that can interact directly with
biomolecules such as DNA, proteins, or membrane lipids
with concomitant toxic effects (Berenbaum, 1987). The lar-
vae of many of the herbivores of apiaceous plants live in
rolled leaves or in webbed inflorescences, possess physical
resistance in the form of body pigments that shield the insect
from damaging wavelengths of light, or quench excited
0 0
imperatorin (29)
<We OCH 3
xanthotoxin (19)
(a 'Y-pyrone)
00,0 Yo
{)cr 0
osthol (31)
136 Coumarins
states (biochemical resistance) by enzymatic degradation of
phototoxic molecules (Berenbaum, 1978, 1987).
Xanthotoxin (19), imperatorin (29), and bergapten (18)
(linear furanocoumarins) occur in all above ground parts
of Pastinaca sativa (Apiaceae), whereas angelicin (30) and
sphondin (15) (angular furanocoumarins) occur only in um-
bels of some individuals (Fig. 9.6). The total furanocoumarin
content is highest in reproductive parts, particularly buds
and seeds (Berenbaum, 1981a). Even in the seeds, furano-
coumarins are not distributed in a homogeneous manner.
The vittae or oil glands, which contain these compounds, on
the commissural side of the mericarp contain over 90% of
the furanocoumarin content of the seed (Berenbaum and
Zanger!, 1986). Generalist insects tend to feed on plants or
plant parts low in furanocoumarin content, whereas parsnip
specialists, notably Depressaria pastinacella (Lepidoptera:
Oecophoridae), feed exclusively on umbels (Berenbaum,
1981a).
Individual plants of wild parsnip (Pastinaca sativa) vary
in both content and composition of furanocoumarins. Fur-
ther, much of this variation is genetically based. The effects
of light and nutrients on furanocoumarin production have
been evaluated (Zanger! and Berenbaum, 1987). Wild par-
snip also varies in resistance to damage by Depressaria
pastinacella which feeds on flowers and developing seeds.
Approximately 75% of the variation in resistance was attrib-
utable to four furanocoumarin characteristics. Resistance is
correlated positively to the proportion of bergapten (18) and
amount of sphondin (15) in seeds and correlated negatively
with the amount of bergapten and proportion of sphondin
in leaves. In greenhouse studies, however, several of the
resistance factors were negatively correlated with potential
seed production, and ostensibly, highly resistant plants, in
the absence of herbivory, would be at a competitive disad-
vantage in the field (Berenbaum et aI., 1986).
When parsnip webworm larvae were fed radioactively
labeled xanthotoxin (19), approximately 95% was metabo-
lized, indicating that metabolic detoxification is important
in tolerance of the insect to furanocoumarins. Excretion of
the remaining xanthotoxin and metabolites occurred both in
the frass and through the silk glands. The silk glands con-
tained half as much tritium as the rest of the body (Nitao,
1989, 1990).
Species of Apiaceae that possess furanocoumarins typi-
cally are those of open habitats (swamps or thickets) or dis-
turbed areas such as roadsides or old fields. This is in keeping
with a role of light in the effects of these plants on herbivores
(Berenbaum, 1981 b).
Butterflies of the genus Papilio (Lepidoptera) often are
associated with members of the Apiaceae. Xanthotoxin (19),
a linear furanocoumarin, occurs in many plants of the Apia-
ceae. This compound is not appreciably toxic to the larvae
of Papilio polyxenes which normally feed on umbelliferous
plants. Most of these insects feed only on plants that have
linear furanocoumarins and, in general, do not consume
plants that make angular furanocoumarins. Angelicin (30)
(Fig. 9.6), an angular furanocoumarin found in only a few
relatively advanced tribes of the Apiaceae, reduces both
growth rate and fecundity in this insect. This finding sug-
gested that, in this instance, plants that produce angular fu-
ranocoumarins may be favored over those that make only
linear furanocoumarins (Berenbaum, 1983).
Midgut and body tissues of the black swallowtail (Papilio
polyxenes) possess high enzymatic activity that catalyzes
the detoxification of linear furanocoumarins, explaining the
tolerance of this species for these compounds. The detoxifi-
cation of angular furanocoumarins occurs at a slower rate
(Ivie et aI., 1987). Other Papilio species, for example, P.
brevicauda, feed exclusively on plants of the genera Her-
acleum, Angelica, Ligusticum, and Petroselinum. The first
three contain angular furanocoumarins (Berenbaum and
Feeny, 1981). As few insects can utilize plants with angular
furanocoumarins, plants that possess pathways that permit
angular attachment of the furan ring may have been favored
in some instances. However, Papilio species that can feed
on linear furanocoumarins may have become even more spe-
cialized herbivores by adapting to feeding on plants with
angular furanocoumarins.
There was no effect on larval growth or survivorship
when angelicin (30) was included in the diet of parsnip web
worms (Depressaria pastinacella) (Nitao, 1989).
Furanocoumarins such as isopimpinellin (27), bergapten
(18), and kokusagin have antifeedant activity against
Spodoptera litura. A number of similar compounds from
umbelliferous plants have been demonstrated to be active
antifeedants against Spodoptera litura, Blattela germanica,
and Stylopyga rhombifolia (Munakata, 1977; Yajima and
Munakata, 1979).
A mixture of volatiles from carrot (Daucus carota, Apia-
ceae) is responsible for oviposition by females of the carrot
fly (Psila rosae). Among these are the phenylpropanoids
E-methyleugenol, E-asarone, a prenylated coumarin, osthol
(31), bergapten (18), xanthotoxin (19), and an acetylenic
compound, falcarindiol (Harhorne, 1986). No single compo-
nent of the mixture is responsible for the behavior of the
fly.
Toxicity of Furanocoumarins to Mammals
Furanocoumarins are rapidly catabolized in mammals. In
rodents, xanthotoxin (19) is metabolized by O-demethyl-
ation, aryl hydroxylation at position 5, oxidation of the 5,8-
dihydroquinone to the quinone, hydrolysis of the pyrone
ring, oxidative opening of the furan ring, and sulfate and
glucuronide conjugation (lvie, 1987; Ivie et aI., 1987).
Plants that contain furanocoumarins have been implicated
in several problems of livestock poisoning. For example, in
the western United States, Cymopterus watsoni (Apiaceae)
has been involved in the poisoning of sheep (Ivie, 1978).
Starved individuals of the rock hyrax, Procavia capensis
syriaca, which is notable for its ability to consume toxic
plants, were killed when they consumed shoots of Pitur-
anthos triadiatus (Apiaceae), which contain furanocoumar-

ins. This animal nonnally eats the young shoots of the plant,
which have much lower concentrations of these compounds
(Harborne, 1986). The toxicity offuranocoumarins to mam-
mals has been reviewed (Ivie, 1987; Ivie et aI., 1987; Seigler,
1983).
Furanocoumarins in Foods
Parsnips and perhaps celery and parsley contain apprecia-
ble levels of the linear furanocoumarins psoralen (17), xan-
thotoxin (19), and bergapten (18). Consumption of 100 g of
parsnip root would expose an individual to 4-5 mg of these
compounds, which are known to be phytotoxic, mutagenic,
and photocarcinogenic. Furanocoumarins are not destroyed
by nonnal cooking (Ivie, 1981).
Contact with plants containing linear furanocoumarins by
humans and subsequent exposure of the area to sunlight re-
sults in painful, vesicated areas on the skin. This problem
has been observed in field workers and others who handle
celery (Anon., 1988; Beier and Nigg, 1992). A similar prob-
lem has been observed in bartenders and others who handle
limes and later are exposed to sunlight. The coumarin con-
tent of lime oils is about 7%. Figs (Ficus carica, Morace3e)
also are known to cause photodennatitis; fig leaves contain
large quantities of psoralen (17) (1.65 mg/g fresh weight)
and bergapten (18) (Beier and Nigg, 1992).
The production of phytoalexins in celery plants infected
with the fungus Sclerotinia sclerotiorum caused workers to
develop severe initation. These plants contain xanthotoxin
(19) and 4,5' ,8-trimethylpsoralene. Uninfected plants of ce-
lery do not contain these coumarins in significant quantities,
although there is evidence that grocery workers have experi-
enced phytophotodennatitis after handling apparently
healthy celery plants. Some of these lines, which contain
levels of furanocoumarins 10-15 times higher than more
usual cu1tivars of celery, had been selected for disease and
insect resistance (Beier and Nigg, 1992).
Medicinal Uses of Furanocoumarins
The ability to bind to DNA has been used to provide
an effective treatment for the stubborn and disfiguring skin
disease, psoriasis, a disorder characterized by the prolifera-
tion of epidennal cells. Oral doses of xanthotoxin (19) fol-
lowed by controlled exposure to ultraviolet irradiation have
shown remarkable success in controlling this problem. An-
gular furanocoumarins do not bind to DNA in the same man-
ner and have little effect (Beier and Nigg, 1992; Brown,
1986; Ivie, 1987; Ivie et al., 1987).
Visnadine (32), an angular pyranocoumarin, has pro-
nounced vasodilatory effects (Berenbaum, 1991).
Khellin (33), an antispasmodic drug that comprises ap-
proximately 1% of the dry weight of plants of Ammi visnaga
(Apiaceae), has a pyrone structure reminiscent of that of
many linear furanocoumarins (Fig. 9.6). This compound acts
directly on smooth muscle, is a bronchial dilator, and is used
in the treatment of asthma (Sneader, 1985).
Coumarins 137
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ZANoERL, A. R. and M. R. BBRENBAUM, Furanocoumarins in wild
parsnip: Effects of photosynthetically active radiation, ultravi-
olet light, and nutrients, Ecology, 63, 516-520 (1987).
ZoBEL, A. M. and S. A. BROWN, Histological localization of furano-
coumarins in Ruta graveolens shoots, Can. J. Bot., 67, 915-921
(1989).
10
2-Pyrones, Stilbenes,
Dihydrophenanthrenes, and Xanthones

Introduction Similar compounds are found in kawa root, kavakava,

2-Pyrones and Styrylpyrones kawakawa or yangona (Piper methysticum, Piperaceae),
Biosynthesis which is used to prepare a beverage widely consumed in the
Systematic usefulness Pacific islands. The beverage is an integral part of the reli-
Biological activity gious and social life and has tranquilizing and sleep-inducing
Stilbenes properties (Lebot, 1991; Lewin, 1931; Schery, 1972).
Biosynthesis The stem bark of Goniothalmus giganteus (Annonaceae)
Biological activity contains the related compounds, goniothalenone (altholac-
Dihydrophenanthrenes and Phenanthrenes tone) (1) and goniothalamin (2), in addition to a series of
Biosynthesis acetogenins (Fig. 10.1) (see Polyketides) (McLaughlin,
Biological activity 1991).
Benzophenones
Xanthones Biosynthesis
Distribution of Xanthones The mechanism for addition of two carbon units is like
Biological Activity that of polyketide synthesis (Birch and Donovan, 1953). The
References starter unit is first converted to the CoA ester and C 2 units
added from malonyl-CoA (Fig. 10.2). The chain then cy-
elizes in several ways which may be determined by the num-
Il'ITKODUCTION ber of units added, the enzyme systems present, and other
factors. Thus, one portion of the molecule is derived from
The enzymatic mechanisms for lengthening of the side chain shikimic acid and the other from acetate. In some cases, it
of cinnamic acids by one or more C 2 units followed by cyeli- is not possible to tell if a C6 -C3 precursor is extended by
zation are widespread in higher plants. Although by far the two acetate units or if a C 6 -C, precursor is extended by
largest group of compounds formed by this route is the flavo- three units (Fig. 10.2). For example, paracotoin (3) [found
noids, several other important structural entities are known in paracoto bark from Aniba pseudocoto (Lauraceae)] can
to arise in this manner. Among these are the 2-pyrones, stil- be derived by either pathway (Fig. 10.3) (Manitto, 1981).
benes, dihydrophenanthrenes, and xanthones. After the chain is extended to six carbon atoms, cyclization
occurs to produce a 6-membered lactone ring.

2·P¥KONES AND STYKYLPYKONES Systematic Usefulness

The bark of the plants Nectandra coto (syn. Aniba coto),
coto, and Ocotea pseudocoto (Aniba pseudocoto), paracoto,
(as well as other species of the Lauraceae) have long been
known to contain biologically active secondary compounds
(Geissman and Crout, 1969). The bark ofthese plants is used
medicinally in South America.
The trunk woods of many species of Aniba (Lauraceae)
contain phenylpropanoid compounds that serve as precur-
sors to neolignans (see Chapters 8 and II); other Aniba spe-
cies contain pyrones and benzophenones, whereas yet others
possess benzylisoquinoline alkaloids and benzyl benzoates.
It is possible to divide Aniba species into those that contain
pyrones and those that contain neolignans (Gottlieb, 1980).

139
140 2-Pyrones, Stilbenes, Dihydrophenanthrenes, and Xant/tones

kawain (5) yangonin (4) methysticln (6)

anlbine 4-methoxyparacotoin paraeotoin (3) pbenylcoumalin

o OH o OCH3
o OH

~ ~ ~
VHO~OH VHO~OCH3 VHO~OCH3
cotoln bydrocotoln metbylbydrocotoin

~:::,..
I H '.:'
• '<::::

H i 0 0
OH H

goniotbalenone (1) gonlothalamln (2)

Fig. 10.1. 2-Pyrones and styrylpyrones.

Biological Activity
Both the beverage, kava or yangona, and the dried root
of Piper methysticum are used as sources of a serles of py-
rones with biological activity. Kavalactones in this plant are
diuretic, soporific, anticonvulsant, spasmolytic, local anes-
thetic, and antimycotic (Lebot, 1991). The dried root con-
tains about 5-6% resin from which six related pyrones [yan-
gonin (4), desmethoxyyangonin, kawain (5), dihydrokawain,
methysticin (6), and dibydromethylsticin] have been iso-
lated. All are more or less potent, centrally acting skeletal
muscle relaxants that also possess antipyretic and local anes-
thetic properties (Tyler et al., 1981).
STlLBEl'IES
Stilbenes are a relatively small, but widely distributed, group
of plant secondary metabolites found mostly as heartwood
constituents in a heterogenous assembly of plant species.
Over 200 naturally occurring stilbenes and stilbene glyco-
sides are known from higher plants and more than 80 from
liverworts (Gorham, 1980, 1989). They are especially impor-
tant in the heartwood of trees of the genera Pinus (Pinaeeae),
Eucalyptus (Myrtaceae), and Madura (Moraceae) (Hart,
1981; Weiss and Edwards, 1980). Stilbenes are common
by-products of paper manufacture (Kindl, 1985). Although
stilbene aglycones are common in heartwood, living tissue
often contains small amounts of stilbene glycosides (Hart,
1981). In several woody plants, stilbenes are accompanied
by dihydrostilbenes or bibenzyl compounds, dibydrophe-
nanthrenes, and phenanthrenes (Kindl, 1985).
The para-hydroxylated compound, resveratrol (7), is the
most widespread stilbene in nature. This compound occurs
in Picea, Pinus, the Fabaceae, Myrtaeeae, and the Vitaeeae
among others (Kindl, 1985). Pinosylvin (8) and its deriva-
tives are mostly restricted to the genus Pinus. The distribu-
tion of stilbenes in plants has been reviewed (Gorham, 1980,
1989) (Fig. 10.4).
Oxidative dimers of stilbenes called goetins occur in both
of the unusual gymnosperms Gnetum and Welwitschia (Fig.
10.5) (Gottlieb and Kubitzki, 1988).
 2-Pyrones, Slilbenes, Dihydrophenanlhrenes, and Xanthones 141

hOH
co~
° r- malonyl-eoA

°y0
},.. CoASH + CO, 0H

~OH ° ,,-'
"-
COW' . --+
OH

° V° malonyl~CoA
dihydropyrone

J
} . CoASH + CO,
OH

CoA
, ,...1

° ° ° styrylpyrone
V-maI0nYloCOA ~OH
I:
~
~COASH+CO' r OH HO r ".

CoAS
, "- 1 a1_dO_I_co_n_de_n_
...~tion ~ I

OH

° ° ° ° ~condensation OH

HO r

OH °
chalcone
Fig. 10.2. Biosynthesis of flavonoids and stilbenes from acetate and cinnamate (modified from Grisebach, 1985; used with pennission of the copyright
owner, Academic Press, Orlando, Fl.,).

OCH3

• .
--
CH3CO,H
C.-C,
°
CH3CO,H

kawain(5)

.
( :oD
~o

--
CH3CO,H
I 0

I ~ • ° °
° b
paracotoin (3) paraeotoln (3)

Fig. 10.3. Labeling of kawain and paracotoin by radioactively labeled precursors (modified from Manitto, 1981).
142 2-pyrones. Sti/benes. Dihydrophenanthrenes. and Xanthones
ooyO HO
resveratrol (7)
pinosylvin (8)
OH
HO
HO
HO
oxyresveratrol (10)
broussonin A (14)
Fig. 10.4. Some important stilbenes and related compounds.
Lunularic acid (9) is found in most liverworts, and a series
of structurally related derivatives are found in mosses and
liverworts (Fig. 10.6) (Zinsmeister and Mues, 1987). Earlier
reports of lunularic acid in algae need to be confirmed.
Stilbenes and related compounds can be separated with
a number of techniques such as thin-layer (TLC), gas liquid
(GLC), and high-performance liquid (HPLC) chromatogra-
phy (Gorham, 1989). The detection and identification of
these compounds can best be accomplished by nuclear mag-
netic resonance (NMR) spectroscopy and mass spectrometry
(Gorham, 1980; 1989).
Biosynthesis
Stilbenes are derived from a pathway similar to that of fla-
vonoids (Birch and Donovan, 1953). These phenolic com-
pounds are of mixed biosynthetic derivation with one ring
from polyketide metabolism and the other from shikimic acid.
Three units of malonate are added to a shikimate-derived
starter unit, probably cinnamic or p-coumaric acid and then
cyclized via an aldol condensation (Gorham, 1980). Instead
of undergoing a Claisen-type condensation (as in the case of
flavonoids), that portion of the molecule undergoes an aldol-
type condensation (Fig. 10.2). Considerable homology of an-
giosperm chalcone synthases with stilbene synthases has been
reported (Stafford, 1991). This condensation is catalyzed by
the enzyme stilbene synthase which has a high Km value for
piceatannol (11)
OH
HO
4 -prenyloxyresveratrol
broussonin B (15)
malonyl-CoA (Kind!, 1985). Mter three units of acetate (via
malonyl-CoA) are added, cyclization occurs via an aldol con-
densation. Stilbenes differ from the better known and more
common flavonoids in that the latter suffer a Claisen-type
condensation (Fig. 10.2). In genera!, stilbenes have hydroxyl-
ation at positions 3 and 5. The resveratrol-forming enzyme
is a dimer with a molecular weight of 90,000. The levels of
stilbene synthase in grape leaves is increased 100-fold by
treatment with fungal or artificial elicitors (Kindl, 1985). 1-
14C-Acetate and 14C-p-coumaric acid were incorporated into
oxyresveratrol (10) during feeding experiments in Morus
alba (Moraceae). Labeling studies with phenylalanine and
acetate indicate that both are incorporated into pinosylvin (8)
in Pinus resinosa and P. sylvestris and into resveratrol (7) in
Eucalyptus sideroxylon (Myrtaceae) (Kind!, 1985; Weiss and
Edwards, 1980). In studies of oxyresveratrul (10) biosyn-
thesis, 1- l4C-acetate was incorporated into carbons 3 and 5
and !3_14C-p-coumaric acid into carbon 8. Piceatannol (11) in
Laburnum anagyroides (Fabaceae) was labeled in a similar
manner (Fig. 10.8). In contrast to chalcone synthesis, the hy-
droxylation pattern of the B ring generally is determined at
the phenylpropanoid level in stilbene biosynthesis (Stafford,
1991). Formation of compounds such as pinosylvin (8) pre-
sumably involves decarboxylation of the aldol-derived por-
tion of an intermediate (Fig. 10.7).
Compounds found in the genus Hydrangea (Hydran-
 2-Pynme.f, Srilhelles, Dihydrol'heJulIllhref1es, and XOllrJwlles 143

OH OH

HO

HO

Gnetum HO

OH

OH

Welwitschio

HO

HO

Fig. 10.5. Gnetins from Gnetum and Welwitschia.

geaceae) (e.g., 12) resemble probable intermediates in the
biosynthesis of stilbenes (Fig. 10.8) (Gorham, 1980).
Prelunularic acid (13) (Fig. 10.6) is the major compound
accumulated by cell cultures of Marchantia polymorpha,
Jungermannia subulata, Lophocolea heterophylla, and Ca-
lypogeia tosana. This compound is converted rapidly to lu-
nularic acid (9) during extraction (Dewick, 1984; Ellis,
1988) (Fig. 10.6).
Biological Activity
Many of the woods from which stilbenoids have been
isolated are highly resistant to decay (Gorham, 1989). These

o OH

,rl-n~~ ~"" """ OH

HO~
o h CO,H
HO

prelnnularic acid (13) lunularic acid (9) (+)·(S)-abscisic acid (19)

Fig. 10.6. Lunularic acid, prelunularic acid and abscisic acid.

144 2~Pyrones, Stilbenes, Dihydrophenanthrenes, and Xanthones

o
HO,C
o

--
o

d
SCoA

+ 3 malonyl-CoA - o

OH

OH

pinosylvin (S)

Fig. 10.7. Biosynthesis of pinosylvin (Haslam, 1974).

~OH
E-cinnamic acid
o

o
- "Or HO pinosylvin (8)

HO~
~OH
-- ""~""
1 OH
HO resveratrol (7)

~
OCH3

HO,:? ~
I ,:::; OH

HO
CO,H
hydrangeic acid (12)
~HO
I .haponligenin

HO~OH
Y HO
-- piceatannol (11)
resveratrol (7)

Fig. 10.S. Biogenetic origin of selected stilbenes (modified from Kindl, 1985; used with pennission of the copyright owner, Academic Press, Orlando.
FL).

compounds cause numerous difficulties in paper manufac-
ture from a number of trees. Pinosylvin (8) is a phytoalexin
in young pine seedlings formed only after the plants have
suffered microbial infection. but it is a constitutive resistance
factor in older trees. Z- and E-Resveratrol (7) are phytoalex-
ins in the peanut, Arachis hypogaea (Fabaceae) (Kuc, 1992);
several C-alkylated isoprene derivatives of resveratrol also
are found in legumes such as the peanut (Kindl, 1985).
Synthesis of a number of antifungal stilbenoids can be
induced by elicitation with fungal preparations or other fac-
tors such as UV light. A family ofphytoalexins from mulber-
ries (Moms spp., Moraceae) possess stilbene structures (Fig.
10.9) (Coxon, 1982). The moracins were isolated from
shoots of Moms alba infected with Fusarium solani f. sp.
mori and were not present in detectable quantities in unin-
fected tissue. Two additional compounds, oxyresveratrol
(10) and 4'-prenyloxyresveratrol (Fig. 10.4), were isolated
from fungus-infected xylem extracts of mUlberry. Although
oxyresveratrol (10) (Fig. 10.4) occurs in heartwood of mul-
berry, this compound is formed in the sapwood as a phyto-
alexin. Two similar compounds, broussonin A and B (14,
15), are found in the shoots of paper mulberry (Broussonetia
papyrijera, Moraceae) infected wilh the same fungus
(Coxon, 1982; Kuc, 1992).
Oligomers of resveratrol, such as a-viniferin (16) and €-
OCH, HoWy
I I
CH, 0~7'I9' I
0
I
OH
CH,O '"
'"
HO
moracinA moracinB
HO
moracinD moracin E
OH
HO
moracin G
Fig. 10.9.
2-Pymlle.I". Sli/helle.I·, Dihydroph('/1(1l1fltrenes. and Xanthones 145
viniferin (17) (Fig. 10.10), are formed following infection
by Botrytis cinerea in grapes (Vitis l'inijera). These phyto-
alexins are highly antifungal (Gorham, 1980).
A similar stilbene (18), that inhibits wood decay fungi,
has been isolated from Diphysa robinioides (Fabaceae),
Schotia brachypetala (Fabaceae), Vouacapoua species (Fa-
baceae), and Maclura pomijera (Moraceae) (Castro el aI.,
1986).
The stilbene piceatannol (11) (Fig. 10.4) is produced
when slalk tissues of sugar cane, Saccharum officinarum, are
inoculated with the red rot fungus, Colletotrichum[alcatum
(Brinker and Seigler, 1991). Piceatannol has antitumor activ-
ity, is fungicidal and algicidal, and inhibits plant growth and
photosynthesis. Piceatannol proved to be the most active
compound from Scirpus maritimus against P-388 lympho-
cytic murine leukemia, and brine shrimp (Artemia salina),
fall army worm (Spodoptera [rugiperda), and duckweed
(Lemna minor) (Powell et aI., 1987). Piceatannol (11) may
act as a specific inhibitor of tyrosine kinase in developing
leukemic cells (McLaughlin, 1991). In these and other assays
for biological activity, piceatannol has greater activity than
most other stilbenes.
The stilbenoid compound lunularic acid (9) occurs in all
liverworts examined thus far and appears to fulfill the same
growth-regulating function in these plants that abscisic acid
0 P
""- I
OH
HO
OCH,
HO
moracinC
CH'O~ I I
CHO'"
, 0
P
I OH
""-
HO
moracin F
OCH,
OH
HO
moracin H
Phytoalexins from mulberries.
146 2-Pyrones, Srilbenes, Dihydrophenanthrenes, and Xanthones

OH

OH

~
YY
OHHO CH iHO
"'CH "" OH

HO~ (18)
OH

HO

OH
OH OH

a·vinlferin (16) E·vlnlferin (17)

Fig. 10.10. Ct- Viniferin and e-viniferin.

(19) (Fig. 10.6) does in higher plants (Gorham, 1980; Man-
dava, 1979; Zinsmeister and Mues, 1987) (see Chapter 23).
Lunularic acid controls drought resistance and dormancy in
Lunularia. However,lunularic acid had no significant effects
on transpiration in the higher plants Lycopersicon, Phaseo-
Ius, or Apium or on the stomatal aperture in epidermal strips
of Commelina (Gorham, 1980). However, at 10-30 ppm,
lunularic acid does inhibit the auxin-induced elongation of
Avena coleoptile segments.
DIHYDKOPHEl'IANTIIRENES Al'ID
PHEl'IANTIIRENES
A number of dihydrophenanthrenes and phenanthrenes pos-
sess antifungal activity and are important as phytoalexins.
Although many of these and related compounds are derived
from pathways discussed in this chapter, others that coinci-
dentally possess phenanthrene stroctures are derived from
isoflavonoid precursors and are discussed under that topic.

o o
~OH ~OH
Y - y---..-~
rnro®
E-cinnamic acid OH OH m·coumaric acid (22)

oo-QO~0 OHHO (23) OCH,HO OCH,HO

~
rn,o-Qb-oo
hircinol (21) loroglossol (24)

~OCH'

o---Q-OH
OCH,
OCH,
orebinol (20) aucuparin (32)

Fig. 10.11. Proposed biosynthetic origin of orchinol and hircinol (Dewick, 1984; modified and used with pennission of the copyright owner, the Royal
Society of Chemistry, Cambridge).
 2-Pyrones, Stilbenes, Dihydrophenanthrenes. and Xanthones 147

batatasin I (24) batatasi. IV (25) batalasi. m (26)

Fig. 10.12. Batatasi. I. IV. and ill.

9,IO-Dihydrophenanthrenes are characteristic of the Or-
chidaceae, Dioscoreaceae, and Combretaceae. Phenan-
threnes and phenanthrene derivatives also have been found
in liverworts (Gorham, 1989).
Biosyntbesls
Biosynthesis of dihydrophenanthrenes is similar to that
of stilbenes but appears to involve dihydrocinuamic acid and
the enzyme bibenzyl synthase, whereas the biosynthesis of
phenanthrenes iuvolves the corresponding unsaturated acids
(Gorham, 1989).
In a series of feeding experiments, it was found that phe-
nylalanine, cinuamic acid, meta-coumaric acid, and dihydro-
m-coumaric acid were good precursors for orchinol (20) and
hircinol (21) in Orchis militaris, but 0- and p-coumaric acids
were not. The production of both meta-substituted com-
pounds in this orchid was confirmed (Dewick, 1984). Incor-
poration of m-coumaric acid (22) proceeds by a pathway
similar to that of stilbene formation (Fig. 10.11) (Dewick,
1984). Wounding of the rhizomes of the orchid Epipactis
palustris caused induction of a bibenzyl synthase which con-
verts m-hydroxyphenylpropionyl-CoA and malonyl-CoA
into 3,5,3'-trihydroxybibenzyl (23) (Gehlert and Kindl,
1991). Production of this bibenzyl compound parallels the
formation of a dihydrophenanthrene. When the bibenzyl
compound was fed to tuber slices of Orchis militaris, orchi-
nol (20) was produced (Brooks and Watson, 1985).
Biological Activity
Dormancy in yam bulbs (Dioscorea hatatas, Dioscorea-
ceae) is induced by three growth inhibitors, batatasins I (24),
IV (25), and III (26). Batatasin I is 6-hydroxy-2,4,7-trimeth-
oxyphenanthrene and batatasin III is 3,3'-dihydroxy-5-me-
thoxybibenzyl (Mandava, 1979) (Fig. 10.12).

OH OH
OH
CH,'O CH,'O
CH,O

CH,.O CH,-O

CH,'O CH,-O
OH OH OH
(27) (28) (29)

OH OH
HO

CH,-O CH,-O

OH OCH,

(30) (31)

Fig. 10.13_ Dihydrophenanthrenes and phenanthrenes from Oncidium cebolleta.

 ,:7
148 2-Pyrones, Sti/benes, Dihydrophenanthrenes, and Xanthones
HO~
~
CO,H
3malonyl-CoA o--.n ~ ~
'~O~__
0
OH
HO
mangostin (35)
HO o
OH
jacarubin (36) OH
Fig. 10.14. Proposed biosynthetic paths to some naturally occurring benzophenones and xanthones (Modified from Manitto, 1981).
The compounds orcinol (20) and hircinol (21) are phyto-
alexins in Orchis militaris and in other species of Orchis
(Orchidaceae) when infected with Rhizoctonia repens
(Brooks and Watson, 1985; Coxon, 1982; Dewick, 1984;
Kuc, 1992). These compounds are active as phytoalexins
against a range of organisms at 10-4 M (Gorham, 1989).
Hircinol has also been isolated from tubers of yam (Diosc-
orea rotundata, Dioscoreaceae) where it is a preformed anti-
fungal compound.
One species of the Orchidaceae, Oncidium ceboletta, is
used by the Tarahumara Indians of Mexico as a replacement
for peyote, a hallucinogenic species of cactus. The whole
green leaf is crushed in water and the mixture consumed.
This plant contains 2,7-dihydroxy-3.4,6-trimethoxyphe-
nanthrene (27), 2,7-dihydroxy-3.4,6-trirnethoxy-9,lO-dihy-
drophenanthrene (28), 2,3-dihydroxy-4,7 ,8-trimethoxyphe-
nanthrene (31), 2,7-dihydroxy-3,4-dimethoxyphenanthrene
(29), and 2,7-dihydroxy-4,8-dimethoxyphenanthrene (30)
(Fig. 10.13) (Stermitz et al., 1983).
Bibenzyls also have antifungal activity. Aucuparin (32)
(Fig. 10.12) was induced in tissues of loquat (Eriobotrya
japonica, Rosaceae) when challenged with the fungus Col-
letotrichum lindemuthianum (Brooks and Watson, 1985).
OH tco,:7
HO"'"
OH
1
0
OH"'"
1-
OH
OH 1,3,S,6-tetrahydroxyxanthone (34)
OH
mangiferin (37)
H
8ENZOPIfflNONES
Benzophenones are derived from several pathways. In higher
plants, most benzophenones arise by cyclization of a polyke-
tide chain of three malonates added to a hydroxybenzoic acid
precursor (ManJttu, 1981). Cyclization occurs via a Claisen
condensation mechanJsm (Fig. 10.14). These compounds
serve as precursors for xanthones in many plants. In some
instances [e.g., in the heartwood of Symphonia globulifera
(Clusiaceae)], the benzophenone and the corresponding xan-
thone co-occur [in this case maclurin (33) and 1,3,5,6-tetra-
hydroxyxanthone (34)] (Weiss and Edwards, 1980).
XANTHONES
About 150 xanthones have been discovered. Many are po-
lyketide derived, although others are formed from combined
shikimic acid pathways combined with acetate-malonate
units. Three units of malonate react with a hydroxybenzoic
acid (Co-C 1 ). Benzophenones may be converted by oxida-
tive ring closure into xanthones (Fig. 10.14) (Weiss and Ed-

wards, 1980). Alternatively, two units of malonate can react
with a C6 -C3 precursor to yield other xanthones. Cinnamic
acid, benzoic acid, m-hydroxybenzoic acid, malonic acid,
and an intermediate benzophenone all proved to be precur-
sors for mangostin (35) (Hostettmann and Hostettmann,
1989). This route seems most likely for compounds such as
jacarubin (36) and mangiferin (37) (Hostettmann and Hostet-
tmann, 1989; Mannito, 1981). Direct coupling of the oxy-
gens seems more likely for xanthones of the lichexanthone
type produced by microorganisms (Mannito, 1981).
Maclurin (33) and two related cydization products that
are found in the heartwood of Symphonia globulifera (Clusi-
aceae) possibly arise by ring closure of a benzophenone pre-
cursor (Weiss and Edwards, 1980).
Distribution of Xanthones
Xanthone aglycones are found in eight families: Clusia-
ceae, Fabaceae, Gentianaceae, Loganiaceae, Lythraceae,
Moraceae, Polygalaceae, and Rhamnaceae. Aglycones and
their corresponding O-glycosides are found only in the Gen-
tianaceae and Polygalaceae (Hostettmann and Hostettmann,
1989). However, C-glycosides, such as mangiferin (37), are
widespread among plants. Among the glycosidic sugars,
only l3-n-glucose is found (Vermes and Wagner, 1986).
Biological Activity
Several xanthones that possess antidepressant activity in-
hibit monoamine oxidases. These compounds have in vitro
cytotoxicity and in vivo antitomor activity (Hostettmann and
Hostettmann, 1989). The xanthone psorospermin (38) from
Psorospermumfebrifugum (Clusiaceae) exhibited antileuke-
mic activity in several test systems. Other xanthones have
tuberculostatic effects (Vermes and Wagner, 1986).
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BROOKS, C. J. W. and D. G. WATSON. Phytoalexins, Nat. Prod.
Rep., 2. 427-459 (1985).
CASTRO, 0., J. LoPEZ, A. VERGARA, F. R. STERMITZ, and D. R.
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680-683 (1986).
COXON, D. T., Phytoalexins from other families, in Phytoalexins
(J. A. Bailey and J. W. Mansfield, eds.), 106-132. Wiley, New
York,1982.
DBWICK, P. M.. The biosynthesis of shikimate metabolites, Nat.
Prod. Rep., 1. 451-469 (1984).
ELLIS, B. E., Natural products from plant tissue culture, Nat. Prod.
Rep., 5. 581-612 (1988).
2-Pyrones. Stilbenes, Dihydrophenanthrenes, and Xanthones 149
OEHLERT, R. and H. KINDL, Induced formation of dihydrophe-
nanthrenes and bibenzyI synthase upon destruction of orchid
mycorrhiza, Phytochemistry, 30. 457-460 (1991).
GElSSMAN, T. A. and D. H. O. CROUT, Organic Chemistry of Sec-
ondary Plant Metabolism. Freeman Cooper, San Francisco,
1969.
GORHAM, J., The stilbenoids, in Progress in Phytochemistry, Vol.
6 (L. Reinhold, J. B. Harborne, and T. Swain, ed.), 203-252,
Pergamon, Oxford, 1980.
GORHAM, J., Stilbenes and phenanthrenes, in Plant Phenolics I (J.
B. Harbone, eds.), Vol. 1 of Modem Methods of Plant Biochem-
istry (p. M. Dey and J. B. Harborne, eds.), 159-196, Academic
Press, London, 1989.
GOTILma, O. R., Towards a scientific status for micromolecular
systematics, Acta Amazonica, 10. 845-862 (1980).
OOTfLlliB, O. R. and K. KUBITZ!(], A chemical link between Gnetum
and Welwitschia. Naturwissenschaften, 75. 575-577 (1988).
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Biodegradation of Wood Components (T. Higuchi, ed.),
291-324, Academic Press, Orlando, FL, 1985.
HART, J. H., Role of phytostilbenes in decay and disease resistance,
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11
Flavonoids

Introduction Isoflavans
Biosynthesis of Flavonoids Pterocarpans
Initial Steps of Flavonoid Biosynthesis Phytoalexins
Chalcones as Intennediates in Flavonoid Biosynthesis Rotenoids
Flavanones Neoflavonoids
Flavones Isolation, Purification, and Characterization of Flavonoids
Dihydroflavonols References
Flavonols
Substitution Patterns of Flavonoids
Flavone and Flavonol Aglycones Il'ITRODVCTIOI'l
Glycosylation and Methylation of Flavones and
Flavonols At least 4000 naturally occurring flavonoids have been de-
Biosynthesis of C-Glycosyl Flavonoids scribed; many are common in higher plants (Harborne,
Biosynthesis of Anthocyanins 1991). Most of the flavonoid compounds reported in the
Systematic Studies with Flavone and Flavonol Glycosides literature are glycosides of a relatively small number of fla-
Biological Activity of Flavone and Flavonol Aglycones vonoid aglycones which often are accumulated in the vacu-
and Glycosides oles of plant cells. These compounds frequently serve as
Biological Activity of Aglycones pigments in plants and are involved in many biological inter-
Biological Activity of Glycosides actions (Harborne, 1991). Flavonoids are based on a CIS
Anthocyanins skeleton and include a chroman ring bearing an aromatic
Factors Responsible for Color ring in position 2,3, or 4 (Hahlbrock, 1981).
Biological Activity of Anthocyanins Of the several hundred flavonoid aglycones (approxi-
Commercial Importance of Anthocyanins mately 200 flavones and 300 flavonols) that have been iso-
C-Glycosylflavones lated from plants (Wollenweber, 1982; Wollenweber and
Biflavonoids Dietz, 1981; Wollenweber and Jay, 1988), only 8 are distrib-
Chalcones uted widely (Figs. 11.1 and 11.2). One or some combination
Aurones of these eight flavonoid aglycones may be expected to occur
Dihydrochalcones in the hydrolyzed extract of most higher plants. All eight
Flavanones aglycones have the same basic hydroxylation pattern in the
The Role of Flavonoids in Pollination and Propagule A ring and differ mainly in the oxidation level of the central
Dispersal Mechanisms pyran ring and in the number of hydroxyl groups in the B
Isoflavones ring. Although all eight are known to occur free in plants,
Biosynthesis these compounds most commonly are found as a part of
Distribution water-soluble glycosides (Harborne, 1991).
Biological Properties Flavonoids may be divided conveniently into 14 classes
Derivatives of Isoflavones according to the oxidation level of the central ring (ring C)
Coumestans (Fig. 11.2). The most common of these are anthocyanins

151
152 Flal'onoids

(such as 1-3), flavones (such as 4 and S), and flavonols
(such as 6-8), Some flavonoids are strongly pigmented; oth-
ers are colorless (Harborne, 1991),
Three of these common flavonoid compounds, pelargoni-
din (4), cyanidin (3), and delphinidin (2), are anthocyanidins.
These colored pigments are found widely in flowers· and
fruits and frequently are involved in the attraction of pollina-
tors and in fruit and seed dispersal, but they also occur in
vegetative portions of plants.
The flavonols, kaempferol (6), quercetin (7), and myri-
cetin (8), have increasing B-ring hydroxylation. These com-
pounds occur as copigments in flowers and fruits, but also
they are found commonly in leaves, stems, and roots. in a
sample of 1000 plant species, over 60% had 1 or more of
these compounds as glycosides, Myricetin tends to be found
in association with tannins in woody plants.
Flavones lack the 3-hydroxy group of flavonols and an-
thocyanins. Although only two flavones, apigenin (S) and
luteolin (4), are common; these compounds are widespread,
especially in herbaceous plants, and occur both as C-glyco-
sides and O-glycosides. Flavonoids that differ in oxygena-
tion pattern from these eight compounds have limited distri-
butions and are uncommon. Other representative
(compounds) are illustrated in Fig, 11.3.
Methylated flavonoids corresponding to the eight com-
mon structures and compounds with unusual hydroxylation
patterns are known; most of these also are restricted in distri-
bution.
The presence of methylation, alkylation, or ester groups
makes flavonoids more lipid-like in nature (Fig. 11.4). in
many cases, aglycones and glycosides are additionally sub-
stituted and occur as esters (acetate, malonate, butyrate, cin-
namate, p-coumarate, femlate, etc.) or ethers. in contrast to
water-soluble glycosides that are usually accumulated in the
vacuole, flavonoid esters and ethers usually are associated
with waxes or found in the cytoplasm.

OH
OH OH

HO
"
OH
0 OH 0
OH OH
OH OH

HO HO
OH

OH 0 OH 0

OH OH

HO HO

OH OH
apigenin (5) pelargonidin (1) OH
OH
OH

HO

OH
OH

delphinidin (2) cyanidin (3)

Fig. 11.1. The eight most common flavonoid nuclei.

 Flavonoids 153

o CO,H HO CO,H HO 0
/O~~ OH _ _ h ~ ~ OH_ _ ~0'lco.~
~ ~ ~OH
o I "'" HO OH ~OH - OH
• H " 1
HO
O--=--O-OH
HO
HO"I

/OHO
~ ~
HO"I°'"
=--.
OHO

«pt
a stilbene / Ja chalcone (9) a flavanone (10)

H0l"'ir0~
~ VOH
HO ~ HO::;;." 0
"1 OH
~
OH 0 ,.. 1 1

an auraDe (11) OH OH 0
an isoflavone (46) a flavone (5)

HO_ ~~OH--O/H
TYV. HO
+ HO
OH

OH 0
a dihydrocbalcone (12)
a rotenoid
/ OH 0

OH a dihydronavonol (13)
HO 0 HO
i OH
OH
OH HO
a navan-3-ol (46)
a pterocarpan (95)
OH
OH OH 0
HO
a flavonol (6)

OH
an anthocyanidin (1) a navan-3,4-diol (33)

Fig. 11.2. Major classes of flavonoids (modified from Weiss and Edwards, 1980; used with pennission of the copyright owner, Copyright© 1980, John
Wiley & Sons, Inc., New York).

Flavonoids vary widely in their biological properties; it
is among the colorless flavonoids that most compounds with
significant physiological activity have been reported.
BIOSYNfHESIS OF FLAVOI'lOmS
Many aspects of the biosynthesis of flavonoids have been
elucidated, but major progress in sorting out certain reaction
steps and the enzymes involved in flavonoid biosynthesis
was not possible before tissue and cell culture of suitable
plants were developed (Hutchinson, 1986). The use of flow-
ers as sources of enzymes has provided the means for pro-
ducing 14C-labeled substrates (Heller and Forkmann, 1988).
Cell cultures of Petroselinum hortense (parsley, Apiaceae)
contain both flavone and flavonol glycosides; most of the
approximately 13 enzymes that catalyze the formation of
flavonoid glycosides have been isolated and studied. Light
is required for the synthesis of flavonoids in this system. An
irradiated culture of parsley petiole tissue produces a high
concentration of both types of flavonoids and high levels of
enzyme activity. The intermediate compounds and enzymes
involved in many of the biosynthetic steps have been charac-
terized (Fig. 11.5). Use of flower cultivars with defined ge-
notypes has proven valuable for correlations of genes with
particular enzymes, as well as for elucidation of some steps
of the biosynthetic pathway (Grisebach, 1985).
The enzymes of flavonoid biosynthesis are compartment-
alized by membranes that surround the organelles and those
which separate cytoplasmic regions into different microcom-
partments. In addition, the association of biosynthetic en-
zymes as loose aggregates, as well as interaction between
constituent enzymes, permit direct transfer of substrates
from one enzyme to another and channeling of intermediates
and final products to the different sites of accumulation
(Hrazdina, 1992; Ibrahim, 1992). Flavonoid derivatives that
 w
154 Flavonoids

OCH,

o "" 1
: 1 1 CH,'O HO

OH 0
OH 0 OH 0
5~hydroxyt1avone digicitrin isorhamnetin
OH OH OR
OH
OR
OHd '
HO HO V 0 "" 1

R-O "" 1 1
OH 0 OH 0
OH 0
gossypetin quercetagetin, R=H chrysoerioJ, R=CH;Jt R'=H (38)

#
patuletin, R=CH3 diosmetin, R=H, R'=CH 3

OH OH

HO V

"" 1
0

1
:1 OH OH

OH
OH 0

#
luteolinldin
methoxyluteolin

OH
OH
OH OH

CH,-O HO r 0 : 1

""I
OH 0 OH 0

rhamnetin (51) eriodietyol (17)

Fig. 11.3. Other representative flavones and flavonols.

OH

OH

OH 0

sideroxylin mulberrin
Fig. 11.4. Alkylated !lavonoids.
 Flavonoids ISS

3 malonyl CoA

4-coumaroyl CoA
-+
,
HO
OH
HO~ ycfJ""I
oH",,1
0H

OH 0

/ a chalcone (9) ;/ a navanone (10)

OH

W
+~
HO~~-!!HO
OH OH
HO 0 "" 1
1 - ~ 1 1
""
OH 0
""
OH 0 ~ OH 0

an aurone (13) a dihydroflavonol (13)

'- o~ a flavone (S)
HO ~ OH OR

OH
an isoflavone (46)
a flavonol (6) a catechin (20)
or flavon-3-ol
OR OR

Hoo:rP~-!!
HO

I -
:::,...
OH
o
an anthocyanidin (3) sulfuretin (73)

a chalcone synthase b chalcone isomerase c flavanone 3-hydroxylase

Fig. 11.5. Proposed biosynthesis of major groups of flavonoids and major enzymes (modified from Grisebach, 1985; used with pennission of the
copyright owner, Academic Press, Orlando, FL).

are hydrophilic usually accumulate in the vacuole, whereas
lipophilic compounds are found in epidermal glandular cells
or on plant surfaces, or are exuded from plant roots (Ibrahim,
1992). Many of the enzymes of flavonoid biosynthesis are
found in the cytoplasm, but are membrane associated. A
model system has been proposed (Stafford, 1990).
Initial Steps of Flavonoid Biosynthesis
Most flavonoids are derived from phenylalanine via cin-
namic and p-coumaric acids by the addition of three malo-
nate units and subsequent cycJization (Hahlbrock and
Grisebach, 1975) (see Chapters 7 and 8). Phenylalanine am-
monia lyase (PAL), which catalyzes the first step of the
biosynthetic process, is found in parenchyma cells of many
plants. PAL activity in vivo may be regulated by end-product
inhibition by flavonoids.
The enzymatic conversion of cinnamic acid to 4-hydrox-
ycinnamic acid (p-coumaric acid) in peas is associated with
a microsomal fraction. This enzyme is a mixed-function oxi-
dase that requires molecular oxygen, NADPH, and mercap-
toethanol for activity. p-Coumaric acid has a strong regula-
tory effect on the enzyme at 3 X 10-7 to 10- 6 M
concentration (Hahlbrock, 1981).
The next major enzyme in the series, p-coumarate : CoA
ligase, was first isolated from illuminated cell suspension
cultures of PetroseUnum crispum (syn. P. hortense) and
shown to be specifically related to flavonoid and stilbene
biosynthesis. The enzyme requires p-coumaric acid,
CoASH, ATP, and Mg2+ for activity (Hahlbrock, 1981;
Hutchinson, 1986). Three malonyl-CoA units are added and
cyclized via a elaisen condensation (see Chapter 5) to pro-
duce a chalcone intermediate (9). Condensation of the same
intermediates via an aldol condensation yields pyrones and
156 FJavonoids
~ ~ -- ~ -
A" ~
NH3+
CO,- CO,-
phenylalanine E-cinnamate
HO
OH o OH
naringenin chalcone (9)
Fig. 11.6, Steps common to the biosynthesis of all flavonoids (Hahlbrock, 1981; modified and used with pennission of the copyright owner, Academic
Press, Orlando, Fl.).
stilbenes [see Fig. 10.2 (Chapter 10)] which co-occur with
flavonoids in some plants.
CbaIcones as Intermediates In Flavonoid
Biosyntbesls
As described above, the fIrst enzyme general to all flavo-
noid biosynthesis, chalcone synthase (naringenin-chalcone
synthase), catalyzes the cyclization of a precursor formed
from p-coumaryl-CoA and three units of malonyl-CoA
(Fig. 11.6) (Dewick, 1989; Gerats and Martin, 1992; Heller
and Forkmann, 1988). The enzyme, usually found in plant
epidermal cells, has a molecular weight of about 42,000,
requires no cofactors, and has been isolated from several
plant cell cultures such as French bean (Phaseolus vulgaris),
parsley (Petroselinum crispum), and the flowers of the car-
nation (Dianthus caryophyllus, Caryophyllaceae) (Hutchin-
son, 1986). p-Coumaric acid and malonyl-CoA are the pre-
ferred precursors. Malonyl-ACP will not serve.
Chalcone synthase from parsley culture cells has a molec-
ular weight of about 77,000 and is composed of two identical
subunits of about 42,000 MW. The cDNA complementary
to the mRNA of chalcone synthase from irradiated parsley
cell cultures has been cloned in Escherichia coli (Grisebach,
1985).
Considerable homology of chalcone synthases with stil-
bene synthases has been found (Melchior and Kind!, 1990).
Because the mechanism of the stepwise addition of C-2 units
OH HO
3 malonyl eoA
CO,-
0 SCoA
4-coumarate 4·coumaroyl·CoA
OH
o
naringenin (10)
to form the A ring may be similar to that of the J3-ketoacyl-
acyl carrier protein offatty acid synthases, that latter enzyme
may be the ancestral type (Heller and Forkmann 1988,
Hutchinson, 1986; Stafford, 1991).
Mutants that lack chalcone isomerase, the next enzyme
in the sequence, accumulate chalcones, not flavanones, and
establish that the initial product of the reaction is a chalcone
(Grisebach, 1985). Recessive genotypes of certain flowers
that lack chalcone synthase accumulate cinnamic acid gluco-
sides (Grisebach, 1985).
Chalcones (e.g., 9) are key intermediates in the formation
of several major groups of flavonoids (see Fig. 11.2). In
some plants, they are converted into aurones (such as 11).
In other instances, chalcones undergo reduction of the exocy-
clic double bond to produce dihydrochalcones (such as 12).
Chalcones and flavanones (e.g., 10) exist in eqUilibrium in
in vitro systems. However, as only flavanones with a (2S)-
configuration are known to occur naturally, this interconver-
sion appears to be enzymatically controlled and does not
involve racemization. Desaturation of flavanones can yield
flavones (such as 4 and 5), whereas introduction of oxygen
at the 3-position gives dihydroflavonols (flavanonols) (such
as 13) which, in tum, are the precursors of flavonols (e.g.,
6-8), anthocyanins (e.g., 1-3), and condensed tannin precur-
sors (Ebel and Hahlbrock, 1982; Hahlbrock, 1981; Haslam
1974) (Figs. 11.7 and 11.8).
In plants that have both 2',4'-dihydroxychalcones and
 Flavonoids 157

~OH

COASy I c:r OH

O~/O­
~C ~
cl
E-CH,COSCoA
"'-'"'=~' " ~~,yYI~ +E+CoASH
o 0
co,
Fig. 11.7. Proposed mechanism for fonnation of chalcone (modified from Grisebach, 1985; used with pennission of the copyright owner, Academic
Press, Orlando, FL).

OH

HO OH HOn;x: O1 OH
OH ------" I OH
~ ""-
both isolable, stable 0
o
butein butin

OH

HO

---------
o
2',4',6' ,4-tetrahydroxychalcone (9) naringenin (10)
(nnstable) (stabilized by hydrogen bonding)
OH
OH

HO
HO
4'
'>

isoliquiritigenin (15) liquiritigenin (14)

o a 5·deoxyflavonoid

HO
~
=--
g>Ki"
~ 1 O""""--...'·'----" •••
H,q

'H" ~
(-H2S)-7,4'-dihydroxyflavanone

OH

Fig. 11.8. Chalcone-isomerase-controlled isomerization (modified from Geissman and Crout, 1969).
158 Flavonoids
2',4',6'-trihydroxychalcones, the chalcone isomerase is ac-
tive with both precursors (Heller and Forionann, 1988).
Flavanones
Flavanones, by virtue of their role as biosynthetic inter-
mediates, occur in most plants, but they are also accumulated
widely (Grayer, 1989). Most of the approximately 320
known flavanones possess the ( - )-(2S)-configuration. Fla-
vanones are common in the Asteraceae and Fabaceae, and
the genus Citrus of the Rutaceae, but they have been reported
in at least 60 other families (Bohm, 1988). However, com-
pounds of this type are overlooked frequently in surveys of
flavonoid composition of plants, and representatives of this
group of compounds may occur more widely in nature.
As described above, chalcones and flavanones are easily
interconverted under mild conditions and the original isom-
erization in plants may have been nonenzymatic (Stafford,
1991). However, because most hydrolyases utilize the (2S)-
isomer, enzymatic control would be more efficient. An en-
zyme capable of catalyzing this interconversion, chalcone
isomerase, has now been demonstrated to be present in a
number of plants. The enzyme has no cofactor requirements.
A proton is introduced specifically into the axial position at
C-3. The effect of illumination suggests that the enzyme
is related to and probably essential for the biosynthesis of
flavonoids.
The chalcone isomerase from parsley is specific for
4,2',4',6'-tetrahydroxychalcone substrates (such as 9). ~uly
5,7-dihydroxyflavonoids (such as 14) are found in the plant.
Chalcone isomerase activity is present in anthocyanin or fla-
vonol-containing genotypes of the china aster, Callistephus
chinensis (Asteraceae), but completely absent from a yellow
line that accumulates the chalcone glucoside isosalipurpuro-
side (16) (Fig. 11.9) (Grisebach, 1985). An enzyme capable
of converting the deoxychalcone isoliquiritigenin (15) into
ROW: OR
p 1 1
""-
OR °
isoliquiritigenin (15)
ROy:;:o0-gIUOOSYIOR
P "'"
""- 1 ::::,.. 1 "'"
OR ° "
isosBlipurpuroside (16)
marein 2, 131,4' ,4·pentahydroxy·4'·glucoside
coreopsin 2,'3 ,4',3,4·pentahydroxy-4'·glucoside
Fig. 11.9. Representative chalcones. flavanones, and deoxychalcones.
liquiritigenin (14) has been isolated from seedlings of Amer-
pha fruticosa (Fabaceae) (Dewick, 1989).
Flavones
The approximately 650 known flavones arise from flava-
nones by oxidative processes (Harbome, 1991). Most of
these are glycosides of 200 flavone aglycones. Both mo-
nooxygenase and dioxygenase types of flavone synthases
have been found (Stafford, 1991). With a soluble enzyme
preparation of irradiated cell suspension cultures of parsley,
conversion of naringenin (10) or eriodictyol (17) (Fig. 11.3)
to the corresponding dihydroflavonol, flavonol, and flavone
was observed; all these reactions require 2-oxoglutarate,
Fe2+, and ascorbate as cofactors (flavone synthase I)
(Grisebach, 1985; Heller and Forkmann, 1988). An enzyme
from parsley that catalyzes the oxidation of naringenin (10)
to the corresponding flavone, apigenin (5), in the presence
of Fe2+ and a nonproteinaceous cofactor has been demon-
strated. In parsley, 2-oxoglutarate (a-ketoglutarate), Fe2+,
and ascorbate are required as cofactors for conversion to
both flavones and flavonols (Britsch et al., 1981).
However, the flavanone naringenin (10) [but not dihydro-
kaempferol (13)1 is the substrate for flavone formation in
snapdragons, Antirrhinum majus (Scrophulariaceae) (fla-
vone synthase m (Fig. 11.10). In this plant, flavones arise
from dehydrogenation of flavanones and not from dehydra-
tion of dihydroflavonols (Britsch et al., 1981). A similar
enzyme system converts dihydroflavonols to flavonols
(Britsch et al., 1981). In other work, the enzyme responsible
for oxidation offlavanones to flavones in snapdragon (Antir-
rhinum majus) was isolated from a microsomal fraction and
shown to require NADPH and molecular oxygen (Britsch et
al., 1981; Dewick, 1989; Forkmann and Stotz, 1981). The
system appears to be a cytochrome P-450-dependent mo-
nooxygenase. This system also is known from Glycine max
,
.
liquiritigenin (14)
,. ,I "'"
.' PI"
S' ""-
°
chalcone
1

HO~OWOH HO
W--
OH 0 OH
(2S)-naringenin (10) 2-hydroxynarlngenin
~
HO
OH 0
OH
dihydrokaempferol (13)
Fig. 11.10. Biosynthesis of apigenin and kaempferol (Heller et at., 1985a; modified and used with pemlission of the copyright owner, Springer-Verlag,
Heidelberg).
(Fabaceae), Verbena hybrida (Verbenaceae), and Taraxa-
cum officinale (Asteraceae) (Dewick, 1989). Chalcones do
not appear to be substrates (Ebel and Hahlbrock, 1982; HahI-
brock, 1981).
Dihydroftavonols
Certain dihydroflavonols are intennediates in the biosyn-
thesis of flavonols, but approximately 110 other dihydrofla-
vonols and dihydroflavonol glycosides are found in a variety
offamilies, especially the Asteraceae and Fabaceae (Grayer,
1989).
Dihydrokaempferol (13) appears to arise by direct hy-
droxylation ofnaringenin (10) at the 3-position, catalyzed by
a dioxygenase, flavanone 3-hydroxylase (Grisebach, 1985;
Heller and Forkmann, 1988; Stafford, 1991). The enzyme
requires 2-oxoglutarate, Fe2+, and ascorbate as cofactors.
(2S)-Naringenin [but not the (2R)-enantiomer] is a substrate
for the enzyme. The product fonned has been identified as
(2R, 3R)-dihydroquercetin. Although the intennediacy of a
chalcone 2,3-epoxide (19) for the synthesis of dihydroflavo-
nols such as taxifolin (18) has been proposed, this synthesis
may occur by hydroxylated intennediates (Fig. 11.11).
F1avonols
Approximately 1030 flavonols are known (Harborne,
1991). Most of these are glycosides derived from approxi-
mately 300 flavonoid aglycones. Flavonol biosynthesis
probably occurs via a 2-hydroxy intennediate with subse-
quent dehydration, in a manner similar to that proposed for
fonnation of flavones. Flavonol fonnation with extracts from
flowers of Matthiola and Petunia requires a soluble 2-oxo-
glutarate-dependent dioxygenase (Heller and Forkmann,
1988).
The conversion of dihydroflavonols into flavonols, antho-
FIQ)'onoids 159
H 0 y r : P ' :OH
~, ,
""-
0 OH 0
apigenin (51)
OH "'" OH
&
OH
0
kaempferol (6)
cyanins, and catechins (such as 20) (flavan-3-0Is; see Chap-
ter 12) has been demonstrated by tracer studies. To date, the
origin of the oxygen of dihydroflavonols in position 3 is not
clear, although an enzyme !hal introduces oxygen into that
position in naringenin has been isolated. The same protein
extract described above for the synthesis of flavones also
has the ability to hydroxylate naringenin (10), yielding dihy-
drokaempferol (13), and the ability to oxidize dihydrokaem-
pferol to kaempferol (6). Dihydrokaempferol serves as an
efficient precursor of cyanidin (an anthocyanidin) and quer-
cetin (7) (a flavonol) in buckwheat (Fagopyrum esculentum,
Polygonaceae) (Kerscher and Franz, 1988).
Substitution Patterns of F1avonoids
The substitution pattern of flavonoids is detennined by
several factors. Hydroxylation at the 4'-position of the B
ring is derived from the p-coumaric acid precursor involved
in the fonnation of most flavonoids. Compounds that lack
this substitution are comparatively tare. Additional hydroxyl
groups appear to be added after the flavonoid is fonned (i.e.,
at least at the chalcone stage) (Stafford, 1991). Although
4-coumaryl-CoA is the most efficient precursor, chalcone
synthase from some plants can also use caffeoyl-CoA and
feruloyl-CoA as substrates; in which case, the correspond-
ing substituted chalcones are formed. Hydroxylation of the
3'- and 5'-positions is the most common type ofB-ring oxy-
genation. A microsomal flavonoid 3'-hydroxylase from par-
sley cell cultures has been demonstrated. This enzyme will
convert naringenin (10) to eriodictyol (17) and will accept
dihydrokaempferol (13), kaempferol (6), and apigenin (5)
as substrates. The enzyme appears to be a cytochrome P-450-
dependent monooxygenase (Grisebach, 1985). ER-Iocalized
cytochrome P-450 monooxygenases, which probably arose
from cinnamic hydrolyase of the phenylpropanoid pathway,
are responsible for 3' and 5' hydroxylation (Stafford, 1991).
160 Flavonoids
R=OH, R'=H; eriodictyol (17)
R
OR
~
",,' ,
R0 7 0 '"""
OR 0
R=OH, luteolin (4)
Fig. 11.11. Proposed biosynthetic schemes leading to taxifolin (Britsch et aI., 1981; modified and used with pennission of the copyright owner, Vedag
der Zeitschrift fUr Naturforschung, Tiibingen).
The actual pattern of oxidation observed may depend on
the nature of the enzyme complex involved in a particular
situation. The eventual substitution of the A ring is deter-
mined by the substitution pattern at the chalcone stage. 5-
Deoxyflavonoids are derived from chalcones without a hy-
droxyl group in the corresponding position (the numbering
system of chalcones is different from that of cyclized flavo-
noids) formed by the action of soluble NADPH-dependent
reductases (Fig. 11.8) (Stafford, 1991).
An enzyme from the flowers of Sinningia cardinalis
(Reichsteinia cardinalis, Gesneriaceae) has hydrolase activ-
ity associated with microsomal fractions and requires
NADPH as an essential cofactor (hydrolyase activity II).
This enzyme converts naringenin (10) and apigenin (5) to
eriodictyol (17) and luteolin (4), respectively (Dewick,
1989). The flavone synthase activity of this enzyme was
abolished completely by treattnent with the cytochrome P-
450 inhibitor ancymidol, but the flavonoid 3'-monooxygen-
ase activity was not altered.
Other enzymes that introduce oxygen into the 3'- and 5'-
positions have been isolated (Dewick, 1984, 1989;
Grisebach, 1985).
Flavone and Flavonol Aglycones
Although the majority of flavones and flavonols in plants
occur as glycosides or other "bound" forms, small amounts
of aglycones frequently are present and occasionally repre-
sent a sizable proportion of the total flavonoid compounds
present in or on the plant. Flavonoid aglycones frequently
are methylated or esterified and the mixture is lipophilic. In
many plants, these compounds are the products of epidermal
glandular trichomes (Rodriguez et aI., 1984; Wollenweber
and Dietz, 1981). Some highly methylated flavonoids are
toxic to mammals and other animals.
R
OR
RO
R'
OR 0
R = OH, R' =H; dihydroquercetin (18)
R =R' =OH; dihydromyricetin (29)
OR
RO
R'
R=OH, R'=H; quercetin (7)
Glycosylation and Methylation of Flavones
and Flavonols
A large number of flavones and flavonols occur naturally
as glycosides. Although there are about 475 flavone and
flavonol aglycones, 720 flavone and flavonol O-glycosides
and 214 C-glycosides (and their O-glycosides) (see below)
have been reported (Markham, 1989). A number of highly
specific flavone and flavonol glucosyltransferases are pres-
ent in parsley cell cultures as well as a number of other plant
sources (Ebel and Hahlbrock, 1982; Grisebach, 1985; Hosel,
1981). In Pisum sativum, three distinct glucosyltransferases
catalyze the stepwise glucosylation of kaempferol (6) and
quercetin (7) to produce a series of triglucosides all of which
have a 3-0-glucoside substitution.
Enzymes that catalyze methylation of specific hydroxyl
groups in flavonols have been isolated (Grisebach, 1985;
Heller and Forkmann, 1988). A quercetin 3-0-methyltrans-
ferase has been isolated from several plants (Poulton, 1981),
and in one plant, at least three distinct flavonol O-methyl-
transferases were found. These enzymes catalyzed the step-
wise methylation of quercetin to mono-, di-, and tri-O-
methyl derivatives (Ebel and Hahlbrock, 1982).
Glycosides of flavonoid sulfates occur in a number of
plants (Fig. 11.12) (Harhorne, 1991). More than 100 flavone
and flavonol sulfates from more than 250 species and 30
families have been characterized; compounds of this type
may be recognized by examination of their UV spectra be-
fore and after addition of HeI and aryl-sulfatase (Barron and
Ibrahim, 1988; Harhorne, 1991; Varin, 1992).
A number of flavonoids possess a malonyl unit linked to
the sugar moieties. Others with malic, oxalic and succinic
acid have been reported (Harborne, 1991).
The techniques for isolation and study of flavone and
 Flavonoids 161

OSO,- OR
OR OCR,

-O,S-O "" CR,O

OR
OR 0 OR 0

luteolin 7,3 1·disulfate tamarixetin 3·sulfate

Chap. 1l,Fig. II

Fig. 11.12. Sulfates of flavonoids.

OR

RO

OR 0
2-hydroxynaringenin (23)
C-glucosyltransferase

RO OR

RO
II OR 0

OR

""
§

OR 0
RO
RO
! ""
OR

OR o
vitexin (21)
Wessely-Moser isovitexin (24)
0
1
O-glucosylaHon

isosmerization
C·glycosylflavone 7·0-g1ucosides

Fig. 11.13. Proposed biosynthesis of flavone C-glycosides (modified from Dewick, 1989 and Chopin and Boulliant, 1975; llsed with permission of the
copyright owners, the Royal Society of Chemistry, London and Academic Press, New York).
162 Flavonoids
flavonol glycosides have been reviewed (Harborne, 1973;
Mabry et aI., 1970; Markham, 1982, 1989) (also see below).
Biosynthesis of OGlycosyJ F1avonoids
Biosynthetic studies in Spirodela polyrhiza demonstrated
that apigenin (5) and luteolin (4) served as efficient precur-
sors of the corresponding O-glycosylated compounds but
were not incorporated into the corresponding C-glycosides
(Wallace and Grisebach, 1973; Wallace et aI., 1969). In con-
trast, naringenin (10) was incorporated in a parallel manner
into both 7-0-glycosides and into vitexin (21) and orientin
(22) (Figs. 11.13 and 11.14) (Wallace and Grisebach, 1973).
2-Hydroxyflavanones are intennediates in the biosynthesis
(Kerscher and Franz, 1988). A C-glucosyltransferase prepa-
ration from buckwheat, F agopyrum esculentum (Poly-
gonaceae), catalyzes the transfer of glucose from UDP-glu-
cose or ADP-glucose to 2-hydroxynaringenin (23)
producing a mixture of vitexin (21) and isovitexin (24) and
to 2,5,7-trihydroxyflavanone (25) giving 8- (27) and/or 6-
C-glucosylchrysin and (26) (Figure 11-14). Thus, C-glyco-
S·C·glucosylchrysin (27)
OD 0
orientin (22)
DO
rhamnosyl-4-ketofucosyl
OD 0
2,5,7-trihydroxyflavanone (25)
Fig. 11.14.
sylation occurs after conversion to flavones (Kerscher and
Franz, 1988).
Biosynthesis of Anthocyanins
The biosynthesis of anthocyanidins has been elucidated
more recently than most other flavonoids. These positively
charged compounds are derived from flavan-3,4-diols via
dihydroflavonols. The hydroxyl group of the 3-position of
anthocyanidins is introduced by flavanone 3-hydroxylase
which converts flavanones to dihydroflavonols (see above).
(2S)-F1avanone 3-hydroxylase from flowers of Petunia hy-
brida catalyzes the conversion of (2S)-naringenin (10) [but
not (2R)-naringeninJ to (2R,3R)-dihydrokaempferol (13).
The hydrolase is a soluble enzyme that requires oxygen, 2-
oxoglutarate, Fez+, and ascorbate as cofactors (Britsch and
Grisebach, 1986). (2S)-Eriodictyol (17) is converted to
(2R,3R)-dihydroquercetin.
Subsequent reduction of dihydroflavonols, catalyzed by
dihydroflavonol 4-reductase, leads to flavan-3,4-diols (Fig.
11.15) (leucoanthocyanidins), which are intennediates in an-
6-C·gJucosylchrysin (26)
OD
OR
OD
isoorientin
DO
OD
OD 0
maysin (71)
Some important C-glycosylflavones.
 Flavonoids 163

OH
OH
o 0 HO

~'"
1~ OH
_~'"
'" OH _ _

«pI:
HO ~

OH
0H
OH ~OH
HO '"
",I
0
_
HOWO
1
~R HO
R

'" OH
OHO OHO
eriodletyol (17)
R=H,(18)
(+)·2,3·/ran,·dihydroquercetin R=H
R=OH
OH
OH
OH

HO HO R

OH 0 OH
R =H, (+)-catechin R =H, a tlavan-3,4-dlol (33)
2,3-cts-dihydroquerc:etin R =OH, (+)-gallocatechln leucocyanidin
R=OH~leUCOd~:hlnldin
OH
~ '" OH
HO 0+ I",
HO
'" ~

"" OH OH
I
h OH OH an anthocyanidin (2)
O~OH
OH OH
procyanidins
cyanldin·3·Q·g1ucoside (34)

Fig. 11.1S. Biosynthetic pathway for the origin of anthocyanins.

thocyanin biosynthesis with flower extracts from Matthiola
incana (Heller and Forkmann, 1988; Heller et al.,
1985a,1985b; Porter, 1988; Stich and Forkmann, 1988) (see
also Chapter 12). The patterns of anthocyanidins in flowers
of Petunia hybrida (Solanaceae) are attributable to the sub·
strate specificity of dihydroflavonol 4·reductases. The en-
zyme preparation catalyzes NADPH-dependent reduction of
dihydroflavonols to 2,3-trans-3,4-cis-flavandiols (leucoan-
thocyanidins). In particular, dihydroquercetin (18) is con-
verted into leucocyanidin (28) and dihydromyricetin (29)
into leucodelphinidin (30). Dihydrokaempferol (13) is con-
verted into pelargonidin (1), but Petunia does not contain
anthocyanins of that series. At least one of the steps is light
controlled (Ebel and Hahlbrock, 1982; Hrazdina. 1982). Re-
duction of the flavanones naringenin (10) and eriodictyol
(17) leads to the biosynthesis of 3·deoxyanthocyanins (Stich
and Forkmann, 1988). Soluble enzyme preparations from
the flowers of Sinningia (syn. Reichsteinia) cardinalis (Ges-
neriaceae) catalyze an NADPH-dependent reaction of (2S)-
naringenin to apiforol (leucoapigeninidin) (31) and (2S)-eri-
odictyol (17) to luteoforol (leucoluteolinidin) (32) (Stich and
Forkmann, 1988) (Fig. 11.16). All the steps leading to 3,4-
diols are shared with condensed tannin biosynthesis (Staf-
ford, 1989). A series of enzymes involved in the reduction
of dihydroflavonols to flavan-3,4-diols (such as 33) have
been reviewed in regard to proanthocyanidin biosynthesis
(Stafford, 1989) (see Chapter 12).
Dihydroflavonols or their glycosides that accumulated in
white flowered mutants were supplied to acceptor mutants
that were blocked in the synthesis of dihydroflavonols (Stich
and Forkmann, 1988). This led to anthocyanin synthesis in
the acceptor mutant. For example, white-flowered mutants
of Petunia hybrida accumulate dihydroquercetin 7-0-gluco-
side, dihydroquercetin 4'-O-glucoside, dihydroquercetin.
164 Flal'onoids
OR
OR
RO
# #
OR
OR OR
I:
lencocyanidin (28)
OR
RO "'" 0 RO
::::,..1
OR OR
apiforol (31)
Fig. 11.16. Selected leucoanthocyanidins.
and dihydrokaempferol 7-0-glucoside. When dihydroquer-
cetin (17) was supplied to these plants, cyanidin 3-glucoside
(34) was formed as the major pigment (Grisebach, 1985).
In contrast to flavones and flavonols, anthocyanidins are
rarely, if every, found free in nature (Heller and Forkmann,
1988). 3-0-G1ycosylation is a likely prerequisite for antho-
cyanin accumulation because of the instability of the flavyl-
ium cation. UDP-Glucose flavonoid 3-0-glucosyltransfer-
ase is involved in formation of anthocyanidin glycosides.
SYSTEl'IAllC S11JDms WITH FLAVOrm
AM> FLAVONOL GLYCOSIDES
No other group of compounds has been as useful as flavone
and flavonol glycosides for the study of problems in plant
systematics (Harborne, 1975; Harborne and Mabry, 1982;
Harhorne and Turner, 1984). Although many flavonoids are
widely distributed, characteristic patterns of flavonoids are
found in many plant groups which permit recognition of
particular taxa.
Study of flavonoids has proven useful for examination
of many problems at the species and genus level for several
reasons. Most plants contain several major compounds (usu-
ally glycosides) that tend to differ in the various taxa (forms,
subspecies, varieties, or species) which are to be examined.
Analysis of these mixtures is reasonably straightforward;
techniques for identification of the compounds have been
reviewed (Mabry et aI., 1970; Markham, 1982). The flavo-
noid compounds present in hybrids often represent an addi-
tive combination of those of the parental types.
The systematics of the genus Baptisia (Fabaceae) has
been studied extensively, and the genus is well known with
respect to the morphology, genetics, and phytochemistry.
Almost all species of Baptisia have distinctive complements
OR
OR
RO
OR
OR OR
I:
leucodelphinidin (30)
OR
0
~ 1 OR
::::,..
OR OR
luleoforol (32)
of flavonoid glycosides. Flavonoid chemistry was especially
useful for analysis of the many hybrid swarms encountered,
some of which involved as many as four different species.
In general, it was possible to recognize hybrid plants because
they had simply additive patterns (i.e., the hybrids often had
a combination of all the compounds found in the putative
parental types). In some hybrids, however, a few compounds
failed to appear and, in others, new hybrid compounds were
observed.
In hybrids of Baptisia leucophaea and B. spherocarpa, the
appearance of a hybrid compound could be explained when
the chemical nature of the compound was ascertained. Com-
bination of the enzymes that produced a 3-0-rutinoside (rutin)
(35) in the former and the 7 -O-glucoside (36) in the latter pro-
duced a 7-0-glucoside-3-0-rutinoside (37) in the hybrids
(Fig. 11.17) (Alston and Turner, 1963; Alston et al., 1965).
In a survey of the flavonoids of the genus, some com-
pounds proved to be common to all species, some were found
only in one species, some only in hybrids, and some ap-
peared sporadically (Alston et aI., 1962; Alston and Turner,
1963; Alston et aI., 1965; Cranmer and Mabry, 1966; Har-
borne, 1975; Markham and Mabry, 1968).
In other instances, flavones and flavonols with particular
patterns of oxidation are of sufficiently restricted distribution
among plant groups to be useful for systematic purposes.
For example, in addition to the usual flavones [apigenin (5),
luteolin (4), and chryseriol (38) (Fig. 11.3), usually as the 7-
O-glucuronidesl, plants of the Lamiaceae, Scrophulariaceae,
and related families frequently contain 8-hydroxyflavones,
6-hydroxyflavones, or 6-methoxyflavones in glycosidic
combination. 8-Hydroxyflavones based on apigenin and lu-
teolin are restricted to the Lamiaceae (Tomas-Barbenin et
al., 1988).
The distribution of flavones and flavonols and their gly-
cosides has been reviewed (Harborne and Williams, 1982).

OH
OH
HO
OH 0 OH
~o
rutin (35)
Baptisia leucophaea
OH
OH
glucosyl- 0
OH 0
quercetin 7-D-glucoside (36)
Baptisio spherocarpa
Fig. 11.17. The origin of a hybrid compound in Haptisia hybrids.
For example, the validity of Dahlgren's proposed Liliiflorae
was appraised by an examination of flavonoids (Williams
et aI., 1988). The flavonols quercetin (7) and kaempferol (6)
occurred in about half the plants tested; the flavones apigenin
(5) and luteolin (4) were found less frequently. The limited
diversity of flavonoid patterns argues for a more conserva-
tive treatment at the family level (Williams et al., 1988).
Other applications of flavonoid data to the understanding
of plant phylogeny include bryophytes, ferns and fern allies
(Markham, 1988), gymnosperms (Niemann, 1988), monoco-
tyledons (Williams and Harborne, 1988) and dicotyledons
(Giannasi, 1988).
BIOLOGICAL ACTIVITY OF FLAVONE AI'ID
FLAVONOL AOLYCONES AI'ID OLYCOSIDES
Because flavonoids are found in virtually all plants, some
animals, and a few fungi, these compounds are found in
many different types of biological interactions (Beier and
Nigg, 1992; Cody et aI., 1986, 1988; Harborne, 1991). Fur-
ther, plant flavonoid content may be influenced by light,
water, temperature, mineral nutrition, sugars, mechanical
damage, pathogens, plant growth regulators, and other fac-
tors. Flavonoids may serve as antioxidants, enzyme inhibi-
tors, pigments for light absorbance, and visual attractants
for pollination,light screens, promotors of inhibitors of plant
growth, plant growth regulators, chemical signals in root
nodulation gene induction, phytoalexins, and other functions
(Beier and Nigg, 1992; McClure, 1975).
Flavonoids 165
OH
O-rutinosyl
OH 0
hybrid compound
quercetin-7-0-glucoside-3-0-rutinoside (37)
In the United States, humans consume about 1 g offlavo-
noids daily; in some cultures, this may be as high as 2-3
glday (Beier and Nigg, 1992). About 40% comes from
cocoa, cola, coffee, beer, and wine. Fruit juices and tea also
are major contributors. The digestive systems of animals are
capable of metabolizing many flavonoids. p-Hydroxyben-
zoic acid, cinnamic acid, phenylacetic acid, and phenylpropi-
onic acid are observed as breakdown products of rutin (35)
and apigenin (5) (Beier and Nigg, 1992). However, certain
other flavonoids, such as epicatechin, are excreted un-
changed (Fig. 11.17).
Of 70 flavonoids tested, 33 were positive in the Ames
assay. Other flavonoids have been associated with carcino-
genic activity. However, flavonoids also have been shown
to have antimutagenic effects (Beier and Nigg, 1992).
Biological Activity of Aglycones
Most flavone and flavonol aglycones occur on the surface
of plants or associated with secretory structures. The isola-
tion and characterization of flavone and flavonol aglycones
have been reviewed (Wollenweber and Jay, 1988).
Flavonoids probably play major roles as internal physio-
logical regulators and chemical messengers in plants. This
may have been their major role in the early evolution of land
plants (Stafford, 1991).
At physiological concentrations (10- 5 M), flavonoids
may either stimulate or inhibit IAA oxidase (an enzyme
which regulates the amount of the plant-growth-regulating
hormone indole acetic acid (IAA or auxin) activity in peas
166 Flavonoids

in in vitro experiments. Stenlid (1970) showed that, in gen-
eral, 4'-hydroxy compounds stimulate and 3', 4'-dihydroxy
compounds inhibit IAA oxidase activity. In general, cin-
namic acids and their derivatives were ineffective.
The process of auxin transport can be inhibited by a group
of synthetic compounds which bind to a specific cell mem-
brane receptor. Several flavonoids, including quercetin (7),
apigenin (5), and kaempferol (6), can specifically compete
with one of the synthetic compounds, naphthylphthalamic
acid, at micromolar levels for binding to the receptor and,
thereby, perturb auxin transport in a variety of plant tissues
(Jacobs and Rubery, 1988). Although quercetin (7) was
highly active, a common quercetin glycoside, rutin (35)
proved inactive.
Certain flavonoids can interrupt the electron transport
chain of respiration and photosynthesis (Arntzen et al.,
1974). In chloroplast thylakoids, the primary effect was on
the ATP-generating pathway. The flavonoids tested did not
appear to be decouplers; in mung bean mitochondria, the
compounds acted primarily as electron transport inhibitors.
Inhibition of substrate oxidation appears to result from alter-
ations and perturbations induced in the inner membrane, as
evidenced by interference with carrier-mediated transport
processes (Moreland and Novitzky, 1987). Thirteen flavones
(of 21 tested) are selective inhibitors of the external NADH
dehydrogenase of the inner membrane of the mitochondria
of potato tubers (Ravanel et al., 1990).
Quercetin (7), morin (39), myricetin (8), and fisetin (40)
(Fig. 11.18) were active inhibitors of induced lipid peroxida-
tion in the presence of ferrous ion. Isovitexin (24) is an
effective antioxidant-being more effective than BHA (bu-
tylated hydroxyanisole) and a-tocopherol. Epicatechin 3-0-
gallate (41) is a potent oxygen free-radical scavenger (Beier
and Nigg, 1992).
Nitrogen fixation by legumes is an essential component
of many natural and agricultural ecosystems. In this process,
atmospheric nitrogen is converted into ammonia, a fonn usa-
ble by plants and other organisms. Species of the bacterium

OCH, OCH,
OCH,
CH,'O
CH,'O

CH,-O
OH
OCH, 0 OH 0
tangeretin (48) ermanin (49)
(5,6,7,8,4'-pentamethoxyflavone)
(7,4'-di·O-methylkaempferol)
OH OH
OH
HO
glucosyl-O

OH 0
4,4'-dihydroxy-2'-methoxychalcone (45) luteoHn 7-0-glucoside (42)

HO~O~OH HO~O~OH
Uy' o
~-
o
7,4'.dihydroxyflavanone (43) 7,4'-dihydroxyflavone (44)
OH
OH OH
HO
HO

OH
OH 0
o
(al isoetin (47) fisetin (40)

Fig. 11.18 (a & b). Selected flavonoids with biological activity.

 Flavonoids 167

OH
OH
HO HO

isoquercitrin (51) morin (39)

«p
OH OH
OH
rhamnosyl- 0:;.-' 0 I /.: oHxylosyl- 0 I'"
1 1 '"
CH3 0 :::-.... OH
OH 0 OH 0
6-methoxyluteoUn '·rhamnoside (57) catechin 7-xyloside (58)

W ,V-
OH
HO '"/- HO,.::0'.J O

OH
OH 0

o«Pl:
OH 0
dihydrokaempferol (13R = H pinocembrin (5)
taxifolin (17) = OH OH

rhamnoglucosyI- OCH,
""I
hesperidin (61 ~

o 0 OH 0

HO
)t.,J
:o~
HO~
_ _ o«P
o=O,
I I
I
OH
OH

Ollfl "-
(b) luteotin '·O-(6"-malonyl)glucoside (62) OB 0

Fig. 11.18 (continued)

Rhizobium are responsible for the nodulation of many spe-
cies; several stages are involved in the nodulation process.
Host-symbiont signaling occurs at an early stage in nodule
development Expression of nodulation (nod) genes is essen-
tial for nodulation, and this gene is induced by host plant-
derived flavonoids (Harbome, 1988a, 1988b; Phillips, 1992;
Towers et aI., 1989). After this induction, rhizobial products
induce root hair curling, cortical cell divisions, and produc-
tion of a receptor-like protein (Hartwig et aI., 1990a, 1990b).
The symbiotic interaction of Rhizobium meliloti and al-
falfa results in the formation of nitrogen-fixing nodules.
Seed coats of alfalfa are the major source of the two major
inducer molecules, chryseriol (38) and luteolin (4), for no-
dABC gene expression in Rhizobium meliloti during nodule
formation (Hartwig et aI., 1990b; Phillips, 1992). Luteolin
7-0-glucoside (42), released from seed exudates, is con-
verted to luteolin (4), apparently by enzymes from either
the host plant or the bacterium (Hartwig and Phillips, 1991;
Peters et aI., 1986). The major flavonoid released, quercetin
3-0-galactoside, does not induce nod genes, but both luteolin
(4) and quercetin (7) increase growth of Rhizobium meliloti
(Hartwig and Phillips, 1991; Hartwig et aI., 1990a, 1990b).
Seed exudates are less active than root exudates. Alfalfa
roots exude three major nod gene inducers; 4',7-dihydrox-
yflavanone (43), 4',7-dihydroxyflavone (44), and 4,4'-dihy-
droxy-2'-methoxychaIcone (45) (Maxwell et aI., 1989). Re-
lease of these compounds is associated with concurrent
biosynthesis (Hartwig et aI., 1990a, 1990b; Maxwell and
Phillips, 1990). The flavonoid active in Trifolium repens,
white clover, is 7,4'-dihydroxyflavone (44) (Towers et aI.,
1989). Both daidzein (7,4'-dihydroxyisoflavone) and gen-
istein (46) (Fig. 11.26) from soybeans induce nod genes in
Bradyrhizobium japonicum. Certain other plant flavonoids
and phenols inhibit nod germination (Towers et aI., 1989).
Flavonoid aglycones frequently serve as pigments in
flowers. For example, isoetin (2'-hydroxyisoetin) (47) is a
yellow pigment in Heywoodiella oligocephala (Asteraceae)
(Harbome, 1991).
168 Flavonoids
Flavonoid aglycones (especially highly methylated ones)
often are found as resinous exudates on plants (Harbome,
1991; Seigler, 1983). These compounds have higher insect
and mammalian toxicity than the corresponding nonmethyl-
ated derivatives. Tangeretin (5,6,7,8,4'-pentamethoxyfla-
vone) (48), which occurs in tangerine peel, is cytotoxic to
humans and causes neonatal death in rats (Harborne, 1991).
The lipophilic material found on the surface of Larrea
species (Zygophyllaceae) is composed of several methylated
flavonoid aglycones and lignans such as nordihydroguaiare-
tic acid (see Chapter 8). This resinous material was shown
to act as an antiherbivore substance and appeared to reduce
digestibility of the plant for several herbivores (Seigler,
1983).
Ermanin (49), 7,4'-di-O-methylkaempferol, from the res-
inous material on the surface of leaves of Passiflorafoetida,
is deterrent to feeding by the larvae of Dione juno. This
insect eats many other Passiflora species (Echeverri et aI.,
1991).
Pinocembrin (50) has been implicated as an attractant to
a bark beetles feeding on fruit trees (Harborne, 1991). In
contrast, the flavonoid aglycone, morin (39) [as well as iso-
quercitrin (51) and several essential oils1, is involved in feed-
ing of silkworm larvae (Bombyx mori) on mulberry plants
(Morus nigra) (Harborne, 1991).
Biological Activity of Glycosides
At least 330 flavone and 650 flavonol glycosides are
known (Harborne and Williams, 1988). Among the sugars
involved in flavonoid glycosides are o-apiose, L-arabinose,
L-rhamnose, D-xylose, D-allose, D-galactose, D-glucose, 0-
galacturonic acid, and o-glucuronic acid. Glycosides may
include a variety of disaccharides and trisaccharides. Both
the sugars and the aglycones may be acylated, or modified
with other substituents. Techniques for the isolation and
characterization of flavonoid glycosides have been reviewed
(Harborne and Williams, 1988).
Flavonoids (both glycosides and aglycones) have been
suggested to serve as sunscreens which absorb harmful fre-
quencies of UV light (UV-C less than 280 nm, UV-B
280-320 nm, UV-A 320-400) and prevent destruction of
important compounds in plants as well as permit entry of
useful wavelengths (Caldwell et al., 1983; McClure, 1975;
Stafford, 1991). Indeed, the epidermal layer where many
flavonoids are accumulated absorbs more than 90% of the
UV-B radiation athninistered (Robberecht and Caldwell,
1978). Most flavone and flavonol aglycones and glycosides
absorb in the range 330-350 nm, the same area of the spec-
trum where NAD and NADP absorb (McClure, 1975). Fla-
vonoids also have a strong absorbance in the area 250-280
nm, where proteins and nucleic acids absorb. Probably the
most sensitive part of the photosynthetic machinery to be
protected is photosystem II (PSII) (Stafford, 1991).
The signals from a number of plants involved in nodula-
tion by Rhizobium bacteria are now known (see above).
Those of Phaseo/us vulgaris, black bean, for Rhizobium /e-
guminosarum bv. phaseolii, are 3-0-glycosides of 10 antho-
cyanidins and flavonols; most important among these were
delphinidin, petunidin, and malvidin. In these cases, the cor-
responding aglycones were less active (Hungria et aI.,
1991a). Three other flavonoids, eriodictyol (17), naringenin
(10), and a 7-0-glycoside of genistein (46) were the most
active compounds from root exudates of the same plant
(Hungria et al., 1991b).
The major flavonoid, quercetin 3-0-galactoside from al-
falfa seeds, promotes spore germination of two fungi respon-
sible for the formation of vesicular-arbuscular mycorrhizal
(VAM) interactions, G/omus etunicatum and Glomus ma-
crocarpum, in vitro. Quercetin (7) produced the maximum
effects in spore germination, hyphal elongation, and hyphal
branching in Glomus etunicatum at 1-2.5 tJM concentrations
(Tsai and Phillips, 1991).
Most flavone and flavonol glycosides are not particularly
toxic to man or other higher animals (McClure, 1975). One
compound of this type, rutin (35), was once considered to
be a vitamin, but is generally not at present (Harborne, 1991).
Compounds of this general structure may be required in the
human diet, but it is difficult to imagine anyone suffering
from such a deficiency, as flavonoids are found in most of
the plant materials that we eat.
Certain flavonoids have antiulcer properties in humans.
These compounds raise prostaglandin levels in gastric mu-
cosa by stimulating cyclooxygenase or by inbibiting 15-hy-
droxyprostaglandin dehydrogenases (Lewis, 1992). Hypo-
laetin 8-0-glucoside (57), from Sideritis mugronensis
(Lamiaceae), stimulates prostaglandin synthetase. The most
widely used antiulcer flavonoid is solon, 2-carbomethoxy-
4,4-bis(3-methyl-2-butenyloxy)chalcone. This compound is
based on the structure of sophoradin (53) from a Chinese
traditional drug gnangdougen, from Sophora subprostrata
(Fabaceae). Solon increases prostaglandin levels by inhibit-
ing 15-hydroxyprostaglandin dehydrogenase (Lewis, 1992).
Other flavonoids such as catechin (20) and naringenin (10)
appear to inhibit histidine decarboxylase and limit tlie forma-
tion of the gastric acid stimulator histamine (Lewis, 1992).
A series of flavonoids from the milk thistle, Si/ybum mar-
ianum (Asteraceae) have antihepatotoxic activity. The indi-
vidually active compounds are silybin (54) (the major com-
pound), silycbristin (55), and silydianin (56), collectively
called silymarin (Fig. 11.19). Silymarin is used in Germany
for treatment of human liver disorders (Vogel, 1976, 1982).
The elimination half-life of silybin is about 2 h (Beier and
Nigg, 1992).
Many flavonoids appear to be toxic or repellent to insects
(Hedin and Waage, 1986). Flavone and flavonol glycosides
may serve as both allomones and kairomones (Fig. 11.18).
A flavone glycoside, 7-a-L-rhamnosyl-6-methoxyluteolin
(57), from alligator weed (A/ternanthera philexeroides, Am-
aranthaceae) serves as a feeding stimulant for Agasic/es bee-
tles. Kaempferol 3-0-xylosylgalactoside stimulates feeding
in the monophagous flea beetle, Phyllotreta armoraciae, on
horseradish, Armoracia rusticana (Brassicaceae) (Nielsen et

HO
HO
HO OCH,
HO OH
HO HO
OH
HO
OH 0
.-7
hypolae~in 8-glucoside (52)
Fig. 11.19. SHybin, silychristin, silydianin, and other medicinally useful flavonoids.
aI., 1979). A catechin xyloside (58) is responsible for feeding
of the smaller European elm bark beetle, Scolytus multistria-
tus, on elm (Hedin and Waage, 1986). Silkworms prefer
food plants with rutin (35), but this compound is repellent
to tobacco budworm (Heliothis virescens) and to the boll-
worm (H. zea). When fed at low concentrations, quercetin
3-rharnnoside, quercetin 3-glucoside, and rutin (35) repelled
feeding by the tobacco budworm, the bollworm, and Ptecti-
nophora gossypiella; however, at concentrations of 0.2% or
more, these common flavonoids killed the larvae (Harbome,
1991). Many other common flavonoid glycosides are toxic
to these insects at the 0.2% level in artificial diets (Harborne,
1988c, 199 I). Toxicity seems to require vicinal hydroxyl
groups [i.e., ortho-dihydroxybenzene groups (catechol)],
and this is a necessary, but not sufficient, condition for bio-
logical activity. Quercetin (7) is toxic to Spodoptera eri-
dania; rharnnetin (59) (Fig. 11.3) is not (Elliger et aI., 1980;
Lindroth and Peterson, 1988).
Many other groups of compounds reinforce the repellent
Flavolloids 169
silychristin (55)
OH
sophoradin (53)
properties of flavonoids. These include alkaloids, glucosino-
lates, cucorbitacins, and cardenolides (Harbome, 1988b).
Foor flavonoids [vicenin-2, hesperidin (60), narirutin, and
rutin (35)] from Citrus unshiu are oviposition stimulants for
Papilio xuthus (Nishida et aI., 1987; Ohsugi et aI., 1985).
However, these compounds are only weakly active alone or
in mixtures. When mixed with two bases, adenosine and 5-
hydroxy-N-methyltryptarnine, which are inactive by them-
selves, 100% of the activity of the plant was observed (Har-
borne, 1988b).
The flavonoid glycosides hesperidin (60) and naringin
(61) (Fig. 11.25) from Citrus natsudaidai stimulated ovipo-
sition by Papilio protenor (Honda, 1986). Again, the com-
pounds were inactive alone, but were active when combined
with a more polar extract of the plant.
Oviposition by females of the black swallowtail butterfly,
Papilio polyxenes, was stimulated by tarsal coutact with
ethanolic extracts of carrot foliage, Daucus carota. Two of
the stimulants were identified as E-chlorogenic acid and lute-
170 Flavonoids
olin 7-0-(6"-O-malonyl)-j3-o-glucopyranoside (62) (Feeny,
1991; Feeny et al., 1988). Although each compound was
inactive alone, in admixture they accounted for 70% of the
ovipositional response of the original extract.
Several flavonol glycosides accumulate in the wings of
certain butterflies. Differences in the compounds seques-
tered and those of the host plants indicate that the butterflies
metabolize the compounds before sequestration (Harbome,
1989, 1991; Wilson, 1987).
Many flavonoids (especially 3-methoxyflavones) are
known to serve as antiviral (Selway, 1986; Vanden Berghe et
ai., 1985; Vlietinck et al., 1986), anti-inflammatory (Vogel,
1976, 1982), and antitumor compounds (Cassady et al.,
1990; Mabry and Ulubelen, 1980).
ANTHOCYANINS
Anthocyanins, glycosides of anthocyanidins, such as (1-3),
are primarily responsible for the red, blue, and violet colors
of flowers and fruits. More than 260 naturally occurring
anthocyanins have been described (Harborne, 1991); the
techniques for isolation, purification, and characterization of
these compounds have been reviewed (Harborne and Grayer,
1988; Strack and Wray, 1989).
Anthocyanins and anthocyanidins are widely distributed
among gymnosperms and both monocotyledonous and most
dicotyledonous angiosperms (except in many members of
the order Caryophyllales or Centrospermae). Six relatively
common aglycones (pelargonidin, cyanidin, delphinidin,
peonidin, petunidin, and malvidin) are found in most cases;
almost all others are rare. Only about 18 naturally occurring
anthocyanin aglycones are known (Fig. 11.20) (Harborne
and Grayer. 1988; Hrazdina, 1982; Timberlake and Bridle,
1975). Most of the numerous derivatives are variants pro-
duced by glycosylation, acylation, and methylation.
OCH,
OH
HO
OH OH
peonidin petunidin R = H
malvidin R = OCH3
CH,O
OH OH
hirsutidin pelargonidin (I) R=R =H
cyanidin (2) R= OH, R = H
delphinidin (3) R R OH
Fig. 11.20. Some representative antbocyanidin chromopbores.
Cyanidin (3) (Fig. 11.1) is especially widespread and is
responsible for the purple coloration of most vegetative parts
of plants; this anthocyanidin is also common in fruits and
flowers. The purple pigments of red cabbage have been
shown, by chromatography on polyvinylpolypyrrolidone
(PVPP), to be a complex mixture of eight acylated cyanidin
glycosides that correspond in properties to the previously
reported "rubrobrassicins." One of the major compounds
is cyanidin-3-(6"-O-p-coumaruylsophoroside)-5-glucoside
(63) (Fig. 11.21) (Hrazdina et al., 1977). White cabbage is
known to have a block in the pathway to these pigments.
Increased accumnlation of anthocyanins is observed in
many plants in response to stress. This includes fall color-
ation of leaves, response to nltraviolet radiation, attack by
pathogens. deficiency of some minerals, mechanical dam-
age, water stress, and many other factors (Hrazdina, 1982).
Factors Responsible for Color
At least seven different factors seem to be important in
flower pigmentation: pH, the nature of the aglycone, the
extent of glycosylation, the concentration of the anthocya-
nin, complexation with metals, the presence of pectins and
sugars, and complex anthocyanins which are linked through
their 4-positions with tannins and other phenols (Brouillard,
1988; Harborne and Grayer, 1988; Harborne et ai., 1975).
Anthocyanins occur as salts within the cell. Extraction
under very mild conditions yields "genuine" anthocyanins
that have been studied electrophoretically. NMR spectros-
copy and mass spectrometry (especially fast atom bombard-
ment or FAB) have been extremely useful for the determina-
tion of structures of relatively intact anthocyanins
(Brouillard, 1988).
Both metallic and nonmetallic pigments have been iso-
lated. At low pH values, anthocyanins usually are red,
whereas at high pH values, they usually shift to blue colors.
OR OCH,
OH
HO
I'"
~
OCH, OCH,
OCH,
capenslnidin
R
R
OH
OH
apigenlnidin R = H
luteolinidin R =OH
= =

cyanidin-3-poocoumaroylsophoroside-S-glucoside (63)
Fig. 11.21. Cyanidin-3-(6"-O-p-coumaroylsophoroside)-5-g1ucoside. the major pigment of red cabbage.
The pH of cell sap of most flowers is such that many antho-
cyanin-containing flowers should be colorless, yet the pres-
ence in nature of colorless anthocyanins is rare. Anthocy-
anidins undergo a series of complex color changes in water
at varying pH (Brouillard, 1988). The flavylium cation of
natural anthocyanins behaves as a weak diacid, whereas a
neutral quinonoid base is at the same time a weak acid and
a weak base. The pH of crude extracts of flowers varies from
2.8 to 6.2.
Anthocyanin and anthocyanidin anhydro bases are known
to be stabilized by formation of highly colored complexes
with metals, such as aluminum, iron, or magnesium, which
can be susceptible to pH changes within narrow limits.
Copigmentation plays an important role in pigmentation
by anthocyanidins (Brouillard, 1988). Most anthocyanins in-
volve copigmentation when present in suitable concentra-
tions. Copigmentation may involve flavones or other pheno-
lic compounds such as chlorogenic acid. The blue pigment
of Hydrangea macrophyl/a flowers is comprised of del-
phinidin 3-glucoside, aluminum, and 3-caffeoylquinic acid.
In another complex case that has been studied, the blue pig-
ment of Comme/ina communis involves a dimagnesium
complex in which six anthocyanin and six flavone molecules
are linked either covalently or by hydrogen-bonding (Har-
borne and Grayer, 1988).
Biological Activity of Antbocyanlns
Anthocyanins typically absorb at 520-560 urn, a region
of the spectrum to which mammalian eyes are most sensitive.
These compounds are important pigments in flowers and
fruits and play major roles in pollination mechanisms and
fruit dispersal (Harborne, 1991). Chlorophyll, carotenoids,
and phytochrome have minimal absorption in this region.
Cyanidin 3-0-glucoside (34) (Fig. 11.15) is an important
factor of resistance in cotton leaves to feeding of tobacco
budworm (Hedin and Waage, 1986).
Flavonoids 171
In the superorder Caryophyllidae (or Centrospermae),
only the families Caryophyllaceae and Molluginaceae pos-
sess anthocyanins. In the other families of the superorder,
anthocyanins appear to have been replaced by alkaloidal be-
talain pigments. These compounds have nearly identical
spectral properties to those of anthocyanins and also serve
in pollination and fruit and seed dispersal. This phenomenon
will be discussed more fully under betalain pigments (see
Chapter 37).
Commercial Importance of Antbocyanins
A number of anthocyanins are used as food additives
(Harborne and Grayer, 1988; Strack and Wray, 1989; Tim-
berlake and Henry, 1988). Anthocyanins also are important
in that they control the marketability and taste properties of
many commercial products. The sale price of many fruits
and vegetables is dependent on full color development.
Some major commercial sources of these natural pigments
are grapes (Vilis vinifera), roselle (Hibiscus sabdariffa),
blueberries (Vaccinium spp.), and red cabbage (Timberlake
and Henry, 1988).
Anthocyanins are especially complex in members of the
Vitaceae, the grape family. In this family, five or six agly-
cones are known and most occur as monoglycosides and
diglycosides. The sugars of anthocyanins often have acyl
groups attached. No wild or cultivated grape has less than
5 and most have at least 10 anthocyanins. These compounds
are important, as they are modified in the aging process of
wine and are partly responsible for the color and the taste
properties of wines. In some instances, anthocyanins may
impart bitterness to the wines (Pierpoint, 1986).
Tea leaves (Camellia or Thea sinensis, Theaceae) contain
cyanidin 3-glucoside (34) and other anthocyanins. Phenolic
materials make up as much as 30% of the dry weight of
fresh tea leaves (Pierpoint, 1986; Sanderson, 1972). The five
major catechins in "green tea" are (+ )-catechin (64) (Fig.
172 Flal'onoids

11.15}, (- }-gallocatechin (68), (+ }-epicatechin (66), (+)- OGLYCOSYLfLAVONES

epigallocatechin (65), and (- }-epigallocatechin (67) (see
Chapter 12). Kaempferol and quercetin glycosides are also
present. To make black tea, the leaves are fermented and
concurrent oxidation of the flavonoid compounds occurs.
These phenolic compounds are substrates for oxidation and
condensation into products desirable for tea quality. The an-
thocyanidins cyanidin (3), delphinidin (2), and tricelinidin
(69) are found in black teas (Fig. 11.22). Two of the major
phenolic fractions after fermentation are theaflavins (such as
70) and thearubigins (such as 71). These polymeric fractions
confer on brewed tea much of its color, palate, and some
of its odor (Pierpoint, 1986; Sanderson, 1972). Theaflavins
(such as 70) are dimeric compounds containing a 7-memb-
ered tropolone ling (Fig. 11.22). The thearubigins (71) are
polymeric materials which are responsible for much of the
color of black tea (Sanderson, 1972).
Glycosides of flavones in which a linkage through a car-
bon-carbon bond involving the anomeric carbon of the sugar
and position 6, 8, or both, of a flavone are found in many
groups of plants (Chopin et aI., 1982). Approximately 310
of these compounds are known (Harborne, 1991). C-Glyco-
sides involving glucose, galactose, xylose, arabinose, and
rhamnose have been isolated (Chopin and Dellamonica,
1988). C-Glycosy1flavones often possess O-glycosides in
addition to the carbon-carbon-linked sugar moiety. Methods
for the isolation and characterization of C-glycosylflavones
have been reviewed (Chopin and Dellarnonica, 1988).
C-Glycosyl flavones have been reported from green
algae, mosses, ferns, and both monocotyledonous and dicot-
yledonous angiosperms (Chopin and Dellarnonica, 1988;
Markham, 1988); records from algae are questionable

OH OH OH
OH OH
HO
OH

OH OH OH (-j-gallocalechin (68) OH ,~,

OH
OK " (65)'
(+)~epigallocatechin

OH
HO
HO
OH

OH
OH
(+)-eplcatechin (66) (-)-epigallocalechin (67)
OH
OH
OH
HO

HOWO~....""'f ~ OH
I - OH
"" OR OH R=galloyl
OH H a structural component of a

"'
thearubigin (71)
a theaflavin (70) OH
R may be H or galloyl
OH ~OH
HO
yyv,(,~ 0
OH
HO

OH - - ~0-v°
IOH
OH

OH 6' OH
(69) epigallocatechin gallate OH

Fig. 11.22. Phenolic materials in tea.


(Markham, 1988). This type of flavonoid is most commonly
found in vegetative parts of plants.
Under acidic conditions, interconversion of 6- and 8-sub-
stituted 5-hydroxy-6-C-glycosylflavones occurs. Attempts
to hydrolyze mixtures of C- and O-glycosides in the labora-
tory often result in isomerization of C-glycosylflavones and
mixtures of both 6- and 8-substituted 5-hydroxy-6-C-glyco-
sylflavones (Fig. 11.14) (Markham, 1989).
C-Glycosylflavones have been isolated as probing stimu-
lants of planthoppers feeding on rice plants, and vicenin-2
is an oviposition stimulant of Papilio xuthus (Chopin and
Dellamonica, 1988). Vitexin deters feeding of Schizaphis
graminum and Myzus persicae on wheat (Chopin and Della-
monica, 1988). Maysin (71) (Fig. 11.14), a C-glycoside from
com, Zea mays, is toxic to the com earworrn (Waiss et 31.,
1979).
BIFLAVOI'lOIDS
The majority of naturally occurring biflavonoids are flavone
and flavanone dimers with a simple 5,7-4'- or, less com-
monly, a 5,7,3',4'-oxygenation pattem. The monomers may
be of the same or of different structural types (Geiger and
Quinn, 1988; Williams and Harbome, 1989a).
The fonnation of biflavonoids may be explained in tenns
of oxidative coupling of two chalcone units and subsequent
modification of the central C3 units (Fig. 11.23) (Geiger and
Quinn, 1975).
Biflavonoids are characteristic of gymnospenns (includ-
ing several cycads and Ginkgo bi/oba), the Psilotales (Psi/o-
tum), and Selaginallales (Selaginella), but have been identi-
fied from six moss species (Williams and Harborne, 1989a),
including as species of Dicranum and two ferns, Osmunda
japonica and Cyathea spinulosa (Geiger and Quinn, 1988;
Williams and Harborne, 1989a) and several flowering plants.
Biflavonoids are not found in the Pinaceae or the Gnetales.
The distribution of biflavonoids is limited and disjunct in
angiospenns, these compounds being found in 15 families,
including the Anacardiaceae, Caprifoliaceae, Casuarinaceae
(Casuarina), Euphorbiaceae, Clusiaceae (Guttiferae or Hyp-
ericaceae), Ochnaceae, and Rharnnaceae (Geiger and Quinn,
1982).
Biflavonoids accumulate in large amounts in a number
of plants. Their most important functions appear to be as
fungitoxins and insect feeding deterrents. For example,
amentoflavone (72) 4'"-mono and 7",4'"-dimethyl ethers have
been shown to be effective against insects browsing on
leaves of Decussocarpus gracilior (Podocarpaceae) and
amentoflavone has been shown to inhibit the growth of sev-
eral fungi (Fig. 11.24) (Williams and Harborne, 1989a).
Techniques for isolation and analysis of biflavonoids
have been reviewed (Geiger and Quinn, 1988; Williams and
Harborne, 1989a).
Flavonoids 173
CHALCOl'IES
Although chalcones, such as (9) (Fig. 11.2), are intennedi-
ates in the fonnation of all flavonoids, they usually are not
accumulated. Most are conspicuously colored yellow com-
pounds and, although found in many plant organs, chalcones
are especially common in flowers. These phenolic com-
pounds are encountered frequently in certain ferns, and in
plants of at least 37 families, including the Acanthaceae,
Asteraceae, Fabaceae, Gesneriaceae, Liliaceae, Oxalida-
ceae, and Scrophulariaceae. Approximately 20 aglycone
structures with varied patterns of hydroxylation and, in some
cases, methylation and prenylation, are known (Bohm, 1975,
1982, 1988). Although many chalcones occur as glycosides,
the majority are found as free aglycones. Chalcones are iso-
merized to flavanones in plants by the enzyme chalcone iso-
merase, but are readily isomerized in vitro in the presence
of acid (see the earlier discussion of flavonoid biosynthesis).
When the chalcone is 2',6'-dihydroxylated (the numbering
system of chalcones is distinct from that of other flavonoids
that have a C-ring system), the isomeric flavanone bears a
5-hydroxy group. The stabilizing influence of 4-carbonyl-5-
hydroxy hydrogen-bonding causes the chalcone-flavanone
equilibrium to lie largely on the side of the flavanone. Thus,
chalcones that occur in nature usually possess 2',4'-hydroxyl
groups or 2'-hydroxy-6'-glycosyloxy groups (Fig. 11.9).
The petals of flowers of Oenothera hookeri ssp. venusta
contain only carotenoids in the distal ends, but the basal
portions contain the chalcone isosalipurposide (16) (Dement
and Raven, 1974).
AUROl'lES
Aurones, (such as sulfuretin, 73) represent a small group
of conspicuously colored pigments that are often, but not
exclusively, found in flowers. Many of these compounds are
golden-yellow in color. Aurones also are encountered in
bark, wood, or leaves of certain plants. These compounds
are isomeric with flavones (Fig. 11.5). They possess Z-ster-
eochemistry at the double bond.
Aurones are found in at least 10 plant families but are
most common in those plants with yellow flowers; they are
especially frequent in members of the Asteraceae, Gesneria-
ceae, and Scrophulariaceae (see tables in Bohm, 1982,
1888). Most, but not all, aurones occur as glycosides in the
plant.
Chalcones and aurones collectively are sometimes called
anthochlors (Harbone, 1991). Techniques for the isolation
and characterization of chalcones and aurones have been
reviewed (Bohm, 1988, 1989).
DIHYDKOCHALCOl'IES
The approximately 75 known dihydrochalcones are accumu-
lated in at least 20 families, but are especially common in
the Asteraceae and Fabaceae (Bohm, 1988). Compounds of
174 Flal'onoids

HO~OH
1 1
'<::: OH -O~H OH
~ '<:::
0yY0H NOH
'" "',&

HO 0
- ",I '" 1,& _
HO 0 ~
HO 0 b
naringenin chalcone (9)

(a)

&omc+d :qfX0H
HOrOH r OH 10H
'(YVD
I
,.. (1.0 0no H
HO '? I
0 ~
0 7
-----+- ochnaflavone
group biOavones

~'RW",H'"
000 1 1 _ ~ I 0 00

W
'" '" OH 0 ~ 1 '"
0 0 0 , &

I:
o OH

fromc+b HO 9" 0

HO~H
l O~-WO
r~I r 0 OH ",OHHO 0 ",I
OHOhlnokillavone
~ ~ ~ I::... 1 h r 1 - groupbiftavonea
OHO::'" ~ ",OH
OHO OHO

fromd+b
HO

(b)

Fig. 11.23 (8 & b). Proposed biosynthesis of biflavonoids.

this type have been reported from a fungus (Phallus impu-
dicus), a liverwort (Radula variabilis), several ferns (Pityro-
gramma, Notholaena, and Adiantum), a conifer (Podocar-
pus nubigena), and from 17 angiosperm families (Grayer,
1989).
Dihydrochalcones [e.g., (12) (Fig. 11.2)] are derived from
chalcones by reduction of the a,l3 double bond. As in the
case of chalcones, the A ring is derived from acetate and
has a phloroglucinol oxidation pattern. Similarly, the B ring
is derived from a phenylpropanoid precursor. These com-
pounds are comparatively rare; they occur as both aglycones
and as glycosides. Dihydrochalcones are colorless and are
not easily detected (Fig. 11.25).
Phloridzin (74) was first found in 1835. This dihydrochal-
cone occurs in the bark of apple trees, apparently confers
disease resistance on the plants, and has been involved in
some a1lelopathic problems. Phloridzin is a feeding stimu-
lant to some insects (Stadler, 1986). When ingested by hu-
mans, phloridzin impairs reabsorption of glucose by the kid-
neys and produces a diabetes-like condition (Le., excess
sugar in the blood and urine) (McClure, 1975).
Although most phytoalexins in the Fabaceae are of isofla-
vonoid origin, a-hydroxydihydrochalcone (75), odoratol
(76), and methylodoratol (77) are formed de novo as stress
compounds in the pods and cotyledons of Lathyrus odoratus
(Fuchs et aI., 1984).

The dihydrochalcone ceratiolin (78), from the foliage of
Ceratiola ericoides (Empetraceae), has little phytotoxic ac-
tivity, but decomposes slowly to yield hydrocinnamic acid
and other products which are inhibitory to seed germination
and radicle growth of test organisms (Tanrisever et al.,
1987).
FLAVANONES
F1avanones are widely distributed (at least 60 families) but
they are accumulated in few plants (Bohm, 1982, 1988).
These flavonoids have a center of asymmetry at C-2 (see
earlier discussion under flavone and flavonol biosynthesis).
The absolute configuration of a number of these compounds
has been established. Dihydroflavonols, or 3-hydroxyflava-
nones, that have two asymmetric carbons, C-2 and C-3, also
are intermediates in the synthesis of several major types of
flavonoids such as flavonols and anthocyanins (see above).
Although the majority of dihydroflavonols possess (2R,3R)-
stereochemistry, compounds with (2S,3S)-stereochemistry
are known.
5'
KO
amentotlavone (72)
KO#'
~ I
OK 0
glnkgetin R = K
scladopitysin R = CK,
FIg. 11.14. Some representative biflavonoids.
Flavonoids 175
F1avanones are accumulated sporadically but they are
most commonly encountered in the Fabaceae and Rosaceae
(see table in Bohm, 1982).
In the genus Citrus (Rutaceae), a balance between bitter-
ness and palatability is important. Naringin (61) (Fig. 11.25),
one-fifth as bitter as quinine, produces an intensely bitter
taste in some grapefruits (Citrus paradisii). Naringenin 7-
rutinoside (79), an isomer of naringin, possesses a I - 6
linkage of the sugar to the aglycone instead of a I - 2
linkage. Curiously, naringenin 7-rutinoside (79) has no taste.
Conversion of naringin to the corresponding dihydrochal-
cone (80) yields a compound 500 times sweeter than sucrose
(Fig. 11.25) (Harborne, 1988c). The dihydroflavonol, dihy-
droquercetin 3-acetate (81), from the young shoots ofTessa-
ria dodoneifolia (Asteraceae) is 80 times sweeter than su-
crose, whereas (+ )-dihydroquercetin (18) was devoid of
sweetoess (Nanayakkara et al., 1988).
Many flavanones and dihydroflavonols have fungistatic
or fungitoxic properties. Naringenin has been established as
a growth inhibitor in dormant peach flowers. Eriodictyol
(17), dihydroquercetin (18), and dihydroquercetin 3-0-
rhamnoside inhibited growth in Helicoverpa zea larvae when
OK
~x;x:P"
OK
:1' ~I ,I
I
hinokiftavone
OR
OK 0
 W WI:
176 Ffal'onoids

OH OH

rhamnosyl-O-g1ucosyl-O 9" ° I: rhamnosyl-O-glucosyl-O 9" °

.,1 ....2 I .,1-+6 1
"'-
"'-
OH ° OH °

y:;P i fI:
oaringin (61)

I: 0H
naringenin 7-rutinoside (79)

OCH3
rhamnosyl-O-glucosyl-O 9" OH
OH
.,1~ 1
rhamnosyl-O-glucosyl-O
9" OH
"'- .,1 __2 "'- 1
OH ° OH °
naringin dibydrocbalcone (SO) neobesperidin dibydrocbalcone

OH OH
OH
HO
HO

OH

W
(a) eriodictyol (17) dihydrochalcone (U) pbloridzin (74)

OH

H0w»oH
9"1 I"" HO
OH
HO
OH
° 1 ""
.&
OH
HO

"'- .& 1
.&
HO ° OH °
a-bydroxydibydrochalcone (75) ceratiolin (78) dibydroquercetin 3-acetate (81)

odoratol (76) metbylodoratol (77)

(b)

Fig. 11.25 (a & b). Some bioactive dibydrocbalcones and flavanones (modified in part from Harbome, 1982).

added to artificial diets, but naringeniu (10), naringin (61),
hesperetiu, and neohesperidiu did not (Elliger et aI., 1980).
TIlE KOLE OF FLAVONOmS IN POLLINATION
AND PKOPAGULE DISPERSAL JllECHANlSJIIS
Although many plants are pollinated by wiud or mechanical
agents, the majority of angiosperms require outside agents
for pollination. This is especially true of dioecious plants
(with male and female flowers on separate plants) and self-
iucompatible plants. When iusects, bats, or birds visit flow-
ers to feed or collect pollen or nectar, they usually pollinate
the plant and both participants benefit from the iuteraction.
Compounds that mediate iuteractions of this type are called
synomones. These compounds may provide scent and odor
or color, or they may contribute to the nutritional value of
the pollen and/or nectar (Harbome, 1988c). Animals other
than pollinators may visit flowers as well. Many come to
"steal" nectar and pollen. Ants are notorious nectar thieves

that are small enough to enter and leave flowers without
touchiog the reproductive organs, but they may inadvertently
be pollioators,
Animals live in a world of chemical communication and
receive both olfactory and visual cues that iodicate appropri-
ate host plants. When the animal has located the flower
against the generally green background, it may be attracted
to the nectar by nectar guides on the petals. These are derived
from differential distribution of pigments withio the flower
tissue. The biochemistry of plant pollination mechanisms
has not been studied extensively.
In general, pollinators visit one or a limited number of
species at one time. Such fidelity is guaranteed by the plant's
morphology, odor, and color. Olfactory cues will be dis-
cussed later under terpenes (Chapter 19). Many plants are
pollinated only by one vector and are characteristically
known as "bee flowers" or butterfly flowers or hummiog-
bird flowers. This mutual coadaptation has many benefits
for both the plant and the animal.
In general, plants pollioated by bats are white to drab
(pale purple to green), but bats and certain other pollioators
are not especially sensitive to color. Flowers attractive to
bees usually are yellow or blue, but some are white. Al-
though bees apparently cannot see red, some bee-pollioated
flowers are red. Bees and some other iosects can see a portion
of the ultraviolet spectrum not seen by humans. Beetle-polli-
nated flowers are usually cream to greenish; many beetles
appear to be color blind. In general, bird-pollioated flowers
are scarlet or have bicolors, such as red and yellow. Butter-
flies tend to prefer vivid colors, iocludiog reds and purples,
whereas nocturnal moths usually pollinate white or pale piok
flowers. Flowers pollinated by flies are generally brown,
purple, or green, some with checkered patterns. Similar color
preferences are observed for wasps (Harborne, 1988c). The
color preferences of many other pollinators have not been
studied.
Flower color is largely due to the presence of pigments
present io cbromoplasts or cell vacuoles of floral tissues. The
colors produced by refraction of light are not as important io
plants as they are io animals. The most important group of
compounds in floral pigmentation is the flavonoids which
provide cyanic colors (orange and red to blue) as well as
yellow and white. Carotenoids principally provide yellows,
along with a few oranges and reds. Other less important
floral and fruit pigments are anthraquinones, betalains, and
chlorophylls.
Anthocyanios are especially important in the production
of cyanic colors. Three compounds, cyanidin (3), pelargoni-
din (1), and delphioidio (2), usually occur siogly, or io com-
bination, to provide the range of colors from pink, orange,
scarlet, and red to violet (mauve), and purple to blue. Factors
which modify the color of anthocyanios were discussed pre-
viously. Often a flavone andlor flavonol which forms a weak
complex with the anthocyanidin and shifts the color pro-
duced is involved. The color of delphioidin is shifted from
mauve to pure shades of blue by this mechanism. Pink colors
Flavonoids 177
often are produced by the presence of pure peonidin. Copig-
mentation with flavones and complexation with metals cou-
pled with mytiad other effects alters the color of anthocyanin
pigments in flowers (Harborne, 1988c).
The color of many yellow flowers is due to the presence
of carotenoids, although chalcones and aurones are responsi-
ble for the color in others, especially those of the family
Asteraceae. Orange flowers are produced by carotenoids
alone, or by pelargouidins and aurones (Harborne, (1988c).
Flowers that appear white or cream colored to the human
eye often contain pigments that bees and other pollinators
can see but humans cannot. Many of these pigments are
flavonols and flavones (both aglycones and glycosides)
(Harborne, 1988c).
Pelargonidio (1), which occurs often io orange-red flow-
ers, is common among trupical plants, but rarely found in
temperate ones. Many of the plants with pelargonidin are
hummingbird pollinated. In the West Indies, where there
are many hummiogbirds, approximately 17% of the flowers
have pelargonidio, whereas io Australia, where humming-
birds are lackiog, only 2% of the plants have this pigment
(Harborne, 1988c). Other types of bird pollinators are pres-
ent io both Africa and Australia, however.
Delphinidio (2) and its derivatives are found frequently
io bee-pollioated plants and are typical of families such as
the Boraginaceae, Hydrophyllaceae, Polemoniaceae, and
Scrophulariaceae. Sometimes the color of flowers of a spe-
cies apparently varies in response to the type of pollioator
present. As an example, one species of Penstemon, a blue,
carpenter bee-pollinated species, hybridizes naturally with
a red, hummiogbird-pollioated species to produce a purple-
flowered hybrid. Although normally this hybrid would fall
outside the limits that the pollioators of the parental species
would pollinate, this purple flowered hybrid is, fortuitously,
pollioated by a wasp (Harborne, 1988c).
Honey or nectar guides are part of the pigmentation of
many flowers, but these features are particnlarly common
in bee flowers.
Many floral features are not visible to the human eye, but
can only be seen in ultraviolet light. These markiogs often
are produced by local concentration of flavonoid pigments
io the petals. In Rudbeckia hirta, the petals are almost uni-
formly yellow io daylight and appear yellow to humans io
normal daylight, but, under ultraviolet light, have dark areas
(ultraviolet nectar guides) at the base. Bees apparently see
the base of the petals as bright yellow and other parts as
purple (Thompson et aI., 1972). Many variations on this
theme occur io nature. However, bees (and a number of other
insects) have trichromatic vision and perceive floral patterns
in a more complex way than is visualized (by humans) by
photography under ultraviolet light. The problems involved
io visualization of flower colors by honeybees have been
reviewed and a photographic visualization for humans devel-
oped (McCrea and Levy, 1983).
In the family Polemoniaceae, anthocyanin chemistry cor-
relates more strongly with pollination ecology than with tax-
178 Flavonoids
onomic affinities of the species examined (Harbome and
Smith, 1978).
ISOFLAVOrms
Isoflavones differ structorally from flavones in that the B
ring is attached to the 3-position; the spectral properties of
the compounds differ markedly from those of regular fla-
vones as the natore of the conjugated system is altered. Most
of the 234 isoflavone aglycones (out of 630 known isoflavo-
noids) are found in the Fabaceae (Dewick, 1988; Williams
and Harbome, 1989b). Many isoflavonoids have marked
physiological effects in biological systems and are often in-
volved in interactions with other organisms. Isoflavones
commonly occur in the plants as glycosides and many have
prenyl groups attached to the phenolic rings. A large number
of other isoflavonoids are derived secondarily from isofla-
vones. These derivatives typically occur as aglycones and
only rarely as glycosides (about 48 glycosides have been
reported). Isoflavonoids are of considerable interest because
of their physiological properties (Williams and Harbome,
I 989b).
Biosynthesis
L-Phenylalanine variously labeled with 1"(; at C-2 and C-
3 and in the carboxyl group is incorporated into formono-
80
oaring.nln (10) R = 08
liquiriligenin (14) R = 8
formononetin (82) R = H 6,7,4'.trihydroxyisonavone (85)
blocbanin A (112) R =08
luteone (86)
Fig. 11.26. Proposed biosynthesis of isoflavones (modified from Kochs and Grisebach, 1986) and some representative isoflavones.
netin (82) (Fig. 11.26) (Barz and Welle, 1992). The distribu-
tion of radioisotope was demonstrated by degradation. These
experiments show that a phenyl migration takes place in the
course of the biosynthesis, and experiments with chalcone
glycosides indicate that the aryl rearrangement occurs after
the formation of the C6 -C3-C6 intermediate. An enzyme,
isoflavone synthase, that requires NADPH and molecular
oxygen, has been isolated from microsomal preparations of
cell suspension cultores of soybean after these cells were
challenged with an elicitor of phytoalexins from Phytophth-
ora megasperma f. sp. glycinea. A microsomal preparation
from elicitor-challenged soybean cell suspension cultores or
soybean seedlings catalyzes an NADPH and dioxygen-de-
pendent rearrangement of (2S)-naringenin (10) to genistein
(5,7,4'-trihydroxyisoflavone) (46) (Barz and Welle, 1992).
(2S)-Liquiritigenin (14) was converted to daidzein (83). La-
beling stodies confirm that the rearrangement is an intramo-
lecular process (Dewick, 1985; Grisebach, 1985; Heller and
Forkmann, 1988). Rearrangement to the isoflavone seems
to take place with the flavanone and not with the chalcone
(Grisebach, 1985). Two enzymatic steps seem to be involved
in the transformation of naringeoin to genistein. The first
step comprises oxidation and rearrangement of naringenin
(10) to 2-hydroxy-2,3-dihydrogenistein (84) (Barz and
Welle, 1992). This step requires NADPH, 0,., and a mem-
brane-bound cytochrome P-450 monooxygenase. The stable
2-hydroxyisoflavanone intermediate is then converted by a
soluble dehydratase to genistein (46) (Heller and Forkmann,
08
(84) genistein (46) R = 08
daidzein (83) R =8
80%",,1°1
80 <?
OC83
° ~ 1
08
08
wighteon. (87)

1988). A radical mechanism seems to be involved (Barz and
Welle, 1992).
Many isoflavone derivatives are formed from precursors
lacking the 5-hydroxyl group. Studies with "c labeling con-
firm that loss of the hydroxyl group usually occurs before
cyclization of the A ring (i.e., at the chalcone stage) (Dewick,
1984). The enzyme chalcone reductase coacts with chalcone
synthase and NADPH as a cofactor in the formation of
4,2',4'-trihydroxychalcone (Barz and Welle, 1992).
An isoflavone O-methyltransferase from elicitor-treated
cell suspension cultures of Medicago sativa exhibited activ-
ity with 6,7,4'-trihydroxyisoflavone (85), as well as a num-
ber of other isoflavones, isoflavans, and pterocarpans (Ed-
wards and Dixon, 1991). Both a 4'-O-methyltransferase and
a 7-0-methyltransferase occur (Barz and Welle, 1992).
Distribution
In contrast to other groups of flavonoids, isoflavones
mostly are restricted to one group of plants, the subfamily
Papilionoideae of the Fabaceae (Leguminosae), although
they occur occasionally in the subfamilies Caesalpinioideae
and Mimoisoidae of the Fabaceae and in the families Ama-
ranthaceae, Asteraceae, Brassicaceae, Chenopodiaceae, Iri-
daceae, Menispermaceae, Moraceae, Myristicaceae, Podo-
carpaceae, Rosaceae, Scrophulariaceae, Stemonaceae, and
Zingiberaceae (Dewick, 1982, 1988; Williams and Har-
borne, 1989b; Wong, 1975). Isoflavonoids also have been
isolated from Juniperus (Cupressaceae) and Podocarpus
(Podocarpaceae) and the moss, Bryum capi/lare (Dewick,
1988).
Isoflavonoids do not have the same UV spectral patterns
as other flavonoids and often are not observed in routine
studies of plant flavonoids. It is quite possible that isoflavo-
noids will be encountered in additional families. The meth-
ods for isolation and purification of isoflavonoids have been
reviewed (Dewick, 1988; Williams and Harborne, 1989b).
The best methods for characterization of these compounds
are NMR and MS (mass spectrometry).
Biological Properties
Most isoflavones are weak estrogens (McClure, 1975;
Wong, 1975). The presence of these compounds in forage
legumes, such as subterranean clover (Trifolium subter-
raneum) and red clover (Trifolium pratense), has been rec-
ognized as the cause of infertility problems in animals graz-
ing on these plants (Williams and Harborne, 1989b). In years
of good rainfall, the plants are relatively low in isoflavones,
but in years of drought, the concentration is proportionately
higher. The population size of certain birds (quail) that feed
in pastures rich in these legume seeds may be affected by
the presence of isoflavones. In dry seasons, the birds lay
fewer eggs.
Two isoprenylated derivatives of ( - )-maackiain from an
unidentified South American plant had high antidote activity
toward venom of the snake Bothrops atrox (Nakagawa et
aI., 1982; Williams and Harborne, 1989b).
F/lII'olioids 179
The isoflavones luteone (86) and wighteone (87) occur
on the leaf surfaces of Lupinus species and appear to be
preformed antifungal defenses; both compounds are fungi-
toxic to He/minthosporium cO/'bonum (Harbome, 1986,
1991).
Derivatives of lsonavones
Several other important groups of secondary metabolites
are derived from isoflavones (Fig. 11.27) and are discussed
below. Many of these compounds have pronounced biologi-
cal properties.
COUMESTA1'IS
Coumestans, such as (88), which possess a coumarin struc-
ture, are derivatives of isoflavones (Fig. 11.28); most of the
31 known compounds of this structural type are restricted to
the Fabaceae (Dewick, 1982, 1988; Williams and Harborne,
1989b). Study of the biosynthesis of coumestans has been
accomplished because elicitors stimulate synthesis of these
compounds in plant cell cultures (Grisebach, 1985). The only
known coumestan glycoside occurs in EcUpta alba (As-
teraceae).
Coumestrol (89) from alfalfa, Medicago sativa, and clo-
ver, Trifolium repens, is a more active estrogenic compound
than simple isoflavones. Although it is 30 times more active
than geuistein (43) or formononetin (82), coumestrol occurs
at lower concentrations and has less total effect (McClure,
1975; Wong, 1975).
ISOFLAV A1'IS
Isoflavans, such as (90), represent the most reduced struc-
tures of isoflavonoids; about 51 structures have been re-
ported (Dewick, 1988; Williams and Harborne, 1989b). The
animal flavonoid metabolite, equol (91), is a representative
of this class of compounds. Equol is formed in animals from
the metabolism of compounds such as formononetin (82).
Other isoflavans are known to occur in plants; for example,
( - )-5'-methoxysativan is found in alfalfa foliage (Fig.
11.29) (Dewick, 1982; Miller et al., 1989).
Most phytoalexins from the family Fabaceae are either
isoflavans or pterocarpans (Barz and Welle, 1992; Dewick,
1982, 1988; Kuc, 1992). More than 400 species of legumes
bave been found to have the ability to produce phytoalexins
(Williams and Harborne, 1989b) (see below). (- )-Vestitol
(92) and sativan (94) (Fig. 11.35), isoflavans from Lotus
species, are phytoalexins. (- )-(3R)-Vestito1 from the resis-
tant pasture legume, Lotus pedunculatus, is a feeding deter-
rent to larvae of Costelytra zealandica (Coleoptera: Scara-
baeidae), a serious agricultural pest in New Zealand.
Pastures containing perennial rye grass (Lolium perenne)
and as little as 20% Lotus peduncularus were relatively resis-
tant to attack by this insect (Dewick, 1982).
 oc:o
180 Flavonoids

OH

o
1

chalcones
O!o
'"
IOH

o
'"
1 ""
0=60
~1 0

o I'"
h
- ",I
o
HO
I'"
h

0+ / a-methyldeoxybenzoim pterocarpam '-....... 2'-hydroxyisoflavans

0(1 ~ _ ex:lt ~_
~- -~Q -LJ)
* "'-.
h

%0 0100
0
isoflavones isoflavanones dehYdroPterocarpan~ 6a-hydroxypterocarpans

o
CJ(j(~
-- K U ~ Jr
",I
O
HO""
1
1 '"
-+ ",I
oH O
I'
"
h
",I

0
""
1 '"
h
2-hydroxyisoflavones 2'-hydroxyisoflavones 2'-hydroxyOavanones coumestans

Jf ~ ~ o
o 1 OCH'_~IO
0
""/-"..--.,, r '" r
"I 0
I "I

--
HO

3-aryl-4-hydroxycoumarins coumaranochromones
2 1-methoxyisoflavones
0
rotenoids
0
+

dehydrorotenoids 12a-hydroxyrotenoids

Fig. 11.27. Major groups of compounds derived from isoflavone precursors (modified from Wong, 1975;

HO~"

-<
1 0 1 _ _H o1U
0 1f u "
OH '" 1 '"
HO 0 "IOH °HO ""OH

daidzein (83) J~ (103)

o
isoliquiritigenin (15) HO%O
:-...1 HO~O
----...~I

o "" I 0 '"
1 ""
OH HO OH

coumestan (8S) 10

CH,O

wedelolactone trifolio. medicagol

Fig. 11.28. Probable biosynthetic pathways to coumestrol and some representative coumestans (modified from Haslam. 1974).
 Flavonoids 181

HO
HO~O HO 0

~ I
""0 aVl~
H

~oH~~D
""

OH OH
OCH,

(3S)-isoflavan (90) equol (91) lonchocarpin

HO~IO ~
HOSO
I
CH,-O

;7 I ~ ;7 OCH,

HO ~ OCH, '>- I HO
CH,-O OCH,
HO OH

vestitol (92) (-)-S'-methoxysativan (93) licoricidin

Fig. 11.29. Selected isoflavans.

PTEROCARPANS co-occurring 3'-hydroxylases) are NADPH-dependent mi-

The second largest group of isoflavonoids is the pterocarpans
[e.g., (95)]. Approximately 139 compounds have been re-
ported (Williams and Harborne, 1989b). The numbering sys-
tem of plerocarpans is different from that of isoflavones (Fig.
11.30).
As is true for coumestans and other related compounds,
elicitation often stimulates the production of pterocarpans
in plant cell cultures and facilitates biosynthetic studies
(Grisebach, 1985).
Oxygenation at the 2'-position of isoflavones is requisite
for formation of pterocarpans. 2'-Hydroxylases (as well as
crosomal monooxygenases (Barz and Welle, 1992; Stafford,
1991). A flexible isoflavanone intermediate, rather than an
isoflavone, may be required for formation of a fused furan
ring (Stafford, 1991). In eicer arietinum, the (6aR; llaR)
pterocarpans ( - )-medicarpin (96) and ( - )-maackiain (97)
(Fig. 11.31) arise from formononetin (82) by 2'- oxidation
(or 5f -oxidation in some isomers) followed by conversion
to the corresponding isoflavanones vestitone (98) and 'i'-
baptigenin (99) (Barz and Welle, 1992; Dewick, 1989). The
enzymes that catalyze these reductions require NADPH and
are specific for 2' -hydroxyisoflavones. The entire enzyme
system is specific for 4'-O-methylisoflavones, such as (82)

o H

o
)
o
H-(6aR,llaR)'pterocarpan (95) preferred configuration (94) (-)·pisatin (101)
CH,-O o
o
CH3-0~1
0 CH,-O p

~.o ~

I~
o ..0
OCH, OCH,

6a-hydroxyphaseollin a dimethoxy- 6a,lla-dehydropterocarpan variabilin

Fig. 11.30. Some common pterocarpans.

182 Flavonoids

HO
NADPH
Hr OI I%
r 0, '" r OH

HO 0 !
NADPHIO ".. I o "..1

HO%
0, OCH, OCH,
caJycosin
formononetin (82)

,:>' I 1

'" °
OCH, 'P
° :
-baptigenin (99) ! 1
°>
O HO%IOI
HO% H I
'" '" °
to 1° : >
7
o ".. I I
NADPH HO 0
.estitone (98) OCH, (U3)

HO 0
H°)X(01
'"
°H °
/
°HO ~ 7 1
0
>
OCH, HO
(-)-medicarpin (96)

°;;
(-)-maackiain (97)

Fig. 11.31. Biosynthesis of (- )-maackiain (Dewick, 1989; modified and used with pennission of the copyright owner, the Royal Society of Chemistry,
Cambridge).

(Barz and Welle, 1992). In both instances, an NADPH:
isoflavone oxidoreductase reduces a 2'- or 5'-hydroxyisofla-
vone to the corresponding isoflavanone. This reaction is fol-
lowed by the fonoation of pterocarpans catalyzed by ptero-
carpan synthase. The pathways in soybean, pea (pisatin), and
alfalfa (medicarpin) all reflect a high degree of homology
(Barz and Welle, 1992).
Pterocarpans [e.g., (95)] occur primarily in legumes, but
are widely distributed in that family (Barz and Welle, 1992;
Dewick, 1982, 1988). These compounds generally occur in
the free state, although some glucosides are known (Fig.
11.30).
The biosyntheses of phaseollin (100) and (- )-pisatin
(101) have been examined and pathways proposed (Figs.
11.32 and 11.33) (Dewick, 1984). In the biosynthesis of
phaseollin, the chalcone, isoliquiritigenin (15), daidzein
(83), and (103), and the pterocarpans (105) and phaseollini-
din (104) were all incorporated, suggesting that these com-
pounds may represent a logical sequence leading to phaseol-
lin (100) (Dewick, 1984). Furthenoore, use of 13C-Iabeled
acetate in cell cultures of Glycyrrhiza echinara yielded only
three pairs of acetate couplings in the product phaseollin.
This indicates that loss of the 5-hydroxyl group occurs early
in the biosynthesis. Biosynthesis of similar compounds with
this hydroxyl present (kievitone, 106) leads to six acetate
13C couplings (Fig. 11.32) (Dewick, 1984).
Seedlings and pods of Glycine max, the soy bean, synthe-
size three major phytoalexins, glyceollin I, II, and III
(107-109). These compounds have been shown to share a
common pathway with phaseollin as far as the pterocarpan
inteonediate (105). Glycinol (110) was incorporated into all
three glyceollins. Prenylation occurs late in the scheme (Fig.
11.33) (Dewick, 1984). Most of these enzymes are mem-
brane-bound cytochrome P-450 monooxygenases. A prenyl-
transferase enzyme has been isolated and studied (Welle and
Grisebach, 1991).
A similar series of feeding experiments with Pisum sari-
vum, pea, indicated that isoliquiritigenin (15), isoflavones
(83, 99, 111-113), and (-)- and (+ )-maackiain (97, 114)
(but not methyl ethers of 83, 97, or 114) were incorporated.
( + )-6a-Hydroxymaackiain (115) also proved to be an effec-
tive precursor (Fig. 11.33) (Dewick, 1984).
An additional enzyme, 6a-hydroxylase, is responsible for
the foonation of many pterocarpan derivatives (Barz and
Welle, 1992; Heller and Forkmann, 1988). 6a-Hydroxypter-
ocarpans [such as (- )-pisatin (101) and 6a,lla-dehydropt-
erocarpan derivatives are well-known antifungal compounds
(see the section on phytoalexins, below).
 FllII'CJl/oitis 183

(- )-Medicarpin (96) and methoxymedicarpin, from al-
falfa roots, Medicago .\'CI/il'll, inhibit seed gennination (at
10- 1 and 10-" M, respectively) and growth of alfalfa seed-
lings (Cutler, 1992; Miller et aI., 1988). Medicarpin occurs
in alfalfa roots as the 3-0-glucoside, medicocarpin.
PHYTOALEXlI'IS
Millier and Borger (1941) defined phytoalexins as com-
pounds that inhibited the growth of fungi, but emphasized
that these bioactive compounds were not produced or acti-
vated until the host came into contact with the parasite. This
defensive reaction occurs only in living cells. The inhibitory
compound(s) is a discrete chemical substance, a product of
the host cell. Most phytoalexins inhibit growth of fungi at
10- 3 _10- 5 M (Kuc, 1992). The phytoalexin is nonspecific
in its action toward fungi; however, fungal species may be
differentially sensitive to it. The basic response in both resis-
tant and susceptible cells is the same, the basis of differentia-
tion between resistant and susceptible hosts being the rate
of fonnation of the phytoalexin. The defense mechanism is
confined to the tissue colonized by the fungus and its imme-
diate neighborhood. The resistant state is not inherited; it is
developed after the fungus has attempted infection (Brooks
and Watson, 1985; Harborne, 1988c). The first phytoalexin
to be chemically characterized was ( - )-pisatin (101), a pter-
ocarpan, from Pisum sativum. This compound was induced
by the presence of conidia of the brown rot fungus, Monilinia
fructicola. Plants of Phaseolus vulgaris also produce a ptero-
carpan phytoalexin, phaseollin (100).
Most of the phytoalexins studied to date are from the
Fabaceae and the Solanaceae (Kuc, 1992), a fact that proba-
bly reflects the economic importance of these families but
may also reflect the stability and ease of isolation and charac-
terization of the phytoalexins. At least 200 phytoalexins are
known (Brooks and Watson, 1985). Although it is widely
accepted that phytoalexins playa major role in disease resis-
tance, their role in disease resistance is less well understood
than their production and metabolism (Dixon et aI., 1983;
Kuc, 1992). Interestingly, in some susceptible reactions be-
tween fungi and plants, phytoalexins accumulate to higher

H0'f"l(0H("yOHHO~O HO~O
~",II
0: I----. 0: I
",11
o --+ ----+
OH HO OH
isollquiritigenin (15) daidzein (83)
(103)

H0 0 Cfu
'O
"I H _ _HO
,....
~O " I OH OH

HO
HO

! OH
glycinol (110)

OH
HO

HO

OH
glyeeollin m (109) glyeeollin I (107)

Fig. 11.32. Proposed biosynthesis of phaseollin and glyceollins I-m (Dewick. 1984; modified and used with pennission of the copyright owner, the
Royal Society of Chemistty, Cambridge),
184 Flavonoids

HO~ HO
: 1 1
"
°HO" 1
........
OCH, OCH,

H0'f"lr0H NoH HO%j HO (~_):6aR~IaR)_medicarpin (96)

~ "I I" "I 1 OH
o ---+ 0 ~I ----.
OCH,
0:'-' OCH
isoUquiritigenin (15) rormononelin (83) (Ill) ,

HO~O.
HO
'" 1
°1 trans HO
reduction
°
Ufu' H
~I I ~ ~ ~ ~ 0
° ° °
:;..0"

",-baptlgenin (99)
"I>
"o/..
/red:~On?
HO
(113)
"I>
° *
HO
"I>
°
H0I""'Ir 0 , HO HO
~H
" °OO~O
~O>- °J °J
(+)-(6a5,llaS)-maackiain (114)
HO
/ HO

°)
°
CH,O CH,O

°) °>
(+)-(6aR,l1aR)-pisatin (102) ° (-)-pisatin (101) °
Fig. 11.33. Proposed biosynthetic pathways to pisatio (Dewick. 1984; modified and used with pennission of the copyright owner, the Royal Society of
Chemistry. Cambridge).

concentrations than in resistant interactions. This effect
probably is due to the timing of production of the fungitoxic
compounds (Kuc, 1992).
The ability of cell cultures from many different species
of plants to produce flavonoid phytoalexins upon induction
with elicitors has been of major importance in elucidation
of the mechanisms and control of biosynthesis (Ellis, 1988).
The amounts of mRNA for chalcone synthase and PAL in
Phaseolus vulgaris suspension culture cells increase within
2 h of treatment of the cells with an elicitor made from
Colletotrichum lindemuthianum cell walls. The amount of
translatable mRNA for these enzymes reaches a maximum
4 h after elicitor treatment. In the case of chalcone synthase
mRNA, this is probably due to in vitro transcription. In elici-
tor-treated cells, 50 proteins increased and 10 decreased
when compared to untreated cells (Kuhn, 1987).
In some cases, conditions other than fungal attack can
induce the formation of phytoalexins. Bacterial, viral, insect,
or nematode attack, stress, and so forth may also do so.
Several phytoalexins are known to inhibit the growth of in-
sect larvae and nematodes (Dewick, 1982).
The largest group of phytoalexins studied to date are pter-
ocarpans and related isoflavones and isoflavans from the
Fabaceae (Fig. 11.34) (Friend, 1979; Harborne, 1982,
1988c). For example, the leaves of Anthy/lis vulneraria and
five Tetragonolobus species inoculated with Helminthospor-
ium carbonum produce 7,4'-dihydroxy-2'-methoxyisoflavan
[isovestitol (116)] and 7,2',4'-trihydroxyisoflavan [demeth-
ylvestitol (117)]. Those of Lotus corniculatus produce de-
methylvestitol (117), vestitol (92) and sativan (94). Lotus
uliginosus produces demethylvestitol (117) and vestitol (92).
The leaves of the European licorice (Glycyrrhiza glabra)
produce 7,2'-dihydroxy-3,4'-dimethoxyisoflavan. Members
of the genus Trigonella produce a variety of isoflavans or
pterocarpan phytoalexins. Seedlings of soybean (Glycine
max) produce the pterocarpan phytoalexins, glyceollins I-III
(107-109) (Barz and Welle, 1992; Friend, 1979). Normal
tissues accumulate mostly daidzein (83) and genistein (46).
Chickpea plants and cell cultures synthesize medicarpin and
 Flavonoids 185

HO

HO CH,-O

isoflavone OCH, o>

Cajanus
(Lupinus, preinfectional) pisatin (101) pbaseollin (100)

HO

-OCH,
HO~IO HO~IO
"'"
o
I~
h
-"'"
OCH, HO
I ~
h
OCH,

isoflavanone pterocarpan isoflavan

Cajanus Baptisia, Cicer, Melilotus, Loteae:
Pisum, many genera Anthyllis, Lotus, Tetragonolobus

Both types found in: Medicago, Trifolium, Trigonella

Fig. 11.34. Phytoalexin phyletic sequence (modified from Harhorne, 1988c);

maael"aln (97) medicarpin (96) isomucronuIatol

OH
glyceollin n (108) glyceoltin m (109)
HO

HO
o
)
o

kievitone hydrate (106) 6a-hydroxymedicarpin R=H (118) 6a-hydroxymaackiain R=H (115)

6a,7-dihydroxymedlcarpin R=OH (119) 6a,1-dihydroxymaackiain (120)

CH,O HO

HO'(}(°l,;

~ CH,O
r~J~) OH
(-)-pisatin (101)
lsoveslitol (116)

HO~"
I ° H O a 01 ~ HO~"
I 0

HO"
~ I OH
~ :00
HO OCH, CH,O
:1 OCH,

demetbylveslitol (117) vestitol (92) sativan (94)

Fig. 11.35. Representative isoflavone-derived phytoalexins from the Fabaceae.
186 Flavonoids
maackiain in response to the fungus Ascochyta rabiei. Nor-
mal tissues primarily accumulate formononetin (82) and bio-
chanin A (112) (Fig. 11.35) in the vacuoles, mostly as the
7-0-glucosides-6"-malonate derivatives (Barz and Welle,
1992). In Cicer cell suspension cultures, labeled formono-
netin was shown to be quantitatively converted to pterocar-
pans upon elicitation and PAL inhibition, strongly suggest-
ing that these isoflavones serve as precursors to phytoalexins
and that de novo flavonoid biosynthesis is not required (Barz
and Welle, 1992).
Resistance to fungal atrack has been rationalized by the
rapid accumulation of phytoalexins. Susceptibility has been
explained by the ability of virulent pathogens to detoxify
these compounds. These detoxification reactions frequently
produce a more hydrophilic product. The susceptibility of
French bean hypocotyls to Fusarium solani f. sp. phasiolli
has been partly explained by the metabolism of the phyto-
alexin kievitone (106) by the fungus. Although the phyto-
alexin initially accumulates, it is rapidly converted to
phaseollin (100), 2'-methoxyphaseollin-flavan, and phaseol-
linisoflavan. All of these compounds accumulate when the
hypocotyl is completely infected. l-Hydroxyphaseollone,
the detoxification product of phaseollin (100), also was pres-
ent (Friend, 1979).
Both pathogenic and nonpathogenic fungi may detoxify
phytoalexins either in vivo or in vitro (Barz and Welle, 1992;
Friend, 1979; Ku6, 1992). Red clover (Trifolium pratense)
produces primarily, medicarpin (96) and maackiain (97)
[formononetin (82) is an intermediate] when inoculated with
Helminthosporium carbonum, but only the nonfungitoxic
:
~ H 0-"-'
HO 7'
:,...
H,N CO,H
o OCH3 •
H
HO
.',.
rotenone (121)
tephrosin (122)
Fig. 11.36. Proposed biosynthesis of rotenone (modified from Crombie. 1984; the Royal Society of Chemistry. Cambridge).
hydroxylated derivatives 6a-hydroxymedicarpin (118), 6a,
7-dihydroxymedicarpin (119), 6a-hydroxymaackiain (115),
and 6a,7-dihydroxymaackiain (120) when challenged with
Colletotrichum coffeanum, a nonpathogen (Friend, 1979).
Degradation of biochanin A (112) from chickpea with Fu-
sarium javanicum involves formation of dihydrobiochanin
A, 8-hydroxydihydrobiochanin A, and a dioxygenase cleav-
age to a diketodihydropyran (Barz and Welle, 1992).
The microbial transformations of isoflavonoids have been
reviewed (Dewick, 1988).
KOTEI'IOIDS
About 60 isoflavone derivatives that incorporate a prenyl
group into the structure are insecticidal and piscicidal (De-
wick, 1988; Harborne, 1991). Plants that contain rotenone
(121) (Derris and Lonchocarpus spp.) have long been used
as natural insecticides and piscicides. These compounds are
best known from the fabaceous genera Amorpha, Derris,
Lonchocarpus, Milletia, Mundulea, and Tephrosia (Dewick,
1988; Harborne, 1991).
Rotenoids are derived from isoflavones and occur in the
same plants that have isoflavones (Fig. 11.36) (Dewick,
1982). The cis-B/C ring coupling of rotenone was estab-
lished by NMR spectroscopy (Carlson et al., 1973). Prenyla-
tion of the isoflavone nucleus is known to occur late in the
biosynthesis of rotenoids. Rotenoids are isoflavanones that
have been modified with an "extra" carbon atom. The extra
OH HO
-- • SAM
. .
OCH,
OCH,
.
OCH3
OCH,
•
 Ffal'onoids 187

carbon has been shown to come from S-adenosyl methio-

nine.
Rotenoids are effective inhibitors of oxidative phosphory-

~
lation in animal mitochondria; this effect is responsible for
the insecticidal properties of this group of compounds (Wil-
liams and Harborne, 1989b). This effect may occur at con-
R
centrations as low as 24 nmol/g of mitochondrial tissue. The HO OH
lethal dose of rotenone in the silkworm is 0.003 mg/g body I HO~OH ~
weight (Harborne, 1991). This series of compounds also in-
hibits other enzymes (McClure, 1975).
HO
~
The rotenoid tephrasin (121) from Tephrosia elata roots
deters insect feeding activity (Williams and Harborne,
1989b). Although generally considered to have low mamma-
lian toxicity, rotenone-containing roots have been used as a
CH'O~O
'" I
source of arrow poisons in Sumatra (Harborne, 1991). o '" H

Methods for the isolation and purification of rotenoids "'I

have been reviewed (Williams and Harborne, 1989b). Most '"
(R)-4-methoxydalbergione
rotenoids can be characterized by means of their NMR spec-
tra (Carlson et aI., 1973).
CH'O~"'I
0", 0
HO

rmoFLAVOl'lOIDS "'I
"
dalbergin
Neoflavonoids resemble flavonoids in their overall structure R=HorOCH3
and properties and arise by processes similar to those leading

to isoflavones (Fig. 11.37). These compounds are found in
the Clusiaceae (Hypericaceae), Fabaceae, Passifloraceae,
Polygonaceae, and Rubiaceae; several structural types and
subtypes are known (Donnelly, 1975; Donnelly and Sheri-
dan, 1988; Gottlieb et al., 1970). The similarity of oxygena-
tion pattern in the dalbergiones, dalbergiquinols, and the 4-
arylcoumarins suggests that they are related. There are many
difficulties in the biosynthetic stndy of heartwood constitn-
ents and the biosynthetic pathway for this group of com-
pounds is not entirely clear.
The notable resistance to decay of rosewoods (usually
from the genera Dalbergia and Machaerium) is due to the
presence of several types of phenolic compounds; the neofla-
vonoids are major among these (Donnelly, 1982; Donnelly
and Cannon, 1986).
In the compound calophyllolide (123) from Calophyllum
inophyllum (Clusiaceae or Hypericaceae), phenylalanine
was incorporated into the 2,3,4-position and the aromatic
ring attached at the C-4 position. Acetate served as a precur-
sor for the aromatic ring with the phloroglucinol substitntion.
Compounds from the Fabaceae generally have a 6,7-oxygen-
ated pattern rather than that of calophyllolide. The possibility
of different pathways cannot be excluded.
ISOLATIOl'L PURlFICATIOl'l Al'ID
CHARACTERIZATIOl'l OF FLAVOl'lOIDS
Techniques for the isolation, purification, and characteriza-
tion of flavonoids have been reviewed (Hostettmann and
Hostettmann, 1982; Mabry and Markham, 1975; Mabry et
Vt
• H CH30 o
'COzH
1 --+
'" NH, I
caliophyllolide (123)
Fig. 11.37. Biosynthesis of neoflavonoids (Gottlieb et aI., 1970;
modified and used with permission of the copyright owner, Academia
Brasileira de Ciencias, Rio de Janeiro).
al., 1970; Markham, 1976, 1982; 1989; Markham et aI.,
1978, 1982; Ternai and Markham, 1976). Many flavonoids
can be separated by HPLC (Banwart et aI., 1985; Porter et
al., 1985, 1986).
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Advances in Research 0. B. Harborne and T. J. Mabry, eds.},
189-259, Chapman & Hall, London, 1982.
WOLLENWEBER, E. and V. H. DIElZ. Occurrence and distribution
of free flavonoid aglycones in plants, Phytochemistry, 20,
869-932 (1981).
WOllENWEBER, E. and M. JAY, Flavones and flavonols, in The
Flavonoids: Advances in Research since 1980 (1. B. Harborne,
ed.), 233-302, Chapman & Hall, London, 1988.
WONG, E.. Isoflavonoids, in The Flavonoids (1. B. Harborne, T. J.
Mabry, and H. Mabry, eds.), 743-800, Academic Press, New
York,1975.
12
Tannins
Introduction
Hydrolyzable tannins
Biosynthesis
Distribution of Hydrolyzable Tannins
Proanthocyanidins or Condensed Tannins
Flavan-3,4-diols
Flavan-3-ols
Procyanidin Dimers
Condensed Units Derived from Proanthocyadin Units
Biological Activity of Tannins
Binding of Tannins to Protein
Tannins in the Diets of Animals
The Cost of Tannin Defenses and Resource Allocation
Other Proposed Functions of Tannins
Medicinal Properties of Tannins
Correlation of Tannin Consumption and Throat Cancer
Tannins and the Production of Leather
Other Types of Tannins
Analysis of Tannins
References
INTRODUCTION
Plant polyphenols, which have the ability to precipitate pro-
tein, collectively, are called tannins. These compounds have
been used for millenia to convert raw animal hides into
leather. In this process, tannin molecules cross-link the pro-
tein and make it more resistant to bacterial and fungal attack.
Molecules in the molecular weight range of 500-2000
(3000) are most effective, but the ability to bind effectively
varies with different tannin structures. Today, however,
many substances considered to be tannins by virtue of their
structure and biosynthetic origin have limited, if any, ability
to make leather (Hagennan and Butler, 1981).
Although vegetable tannins are invariably polyphenolic
substances, not all phenolic materials are tannins. Gallic acid
(1), chlorogenic acid (2), and ( + )-catechin (3), for example,
have been referred to in the literatore as tannins, but they
do not possess the ability to precipitate proteins (nonetheless,
these compounds may bind or interact with proteins). The
C.-C 1 tribydroxy compound, gallic acid (1) appears to be
the biological equivalent of the C.-C3 compounds, cinnamic
acid, p-coumaric acid, caffeic acid, and so forth. (Bate-
Smith, 1962) (see Chapter 8); many types of gallate esters
are found in natore. Among these are compounds such as
the turgorins from Acacia !<aroo (4-6) (Fig. 12.1), that are
involved in leaf movement in plants (Haslam and Lilley,
1986).
Tannins usually are located in the vacuoles of plant cells
and, in many cases, make up a sizable proportion of the dry
weight of plants. Tannins often are concentrated in epider-
mal tissues and in the bark of woody plants, but these pheno-
lic compounds may be found in leaves, roots, stems, fruits,
bark, wood, or other plant parts. Tannin content may vary
widely during the growing season in a particular plant part.
There are two major structural types of tannins-conde-
nsed tannins and hydrolyzable tannins. Condensed tannins,
or proanthocyanidins, are compounds that should produce
anthocyanidins on hydrolysis (although, in practice, many
recently isolated compounds of this group are known not to
yield anthocyanidins) (Hemingway, 1989). These tannins
are derived from flavonoid precursors. Hydrolyzable tannins
(or gallotannins and ellagitannins) are derived from the shik-
imic acid pathway intennediate, dehydroshikimic acid (7)
(Fig. 12.3). Ellagitannins appear to be much more common
that gallotannins. Furthennore, ellagitannins generally differ
from other types of tannins in that individual compounds
can be isolated as a comparatively stable entity that can be
handled as a single compound of defined structure. Gallotan-
nins usually occur as complex mixtores (Okuda et ai.,
1989b).
Evolutionarily, condensed tannins preceded hydrolyzable
tannins; these flavonoid-derived phenolics are found in
193
194 Tannin.f

H o y q0: 8
'. ">...
HO
~ ~I
OH

H o y : ) : 0 ">...
J8(HOOH
~
I
HO

iIY
CO,H

I "I" OHHOAf
.">... .'OH ">... OH OH
OH OH

(-)-epicatechin (30) (-)-epigallocatechin (34) gallic acid (1)

a tlavan-3-o1
HO
HO

0
CO,H
OH

HO
OH
HO , OH
•
OH
OH OH
(+ )-catechin (3) (+ )-gallocatechin (33) shikimic acid (12)

~ o~OH
OSO'H OSO,H

H~

(S)r
HSO~O O~
HOHO 0 OH
OH 7 OH
H I H
7
I
HO '" CO,H HO '" CO,H
(4) HO OH
71

o
'"
~
CO'H 0 OH 1

HO HO 0 ~
OH 7 I OH

HHO '" CO,H

HO,e. ~OH
~rr chlorogenicacid (2)
(a) (6) OH OH

Fig. 12.1 (a & b). Nontannin phenolic compounds and {3-pentagaIloylglucose.

ferns, gymnospenns, and angiospennous plants, whereas hy- HYDKOLYZABLBT~

drolyzable tannins are found only in a number of relatively
advanced dicotyledonous plant families. Hydrolyzable tan-
nins are abundant in the leaves, fruits, pods, and galls (some-
times bark and wood) of a number of dicotyledonous fami-
lies (Lewis and Yamamoto, 1989). Plant extracts may
contain both hydrolyzable and condensed tannins. For exam-
ple, in some Acacia species, leaves contain primarily hydro-
lyzable tannins, whereas bark contains mostly condensed
tannins. Hydrolyzable tannins also predominate in the imma-
ture fruits of some of the same species (Readel et aI., unpub-
lished data).
Treatment of hydrolyzable tannins with acid or alkali and,
in some cases, hydrolytic enzymes splits them into sugars
and phenolic carboxylic acids. Condensed tannins do not
break down readily in this manner nor do they contain sugar
moieties as a part of their structure (Haslam, 1979). How-
ever, gallic acid units are sometimes associated with con-
densed tannins (Lewis and Yamamoto, 1989).
Complex esters of gallic acid with a carbohydrate (usually
glucose), called gallotannins, are widely distributed among
dicotyledonous plants. The most common gallotannin is 13-
pentagalloylglucose (8). Additional galloyl units can be
added via depside (ester) linkages, usually at the C-3 position
of gallic acid. Esters involving a dimer of gallic acid, hexa-
hydroxydiphenic acid (9) [nonnally isolated after hydrolysis
as the dilactone, ellagic acid (10)] are called ellagitannins
(Fig. 12.2). Hexahydroxydiphenic acid occurs in two opti-
cally active fonns in tannins. Ellagitannins (such as II, cori-
lagin) often co-occur with gallotannins, but are especially
important in oak, eucalyptus, chestnut, some Caesalpinia
species, and Terminalia chebula. Collectively, the two
groups are called hydrolyzable tannins. As the name implies,
these compounds may be degraded into simpler fragments
under hydrolytic conditions. Hydrolyzable tannins usually
are classified by the phenolic acid(s) liberated on hydrolysis.
 Tannin I 195

'r1
OH

OH
r OH
OH

quinic acid (lJ) scyllo-quercitol (14) (+)-proto-quercito) (15)

"O~
::'0 o~o 0>-QoH
ro.

°
~° ° ~
10H
fi

Hoi[
° ° ° OH

O~O"
HO OH VOH
HO

rrOH
j3-pentagalloylglucose (8)

Hoyyoi'·'·O'V
yY° OH

naringenin (31) liquiritigenin (32)

(b)

Fig. 12.1. (continued)

Tannins involving (- )-shikimic acid (12), quinic acid
(13), scyllo-quercitol (14), and proto-quercitol (15) (Fig.
12.1) cores are known. Most of the unusual types that have
been studied are from the genus Quercus (oaks) and other
members of the family Fagaceae (Porter, 1989).
Hydrolyzable tannins involving depsides are known from
the Aceraceae, Anacardiaceae, Combretaceae, Ericaceae,
Geraniaceae, Hamamelidaceae and Paeoniaceae (Porter,
1989). The major sources of commercial ellagitannins are
myrabolans, divi-divi, algabobilla, valonea, and the bark of
oak and Spanish chestnut (Haslam, 1981). Unfortunately, few
structures of hydrolyzable tannins other than those from a
small number of economically important plants have been
studied.
Biosynthesis
Although gallic acid has been proposed to arise by 13-
oxidation of C6-C3 compounds such as p-coumaric acid or
the corresponding oxygenated acids, Conn and Swain (1961)
showed that 14C-phenylalanine was incorporated into both
quercetin and myricetin, but not into gallic acid in Geranium
pyrenaicum. However, 14C-glucose significantly labeled
gallic acid. Subsequent studies demonstrated that [14C]shiki-
mic acid was a more efficient precursor of gallic acid than
[14C]phenylalanine in Rhus typhina and in Camellia sinensis
(Dewick and Haslam, 1969; Saijo, 1983). Further, incorpora-
tion of the label did not appear to be specific in feeding
experiments with phenylalanine. Additional supporting evi-
dence for C6C I origin of gallic acid has been obtained by
studies with specific inhibitors for the respective pathways.
The addition of L-2-aminooxy-3-phenylpropionic acid
(AOPP, inhibits PAL activity) to cell suspensions of Quer-
cus rabur (Fagaceae) had no effect, whereas N-(phosphono-
methyl)glycine (glyphosate), which inhibits enzymes rela-
tively late in the skimimic acid pathway, resulted in
accumulation of additional gallic acid (Lewis and Yama-
moto, 1989). Thus, a body of current evidence seems to
196 Tannins

OH

HOllCO,H ,<:::
HO

HO 0 ./ OH
/''-1
1
HO OHHO OH

__"';, ~ .o~oo·'" OH
bexabydroxydipbenic acid (9)

:v~OOOO HO
OH

OH
o
OH OH
corilagin (11) (myrobalans, divi-divi)
OH
an eIlagitannin

Fig. 12.2. Coriiagin, an ellagitannin, gallic acid, hexahydroxydiphenic acid and eUagic acid.

favor gallic acid being formed directly from shikimate (Fig.
12.3). However, in other plants (e.g., Lithospermum), proba-
bly also depending on the stage of development, these com-
pounds may be derived via pheny1alanine-cinnamate
(Gross, 1992).
Enzyme preparations :rom Quercus robur leaves indicate
that the fIrst product is J3-0-g1ucogallin (16). Gallic acid is
activated via the UDP-glucose not the CoA derivative (Gross,
1992; Lewis and Yamamoto, 1989). J3-0-G1ucogallin serves
as both donor and acceptor in the sequential biosynthetic steps
(Fig. 12.4). An enzyme responsible for the formation of 1,6-
digalloylglucose also was isolated from this source (Gross,
1992), an enzyme for the formation of 1,2,6-trigalloylglucose
from Rhus typhina, and another for the formation of 1,2,3,6-
tetragal10ylglucose, followed by another enzyme that forms
1,2,3,4,6-pentagalloylglucose (Gross, 1992).
The hexahydroxydiphenyl group of ellagitannins appears
to arise by coupling of galloyl units in gallotannins. Indeed,
two galloyl units in gallotannins of Liquidambar formosana
seem to be replaced by a hexahydroxydiphenyl group later
in the growing season (Okuda et al., 1989b). Liquidambin
(17) (Fig. 12.5), a compound with an aldehydic function, is
possibly an intermediate in the synthesis of C-glucosidic
ellagitannins (Okuda et al., 1989b).
Other tannins of this type (Fig. 12.6) contain modifIed
acids such as chebulagic acid (18) and peduncu1agin (19), and
the brevilagins I (20) and 2 (21) which are normally consid-
ered ellagitannins (Haslam, 1979). When the galloyl groups
are in the diaxial position, radical coupling can occur to pro-
duce compounds such as chebulinic acid (22) (Fig. 12.7).
Some plants produce simple esters of gallic acid and glu-
cose (Fig. 12.8). Others make J3-penta-O-gal10yl-o-glucose
(8), a "biosynthetic watershed" from which three broad and
distinctive pathways diverge. One pathway (a) leads to the
gallotannins, by the addition of further gallic acid molecules
linked as meta-depsides (complex esters with gallic acid)

HOllCO'H
HO
1'<:::
0

OH OH

n
dehydroshikimic acid (7) gallic acid (1)

Fig. 12.3. Biogenesis of gallic acid.

 Tannins 197

OH OG

~
) P'Q.gluC'ogallin~) p·O-gluC'ogallin
HO IIHO II
OG OG
HO OH HO OH
H H
p-O-glurogallin (16)
OG

~
P-O-glucogallin
HO •
OG
GO OG
H

o
G~OG
0
H,'<::::
Oif
OG G=galloyl
GO OG HO ~
H
OH
p-penta-O-galloyl-D-g1ucose (8)

Fig. 12.4. Biosynthesis of j3-pentagalIoylglucose (Gross, 1989; modified and used with permission of the copyright owner, the American Chemical
Society, Copyright 1989).

(Fig. 12.8). Two further pathways (b) and (c) diverge to
ellagitannins by oxidative coupling of appropriately dis-
posed galloyl groups (Fig. 12.8). Enzyme extracts of Rhus
typhina leaves catalyze the galloylation of 1,2,3,4,6-penta-
galloylglucose, yielding a mixture of numerous hexa-,
hepta-, octa-, and nonagalloylglucoses (Gross, 1992).
~-GlucogalIin is the principal source of galloyl units.
Compounds belonging to the fIrst of these ellagitannin-
forming groups (pathway b) involve relatively simple link-
age of the galloyl groups attached to a sugar nucleus (Fig.
12.9). Hydrolyzable tannins, such as telemagrandin II, eu-
HO
geniin, telemagrandin I (23), casuarictin (24), pedunculagin
(19), and potentillin (25), arise in this manner.
Io a relatively small group of plants, more complex oxida-
tive coupling occurs via pathway (c) to produce distinctive
metabolites such as those found in some Geranium, Euphor-
bia, andAcer species (Fig. 12.10) (Haslam and Lilley, 1986).
Geraniin (26), widespread in plants, is one of these (Porter,
1989).
Distribution of Hydrolyzable Tannins
Hydrolyzable tannins occur in a series of relatively ad-
vanced families mostly in the Rosales and Myrta1es (Bate-
Smith, 1984; Dahlgren et aI., 1981; Haddock et aI., 1982a,

o oJ
1982b, 1982c). Among these families are the Aceraceae, Ana-
cardiaceae, Betulaceae, Casuarinaceae, Cercidiphyllaceae,
Cistaceae, Clusiaceae, Combretaceae, Coriariaceae, Coma-
ceae, Cunoniaceae, Dilleniaceae, Dipterocarpaceae, Drosera-
o 0 0/ ~-OH

O~CHO
ceae, Ebenaceae, Ericaceae, Euphorbiaceae, Fabaceae (Cae-
HO salpiniodeae), Fagaceae, Fouquieraceae, Geraniaceae,
OH
Guoneraceae, Haloragaceae, Hamamelidaceae, Juglanda-
o 0
ceae, Lecithydaceae, Loranthaceae, Lythraceae, Melastoma-
taceae, Myricaceae, Myrtaceae, Nympheaceae, Nyssaceae,
Onagraceae, Plumbaginaceae, Polygonaceae, Rbizophora-
ceae, Rosaceae, Santaiaceae, Simaroubaceae, and Theaceae
OH (Bate-Smith, 1984). The distribution of complex ellagitan-
HO
OH nins also is restricted (Haslam, 1986). Wolter-Filho et aI.
(1989) have used the presence of ellagitannins in Rhabdoden-
dron (Rbabdodendraceae) species to argue for placement of
liquidambin (17)
this enigmatic family in the Rosiflorae or Myrtiflorae and not
FIg. 12.5_ Liquidambin. in the Caryophyllales or Rutales, as others have argued.
198 Tannins

OH

HO~O ~ I peduncuJagin (19)

HO
HO
OO~
0
I~
~ 0
00 0 00
HO 0

HO OH
OH OH

HO~"H""~"
HO ~ I O~O
o
0J-QoH
Ii OH
o 2 0 ~

HO){O "~k""OH'
HOVo - orO: OH
HO ~ /,
"H
OH
tannic acid, Chinese gallotannin 0 ~ /;
OH 0
n =0,1, 2; C-I galloyl group may be absent OU
(a)

0
0
0
0

0 0

OH OH

OH
OH OH

(b) brevilagin I (20) brevilagin 2 (21)

Fig. 12.6 (a-c). Some representative hydrolyzable tannins.

PKOAl'ITHOCYAl'IIDIl'IS OK COl'lDEl'ISED between flavonoid units, hydroxyation patterns, stereochem-

TAl'Il'IIl'IS
Proanthocyanidins are widely distributed, but are particu-
larly common in conifers. The structures are based on oligo-
meric flavonoid precursors and vary in the type of linkages
istry of carbons 2, 3, and 4 of the pyran ring, and the presence
of additional substituents (such as gallic acid) (Lewis and
Yamamoto, 1989). More than 100 proanthocyanidins with
subtle, but well-defined, structural variations have been iso-
lated and characterized. Most interflavonoid linkages occur
 Tannins 199

HO

o
~
H

o '"
\ h OH
OH

o
cbebulagic acid (18)

Ho,e

o
(e)

Fig. 12.6. (continued)

RO

OR RO
N~
R.O~O
RO~
" , - : : ; - H ROR
ORYOR H
o - o 0 0

OR OR
(3·pentagalloylglucose (8)

HO OH
RO

N~ terchebin

o 0 0 OH
HO
eo,H

HO
OH OH
chebulinic acid (22) OH
(9) ~
OH
eO,H HO

eO,H

HO HO~ OH

OH OH
HOY ellagic acid (10)
chebulic acid
OH
R =galloyl

Fig.!2.7. Biogenesis of chebul"lnlC .

aCId (modified f rom Haslam, 1974).
200 Tannins

at C-4, C-6, and C-8, but those at C-2 and C-7 also are
known (Lewis and Yamamoto, 1989). The flavonoid skeleta
can be divided into two broad categories, those containing
either phloroglucinol or resorcinol (5-deoxy) substitution
patterns.
Colorless compounds that yield anthocyanidins upon
heating with acid are called proanthocyanidins. Compounds
that yield cyanidin are called procyanidins and so forth.
Monomeric proanthocyanidins are often referred to as leu-
coanthocyaninidins, but the term leucoanthocyaninidin
sometimes has been used ambiguously in the literature. Most
important in this group of compounds are flavan-3,4-diols
and flavan-4-0Is.
Condensed tannins arise from monomeric flavan-3-01
(catechins) and flavan-3,4-diol units.
F1avan·3.4·diols
The presence of monomeric proanthocyanidins or flavan-
3,4-diols in plants has long been known. In hot acid, almost
all flavan-3,4-diols are converted to the corresponding an-
thocyanidin. The first structure determined for a member of
this class of compounds was that of melacacidin (27) from
Acacia melanoxylon (Fig. 12.11). Flavan-3,4-diols do not
possess an affinity for collagen substrates and, hence, lack
tanning properties. Some flavan-3,4-diols are modified to
other cyclic systems. The mopanols (such as 28) and pelto-
gynols (such as 29) are representatives of this sort of modifi-
cation (Fig. 12.11).
The reduction of 3-hydroxyflavones (dihydroflavanols)
to 3,4-diols (Ieucoanthocyanidins) was first demonstrated in
cell-free extracts of Pseudotsuga menziesii and Ginkgo bi-
loba, by the reduction of ( + )-dihydroquercetin with dihy-
droflavonol 4-reductase in the presence of NADPH to a 2,3-
trans-3,4-cis-diol which differs from the product of nonen-
zymatic reduction, 2,3-trans-3,4-trans-diol (2R,3S,4R)-
(+ )-3,4,5,7,3',4'-hexahydroxyflavan (Fig. 11.15 of Chapter
11). This result has now been confirmed in several other
plant systems (Heller and Forkmann, 1988; Stafford, 1989).
A similar dihydroquercetin reductase activity has been
shown to be a key step in the biosynthesis of anthocyanidins
(Stafford, 1989). The enzyme from Dahlia has a molecular
weight of about 41,000. However, there is evidence that the
specificity of 3-hydroxyflavanone reductases of anthocy-
anidin biosynthesis are distinct from those of flavan-3,4-diol
biosynthesis (Stafford, 1989) (see Chapter 11).
The conversion of (+ )-dihydromyricetin to the corre-
sponding 3,4-cis-isomer by an NADPH-dependent reductase
has been demonstrated in cell cultures of Ginkgo bi/oba that
accumulate large quantities of prodelphinidins (Stafford,
1989).

OH

gallotannin. O~:: OH

HO~ ~~O, 0 &OH

~ o.,.O.O~O~OH
additiOnOf
HO
;~~O_ 0 zo H 0 &OH
HO

gallic acid HO:\ I. ..... 0 ~OH

as m-depsldes HO OH "I ~O
./ HO 0 -
OR /_, HO \ , OH
.... <
R·O '\~~ ' \
~O
OR
(a) OH HO

R~YH (b) coupling of 4 and 6

olig~:'~l~~on Jr
and/or 2 and 3 gaIloyl groups
OH

H'
ellagitannins OH
oxidative coupling of pedunculagin (19)
vicinal galloyl ester o
OH
groups

OR OR
coupling of 1 and 6,
p-penta-O-galioyl-D-g1ucose (8) 3 and 6 and/or 2 and 4
o ~
HO~=
galIoyl groups
gslloyl geraniin (26)
H O Y R,
OH
OH HO
OH
Fig. 12.8. The overall patterns of metabolism of j)-pentagalloyl-n-glucose in plants.
 Tannins 201

G =galloyl H O i f I ~
HO b
OH OH
OH

G~O,
-G~
OG
HO
H

!
p-penta-O-gaIloyl-D-glucose (8)
G -G = hexabydroxydipbenoyl-
coupling of 4 und 6 galloyl group•

(Y'O~'
'0'
0
GO OG
H
OG
-- ..t'0~' '0 •
GO
0
OG
H
OH

telemagrandin H, eugeniin telemagrandin I (23)

~ coupling of 2 and 3 gaUoyl groups

G 6 G.... 6

G'O~
...... 0
4 1 --+- G,o~
0 4 2

o
\
3
__
G
-0 H
OG
0, __ G-O
G
3

H
OH

pedunculagln (19)
casuarictin (24)

'"
G •
I
G':O~lO
0, __ G-O 3 H

G OG
potentillin (25)

Fig. 12.9. Ellagitannins fonned by simple linkage of galloyl groups (modified from Gupta et aI .• 1982; modified and used with pennission of the
copyright owner, the Royal Society of Chemistry, Cambridge).

F1avan-3-ols pounds give similar color reactions to Ihose produced by

Flavan-3-0Is, often known as calechins (Fig. 11.16 of
Chapter 11), are widely distributed. The most widely distrib-
uled members of this class of compounds are catechin [( + )-
(2R,3S)-calechinj (2,3-trans) (3) and epicatechin [( -)-
(2R,3R)-epicalechinj (2,3-cis) (30) (Fig. 12.1) which usually
occur as free aglycones and nol as glycosides. The known
(2R,3S)-proanthocyanidins are labulated by Porter (1988).
The enantiomeric compounds are ent-calechin [( - )-
(2S,3R)-calechinj (2,3-trans) and ent-epicalechin [( +)-
(2S,3S)-epicalechinj (2,3-cis). Some 2S-flavan-3-0Is are
found free and as gallale eslers in plants (Slafford, 1989).
Tissues that contain flavan-3-0Is oflen contain procyanidin
dimers and trimers (Haslam, 1975). Some flavan-3-01 com-
flavan-3,4-diols and, occasionally, have been calledleucoan-
thocyanins.
Flavan-3-0Is are derived from flavanones, via 3-hydroxy-
flavanones (or dihydroflavonols). Naringenin (31) gives rise
to 5,7-dihydroxyproanthocyanidins, whereas Jiquiritigenin
(32) (Fig. 12.11) appears to be Ihe precursor for 5-deoxy-
proanthocyanidins, both via the intermediacy of flavan-3-
ols and the same basic pathway as in Fig. 11.16 (Heller
and Forkmann, 1988; Lewis and Yamamolo, 1989; Stafford,
1989).
The conversion of flavan-3,4-diols 10 flavan-3-0Is and to
their oligomeric proanthocyanidin forms is the beginning of
the palhway unique 10 the biosynthesis of these secondary
products (Stafford, 1989). Two basic types of hydroxylases
202 Tannins

::x;T'
o

R=
OH
R_R=
HO~QO
t~ 0
H:R-o l o
HO OH OH

HO~O
-
'" OH
I""
"1
O"'OHOR OR
R-R = HO ~ I - OH davidiin
aU' Davidia involucrata
f
'd
~0 g :.:;:cose 1 to 6 gaUoyl coupling

R
\
+
OR 0
"""""'- <OR --,0 /(c)
jI HO
~O, (a) RO\~OR
~R~OR - RO ORH
R H
Rhus, Acer, Pe/argonium speci.. (b) p-penta-O-galloyl-D-glucose (8)

+(b)
4 to 6 gaUoyl COUPling"/
/0--....J'r
' 0
.~~~OR /~o-l
o 0 6~0'1/
OH 0 0 0 OR' R
H090H 0 0 OH
1 '"
~ 0
'" 1 OH" 1
:-... -HO':-'" OH
O~OH'
I ~ vescalagin
o OIi:OH HO OH""
o
~ OH 0 0

Z
• OH
.. 0 OH 4to6and2to3 ~O O ...... R
OR _ _ it gaUoyl coupling 0 1
rugosin D (51) sanguin H·6 0 'R HO HO OH
Rosa sp., FiUpendula ulnwria Rubus, Geum and OR _ _ ~ OH OH
Poumtilla species Quercus species

Fig. 12.10. More complex ellagitannins (Haslam and Lilley, 1986; modified and used with pennission of the copyright owner, Akademiai IGado,
Budapest).

are involved in the synthesis of 2,3-trans-flavan-3-ols_ One
is a microsomal cytochrome P-450 monooxygenase requir-
ing oxygen and NADPH for 3' and 5' hydroxylations of the
B ring_ The soluble 3-hydroxylase from Petunia has been
purified and has a molecular weight of 74,000_ In addition,
a "soluble" cytosolic dioxygenase that requires Oz, 2-oxog-
lutarate, Fez+, and ascorbate is involved in stereospecific
insertion of oxygen at C-3 to produce the common 2,3-trans-
isomer (2R,3R) of 3-hydroxyflavanones (Stafford, 1989).
The NADPH-dependent reduction of the 2,3-trans-3,4-cis-
diol with a dihydroxy B ring to the flavan-3-01, ( + )-catechin
(3), was first shown in soluble extracts of Douglas fir cell
cultures. The comparable reduction to (+ )-gallocatechin
(33) from the corresponding 3,4-diol produced by dihydro-
myricetin reductase activity was demonstrated with a soluble
enzyme requiring NADPH in extracts of Ginkgo hi/aha
(Stafford, 1989).
The pathways to 2,3-cis-flavan-3-0Is, such as (- )-epica-

HO
OH
~ OR

HO
~I OH yOH
HO I
~
OH
H0'O(X0
I OH

OH ~ , 0
! OH
melacaddin (27) OH
• peltogynol (29)
a mopanol (28)

Fig. 12.ll. Melacacidin, a flavan~3.4-diol. and related compounds.


techin (30) (Fig. 11.1) and epigallocatechin (34) are not well
known (Stafford, 19X9).
I'rocyanidin Dimers
In addition to monomeric flavan-3-0Is and flavan-3,4-
diols, many plants contain mixtures of dimeric procyanidins
such as (35-38) (Fig. 12.12). Procyanidins are common in
fruit, fruit pods, seed, and shells, either as their peracetates
or as the free phenolic forms.
The structures of procyanidins 35-38 were assigned on
a basis of lH-NMR spectra of the decaacetates. The absolute
stereochemistry has been determined as (4S) for compounds
(38) and (36) and (4R) for compounds (37) and (35). Mix-
tures of these particular dimers have not been found, but
other dimers and trimers have been detected with them
(Hillis, 1985; Porter, 1988). 13C_NMR spectra are especially
useful for analyses of these compounds because a pro-
nounced 'Y effect ( - 4.5 ppm) is observed and the chemical
shift of C-2 is dependent on the orientation of the substituent
at C-4 of the flavan system. All major natural procyanidin
dimers possess a trans-orientation of the hydroxyl group at
BO
OR
procyanidin B~2 (35)
apple, hawthorn, cocoa bean,
Cotoneaster, quince, cherry,
horse chestnut
BO
OR
OR
epjcatechjn·(4~ ..... 8)·catechjn (B.l) (37)
grape, sorghum, cranberry,
pine cones
Fig. 12.12. Common dimeric proantbocyanidins (modified from Haslam, 1981; used with pennission of the copyright owner, Academic Press, New
York).
Ttl/millS 203
C-3 and the flavan substituent at C-4 in the "upper" flavan
unit (Hillis, 1985 J.
A number of anomalous features in NMR spectra are
observed because rotation around the interflavan bond is
hindered. in most cases, one preferred conformation proba-
bly exists, but the energy barriers are not sufficient to permit
isolation of the different conformational forms of proantho-
cyanidins.
incorporation of labeled phenylalanine and cinnamic acid
into dimeric proanthocyanidins occurs asymmetrically, with
differences in the amount of precursors incorporated into the
two portions of the molecule (Stafford, 1989). Further, the
pool of free flavan-3-01 monomers including ( + )-catechin
(3) and ( - )-epicatechin (30) contained much higher levels
of radioactive label than the comparable initiating (or termi-
nating) unit. Tritium label at the C-2 position is retained,
whereas that at the C-3 position is lost in the dimers (Staf-
ford, 1989).
The proton H. at C-2 and C-2' is retained in both flavan
units of the dimers. Proton He from the cinnamic acid precur-
sor is lost. Differential labeling is observed in the "upper"
and "lower" part of the dimers. When cinnamic acid labeled
OR
BO
OR
OR
enl·epicatec:hin·(4~ ~8)·ent·catechin (36)
raspberry, blackberry
procyanidin D·3 (38)
willow and poplar catkins,
strawberry, rose hips, hops
204 Tannins

R R

HO HO

OH 0
3-andS-

!
OH,3-0H
"upper" extension unit
NADPH R
OH HO

HO quinone methide
R
or carbocation intermediates
OH
NADPH
n=Ot08
or more
3,4-cis·diol OH
reductases
OH R
"lower" initiating unit
HO
R HO

oligomers
OH
navan-3-ols
Fig. 12.13. Proposed biosynthesis of procyanidin oligomers.

in the benzyl carbon is fed to plants, and the catechin and
procyanidin dimers produced are isolated, the label is found
in C-2 of the catechin and in the corresponding positions of
both portions of the dimeric compounds (Fig. 12.13) (Has-
lam, 1981; Porter, 1988). It is known that the oligomeric
forms of proanthocyanidins are synthesized by the sequential
addition of an intermediate derived from the flavan-3,4-diols
to a preexisting chain or to a flavan-3-01 that initiates (or
terminates) a chain, rather than being self-condensation
products of the diols. Although the condensation step can
be done nonenzymatically in so-called biomimetic synthe-
ses, the presence of enzymes is probable. A model for en-
zymic control of synthesis of these compounds has been
proposed (Stafford, 1989).
If the supply of NADPH is rate limiting, intermediate
C-4 carbocations with either (2S)- or (ZR)-stereochemistry
could react with either ( + )-catechin (3) or ( - )-epicatechin
(30) (Fig. 12.1) to produce dimers or oligomers of procyanid-
ins. The nucleophilic character at C-6 or C-8 can be used
with either cation. The reactions would be regulated by the
stability of the cations arising from flavan-3,4-diols. Further-
more, substitution occurs more readily at C-8 than at C-6.
Substitution at nucleophilic centers is highly sensitive to ste-
ric factors and reactions occur preferenially at the least hind-
ered sites (Hillis, 1985).
A number of aspects of the biomimetic synthesis of di-
mers and trimers based on flavan-3,4-diols and flavan-3-0Is
have been reviewed (Roux and Ferreira, 1982). This analysis
includes stereochemical and NMR analysis of the products,
most of which also occur in nature. It is evident that in
vivo condensations follow the path of least resistance, being
regulated by the stability of the carbocation arising from the
flavan-3,4-diol, by steric factors contributed by both elec-
trophile and nUcleophile, 2,3-trans or 2,3-cis-stereochemis-
try of the electrophile, and the relative concentrations of the
reactants (Roux and Ferreira, 1982).
Treatment of procyanidin dimers with acid gives the ap-
propriate catechin unit corresponding to the lower half of
the molecule and a carbocation that normally collapses to
cyanidin (an anthocyanidin) under the reaction conditions.
Condel1!iled Units Derived from
Proanthocyanldin Units
Most of the tannins important in the leather industry today
are condensed tannins. Tannins from quebracho (Schinopsis
lorentzii, S. balansae), gambier (Uncaria gambier), cutch
(Acacia catechu), mangrove (Rhizophora mangle), myrtan
(Eucalyptus spp.), and wattle (Acacia meamsii) are all of
the condensed tannin type. Tannins from quebracho primar-
ily are (2S)-profisetinidins (39) (Fig. 12.14), whereas those
of wattle are (ZR)-profisetinidins (Hemingway, 1989). Of
these, the tannins of wattle have been the most studied. Most
of the proanthocyanidins isolated from plants have ZR abso-
lute-stereochemistry (Hemingway, 1989). Major exceptions
are the proanthocyanidins of monocotyledonous plants, and
 Tannins 205

~OH

Q ".",'V
HO
HO
OH

OH
HO
y¥01-""""'"I
~
(foH
HO OH

o
, OH
HO'
Y¥l 0 1"".,,""'-' ' '
v
I
V00H ~OH HO
a proguibourtinidin (40)

H°Yy°1"",J,J
~ OH YOH
OH
a profisetinidin (39)

(XI oH
HO

'(XXI

"Ow""
HO 0 "..-,,''''-.
"'-. OH
OH

OH OH

a prorobinetinidin (41)

(a) a promelacacidin (42)

HO
.)-y0H

HO
"""V
OH

o
HO""'"

~OH
o
a procyanidin (43)

a prodelphinidin (44)

(b) OH
Fig. 12.14 (a & b). Selected proanthocyan'd'
1 InS.
206 Tannins

those of Uncaria, Polygonum, Rhapheolepis, Rhus, and que- f"'y0H

bracho (Schinopsis). 5-Deoxyproanthocyanidins mostly are OH o
based on the proguibourtinidin (40), profisetinidin (39), pro- ~
HO "'~OH
robinetinidin (41), and promelacacidin (42) skeleta and have H°Yy°'(~OH OH
2,3-trans-stereochemistry in the chain extender units. Most ~OH OH
OH
plants, other than those of the Fabaceae and Anacardiaceae,
contain 2,3-cis-(2R,3R)-procyanidins (Hemingway, 1989). mollisacacidin (45)

The vast majority of tannins in the procyanidin (43) and

~
HO ....·
prodelphinidin (44) classes are of mixed stereochemistry
with 2,3-cis- to 2,3-trans-ratios between 90: 10 and 50: SO.
Almost all natural and synthetic 2,3-cis-proanthocyanidins
HO~Oy.OOH
OH
A
VOH

have 3,4-trans-stereochemistry. In procyanidins and prodel- ~OH HO

O
phinidins, C-4 to C-8 and C-4 to C-6 linkages (in a ratio of both 4R and 4S
OH
about 3 : 1) are the most common. All known polymers of this "I
type are of the "linear" type. Linkages involving oxygen are HOYjfOi·""-'::-'" OH

rare. The terminal units of most natural proanthocyanidins
contain flavan-3-01s (Hemingway, 1989).
In almost all tissues that contain proanthocyanidin di-
mers, oligomers and higher polymers also exist. Polymers
up to about 7000 MW usually are soluble, whereas higher-
molecular-weight compounds will not dissolve. Polymers
with molecular weights as high as 20,000 are thought to
occur. It has been suggested that procyanidins are covalently
bound to a saccharide matrix within plant cells (Haslam and
Lilley, 1985). Polymeric forms predominate over the soluble
forms by 10: 1 or 20: 1 (Haslam and Lilley, 1985).
Many structural types occur; these have been reviewed.
Most are based on hydroxylation variations in the starter
and extender units. In addition, there are variations in 0-
methylation, C - and O-glycosylation, and O-galloylation
(Hemingway, 1989).
Elaboration of oligomeric forms of procyanidins by the
addition of flavan-3-ol units based on (- )-epicatechin (30)
or ( + )-catechin (3) leads to formation of two different heli-
cal structures. Those based on ( - )-epicatechin (procyanid-
ins 35 and 37) produce a left-handed helix, whereas those
based on (+ )-catechin (procyanidin 38) form right-handed
helices.
Other proanthocyanidins involve flavans as one of the
condensing units (Porter, 1988).
Roux and his collaborators have isolated a group of profi-
setinidins from the wood of Acacia mearnsii. These com-
pounds were accompanied by their apparent precursor 2,3-
trans-3,4-( + )-mollisacacidin (45) (fisetinidol-4u-ol) (a fla-
van-3,4-diol). Furthermore, these workers were able to con-
dense ( + )-mollisacacidin (45) and ( + )-catechin (3) to give
good yields of procyanidins that are naturally occurring in
black wattle or "mimosa extract" from Acacia mearnsii.
These observations support the view that flavan-3,4-diols
(via their derived 4-carbocations) and flavan-3-01s condense
to form proanthocyanidins in the wood and bark of many
trees (Fig. 12.15) (Haslam, 1982).
Proanthocyanidins are those compounds that produce an-
thocyanidins on hydrolysis. As previously observed, mono-
meric proanthocyanidins (leucoanthocyanidins) do not pos-
sess an affinity for collagen substrates and lack tanning
N
o:;
~OH ~OH
H°Ylr°'l. . "~OH OH
VV'OH "I
OH
HO ,
o
(+)-catechin (3)
f)
VOH
OH
Fig. 12.15. Biogenesis of wattle condensed tannins (modified from
Haslam. 1981; used with pennission of the copyright owner, Academic
Press. Orlando, FL).
properties. Condensed proanthocyanidins, however, do pos-
sess these properties. Dimers, trimers, tetramers, and other
oligomers are capable of precipitating proteins. When tan-
nins are consumed by man (and presumably other organ-
isms), they often have astringent properties. This property
is caused by the cross-linkage of proteins and glycoproteins
and a corresponding loss of lubrication in the mouth and
throat. Maximum tanning and astringency occur with con-
densed proanthocyanidins with a molecular weight range of
500-2000 (3000). Proanthocyanidins are common in fruits,
fruit pods, seeds, and shells, either as peracetates or in free
phenolic forms. The loss of astringency that occurs during
the ripening of fruit may be a reflection of the increased
degree of polymerization and, hence, molecular size of the
associated tannins (Hagerman and Butler, 1989).
Although tannins are extracted in many types of solvents,
methanol-water and acetone-water mixtures are often em-
ployed (Hagerman, 1988). Hot water is usually used for com-
mercial extraction. For many laboratory procedures, 70%
acetone-water is an excellent solvent, although condensed
tannins are less stable in this solvent than in aqueous metha-
nol (Cork and Krockenberger, 1991; Hagerman and Butler,
1991). Procedures for extraction of tannins from fresh and
preserved leaves have been reviewed recently (Cork and
Krockenberger, 1991; Hagerman, 1988). Ellagitannins are
less soluble than other types and are hard to extract from
tissues (Hagerman and Butler, 1991). Condensed tannins are
sensitive to both temperature and light during extraction pro-

cedures. The plant tissue should be preextracted with a lipo-
philic solvent to remove lipids and chlorophyll (Porter,
1989). The yield of tannins can be increased 30-75% by the
addition of antioxidants such as ascorbic acid or sodium
metabisulfite to 50% aqueous methanol solvents (peng and
Jay-Allemand, 1991). Differences in tannin assays can be
due to differences in tannin extractibility as well as to dif-
fences in the amount of taunin present (Hagennan and But-
ler, 1991).
BIOLOmCAL ACTIVITV OF TANNII'IS
In tenns of function, condensed taunins apparently act
mainly against the action of microbes, whereas hydrolyzable
tannins defend primarily against chewing phytophagous in-
sects or animals (Lewis and Yamamoto, 1989). Because tan-
nins bind salivary proteins, most tannins are astringent to
mammals. Many insects, as well as other animals, avoid
plants rich in tannins. On the other hand, tannins may also
serve as phagostimulants and feeding cues (Schultz, 1989).
Tannins playa central role in the fonnation of soil humus
in the development of soil profiles by producing complexes
with proteins and carbohydrates that are resistant to micro-
bial decay (Ya et aI., 1989).
Although many of the properties of taunins are linked to
their ability to bind proteins, this role has been over empha-
sized (Hagennan and Butler, 1991), and individual tannin
molecules may exhibit more specific biological activity
(Zucker, 1983). Many taunins are toxic to animals (Hag-
ennan and Butler, 1991). This activity may be due to several
effects such as binding to biologically active molecules (pro-
teins, carbohydrates, and nucleic acids) or complexation of
nutrients or cofactors required for growth of the animal (Has-
lam, 1989; Haslam et al., 1989; Okuda et aI., 1989b; Spencer
et al., 1988; Zucker, 1983). Only recently, have scientists
begun to view the general properties of the collective taunin
mixtures independently of the biological activity of specific
tannin molecules produced by a plant (Okuda et al., 1989b).
Binding of Tannins to Protein
Tannins (as discussed above) are a heterogeneous group
of compounds that vary widely in physical and chemical
properties. Many enzymes, such as (3-glucosidases, are deac-
tivated by the addition of tannins, but others are unaffected.
Depending on a number of factors, these tannin-protein
complexes may precipitate or remain in solution. Both solu-
ble and insoluble complexes are stabilized by reversible,
noncovalent bonds between protein and taunin. Although
few studies have been catried out with single, purified tan-
nins and single, purified proteins, it is clear that the ability
of tannins to precipitate proteins varies widely (Blytt et aI.,
1988; Hagennan, 1989, Harbome, 1989; Mole and Water-
man, 1987c). The ability of a particular tannin to complex
proteins depends on the molecular size and shape, relative
number and orientation of hydroxyl groups, structure, solu-
Tannins 207
bility, and ease of oxidation of the tannin. Generally, proteins
are precipitated most readily by proanthocyanidins at pH
values near the isoelectric point of the protein. Proline-rich
proteins bave a very high affirtity for tannins. Tightly coiled
globular proteins have lower affinities than confonnationally
loose proteins (Hagennan, 1989; Hagennan and Butler,
1981; Mole and Watennan, 1987c). Less attention has been
paid to protein precipitation by hydrolyzable tannins, but
binding to protein is, in part, a function of molecular size.
In the galloyl D-glucose series, association with protein is
enhanced by the addition of each galloyl group and reaches
a maximum in the flexible disk-like structure of (3-penta-O-
galloyl-D-glucose (7) (Haslam and Lilley, 1985; Spencer et
al., 1988). Confonnational mobility and flexibility is as sig-
nificant as molecular size. When vicinal galloyl groups are
constrained by the fonnation of intramolecular biphenyl
linkages and the generation of hexahydroxydiphenoyl
groups, the loss of confonnational freedom is reflected in a
reduced capacity to bind to protein (Haslam and Lilley,
1985; Spencer et al., 1988). The effects of water of solvation
are also important (Haslam et al., 1989).
Tannins in the Diets of Animals
In instances when tannins are consumed in the diet, it
has been postulated that reduction in fituess occurs because
taunins bind to proteins and make the prorein less available
to the animal. Plant proteins are the ultimate source of almost
all dietary amino acids for herbivores, carnivores, and detri-
tus-feeding animals; any factors that reduce the levels of
these nutritive compounds would be predicted to have dra-
matic effects on the whole ecosystem. In excess, taunins
should reduce the effectiveness of the digestive process in
the animals's gut by inhibiting digestive enzymes. These
factors have lead some to suggest that tannins may serve as
all-purpose, dose-dependent, digestibility-reducing defen-
sive substances. In practice, none of these has been conclu-
sively demonstrated (Mole and Watennan, 1987a).
When tannins (either hydrolyzable or condensed types)
are added to artificial diets, the fitness and growth rate of
animals (especially mammals) eating these diets is usually
reduced (Mole and Watennan, 1987a; Schultz, 1989). The
percentage of tannins in plant materials often is in the range
5-10%, but can be much greater. The rejection limit of most
vertebrates is about 0.05% for hydrolyzable tannins. Many
animals refuse to eat diets containing sizable quantities of
tannins.
Tannins from deciduous browse stems for mule deer
(Odocoileus hemionus), white-tailed deer (0. virginianus),
moose (Alces alees), carboulreindeer (Rangifer tarandus),
and elk (Cervus elephus) did not lower protein availability,
but taunins from flowers, forbs, and tree and shrub leaves
did. Tannins must be taken into account in understanding
the defensive strategies of flowers and leaves (Robins et al.,
1987). Furthennore, lesions are found in the gut of animals
that nonnally do not consume taunins in quantity, whereas
they are absent from animals that do. For example, Papilio
208 Tannins
polyxenes (which feeds on herbs of the family Apiaceae)
develops lesions and Papilio glaucus (which eats tanninifer-
ous trees of several families) does not develop lesions when
tannins are included in artificial diets fed to the animals
(Steinly and Berenbaum, 1985). Usually, hydrolyzable tan-
nins are responsible for gut lesions in insects (Schultz, 1989).
In contrast, many coadapted animals have the ability to
eat plants containing large amounts of tannins. Some of these
animals even require tannins in the diet (Bernays and Wood-
head, 1982; Harborne, 1986; Schultz, 1989). Tannic acid,
gallic acid, and certain 3,4'-dihydroxyphenols were shown
to increase the growth rate of Anacridium melanorhodon
(Acrididae) when added to a diet deficient in them. These
phenols appear to replace phenylalanine in the production
of cuticular tanning agents (Bernays et al., 1983). Other ani-
mals, especially mammals, produce saliva with large num-
bers of proline residues which bind to tannins and presum-
ably prevent them from binding other proteinaceous
materials (Austin et ai., 1989; Hagerman and Butler, 1989;
1991; Mehansho et al., 1983). The affmity and specificity
of binding is associated with the presence of oligosaccharide
moieties in these proteins. The sugar portion (up to 40%) also
increases the solubility of the resulting tannin-carbohydrate
complex (Harborne, 1989).
Although there is an increase in excreted nitrogen when
tannins are added to the diet of animals, this is probably
associated with a reduction in the utilization of digested and
absorbed nutrients, rather than availability of protein (Hag-
erman and Butler, 1991). Further, some components of con-
densed tannin appear to be absorbed and produce systemic
effects (Hagerman and Butler, 1989). In any case, binding
of many digestive enzymes, such as trypsin, is lower than
that for many other proteins. Also, formation of tannin-pro-
tein complexes often does prevent utilization of the protein
in animal digestive systems. With concentrations of tannins
and proteins and pH conditions that might be expected to
occur in insect herbivores and approaching those of the small
intestine of mammals, soluble tannin-protein products are
formed (Hagerman and Robbins, 1987; Mole and Waterman,
1985, 1987a). Additionally, some enzymes are still active,
even though they are complexed with tannins (Mole and
Waterman, 1987a). The addition of the bile constituents cho-
lic acid and glycocholate dissolves many tannin- protein
complexes at pH 6.2. The addition of cholic acid substan-
tially diminishes the inhibitory effect of tannins on the tryptic
proteolysis of several proteins (Mole and Waterman, 1985),
1987a). Although the digestive enzymes, alkaline phospha-
tase and 5'-nucleotide phosphodiesterase, are strongly inhib-
ited by condensed tannins from sorghum seeds and quebra-
cho, this inhibition was reversed by the addition of
detergents, soluble polyvinylpyrrolidone, or by phophatidyl-
choline (a membrane component) (Blytt et al., 1988).
Tannic acid and quebracho precipitate many times their
weight of ribulose-1 ,5-bisphosphate carboxylase (RuBPC),
the most abundant protein in most plant leaf tissues. At
mildly alkaline pH, RuBPC is not precipitated by tannins,
despite the fact that there is sufficient tannin in leaves of
some oak species to fully precipitate all RuBPC present
(Martin and Martin, 1982, 1983). Further, the rate of hydrol-
ysis of ribulose-1,5-bisphosphate carboxylase (RuBPC) in
enzymatically active gut fluid of Manduca sexta larvae is
very rapid and is unchanged by addition of tannic acid (Mar-
tin et al., 1987).
Purified samples of tannins from bitterbrush (Purshia tri-
dentata) and blackbrush (Coleogyne ramosissima) (both
Rosaceae) differ in the acceptability to snowshoe hares
(Lepus americanus). The two series of tannins differ in their
overall stereochemistry at C-3 and C-4. Because the tannins
were highly purified, these differences in stereochemistry of
the condensed tannins themselves must be important in these
preferences (Clausen et al., 1990; Zucker, 1983).
Geraniin (26) (Fig. 12.10), a hydrolyzable tannin from
the leaves of Geranium species, releases ellagic acid on hy-
drolysis. Ellagic acid (10) is an antinutritional factor because
of its ability to bind essential metals (Harborne, 1989).
Tannins also have been reported to bind to carbohydrates,
and, in contrast to binding with proteins, this binding is rela-
tively pH independent. Molecular size, flexibility, and water
solubility are important factors. In instances when the poly-
saccharide can sequester the hydrophilic aryl residues of the
polyphenol (such as in holes in a crystal lattice or in hydro-
phobic cavities), complexation is substantially enhanced
(Bilgener, 1988; Hagerman, 1989; Haslam and Lilley, 1985;
Spencer et ai., 1988; Ya et al., 1989). This binding can be
strong; for example, the hydrolyzable tannins rugosin D (51)
(Fig. 12.10) and sanguin H-6 bind tightly to Sephadex G-
25 and G-50 [a n-(l,6)-linked polymeric glucan (90-95%)]
and do not desorb from those materials (Haslam et al., 1989;
Spencer et al., 1988; Ya et al., 1989). The nature of binding
of tannins to plant carbohydrates has yet to be ascertained.
The Cost of Tannin Defenses and Resource
Allocation
Calculations by Lewis and Yamamoto (1989) indicate
that the cost of production of tannins, lignins, and lipids are
among the highest for any plant-produced compounds. The
actual cost of lipids is less than calculated because these
energy-reserve compounds are recycled within the piant, but
tannins and lignins represent a uuidirectional flow of energy.
The cost of condensed tannins is almost double that of hydro-
Iyzable tannins, if one assumes no reutilization of the latter
by the plant (Lewis and Yamamoto, 1989). The cost for
proanthocyanidins and lignin is similar to that of protein.
Synthesis of proanthocyanidins and lignin require major
commitments to the synthesis of phenylalanine, the second
most expensive amino acid (after tryptophan). Further, be-
cause large quantities of proanthocyanidins and lignin are
deposited in plant tissues, the products of the phenylala-
uine-cinnamic acid pathway serve as a major sink for assim-
ilated carbon. Because of the importance of these processes,
most vascular plants have high phenylalanine requirements.
One can argue that a ml\ior function of activation of the

phenylalanine-cinnamic acid pathway is to provide nitrogen
for other metabolic processes (Lewis and Yamamoto, 1989).
When plants are grown under limited nitrogen supply, they
often respond by increased synthesis of phenolic com-
pounds, many of which are based on phenylalanine precur-
sors. In this way (via dearnination of phenylalanine), optimal
use of plant nitrogen is made (Lewis and Yamamoto, 1989).
Several theories relating the cost of plant defensive com-
pounds, availability of nutrients, and resource allocation
have been proposed. A correlation of the type of defensive
compounds present and "apparency" or "nonapparency"
to plant herbivores was noted by both Feeny (1976) and
Rhoades and Cates (1976). Feeny considered two fundamen-
tally different types of chemical defenses in plants. He con-
sidered tannins, which represented the major chemical de-
fense of mature oak leaves, present in large amounts (up to
5% dry weight or more), to belong to a "quantitative" type
of defense and suggested that the potential for counteradap-
tation by insects is limited (Feeny, 1976). He considered
low-molecular-weight compounds, such as glucosinolates,
to act as "qualitative" barriers to herbivory and to be sus-
ceptible to rapid detoxication by coadapted insects. Further,
he considered plants that produce the latter type to be ephem-
eral, characteristic of early stages of community succession
and likely to be hard to find by their adapted enemies, relying
primarily on escape in time and space. Oaks, in contrast, are
climax forest dominants and are "bound to be found" by
their enemies. In such plants, allocation of energy and nu-
trients required for quantitative defense would be likely to
bring increases in fitness. At almost the same time, Rhoades
and Cates (1976) proposed that tissue availability and pre-
dictability were major determinants of the type of defensive
compound used by the plant. They suggested that more toxic
substances were associated with ephemeral tissues and di-
gestibility reducing compounds were characteristic of pre-
dictable tissues. However, in terms of cost to the plant, most
compounds are actively turned over. This process requires
energy. Condensed tannins tum over very slowly, if at all,
and the relative metabolic cost for making them may com-
pare favorably to that of synthesizing compounds involved
in active turnover (Swain, 1979). Further, many predictable
plants contain qualitative or toxin-type defenses and a large
number contain tannins in addition to other defenses, such
as alkaloids.
After determining that herbivory and defense of tropical
plants in Panama were not correlated with apparency, Coley
(1987) observed that slow-growing plants invest more heav-
ily in defense because herbivory of a given amount would
represent a proportionately greater loss than for rapidly
growing plants. In general, growth rates of plants have
evolved in response to resource availability of the habitat.
The limiting resource may be light, water, nitrogen, or a
number of other factors. Defenses may be physical (such as
toughness ofleaves) or chemical. Several other workers have
found greater commitment to defensive substances in re-
source-limited habitats (Coley, 1987). For example, con-
Tannins 209
densed tannins were found to be more common in nutrient-
poor forests in Africa (McKey et aI., 1978). In general, these
theories predict that carbon-based defenses will be most im-
portant in habitats in which nitrogen is limiting in accord
with the conclusions of Lewis and Yamamoto (1989), based
on plant biochemistry (see above and Chapter I).
Additionally, the type of defense used is determined by
the phylogeny of parricular plants. Because the vegetation
of any system is determined by its past history and a number
of phytogeographic effects, it seems unlikely that any gen-
eral theory will suffice for all instances.
Other Proposed Functions of Tannins
Although many of the properties of tannins are linked to
their ability to bind proteins, individual tannins also may
exhihit biological activity. For example, tannic acid is a hep-
atotoxin (Zucker, 1983). Tannins may inhibit pathogens by
complexing with extracellular enzymes that the pathogens
produce or by interfering with metabolism of the pathogen
itself.
Tannins often possess molluscicidal activity against the
schistosomiasis-transmitting snail, Biomphalaria glabrata,
.an intermediate host of Schistosoma mansoni. The active
molluscicidal and piscicidal compounds from Mammea sia-
mensis (Clusiaceae), Polygonum stagninum, and Diospyros
diepenhorstii are all proanthocyanidin polymers (Baiza et
al., 1989).
Medicinal Properties of Tannins
Tannins are components of many traditional herbal medi-
cines. Among these are tree paeony root bark (Paeonia lac-
tiflora), bearberry (Arctostaphylos uva-ursi), agrimony
(Agrimonia spp.), geranii herba (Geranium maculatum),
meadowsweet (Filipendula ulmaria), and raspberry (Rubus
idaeus) (Haslam et al., 1989; Okudaet aI., 1989b). The outer
portion of the root of the tree paeony (Paeonia lactiflora)
has been used to treat disorders of the bloodstream for at
least 2000 years. Although many medicinal uses are based
on the astringent properties of the plants, others appear to
involve specific effects of tannin molecules (Haslam et al.,
1989).
Many tannins are cytotoxic to cell cultures. Tannins may
exhibit antibiotic activity by complexation of extracellular
enzymes that the pathogens produce or by interference with
the metabolism of the pathogen itself.
Several ellagitannins inhibit lipid peroxidation in rat liver
mitochondria and microsomes. Inhibition of 5-lipoxygenase
in arachidonate metabolism in rats also was observed with
comparatively low levels of the ellagitannins geraniin (26)
(Fig. 12.10) and corilagin (11) (Fig. 12.2). Geraniin and tan-
nic acid strongly inhibit autoxidation of ascorbic acid. The
reduction of several metallic ions (Cu2+, Fe3+, and Cr6+)
occurs in the presence of tannins at room temperature
(Okuda et al., 1989b).
Many tannins have weak antiviral and antitomor activity.
210 Tannins
However, a number of oligomeric hydrolyzable tannins ex-
hibit marked antitumor and anti-HIV activity. The dimeric
ellagitannins coriariin A (48), rugosin E (46), and oenothein
B (47) show the greatest antitumor activity (Fig. 12.16).
Orally administered oenothein B also has activity against
certain solid tumors, such as the Ehrlich ascites tumor. These
antitumor activities are thought to be due to enhancement
of the immune response of the host animals (Okuda et aI.,
1989b).
The same dimeric ellagitannins inhibited replication of
human immunodeficiency viruses (HIV). Oenothein B (47)
inhibited vitus growth at concentrations of I and 10 fLg/ml.
The inhibitory effect may be due to the blocking of adsorp-
tion of mv on the cells and also inhibition of reverse tran-
scriptase activity (Okuda et aI., 1989b). A variety of other
gallotannins and eliagitannins had similar activity. Gallotan-
nins with a quinic acid core were especially active (Nonaka
et aI., 1990). Geraniin (26, from Spondias mombin leaves,
has pronounced antiviral activity (50 fLg/ml) against Cox-
sackie and Herpes simplex viruses (Corthout et aI., 1991).
Several eliagitannins, for example, geraniin (26), inhibit
mutagenicity of carcinogens. Ellagic acid (10), derived from
ellagitannins in plants, also has anticarcinogenic activity
(Okuda et aI., 1989b).
Correlation of Tannin Consumption and
Throat Cancer
A correlation between consumption of beverages contain-
ing large amounts of tannins and increased incidence of
esophageal cancer has been noted (Morton, 1972, 1978,
1989). This has been noted in particular with the consump-
tion of hot tea (Japan, China, Soviet Asia, etc.), kaffir beer
(made from Sorghum spp.) in southern Africa, some folk
medicines (such as Krameria spp. in Curacao), dry red wines
(western Europe and the United States), cider (the Normandy
peninsula of France-where cider is made from apples too
astringent to eat), users of betel in southeastern Asia, and
khat (Catha edulis, Celastraceae) in Djibouti. As mentioned
previously (see Chapter 11), approximately 30% of the dry
matter of tea leaves (Thea sinensis) is phenolic in nature.
The leaves are rich in flavan-3-0Is, principally as their 3-0-
gallate esters, but the level of procyanidin is minimal (Has-
lam and Lilley, 1985; Porter, 1989; Sanderson, 1972). Thear-
ubigins are primarily prodelphinidins and their gallate esters
(Hemingway, 1989). Theaflavins in black tea result from
oxidative coupling of thearubigins (see Chapter II). Interest-
ingly, in England, no elevated incidence is noted. Milk is
usually added to tea and presumably precipitates the tannins
present. Many wines contain tannins, which are responsible
for the astringent taste especially of red wines (see Chapter
11). Wines without enough tannins seem flat and insipid,
but those with too much have a harsh and rough taste (Has-
lam, 1981). Similar considerations apply to cider and several
other fruit-derived beverages.
TAI'Ii'IIl'IS AND THE PRODUCTION OF LEATHER
Tannins have been used for millenia to convert raw animal
hides into leather (Schmidt and Mayer, 1956). In this pro-
cess, tannin molecules cross-link the protein and make it
more resistant to bacterial and fungal attack. Molecules in
the molecular weight range 500-2000 (3000) are most effec-
tive, but the ability to bind effectively varies with different
tannin molecules. Many naturally occutring galloyl esters
and gallotannins do not have tanning ability.
Binding to protein is, in part, a function of molecular size.
In the galloyl n-glucose series, the association with protein
is enhanced by the addition of each galloyl group and reaches
a maximum in the flexible disk-like structure of j3-penta-O-
galloyl-n-glucose (8) (Haslam and Lilley, 1985). Effective
hydrolyzable tannins for tanning often have a chain of dep-
sidicaliy linked galloyl units in addition to simple galloyl
ester groups. Conformational mobility and flexibility is as
significant as molecular size. In the galloyl n-glucose series,
where vicinal galloyl groups are constrained by the forma-
tion of intramolecular biphenyl linkages and the generation
of hexahydroxydiphenoyl groups, the loss of conformational
freedom is reflected in a reduced capacity to bind to protein
(Haslam and Lilley, 1985).
OTHER TYPES OF TAI'Ii'IIl'IS
In addition to these well-kuown types of tannins, other mate-
rials are kuown to precipitate proteins and have tanning ac-
tivity. Among these are some lignans, such as nordihydrogn-
aiaretic acid (NDGA) from Larrea divaricata (Rhoades and
Cates, 1976) (see Chapter 8), and phlorotannins from brown
algae (Glombitza et aI., 1973, 1977; Koch and Gregson,
1984). The latter group is found in brown algae of the family
Cystoseiraceae and consists of polymeric phloroglucinol de-
rivatives.
Al'IALYSIS OF TAI'Ii'IIl'IS
Tannins can be assayed by either determination of specific
functional groups associated with particular structures or
protein-binding assays (Hagerman and Butler, 1978, 1989).
Numerous types of assays have been carried out, often de-
pending on the goals and need for the information. The hide-
powder method is still the standard of the tannin industry
(Okuda et aI., 1989a). Many workers have utilized oxidative
analyses for phenols, either as a sole measure of tannins, or
before and after precipitation of tannins with protein. The
most commonly used Folin-Denis assay is subject to inter-
ference from phenolic groups present in protein and ascorbic
acid, if present. Hagerman and Butler (1989) recommend
the Prussian Blue assay for this purpose, as it is less sensitive
to interferences, although some other limitations have been
noted (Mole and Waterman, 1987b). Hagerman and Butler
 Tannins 211

(a)

OH~.o0H0 "
~
HO OH

,
H j : ( 1 00 0 0

00
0"'_' :~o ~-o"~o
"".
~O~ \ '~" o~ "'"~O"
HO 0 0 ,\
OH

0?:t"
ret}-(.
OH

~
HO

I fi OH "- I OH 0 HO 0'
HO OH HO OH

(b)
coriariin A (48) ble tannins.
Fig. 12.16 (a & b). Some biologically active hydrolyza
212 Tannins
suggest that the acid-butanol (or proanthocyanidin) assay
is relatively specific for proanthocyanidins and is quite sensi-
tive. Another method, the vanillin assay is useful for the
determination of flavanols (Hagerman and Butler, 1991;
Mole and Waterman, 1987b; Porter, 1989). Although often
used, the iodate method for gallotannins is subject to many
interferences, and Hagerman and Butler suggest use of a
newer assay with rhodauine (Inoue and Hagerman, 1988).
A general, rapid, and highly reproducible method for deter-
mination of tannins involving an agarose-gel-containing pro-
tein (called the radial diffusion method) is useful for the
examination oflarge numbers of samples (Hagerman, 1987).
Difficulties and flaws in the analyses of tannins have been
reviewed (Schultz, 1989).
The enzyme tannase, produced by Aspergillus niger, spe-
cifically cleaves the galloyllinkage to yield gallic acid and
a polyol, but it does not cleave hexahydroxydiphenyl-con-
taining esters. This reaction can be used to estimate the num-
ber of galloyl units per polyol. The same enzyme cleaves
condensed tannins to yield flavonoids (porter, 1989).
Purification of tannins is laborious but can be accom-
plished by a variety of techniques (Hagerman and Butler,
1991).
Characterization of hydrolyzable tanuins can be accom-
plished by hydrolysis and identification of the fragments
by standard techuiques such as cochromatography on paper,
TLC or HPLC and NMR, UV, and MS (Karchesy et al.,
1989; Okuda et al., 1989a; Porter, 1989). Condensed tannins
can be cleaved in mild acidic solution to form a flavan-3-01
and a quinone methide. The quinone methide can be captured
with a suitable nucleophiJe (e.g., -SCH2Ph) to form 4-thio-
benzyl derivatives and permit determination of the constitu-
ent flavonoid units (Porter, 1989). The 4-thiobenzyl deriva-
tives may be reduced with Raney-nickel to yield flavan-3-
ols (Porter, 1989).
The characterization of condensed tannins has been
greatly aided by structural and conformational analysis by
NMR spectroscopy (Ferreira and Brandt, 1989). Both 'H_
and 13C_NMR spectroscopy has been used to assign atoms
in these complex structures. Fast atom bombardment (FAB)
mass-spectral analysis permits observation of the parent ion
as well as fragments of these compounds (Barofsky, 1989;
Haslam and Lilley, 1986; Okuda et al., 1989a; Porter, 1989).
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(1987c).
MORTON, J. F., Further associations of plant tannins and human
cancer, J. Crude Drug Res., 12, 1829-1841 (1972).
MORTON, J. F., Economic botany in epidemiology, Econ. Bot., 32,
111-116 (1978).
MORTON, J. F., Tannin as a carcinogen in bush-tea, tea, mare, and
khat, in Chemistry and Significance of Tannins (R. W. Heming-
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NONAKA, G., 1. NISHIOKA, M. NISHIZAWA, T. YAMAGISHI, Y. KASHI-
WADA,G. E. DUTSCHMAN, A J. BODNER, R. E. Kn.KUSKlE, Y.
CHENG, and K. LEE, Anti-AIDS agents, 2. Inhibitory effects of
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OKUDA, T., T. YosHIDA,andT.HATANo,Newmethodsofanalyzing
tannins, J. Nat. Prod., 52, 1-31 (1989a).
OKUDA, T., T. YOSHIDA, and T. HATANO, Ellagitannins as active
constituents of medicinal plants, Planta Medica, 55, 117-122
(1989b).
PENO, S. and C. JAy-ALLEMAND, Use of antioxidants in extraction
of tannins from walnut plants, J. Chern. Ecol., 17, 887-896
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PORTER, L. J., Flavans and proanthocyanidins, in The Flavonoids:
Advances in Research since 1980 (J. B. Harbome, ed.), 21-62,
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PORTER, L. J., TANNINS, in Plant Phenolics (J. B. Harbome, ed.),
Vol. I of Methods in Plant Biochemistry (P. M. Dey and J. B.
Harbome, eds.), 389-419, Academic Press, New York, 1989.
RHOADES, D. F. and R. G. CATES, Toward a general theory of plant
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Recent Advances in Phytochemistry, Vol 10), 168-213, Plenum
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ROBBINS, C. T., T. A. HANLEy, A E. HAGERMAN, O. H1EL:FORD,
D. L. BAKER, C. C. SCHWARTZ, and W. W. MAUTZ, Role of
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13
Nonprotein Amino Acids

Introduction usually occur as components of peptides or proteins and are

Nonprotein Amino Acids Derived from Aspartic Acid linked by peptide bonds (Fig. 13.1) or free only in small
Lysine-Derived Nonprotein Amino Acids amounts, although, under unusual circumstances, free pri-
Pipecolic Acid and Related Compounds mary amino acids sometimes accumulate in unusual quan-
L-Mimosine tities. Examples are histidine (1) in ripening bananas, argi-
Homoserine nine (2) in apple trees and some Vida species, and proline
L~Canavanine (3) in Caragana wood. A few primary amino acids such as
Canaline cystine (4) and trans-4-hydroxY-L-proline (5) do not occur in
L-Azetidine-2-carboxylic Acid and Related Amino Acids protein but are synthesized secondarily from primary amino
Nonprotein Amino Acids Derived from Isoleucine acids. The latter of these is found in the cell wall proteins
L-Hypoglycin A and B of higher plants.
L-Homoarginine and Related Compounds from the Genera In addition to these ubiquitous amino acids, an additional
Lathyrus and Vida (Fabaceae) 700 amino acids that are not involved in primary metabolism
L-Homoarginine have been reported. About 300 of these are found in plants
L-Lathyrine (Hunt, 1991). Most nonprotein amino acids occur free, as
Amino Acids from 3-Cyano-L-a1anine and Asparagine their 4-glutamyl (or 'Y-glutamyl) derivatives, or linked to
Nonprotein Amino Acids Developed from Glutamic Acid carbohydrate moieties. There are two main types of nonpro-
Other Nonprotein Amino Acids tein amino acids. A number of nonprotein amino acids are
Sulfur-Containing Amino Acids similar to primary amino acids; others are unrelated to any of
Djenkolic Acid these. Members of the first group may arise in three principal
L-Indospicine
ways. Some nonprotein amino acids arise by simple struc-
A1biziine
taral modifications of protein amino acids; others arise by
5-HydroxY-L-tryptophan
modification of the pathways leading to protein amino acids;
3,4-DihydroxY-L-phenylalanine (L-dopa)
a third group arises by novel routes.
Selenium-Containing Amino Acids
As an example of the first type, tryptophan (6) is con-
Nonprotein Amino Acids in Seeds of the Cucurbitaceae
verted to 5-hydroxY-L-tryptophan (7), which occurs in plants
Compounds Involved in Iron Metabolism in Plants
as its acetyl, 4-glutamyl, and oxalyl derivatives (Fig. 13.2).
Ethylene and Its Precursors
An example of pathway modification (the second type)
Trigonelline, a Hormone Which Controls the Cell Cycle
in Plants is the production of meta-substitoted amino acids such as
Miscellaneous Nonprotein Amino Acids 3(3-carboxyphenyl)a1anine (8) via a modified shikimic acid
Distribution of Nonprotein Amino Acids in Plants pathway (Fig. 13.3) (Bell, 1976).
References An example of the third type (novel pathway) is the pro-
duction of erythro-4-methylglutamic acid (9) from L-Ieucine
(10) in Gleditisia triacanthos (honey locust, Fabaceae) and
INI'RODVCTIOI'I
not from glutamic acid and SAM or from lysine as in many
Approximately 25-30 amino acids are involved in primary other plants (Fig. 13.4).
metabolism (Miflin, 1980; Rosenthal and Bell, 1979). Many Where L-amino acids are concerned, the a-carbon atom
of these are listed in Fig. 13.1. These primary amino acids is usually designated by the prefix D- or L- in accord with

215
216 Nonprotein Amino Acids

co,H
cro,H Co,H co,H

HNO
co,H
I I
I .... H

-<
NB,·C-H NB,-C-H I
NB,C-H NB,C-H
I
CH,

L-oIoDIne
A
~"allne L-leudlle (10)
~
L-........I•• (15) L-p....Une (3)
co,H CO,H
I I

8
NB,~-H NH,.~-H

yu. NH.-~-H
co,H
I
CR,

I
~ ?Iz
SH
CR,
l.-cyItel.e (U) L-..rI.. (11)
L·melhIonIne (16) L-pheJIyIal.nlne
co,H co,H
co,H L-trnotop.... 1
COzH I NB,C·H I

¢
NB,·C-H 1 NH.·C-H
I I
NH:r~-H I co,H CB,
H-C-OH ?liz I
NH,-CH, yu.
I
I
CH, f~0
CR, c:u:C~o
OH
L-threonlne (14) L-aipanoglne (93) glycine L-/yruoiDe L-glu!amloe (Al
co,H CO,H co,H
COzH co,H
I I
I I I NB,C-H NH2"~-H
NH,C-H NH,·C-H
I
NH:r C - H
I
(~ (6JI zl,
[1
CR, CR,
I
co,H I NH

f' ~H, I
C=NH
Co,H NH, I
NHl
(a) L-a&partl. add (22) L-glutamle add (67) L-Iysl•• (23) L-arginine (%) L-bIsIIdlne(l)

CO,H

HO HO
NH,-C-H
I

~CO'H ~CO'H
I
(CH,),
I
I
CH,
CH,
I
NH,
trans-4-hydroxyproline (5) N-metbyl-trans-4-hydroxyproline (72) L-ornithine (71)

CO,H
I CO,H CO,H
CO,H NH,·C-H I I
I
NH,C-H I NH,-C-H NH,-C-H
I CH, I I
CH, I CHz CH:z
I
0---f:..0 CH,
I I
s---s
I
OH

O·••elyl·L..erlne (36) L-homoserine (13) L·eystlne (4)

(b)

Fig. 13.1 (8 & b). Fonnation of the peptide bond and some primary amino acids.

CJc():,
"'" I I NHz
COZH
NH
L-tryptophan (6)
Fig. 13.2.
the structure of D- or L-serine (11) (Rosenthal, 1982). L-
Amino acids other than cysteine (12) are (S)-aminoalkanoic
acids. One major problem is the establishment of chiral cen-
ters in the molecules (Hunt, 1991). The prefixes of carbohy-
drate nomenclature, erythro and threo, are still used. It is
common practice to use the terms cis and trans to refer to
the positions of hydroxyl or other ring substituents with re-
spect to the carboxyl groups in proline or pipecolic acid
derivatives. Greek letters are being replaced with numbers,
but are often seen in the literature. Many workers still prefer
to give trivial names to novel amino acids (Hunt, 1991; Ro-
senthal, 1982).
The toxicity of many nonprotein amino acids to the
bruchid beetle Callosobruchus maculatus (the southern cow
pea weevil) has been evaluated; the larvae normally feed on
the seeds of Vigna unguiculata) (Janzen et aI., 1977). These
beetles are adapted to the amino acids accumulated in seeds
of the host plant, but they are poisoned by many other non-
protein amino acids at the level of 0.1 % in artificial diets.
The role of nonprotein amino acids as ecological factors in
the life history of insects has been reviewed (Bernays, 1983).
Nonprotein amino acids usually occur free in plants, or
as their 4-glutamyl derivatives. These amino acids generally
are extracted with ethanol or with alcohol-water mixtures
(Rosenthal, 1982, 1991). Most amino acids can be detected
by the characteristic reaction with ninhydrin, which produces
blue to purple colored chromophores (Rosenthal, 1991).
Most of the early work with nonprotein amino acids was
done using paper-chromatographic and thin-layer techniques
chorismic acid
isochorismic acid
HOZC~COZH
I 3(3-carboxyphenyl)alanine (8)
"'"
Fig. 13.3. Biogenesis of isoprephenic acid and 3(3-carboxyphenyl)alanine (modified from Rosenthal, 1982; used with permission of the copyright
owner, Academic Press, Orlando, FL).
Nonprotein Amino Acids 217
----+
HO~COZH
I I NH
"'" NH Z
5-hydroxy-L-tryptophan (7)
Biogenesis of 5-hydroxY-L-tryptophan.
(Fowden et aI., 1970; Fried and Sherma, 1982; Hunt, 1991;
Rosenthal, 1982). A number of gas-chromatographic meth-
ods have been devised for the determination of amino acids
(Jaeger et aI., 1981). Electrophoresis has also been widely
used. By changing the buffer pH, it is possible to effect
separation of different compounds. However, most amino
acids are identified and quantified by means of ion-exchange
resins and automated equipment. High-performance liquid
chromatograph (HPLC) with reversed-phase and ion-ex-
change supports has played a major role in simplification of
the analyses of amino acids (Hunt, 1991; Rosenthal, 1991).
Various aspects of the purification and characterization of
nonprotein amino acids have been reviewed (Hunt, 1991;
Rosenthal, 1982).
Most amino acids exist as charged species or zwitterions
at physiological pH. No attempt has been made to draw
structures in the ionized form in this chapter.
NOl'lPROTEIN AMINO ACIDS DEKIVED FROM
ASPARTIC ACID
Homoserine (13), threonine (14), isoleucine (15), methio-
nine (16), and cysteine (12) are all derived from aspartic
acid (22). Lysine (23) (Fig. 13.1) is derived via 3-aspar-
tylsemia\dehyde and is, in tum, involved in formation of
many nonprotein amino acids such as pipecolic acid (17)
and mimosine (18) (Figs. 13.5 and 13.6) (Rosenthal, 1982).
D-Lysine is a precursor of L-pipecolic acid in many plants
isoprephenic acid
NHz
218 Nonprotein Amino Acids

CH, NH,
CH3
I I
NH2 Gledilsla triacanthos I
HO,CCHCH,CHCO,H
I other plants
lysine
CH,CHCH,CHCO,H F.b.....
ery,hro-4-methylglutamic .cid (9)
L-I.ucin. (10)

NH,

HO,CCH,CH,CHCO,H
I
glutamic acid + methyl

Fig. 13.4. Biogenesis of erythro-4-methylg1utamic acid.

and bacteria. L-Pipecolic acid, in tum, gives rise to L-Iysine
(Fangmeier and Leistner, 1981).
A number of other nonprotein amino acids are involved
in the biosynthesis of lysine (Fig. 13.5). Among these are
2,3-dihydrodipicolinic acid (19), N"-succinyl-2,6-diaminop-
imelic acid (20), and 2,6-diaminopimelic acid (21).
Lysine (23) also serves as a precursor for several major
types of nonprotein amino acids, (e.g., pipecolic acid (17),
mimosine (18), 4-methyl glutamic acid (9), 4-methyleneglu-
tamic acid (26), and a series of compounds found in the
families Aceraceae, Hippocastanaceae, and Sapindaceae
(see below).
LYSIl'IE·DERIlIED NOl'lFROTEIN AMINO ACIDS
Pipecolic Acid and Related Compounds
Pipecolic acid (17) can arise from lysine via two distinct
mechanisms (Fig. 13.6). This synthesis can occur by a trans-
amination reaction, cyclization to a I-piperidine-2-carbox-
ylic acid (25) and reduction to pipecolic acid or by initial
conversion to a semialdehyde and conversion to a I_piperi_
dine-6-carboxylic acid (24) prior to the formation of pipeco-
lic acid (17) (Rosenthal, 1982). Pipecolic acid is derived
from L-Iysine in fungi and D-Iysine in higher plants.
Several other nonprotein amino acids are formed from
pipecolic acid. Among these are a number of compounds
illustrated in Fig. 13.7. Fowden (1970) has integrated the
possible metabolic relationships of this group of compounds
into a coherent scheme. In this model, rearrangement of exo-
(cis)-3,4-methanolproline (27) can produce baikiain (28) or
methyleneproline (29) (Rosenthal, 1982).
Ring openings interrelate cis-3- and cis-4-methylated pro-
line (30, 31) as well as pipecolic acid (17) into these meta-
bolic pathways. Addition of water to baikiain (28) can lead
to trans-4- and/or trans-5-hydroxypipecolic acid (32, 33).
4-Methylglutamic acid (9) can feed into cis-4-methylproline
(31), 4-methyleneglutamic acid (26) into 4-methylenepro-

aspartic acid (22)

- 3-aspartyl
phosphate
---+- 3-aspartyl
semialdehyde
- o HO,C N CO,H

2,3·dihydropicoJinic
-
o
acid (19)

HO,C N

.6,1'piperidine.2,6.
CO,H- N'.succlnyl·2·amino.6.oxo.
plmelicacld - H,N-CiH
?O,H

(CIH,),
fo,H
?H, -
?H,

- /
dicarboxyJic acid ~O,H H-C - - NH--<:=O
I
H,N-CIH CO,H
lysine (23)

HO/=\ f' (lH,),

H-~-NH,
N'-succinyl.2,6.
diaminopimelic acid (20)
0\J-CH,-CH-CO,H
CO,H

L-mimosine (18) meso·2,6·diaminoplmeJic

acid (21)

Fig. 13.5. Biosynthesis of lysine from aspartic acid in higher plants (modified from Rosenthal, 1982; used with pennission of the copyright owner,
Academic Press. Orlando, FL.).
 Nonprotein Amino Adds 219

<
NH, 2.ox~6~aminohexanoic acid

(C,H')4

H-~-NH, ,11.piperidine-2.carboxylic acid (25)

:,0~
CO,H
2-aminoadipic semialdebyde
lysine (23) pipecolic acid
(17)

~1-piperidine.6.carboxylic acid (24)

Fig. 13.6. Possible biosyntbetic pathways to pipecolic acid (Rosenthal, 1982; modified and used with pemrission of the copyright owner, Academic
Press, Orlando, FL).

line, and 2-aminoadipic acid into pipecolic acid (17). Finally,
the conversion of cis-2-(carboxycyclopropyl)glycine (34) to
exocyclic proline can be related to the formation of certain
c.-imino acids (Rosenthal, 1982).
exo-cis-3,4-Methanoproline (27) is found in Aesculus
parviflora (Hippocastanaceae). Pipecolic acid (17) is found
in many legume seeds, especially in the genera Acacia and
Prosopis (Rosenthal, 1982). A sulfate of pipecolic acid,
trans-4-hydroxypipecolic acid-4-sulfate (35), has been re-
ported from Peltophorum africanum (Fabaceae) (Evans et
al., 1985).
L-Mimosine
L-Mimosine (18) (Fig. 13.5) is a toxic heterocyclic amino
acid that has been reported from several legumes. Among
the plants that contain mimosine are Mimosa pudica and
Leucaena leucocephala. The latter is often cultivated in trop-
ical countries as a windbreak, a forage crop, and as a shade
crop for coffee, tea and cacao (Rosenthal, 1991). This native
of Mexico is capable of fixing nitrogen and is a quite agres-
sive species.
O-Acetylserine and 3,4-dihydroxypyridine give rise. to
minIosine in the presence of an extract of Leucaena. An L-

tmns-4-hydroxypipecolic cis-3-methylproUne (30) cis-4-methylproline (31) 4-methylglutamic acid (9)

aeid(32) '" , , / h
A
Q NH
++
CO,H
A
~ A
-- ( __
__
NH CO,H
)-.CO,H
NH _ HC
,~
NH
I'
HOD¥ baikiain (28) 4-metbyleneprollne (29) ;-CCH,CHCO,H
exo-3,4-metbanoproline HO,C

/ t
NH C02H (27) 4·methyleneglutamlc acid

f'
(26)

n
trans-5-hydroxypipecolic ISO,"
aeid(33)
NH, ~HO,C(CH,)JCHCO,H r"l
HO'CAJHCO'H ~ __A
NH CO,H
2-aminoadipJcacid ~_._A
NH CO,H
H H

cts-2-(carboxycyclopropyl)glycine (34) pipecolic acid (17) 1rans4·hydroxypipecolic acid-

4-sulrate (35)

Fig. 13.7. Proposed sequence of rearrangements leading to cyclopropanoid and cyclopentanoid nonprotein amino acids (Fowden. 1970; Rosenthal,
1982; modified and used with pennission of the copyright owners, John Wiley and Sons, Ltd, Chichester, and Academic Press, Orlando, FL).
220 Nonprotein Amino Acids

0 0 OR This compound is known from at least 1500 species in 240

IC-O.PO)H I I genera of that subfamily (Bell et aI., 1978). The seeds of
C02K

I
1 C·R ,Hz many of these plants contain 2-4% of L-canavanine and a
I I
r
CR, CR,
number contain 10-15%. In certain legumes, the total pro-
CR,
I
H.C.NHl
--+
I
H.C.NHl
-+
I
H.C.NH1
portion of seed nitrogen allocated to canavanine may repre-
sent 95% of the total amino acid nitrogen of the seeds (Ro-

I
H-C-NHl

COlK
I
COl"
I I
COlK
CO2"
aspartic 3..aspartyl- 3-aspartyl- homoserine (13)
acid(Zl) phosphate semiaJdebyde
Fig. 13.8. Biosynthesis of homoserine from aspartic acid (Rosenthal,
1982; modified and llsed with permission of the copyright owner,
Academic Press, Orlando. FL).
mimosine synthase has been isolated from Leueaena /eueo·
eepha/a. Some cysteine synthases also cause fonnation of
similar amino acids. One isozyme of such an enzyme from
Leueaena /eueoeepha/a is capable of producing L-mimosine
in the presence of O-acetyl-L-serine (36) (Fig. 13.1) and ap-
propriate precnrsors, in this case 3,4·dihydroxypyridine
(Jkegami et al., 1990; Rosenthal, 1982). It is probable that
these two enzymes are identical.
Although considered a promising forage crop, the leaves
of Leueaena /eueoeepha/a contain as much as 2% mimosine
dry weight and cause loss of hair and grossly enlarged thy-
roid glands when used as a food plant for animals. Mimosine
inhibits proline hydroxylation and, hence, collagen fonna-
tion and hair growth. It has been suggested that the pnre
mimosine can be used to "shear" sheep chemically, but this
nonprotein amino acid has proven too toxic for practical use
in this regard.
Although it has been suggested that mimosine may serve
as a tyrosine antimetabolite, the evidence is equivocal (Ro-
senthal, 1991).
HOJIIOSERIl'IB
Homoserine (13) is an intennediate in the synthesis of threo-
nine (14), isoleucine (IS), methionine (16), and cysteine (12)
and, thus, found in all plants (Fig. 13.8). Homoserine is accu-
mulated and has been studied in Pisum sativum (pea, Faba-
ceae). This amino acid is not found in the ungenninated
seed, but during the first week of gruwth, homoserine consti-
tutes 70% of the soluble nitrogen and 12% of the seedling
dry weight (Rosenthal, 1982).
L-Canavanine [the L·2-amino-4-(guanidinooxy)butyric acid
structural analog of L-arginine1 (37) is widely distributed in
the subfamily Lotoideae (Papilionoideae) of the Fabaceae
and, despite some reports to the contrary, is restricted appar-
ently to that family (Bell, 1981; Turner and Harborne, 1967).
senthal, 1982).
A proposed metabolic cycle involving canavanine (37) is
illustrated in Fig. 13.9 (Rosenthal, 1982):
The amount of canavanine (37) declines rapidly upon
gennination of the seed; one function of canavanine is to
serve as a nitrogen storage reserve in the plant. Radioactively
labeled canavanine and related metabolites were converted
into glutamic acid, glutamine, and alanine in cotyledons of
Canavalia ensiformis (Rosenthal et al., 1988).
The potent antimetabolic properties of canavanine result
primarily from its ability to function as a highly effective
antagonist of arginine (2) metabolism because of its stroc-
tural similarity to that acid. This structnral similarity ac-
counts for the ability of arginyl-tRNA synthetase to activate
and attach canavanine to the tRNA that nonnally carries
arginine to the protein assembly site (Rosenthal, 1991). Ca-
navanine is incorporated into the proteins of canavanine-
sensitive organisms, but it is rarely, if ever, encountered in
the proteins of the plants that produce it (Rosenthal, 1988,
1991).
The bruchid beetle, Caryedes brasiliensis, feeds only on
the seeds of Dioclea megaearpa, a legume of Costa Rica
(Rosenthal, 1983). These seeds contain up to 13% of the dry
weight as canavanine (37) (Rosenthal, 1977). Gravid beetles
deposit egg clusters on the ovary wall of the fruit, and the
newly hatched larvae bore into the pericarp, locate the seeds,
and consume the cotyledonous tissues (Rosenthal, 1983).
Although this amino acid is potentially toxic, the insect has
an arginyl-tRNA synthetase capable of distingnishing be-
tween canavanine and arginine, and canavanine is not incor-
porated into protein (Rosenthal, 1983). Most of the total
ninhydrin response (96%) in these seeds is contributed by
canavanine (Rosenthal, 1982, 1983).
The insect uses canavanine as a sonrce of dietary nitrogen
for the developing larvae (Rosenthal et al., 1982). Arginase
activity that hydrolyzes arginine to orinithine also hydro-
lyzes canavanine to canaline (38) and urea. Urea cannot be
assimiliated directly, rather it is first converted to ammonia.
This insect produces about 30 times more urease that most
other related insects. Thus, a potentially toxic plant sub-
stance is converted into a useful resource. The canaline pro-
duced is converted apparently to homoserine (13) and am·
monia and thereby detoxified (Rosenthal, 1982; Rosenthal
and Berge, 1989).
The generalist feeding insect Heliothis vireseens, the to·
bacco budwonn, has relatively high resistance to canavanine
but not to a number of other nonprotein amino acids (Berge
et al., 1986). In this case, canavanine (37) was shown to be
neither excreted nor sequestered, but rather metabolized by
the insect. In Caryedes brasiliensis, Sterneehus tubereu/atus
 Nonprotein Amino Acids 221

NH,
I
c=o
I Q-ureidohomoserine

i
NH

r
ry
aspartic acid

~(rJ'.~'l:ile I ,~ATP'Mg fO,H

OH IH
, J-NH-CH

I I CH,
I
k!H
CH,
I I'
CH I I'
I
H-C-NH,

t-- r'
° CO,H
r' ~
NAD' CHz

H-C-NH,
I
CO,H
INH
H-f- ,
CO,H
CO'Hi'

C=NH
r'
CH,
homoserine (13) canaUne I I
(38) urea NH
I fumaric I
H-C-NH,

°
acid
CO,H
I
CH,
canavaninosuccinic add

I
canavanine
(37) IH,

H-C-NH,

CO,H

Fig. 13.9. Proposed metabolism of canavanine (Rosenthal. 1982; modified and used with pennission of the copyright owner, Academic Press, Orlando,
FL).

(canavanine-using insects), Canavalia ensiformis (a cana-
vanine-storing plant), and Heliothis vireseem (a canavanine-
resistant insect), canavanine was not incorporated in protein,
whereas in Manduea sexta (a canavanine-sensitive insect)
and Glycine max (a canavanine-sensitive plant), canavanine
was incorporated into proteins in place of arginine (2) (Ro-
senthal et al., 1987). Because a number of insects can de-
grade canavanine via arginase and others can convert this
compound to ammonia via urease, the ability to prevent in-
corporation of canavanine into proteins is probably the most
important step for utilization of canavanine-containing
plants as hosts (Bleiler et al., 1988). Proteins of vitellogenin
from female migratory locusts (Loeusta migratoria migra-
torioides) that have consumed L-canavanine have disrupted
tertiary and quaternary structure (Rosenthal et al., 1989).
Canavanine has been found in many advanced members
of the subfamily Papilionoideae, but not in the Mimosoideae
nor in the Caesalpiniodeae (all Fabaceae) (Bell et al .. 1978).
This suggests tbat the ability to synthesize this compound
arose after the first two subfamilies diverged from the ances-
tral stock leading to these plants, but not long after the diver-
gence of the Papilionoideae. Most of the plants that contain
canavanine are considered relatively advanced within the
family (Bell, 1981).
CANALII'IE
Canaline (38) [the 2-amino-4-(aminooxy)butyric acid ana-
log of ornithine and the arginase-mediated hydrolysis prod-
uct of canavanine (37) is usually found in small amounts in
the same legumes that have canavanine (Rosenthal, 1991).
Canaline reacts with carbonyl groups and is highly toxic in
its own right (Rosenthal, 1991). Canaline exhibits insectici-
dal properties in larvae of the tobacco hornworm, Manduea
sexta, and is a powerful neurotoxin in the adult moth (Rosen-
thal et al., 1989). This compound is similar in structure to 4-
arninobutyric (or 'Y-aminobutyric) acid and is also a powerful
inhibitor of pyridoxal phosphate-containing enzymes (Ro-
senthal, 1982). As mentioned above, the canaline produced
is apparently converted to homoserine and ammonia and
thereby detoxified (Rosenthal, 1982; Rosenthal and Berge,
1989). Canaline is converted to a novel stable oxime formed
with canaline and glyoxylic acid in jack beans (Rosenthal
et al., 1989).
222 Nonprotein Amino Acids
OH
I
CH,
I
CH,
I
H'I'NH,
- I
H-1-NH
CO,H
homoserine
2,4·diaminobutryic
acid
o-CO,H
N
- o-CO,H
l-azetine-2-carboxyllc
acid
Fig. 13.10. Proposed biosynthesis of azetidine-2-carboxylic acid (Rosenthal, 1982; modified and used with pennission of the copyright owner,
Academic Press, Orlando, Fl.).
...AmTIDIl'IE·2·CARBOXYLIC ACID
AI'ID RELATED AMINO ACIDS
Azetidine-2-carboxylic acid (39) was the fIrst azetidine ring-
containing nonprotein amino acid described, but several
other compounds with this structural feature are now known.
Azetidine-2-carboxylic acid is known to occur in a number
of plants, including: Convallaria majalis (Liliaceae), Poly-
gonatum officinalis (Liliaceae), Busse massaiensis, Delonu
regia, Parkinsonia aculeata, Peltophorum inerme, Schi-
zolobium parahybum, and P. africanum (all Fabaceae). This
unusual compound has been detected in small quantities in
the residues from sugar beet processing (Beta vulgaris, Che-
nopodiaceae) (Fowden, 1972). cis-I-Amino-3-hydroxy-
methylcycIobutane-l-carboxylic acid (40) has been reported
from seeds of Atelia herbert-smithii (Fabaceae) (Austin et
aI., 1987).
Azetidine 2-carboxylic acid (39) is toxic both to plants
and animals. When introduced into mung bean (Phaseolus
aureus), a plant that does not nonnally have the compound,
deleterious effects were noted. Azetidine 2-carboxylic acid
is incorporated into protein instead of proline. Many of the
Liliaceae have an altered prolyl !RNA synthetase that per-
mits them to discriminate against 2-azetidine carboxylic acid
(Rosenthal, 1991).
2-Azetidinecarboxylic acid is synthesized in the plant
from homoserine (13) (Fig. 13.10) (Rosenthal, 1982).
1'I0I'IPR0TE1N AMINO ACIDS DERIVED FROM
ISOLEUCIl'IE
A number of C7 -amino acids are found in plants of a number
of genera of the Aceraceae, Hippocastanaceae, and Sapinda-
ceae. These compounds appear to be based on nonprotein
r H,
CH,
1
--+
t,
CH,
I
I
H,
C=O
--L
H,O
CO,H
I
CO,H
2-oxo-4-aminobutyric
acid
NH
HOC~NH'
H~CO'H
azetidine-l-carboxylic cis-I-amino-3-hydroxycyclobutane-
acid (39) I'carboxylic acid (40)
amino acids such as 2-amino-4-methylenehex-4-enoic acid
(41) (Fig. 13.11). Labeling studies have shown that uni-
fonnly labeled isoleucine was the best precursor for this
compound of several tested. However, label from carboxyl-
labeled isoleucine was not incorporated into 2-amino-4-
methyIhex-4-enoic acid, suggesting that loss of at least the
carboxyl carbon occurs, possibly by decarboxylation, prior
to the biosynthesis of 2-amino-4-methylenehex-4-enoic acid
(41). Acetate also is incorporated into this acid, suggesting
that a C, unit is added to the portion of the molecule derived
from isoleucine (Fig. 13.11) (Rosenthal, 1982).
Several amino acids of this type are stored in the seeds
of Aesculus californicus-, after for example, 2-amino-4-
methyIhex-4-enoic acid (41), 2-antino-4-methyl-6-hydrox-
yhex-4-enoic acid (42), 2-amino-4-methylhexanoic acid
(43), and 2-(methylenecycIopropyl)-3-methylalanine
(44)-whereas Blighia unijuga (Sapindaceae) stores iso-
meric 2-amino-5-methyl-6-hydroxyhex-4-enoic acid (45)
and the related compound trans-2-(2-carboxymethylcycIo-
propyl)glycine (46). Related compounds with ethylenic and
acetylenic linkages (47-50) are found in Euphoria longan
(Sapindaceae). Compounds 51 and 52 occur in Aesculus par-
viflora. (Fig. 13.12) (Rosenthal, 1982).
...IIYFOOLYCIN A AI'ID B
Seeds of the sapindaceous tree, Blighia sapida, produce an
outgrowth which covers the seed, called an aril, that contains
the toxic amino acid hypoglycin A (53) (0.001 % weight).
The 4-glutamyl derivative (hypoglycin B) (54) is also pro-
duced (Fig. 13.12). This tree, the akee, was introduced from
West Africa and is the "national food" of Jamaica today.
The ripe aril (the least poisonous portion of the plant) is

isoleucine (15)
CH3CH"
!
transamination
CH3CH,,,
CH,CO,H
CH3CH, I
/CHCCO,H _ CHCCO,H__
II / I
CH]
I 0 ~ CH3
CH( transamination
CO, ~ CH3C~A
CH CH
3 ~ CH3CH,
OH
I CH3CH ~
/CO,H '>:CCHCH CO H _ _
CH3 ------.,/ 1 1
CH3
tiglicacld
Fig. 13.11. Proposed pathways for the biosynthesis of certain
pennission of the copyright owner, Pergamon Press, Oxford).
commonly eaten and is responsible for the disease known
as "vomiting sickness." The problem is most severe in chil-
dren and in adults who are malnourished. The immature arils
and the seeds are highly toxic.
The aril of the unripened fruit is richer in hypoglycin A
than the fully matored aril. Both hypoglycin A and B are
found in the unripened aril and the seed (Kean, 1976). These
two compounds also occur in several species of Blighia and
Billia (Hippocastanaceae) and in members of the genus Acer
(Aceraceae, the maple family) (Fowden and Pratt, 1973).
The most striking manifestation of hypoglycin consump-
tion is hypoglycemia, a condition in which the blood sugar
falls to a very low level. It has been suggested that this effect
is produced by inhibition of the oxidation of long-chain fatty
acids by hypoglycin A and B.
A lower homolog (55) of hypoglycin A has been isolated
from Litchi chinensis (Sapindaceae), Billia, and Acer seeds.
In the last two plants, this lower homolog co-occurs with the
corresponding 4-glutamyl peptide. These lower homologs of
hypoglyine A and B also have hypoglycemic activity (Fow-
den and Pratt, 1973).
....HOMOARGIl'IINE Al'ID RELATeD COJIIPOlJl'lDS
FROM THE GEl'IERA LAmYRUS Al'ID VlClA
(I'ABACEAE)
Lathyrus and Vida are closely related genera of the Faba-
ceae; both are of considerable economic importance. Al-
though the seeds of some species such as Vida faba and V.
sativa, are edible, those of many species of both genera are
poisonous. Consumption of seeds of the genus Lathyrus (Fa-
baceae) by man and many of his domestic aJ)imals produces
a syndrome called lathyrism, which may be subdivided into
neurolathyrism and osteolathyrism. The most important spe-
cies that cause neurolathyrism are Lathyrus sativus, L. sylv-
estris, L. cicera, L. latifolius, and L. clymenum (Rosenthal,
Nonprotein Amino Acids 223
II CH3CH,
NH,
I
°
'CHCH,CCO,H- ':::CHCH,CHCO,H
OR
CH]
2-amino-4--metbylbexanoic
t~ acid (41)
°II NH
I'
CH3CII::"..
~
CCH,CCO,H - - + /CCH,CHCO,H
/ transamination CH]
CH3
Z-anlino-4-methylhex-4-enoic
acid (40)
~ nonprotein amino acids (Fowden and Mazelis, 1971; modified and used with
1991). Osteolathyrism involves bone and mesenchymal tis-
sue aberrations. Consumption of seeds of Lathyrus odoratus
often leads to this malady. Other species, such as Lathyrus
hirsutus and L. pusillus, give rise to both (Rosenthal, 1991).
Although not often implicated, other genera of plants contain
some of the same amino acids.
Among the amino acids from Lathyrus are 2,4-diamino-
butyric acid (56) (a neurologically active factor) (see above),
N3 -oxalyl-2,3-diaminopropionic acid (57) (a potent neuro-
toxin), 3-cyanoalanine (58) (a neurotoxin), and the 4-gluta-
myI derivative of 3-cyanoalanine. The decarboxylation prod-
uct of 3-cyanoalanine, 3-aminopropionitrile (59), and its 4-
glutamyl derivative induce many of the osteolathyritic skele-
tal abnormalities (Rosenthal, 1991) (Fig. 13.13).
At least 17 species of Vida are able to synthesise the
arginine derivative, 4-hydroxY-L-arginine (62) ("'(-hydroxy-
L-arginine) (Bell and Tirimana, 1963). This hydroxy amino
acid is also found in a number of marine animals. 4-Hy-
droxy-L-arginine cyclizes to form a lactone that has been
isolated from other Vicia species. 4-Hydroxyhomoarginine
(63) (",(-hydroxyhomoarginine), a derivative of homoargi-
nine, is found in Lathyrus species along with homoarginine
(Rosenthal, 1982) (Fig. 13.13). erythro-4-Hydroxyhomoar-
ginine (63) has been isolated from Lonchocarpus costari-
censis (Evans et al., 1985).
....Homoarginine
Homoarginine (L-2-amino-6-guanidinohexanoic acid)
(60) (Fig. 13.13) has been isolated from a large number of
Lathyrus species. This nonprotein amino acid is toxic when
fed to the larval bruchid beetle Callosobruchus maculatus
at the 5% level in artificial diets (Rehr et al., 1973b).
....Latbyrine
Lathyrine (61) was first recognized on paper chromato-
grams because of the unusual vivid red-orange color pro-
224 Nonprotein Amino Acids

CH3 NH, CH3 NH,

I I
H3CCU=CCH,CHCO,H
I
H3CCH,CHCH,CHCO,H
I (43)
2-amino-4-methylhex-4-enoic acid (41)

,H3 iH, H
3 iH
' 7
HOCH,CH=CCH,CHCO,H HOCH,CH,C=CHCH,CHCO,H (45)
2-amino-4-methyl-6-hydroxyhex-4-enoic acid
(42) H

A1:~ VCH'CH(NHR)CO'H

HO,CCH,

tmns-2-(2-carboxymethyl- (53) R = H, L-hypoglycin A

(54) R = OCCH,CH,CH(NH,)CO,H,
cyclopropyl)g1ycine (46)
L-hypogJycin B

VCH(NH,)CO,H

3-(2-metbyJenecyciopropyl) a-(methylene-
(a) 3-methyJalanine (44) cyciopropyJ)gJycine (55)

CH3 NHz CHzOHNHz

I
HC5CCHCHzCHCOzH
I I
HC9::CHCHzCHCOzH
I
(47) (48)

(49)
(50)

-6-
H

H H

trans-2-(2-carboxycyclo- cis-2-(2-carboxycyclo-

(b) propyl)glycine (51) propyl)glycine (52)

Fig. 13.12 (a & b)_ Nonprotein amino acids from plants of the Aceraceae, Hippocastanaceae, and Sapindaceae.
 Nonprotein Amino Acids 225

ro'H
ro
°II
I
C-NH,
I
NH, r
CH,
neurolathyrogen
eHz --+- I
I
CHz ----+
I H-C-NH,
H-C-NH,
H-C-NH, I
I
CO,H
bO,H N'-OxaIYI-2'3-diamin:~;:.nic acid (44)
asparagine (64) 2,3-diamino- fO,H
propionic acid (69)

1
C=O

F,
NH,
I
<EN
I r'
r'
H-C-NH,

I
CO,H
--- r'I --- r'I
H-C-NH,

CO,H
H-C-NH,

CO,H

3-cyanoalanine (58) 2,4-diamino- N'-oxaIyl-2.4-

neurolathyrogen butyric acid (56) dlaminobutyric acid (65)
neurolathyrogen neurolatbyrogen

C:N NHCH3
I I
serine or
r' fH,

r'
cysteine HCNH,

NH,
I
CO,H
3-aminopropionitrile (59) N3.methyl-L-2,3-diaminopropionic acid
(a) osteolatbyrogen (66) osteulathyrogeu

HO,CCH(CH,)4NH-C-NH, H'NyNyyCO'H
I II
NH, NH NV NH,
L-homoarginine (60) L-lathyrine (61)

4-hydroxy-L-arginine (62) H,NC(NH)NH-CH,-CHOH-CH,-CH(NH,)CO,H

(b) 4-hydroxybomoarginine (63) H,NC(NH)NH-CH,-CH,-CHOH-CH,-CH(NH,)CO,H

Fig. 13.13. Biogenesis of 3-cyanoalanine and lathryogenic compounds of the genera Lathyrus and Vida (Fabaceae) (modified from Rosenthal. 1982;
used with pennission of the copyright owner, Academic Press, Orlando. FL).
226 Nonprotein Amino Acids

duced with ninhydrin. In the roots of Lathyrus tingitanus,
introduction of labeled L-guanidinohomoarginine leads to
the formation of lathyrine. Recent work suggests that lathyr-
ine is formed from orotate and uracil (Rosenthal, 1982).
Tetrahydrolathyrine has been isolated from the seeds of
Lonchocarpus costaricensis. The configuration of the a-car-
bon atom was established by the large positive molar elliptic-
ity in acid solution (Fellows et a1., 1979).
quickly reproduces the symptoms in monkeys (Spencer et
a1., 1987). The incidence of this progressive dementia has
plummeted with replacement of local foodstuffs with im-
ported foods.
NOM"KOTEIl'I AMINO ACIDS DEVELOPED
FROM GLUfAJIIIC ACID

The numerous derivatives of glutamic acid (67) and its amide

AMINO ACIDS FROM 3·CYAl'IO·L-ALAI'IIl'IE Al'ID glutamine (68) (Fig. 13.1) constitute the largest group of
ASPAKAGII'IE nonprotein amino acids found in higher plants. Leucine (10),
a derivative of glutamic acid, is also an important precursor
of these compounds. Glutamic acid is formed by transamina-
3-Cyanoalanine (f3-cyanoalanine) (58) is the only nonprotein
tion of 2-oxoglutaric acid from the Krebs cycle; a parallel
amino acid with a cyano group. Normally, cyanide in plants
set of reactions leads to the formation of the oxo derivative
is incorporated into asparagine, but in Vicia sativa, the 4-
of 2-aminoadipic acid, the higher homolog of glutamic acid.
glutamyl derivative of 3-cyanoalanine is produced. The most
4-Methylglutamic acid (9), (2S, 4S)-4-hydroxy-4-meth-
efficient amino acid precursors for 3-cyanoalanine are serine
ylglutamic acid (70) and 4-methyleneglutamic acid (26) ap-
(11) and cysteine (12) (Fig. 13.15) (Rosenthal, 1982).
parently are derived from leucine (Fig. 13.14) (Rosenthal,
3-Cyanoalanine (58) can be decarboxylated to f3-gluta-
1982). All these compounds are found in honey locust,
mylaminopropionitrile (59).
Gleditsia triacanthos (Fabaceae). 4-Methyleneglutamic acid
N'-Oxalyl-L-2,3-diaminopropionic add (57) is derived
(26) is also stored in the peanut, Arachis hypogaea (Faba-
from 2,3-diaminopropionic acid (69), which, in turn, is de-
ceae).
rived from asparagine (64) (Fig. 13.13). The oxalyl deriva-
Ornithine (71) (Fig. 13.1), widely distributed in plants,
tive (57) is a potent neurotoxin found in Lathyrus sativus
can be derived from glutamic acid (orinithine also can be
and certain other legumes. The corresponding N' -methyl de-
derived from arginine). This amino acid serves as an inter-
rivative occurs in certain cycads such as Gycas circinalis
mediate and as a precursor in numerous biosynthetic path-
(Rosenthal, 1991).
ways (for example, see Chapters 29 and 30).
L-2,4-Diaminobutyric (L-a;y-diaminobutyric) acid (56) is
Proline (3) is derived biosynthetically from glutamic acid
derived from 3-cyanoalanine (58). This compound also is
(67). This dicarboxylic acid is activated with ATP and then
found in a number of Lathyrus species. The corresponding
reduced to the corresponding semialdehyde, which sponta-
oxalyl derivative (65) co-occurs with L-2,4-diaminobutyric
neously cyclizes to /lJ-pyrroline-5-carboxylic acid and is
acid (Rosenthal, 1982).
reduced to proline by reduced NAD. Ornithine can be di-
Consumption of seeds of the genus Lathyrus (Fabaceae)
rectly converted to 4-glutamylsemialdehyde, providing an-
by man and his domestic animals produces a syndrome
other route to proline.
called lathyrism. Different amino acids produce the two
4-Hydroxyproline (5) is a major constituent of the cell
forms of this malady: neurolathyrism and osteolathyrism. 3-
walls of plants. This compound is generated by posttransla-
Aminopropionitrile (f3-aminopropionitrile) (59) is the active
tional hydroxylation of peptidyl proline; both plants and ani-
osteolathyritic factor in Lathyrus species. Several factors are
mals require diatomic oxygen for this reaction (Prockop et
responsible for neurolathyrism. 3-Cyanoalanine (58), its 4-
al., 1962). trans-4-Hydroxyproline accounts for as much as
glutamyl derivative, 2,4-diaminobutyric acid (56), and the
20% of the protein amino acids of primary cell walls.
N-oxalyl derivative of 2,3-diaminopropionic (a,f3-diamino-
The imino acid N-methYI-trans-4-hydroxY-L-proline (72)
propionic) acid (57) are all known to be involved. These
(Fig. 13.1) has been isolated from the leaves of two Gopaij-
compounds are found primarily in plants of the genus Lath-
era species (Fabaceae) (Figliuolo et a1., 1987).
yrus. 3-Cyanoalanine (58) and its 4-glutamyl derivative are
also common in Vicia species. Several related series of com-
pounds are found in other members of the Fabaceae.
OTHER NOM"KOTEIl'I AMINO ACIDS
N'-Methyl-L-2,3-diaminopropionic acid (66) (Fig. 13.13)
is found in plants of the genus Gycas, Cycadaceae, a gymno-
Sulfur.Containing Amino Acids
spermous family. Several of these plants are used as human
food sources in Oceania, whereas others are eaten by animals Several sulfur-containing amino acids, other than cyste-
in the South Pacific and in Australia. A form of amyotrophic ine, cystine, and methionine, are found in higher plants. Al-
lateral sclerosis (ALS or Lou Gehrig's disease) used to be lium (LiJiaceae) species often contain sulfur compounds that
endemic among the Chamorros of Guam. An unusual amino are lachrymatory in nature (Fig. 13.17). Among these species
acid N'-methyl-L-amino-2,3-diaminopropionic acid (N~­ are chives, garlic, onion, and leeks. The compounds involved
methylamino-L-a1anine) (66), found in Gycas species, are S-substituted cysteine sulfoxides and their hydrolysis
 Nonprotein Amino Acids 227

CH, OH NH, CH, OH NH,

I I I -- II I
HO,C- C - - CH- CH- CO,H
I
HO,C- CH- CH- CH- CO,H

3-hydroxy-4-metbylglutamic acid 3·hydroxy.4-methyleneglutamic acid

CH, i NH,
I I
CH,-CH-CH,-CH-CO,H
leucine (10)

CH, ~ NH,
I I
° CH, NH,
I I r=== H,N -CII -CH-CH,-CH-CO,H
>
HO,C-CH-CH,--CH- CO,H

4-methylglutamlc add (9) 4·methylglutamine

CH,
~ NH,
I I
HO,C-C -CH,-CH-CO,H
I
OH

4-hydroxy-4-methylglutamlc add (70)

CH,
! NH, ° CH, NH,
II I II II I
HO,C- C - - C H , - CH- CO,H r=== H,N -C -C-CH,-CH-CO,H
>

4-methyle.eglutamlc add (26) 4-methyleneglutamine

Fig. 13.14. Nonprotein amino acids derived from leucine (Rosenthal, 1982; modified and used with pennission of the copyright owner, Academic
Press, Orlando, FL).

products. Co-occurring enzymes convert these amino acid
derivatives into more volatile compounds (Virtanen, 1965).
Alliin (S-allylcysteine sulfoxide) (73), cycioalliin (3-methyl-
1,4-thiazane-5-carboxylic acid) (74), S-ai1ylcysteine (75), S-
aliylmercaptocysteine (76), S-(2-carboxypropyl)cysteine
(77), S-n-propylcysteine (78), S-(prop-l-enyl)cysteine (79),
and a series of related compounds are found in Allium spe-
cies, and S-(l,2-dicarboxyethyl)cysteine (80) is found in as-
paragus, Asparagus ofJicinalis) (Rosenthal, 1982).
Alliin (73) in onions decomposes to yield the lacbryma-
tory (tear-producing) compound syn-propanethial S-oxide
(81) (Fig. 13.15). 10 the presence of water, this compound
is hydrolyzed to propionaldehyde, sulfuric acid, and H2S
(Luckner, 1990).
Several species of insects are associated with Allium spe-
cies. For example, both adults and larvae of Delia antiqua,
the onion fly, are attracted to disulfides characteristic of
these plants (Stiidler, 1992). Another specialist, the leek
moth, Acrolepiopsis assectella, was found to respond to the
same group of compounds. However, dipropyl sulfmate, the
precursor of the disulfides, is even more stimulatory. A para-
site of the leek moth, Diadromus pulchellus (Ichneumoni-
dae), reacts mainly to the disulfides that emanate from leaves
damaged by the leek moth (Stiidler, 1992).
The behavioral responses of many insects to these com-
pounds and their derivatives have been reviewed (Stadler,
1992).
Djenkolic Acid
The sulfur-containing amino acid, djenkolic acid (82), is
found in seeds of many species of Pithecellobium, Acacia,
and Mimosa (Fig. 13.16). This compound produces human
toxicity in Java when the seeds of P. lobatum are eaten.
Related suifur-containing amino acids are found in these and
other mirnosoid legumes.
....lndospicine
Indospicine [L-2-amino-6-(amidino)hexanoic acid] (83)
(Fig. 13.16) has been isolated from Indigofera spicata, a
legume that is widely cultivated as a forage crop. The amino
acid is quite toxic and causes abortion and hepatotoxicity.
Nothing is known of the biosynthetic origin of indospicine
(Hegarty, 1970, 1978).
Albiziine
Albiziine (84) is found in the seeds of many species of
the genera Acacia and Albizzia (Fabaceae: Mimosoideae)
228 NOlIl'l"Ordll Ami/lo Acids

(Fig. 13.16) (Seneviratne and Fowden, 1968). This amino
acid has been isolated recently from the genus Dislium (Fa-
baceae: Caesalpinioideae). Albiziine often constitutes the
principal component of the free amino acids of the seeds.
The similarity of the structure of albiziine to glutamine
suggests that it could act as an competitive antagonist. Al-
though albiziine has not proven toxic in many types ofbioas-
says, in studies with Locusta and Chortoicetes, two grami-
nivorous feeders, this amino acid was one of the most toxic
nonproteins tested (Rosenthal, 1982).
Griffonia simplicifolia proved to be highly toxic to the larvae
of southern army worms in artificial diets; 0 normal adults
were produced by the insects fed the diets with this com-
pound as compared with control values of about 20 (Rehr
et aI., 1973b; Rosenthal, 1982).
Although serotonin is involved in central nervous system
function, this amine cannot cross the blood-brain barrier,
whereas 5-hydroxytryptophan can. An excess of sertonin
produces an array of toxic symptoms.

5-HydroXY-L-tryptophan 3,4·DihydroXY-L-phenylaianine (L-dopa)

In mammals, conversion of L-tryptophan to 5-hydroxy- 3,4-DihydroxY-L-phenylalanine (L-dopa) (85) (Fig.

tryptophan (7) is the first step in the formation of the biologi-
cally active amine serotonin or 5-hydroxytryptamine (Fig.
13.16) (Udenfriend et al., 1956). 5-Hydroxytryptophan has
been isolated from the legume Mucuna pruriens as well as
from cotton and bananas (Rosenthal, 1982).
5-Hydroxytryptophan (7) also occurs in large amounts
(6-10%) in the seeds of Griffonia simplicifolia, a west Afri-
can legume. In all tissues except the mature seed, tryptophan
serves as a precursor of the 5-hydroxy compound. Seeds of
13.16) is known to occur in a number oflegumes. This amino
acid has been found in seeds of plants from the genera Vicia,
Baptisia, Lupinus, Mucuna, and also in Euphorbia lathyrus
of the Euphorbiaceae. A massive screening program showed
that it occurs above the 0.5% level only in the seeds of
Mucuna species, where it constituted 3-7% of the weight of
the seeds (Daxenbichler et al., 1972). L-Dopa is the principal
nonprotein amino acid in many of these species (Rehr et al.,
1973a). The compound may occur free or as a glycoside.

CH,
II alliin_ c) ~ H)=S ~ H)=O
HI/- '\
CH _
I tyase
H.c CH,-CH, 0 CH,- CH,
CH,

~!,.) NH
"
Al~propenylsulfenic acid
(allylsulfenic acid)
syn-propanethioal
S·oxide (81)
propionaJdehyde
+H2S04 +H2S
CH'l:-~ - CO,H CH, CH, o
!
CH, CH,
H
alliin (73)
~ II
CH
II
CH __
II II
CH CH
I I I I
JN~CO'H
lachrymatory precursor
(S~allylcysteine sulfoxide) CH, CH, CH, CH,
I
,e--S--S
I I I
S--S
o diallylsulfide cycloalliin (74)
allicin

NH,
CHz===( ---+-
CH3~
°1/ +NH,
CO,H CO,H

S~a1Iylcysteine (75) H,C:C.CH,.S.CH,.CH(NHz}CO,H

S~allylmercaptocysteine (76) H,C=CH·CH,·S·S·CH,CH(NHz}CO,H

S-(2-carboxypropyl)cysteine (77) HO,~

CH·CH,·S·CH,·CH(NHz}CO,H
CH,/'

S-n-propylcysteine (78) CH,(CH,h·S·CH,·CH(NH,)CO,H

S-(1,2~dicarboxyethyl)cysteine (80) HO,C(CH,),S·CH,.CH(NHz}CO,H

S·(prop·l·enyl)cysteine (79) CH,·CH:CH·S·CH,·CH(NHz}CO,H

Fig. 13.15. Sulfur compounds found in Allium species and fonnation of syn-propanethial S-oxide (Luckner. 1990).
 Nonprotein Amino Acids 229

7
NH,
H
1 ' NH, ,H,
HO,CCHCH,SeCH,CH,CHCO,H
1 ~
~
L-seJenocystathionine (87) 1
tH iH,
NH,
,H,
HO,CCHCH,Se-SeCH,CHCO,H
1 iH, ,H,
H-C-NH, H-,-NH,
L-selenocysteine (86)
I
CO,H CO,H

,H, ,H,
L-albiziine L-glutamine (68)
HO,CCHCH,SCH,CHCO,H
(84)

djenkolic acid (82)

OH

HO'():)):CO'HHofu
I I :::0'1 NH,
::::,... NH, ::::,...
NH CO,H
indospicine (83) 3,4-dihydroxy-

O 0'
5-hydroxy-L-tryptophao (7)
phenylalanine (85)
H CO,H (L-DOPA)
- H
v.CO,H- - --v
H CO,H
(+)-nicotianamine (89) HN

N/~"""""NH~NH,

0 ... -
---COH
H CO,H '
)(~' ~ --v mugineic acid (91)
H COH H CO,H
NH
N' Y . . . NH~OH
OH cucurbitine (88)

H CO,H H CO H H CO,H
~ ~ V' ' --,I avenicacid (90)
HO HN/ ~NH~NH,
Fig. 13.16. Biologically active nonprotein amino acids.

Phenylalanine is not a precursor for L-dopa. Whereas ty-
rosine is incorporated into excised hypocotyls of Vicia faba
seedlings, attempts at isolating a tyrosine hydrolase proved
unsuccessful (Griffith and Conn, 1973).
L-Dopa has been used medicinally to treat Parkinson's
disease. The amino acid apparently crosses the blood-brain
barrier and is decarboxylated to produce dopamine, a bioge-
netically active amine.
Selenium-Containing Amino Acids
Selenium, normally a minor soil component, is toxic to
most plants at low levels, but under certain conditions, it
accumulates in higher plants well in excess of the soil con-
centrations (Shrift, 1969). Of these plants, the best known
are about 20 species of the genus Astragalus (Fabaceae).
Generally, the compounds formed in Astragalus species are
analogous to common sulfur-containing compounds. Out of
the approximately 1500 species of Astragalus, only a few
are active selenium accumulators. Some accumulate as much
as 15,000 ppm of selenium, mostly as Se-methylselenocyste-
ine (86) and selenocystathionine (87) (Fig. 13.16). This phe-
nomenon is also known in the fruit of Lecythis ollaria, a
Central and South American nut that is sometimes eaten. In
this case, the compound responsible is selenocystathionine
(Rosenthal, 1991).
Selenium poisoning is a major problem in Australia;
Morinda amplexicaulis and Morinda reticulata (Rubiaceae)
are the major species involved. In Morinda species, a selen-
ium compound represents about 20% of the total nitrogen of
the plant.
Nonprotein Amino Acids in Seeds
of the Cucurbitaceae
A number of nonprotein amino acids are found in seeds
of members of the Cucurbitaceae. Cucurbitine (88) is active
230 Nonprotein Amino Acids

against Schistosoma japonicum (Fig. 13.16). When mice
were given 400 mg/kg oral cucurbitine for 28 days, the de-
velopment of schistosomula was greatly retarded (Borris and
Schaeffer, 1992). Relatively simpleN-substituted asparagine
derivatives are formed from asparagine (but not from aspar-
tic acid) in Ecballium (Cucurbitaceae) seedlings. The N"-
ethyl, methyl, and hydroxyethyl derivatives are known to
occur (Dunhill and Fowden, 1965). The enzymes that lead
to nonprotein amino acids in some cucurbits may be closely
related to those responsible for the synthesis of mimosine
(Jkegami et aI., 1990).
Compounds Involved in Iron Metabolism
in Plants
A number of amino acids and amino acid derivatives such
as ( - )-nicotianamine (89) are involved in iron transport in
plants (Fig. 13.16) (Winkelmann et al., 1987). This com-
pound was identified as the normalizing factor which re-
stores chlorophyll synthesis and growth in an auxotroph mu-
tant of Lycopersicon esculenlum. The specific role played
is not clear, however. ( + )-Nicotianamine, derived from syn-
thesis, has the same effects in the mutant. The minimum
amount that produced a response was 10- 8 mol/plant. It is
possible that the compound functions by serving as an iron
chelating agent and is involved in transport of iron to the
sites of chlorophyll synthesis (Ripperger et aI., 1982).
The amino acids avenic acid (90) and mugineic acid {N-
[3-(3-hydroxy-3-carboxypropylamino)-2-hydroxy-3-
carboxypro pyl]-acetidine-2-carboxylic acid} (91) are sider-
ophores (active scavengers of iron) produced by the roots
of grasses in response tu iron depletion. Avenic acid from
oats (Avena sativa, Poaceae) was characterized largely on a
basis of its mass and NMR specta; the positive Cotton effect
in the circular dichroism (CD) spectrum suggested that both
chiral centers had the S-configuration (Hunt, 1991).
Ethylene and Its Precursors
The naturally occurring plant growth regulator ethylene
is derived from the nonprotein amino acid, I-aminocyclopro-
pane-I-carboxylic acid (92) (Fig. 13.17) (Yang, 1981). The
formation of ACC from S-adenosylmethionine is catalyzed
by ACC-synthase and this is considered to be the rate-con-
trolling step in ethylene biosynthesis (Amrhein et al., 1981).
An ethylene-forming enzyme has been observed in plant
tissues; the reaction is oxygen dependent and activated by
carbon dioxide (Yang, 1984). As expected, levels of this

Jl'j8denine
CR, CR,
I
1 ATP PP,+P,
+
I
yR' '>- L. yR, R R CR,=CR,
fR, CR, R R +RCN + CO,

R-C-NR,
R-+NH, OR OR [ > < 0 ' ; NR,
!O'R CO,R

Q
L-methionine CO,R
S~adenosylmethionine

RO rl.aminOCYeiopropane

'--~
OR OR
CR, CR,
I I

CR, R 7\ R R
I
fR,
adenine H20 H
OR OR OR OR

R-1- NR,
S-methylthioribose 5 -methylthioadenosine
O,R
L·homoserine

Fig. 13.17. Biosynthesis of ethylene and l-aminocyclopropane-l-carboxylic acid (ACC) and the biosynthesis of ethylene (modified from Adams and
Yang. 1984); used with pennission of the copyright owner, the American Society of Plant Physiology. Rockville. MO).

V
H CH,
NHC(O)(CH,J,CHCNHz}CO,H
CH,
__ CO,H
H H
(%)
Fig. 13.18. Additional biologically active nonprotein amino acids.
enzyme are low in preclimacteric fruit tissue and young pet-
als of camation flowers but increases rapidly as these tissues
undergo ripening or the senescence process (Yang, 1984).
When ACC is applied to a number of different plant tissues,
ethylene is generated. This suggests that the ethylene-gener-
ating enzyme is constitutive in those tissues. Uncouplers of
oxidative phosphorylation are potent inhibitors of ethylene
formation. Further, ethylene formation is linked to mem-
brane integrity (Yang, 1984). The activity of ethylene-form-
ing enzyme is induced by the presence of ethylene (Manning,
1986).
ACC is oxidized by a hydrolase and then fragmented into
ethylene and cyanoformic acid. Cyanoformic acid is labile
and degraded spontaneously to carbon dioxide (derived from
the carboxyl group of ACC) and hydrogen cyanide (derived
from C-l of ACC). In many plants, hydrogen cyanide is
converted rapidly into asparagine (93), 3-cyanoalanine (58),
and 'Y-glutamyl-3-cyanoalanine (Adams and Yang, 1977;
Yang, 1984).
TrlgonelUne. a Hormone Which Controls
the Ceu Cycle in Plants
Trigonelline (94), G2 Factor, is commonly found in the
cotyledons of dried seeds and is found in a wide variety of
plants (Fig. 13.18). This compound is present in the cotyle-
dons of Pisum sativum and transported to the roots and
shoots after germination. Trigonelline promotes preferential
cell arrest in G2 of the cell cycle (Tramontano et al., 1982).
In Pisum sativum, in the absence of trigonelline, root cells
arrest only in G I . Trigonelline is the first chemically identi-
fied hormone that controls the cell cycle in plants or animals
(Tramontano et al., 1982).
JllisceUaneous l'Ionprotein Amino Acids
A neurotoxic principle, glabrin [S-(3-amino-3-carboxy-
propyl)-S-methyl sulfoxime] (95), found in all parts of
enestis glabra (Connaraceae), possesses an unusual sulfur-
bearing functionality (Jeanodda et al., 1985).
A nonprotein amino acid (96) has been reported recently
as a component of the defensive secretion of the Colorado
potato beetle (Leptinotarsa decemlineata) (Harborne, 1989).
Nonprotein Amino Acids 231
CO,H
H,N-+-H
i
(jHz),
O=S=NH
I
I
CH,
g1abrin (95) trigonelline (94)
DlSTRlBVl10l'l OF l'I01'lPK0TE1l'I AMIl'IO ACIDS
Il'IFLAl'ITS
Nonprotein amino acids are most commonly found in the
Aceraceae, Agavaceae, Amaryllidaceae, Cucurhitaceae, Fa-
haceae (Leguminosae), Hippocastanaceae, Liliaceae, and the
Sapindaceae, but are especially common in the Fabaceae.
The families Aceraceae (the maple family), Hippocastana-
ceae (the horse chestnut family), and Sapindaceae are closely
related; some phylogenists have placed all three into one
family. The distribution of nonprotein amino acids would
tend to support this move.
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14
Peptides

Introduction Many nonprotein amino acids occur in plants as their 'Y-

Peptides glutamyl derivatives and are discussed in Chapter 13.
Peptide Antibiotics
Antimetabolites and Antitwnor Peptides
Peptide Antibiotics
Peptides from Fungi
Phytotoxins Produced by Bacteria and Fungi A number of peptides, especially those from microorga-
Opines nisms, have antibiotic properties. These compounds often
Peptides from Blue-Green Algae have molecular weights in the range 300-2000, contain non-
Siderophores protein and D-amino acids, are cyclic, and tend to occur in
Peptides from Higher Plants families in which individual amino acids are replaced by
Glutathione others. For example, polymyxin B (1) (Fig. 14.1), from the
'Y-Glutamyl Peptides
bacterium Bacillus polymyxa, contains 10 amino acid units.
Phytochelatins
Among these are six units of n,'Y-diaminobutyric acid and
Proteins
one of D-phenylalanine. Polymyxin D has D-leucine instead
Phytohemoglobins
of D-phenylalanine, and leucine instead of threonine. Inter-
Lectins or Hemagglutinins
estingly, L-amino acids are better incorporated than D-amino
Biological Activity of Lectins
acids, suggesting that the L-form is converted to D-amino
Proteinase Inhibitors
acids in the producing organism. Chloramphenicol, puromy-
Sweeteners
cin, and tetracycline inhibit protein synthesis when added to
References
cultures of Bacillus polymyxa, but do not inhibit polymyxin
biosynthesis (Berdy, 1980-1985; Gottlieb and Shaw,
1967-1983). Gramicidin S (2), from Bacillus brevis, con-
Il'ITRODVCTIOI'l tains only five different amino acids (Sneader, 1985).
Penicillins and cephalosporins contain a [I-lactam ring,
Peptides, molecules comprised of two or more amino acid which is fused with a thiazolidine ring. These types of com-
units joined by peptide linkages, are widespread and occur pounds are synthesized by both prokaryotic and eukaryotic
both free and as components of proteins in bacteria, fungi, microorganisms, including Streptomyces, Penicillium, As-
animals, and plants. Some peptides arise from degradation pergillus, and Cephalosporium species (Luckner, 1990). Im-
of proteins, whereas others are formed from activated amino portant precursors are L-2-aminoadipic acid, L-cysteine, and
acids (Luckner, 1990). Because peptides were difficult to L-valine. An important intermediate is 6-(L-aminoadipyl)-L-
isolate and study, those that were toxic or had some impor- cysteinyl-D-valine (Luckner, 1990). The valine unit with a D-
tant physiological property tended to be studied preferen- configuration found in one portion of the molecule is labeled
tially. Today, new analytical and separation techniques have when radioactively labeled L-valine is added to the culture.
greatly simplified work with this group of compounds. Re- The most important antibiotic of this group, penicillin G (3)
cent studies in molecular biology suggest that peptides are from Penicillium spp., is derived from similar precursors.
important in virtually all aspects of cell development. Penicillins and cephalosporins inhibit cell wall formation

234
 Peptides 235

leu-Dab

/
n.phe
"- nab

IDab thr
I
""--nab / '
I
nab
I
thr
I
nab.0C(cH,J4~H1H,

CH3 CH3

polymyxin B, (1) actinomycin D

Dab = L-2,4-diaminobutyric acid sar = sarcosine
meval = N-methylvaline

()YNHtQ<H
~ H'N~N)j~S
N N,9 0,/
o 0 ~
CO,H CO,H 0
benzyl peniclllln cephalosporin C (2)
(penicillin G)

HO

I ~H3 o~'(~T
MeVai "-

cyclosporin A (5)

(a) MeLeu - MeLeu-D-Ala-Ala -MeLeu-Vat

Fig. 14.1 (8-C). Some polypeptide antibiotics.

in bacteria. These antibiotics are inactivated by bacterial 13-
lactamases and stomach acid (Luckner, 1990).
The history of the development of penicillin and a series
of antibiotic substances from bacteria of the genus Cepha·
losporium [e.g., cephalosporin C (4)] has been reviewed
(Sneader, 1985).
AntimetaboUtes and Antitumor I"eptides
A number of peptides of animal origin were shown to
playa role in cancer therapy as antimetabolites. Later, sev-
eral peptide antibiotics were demonstrated to have similar
properties. One of these, cyclosporin A (5), produced by
certain fungi imperfecti, was shown to prevent attack on host
tissues by transplanted cells (Sneader, 1985). Another series
of peptides from Streptomyces verticillus, of which bleomy-
cin A2 (Fig. 14.2) is the main component used clinically,
has pronounced antitumor activity. The most striking feature
of this drug is that it does not cause bone marrow depression
(Sneader, 1985). Its main clinical value is in the treatment
of squamous cell carcinoma and it is administered to treat
head and neck tumors, non-Hodgkin's lymphoma, and testic-
ular teratomas (Sneader, 1985).
I"eptides from Fungi
Most members of the genus Amanita are poisonous, but
several species that produce cyclic peptides are mong the
most poisonous fungi in the world (Bresinsky and Besl,
1990; Litten, 1975). Amanita species are common in both
Europe and the United States. Most important among these
are Amanita phalloides, A. verna, A. virosa, and A. panth·
erina. Furthermore, most fatalities from eating poisonous
mushrooms are attributable to this genus (about 90% in Eu·
rope) (Bresinsky and Besl, 1990). Similar peptides are found
in a number of Galerina species and in some Lepiota species
(Bresinsky and Besl, 1990).
236 Peptides

(b) bacitracin A

gramicidin S (3)

Fig 14.1 (continued)


C I
, ~, x~~r. ~,u---r
H
,
.. J-...NH~CONH'
l' T
AJl.#o
N 9' N CH':t.
HN- 0 H
NH
ooild lj
OH ~OH
o OH
OH 0 NH,
Fig. 14.2. Bleomycin A2.
When cooked, these mushrooms apparently taste good.
The estimated lethal dose of amatoxins for man (depending
on body weight) is only 5-7 mg, the amount found in ap-
proximately 50 g of fresh fungus (less than a single fruit-
body of Amanita phalloides (Bresinsky and Besl, 1990).
Onset of poisoning typically requires 8-12 h (6-24 h), sev-
eral phases follow, and death often ensues within 6-8 days.
The liver is usually the most affected organ (Bresinsky and
Besl, 1990; Kingsbury, 1964). There is no entirely effective
treatment, although removal of toxins from the digestive
tract, chemotherapy (in Europe, thioctic acid often is used),
and symptomatic treatment are used. In the United States,
liver transplants have been used in some instances. Mortality
is about 50-90% compared to about 10% for a typical small-
pox epidemic. Those who contemplate eating wild-collected
mushrooms should read accounts of poisoning (Bresinsky
and Besl, 1990; Kingsbury, 1964).
Two major types of cyclic peptides have been isolated
from Amanita species. Phallotoxins, such as phalloin (6),
have seven amino acids in the ring, whereas, amatoxins [e.g.,
,,-amanitin (7)], have eight (Fig. 14.3). Certain portions of
the molecules are crucial for toxicity; for example, in the
amatoxin amanullin (8), elimination of a single hydroxyl
group from one amino acid eliminates activity. However,
generalizations about the effects of structure changes on tox-
icity cannot yet be made reliably.
The toxicity of ,,-amanitin is 10-20 times greater than
phallotoxins, despite its slower action. ,,-Amanitin (7) inhib-
its RNA-polymerase II in the cell nucleus, resulting in a
decrease in RNA content. The transcription of DNA by
mRNA is completely inhibited by an amanitin concentration
as low as 10- 8 M (Bresinsky and Besl, 1990).
Phallotoxins also attack liver cells. These peptides alter
membranes because they have affinity for actin filaments,
Peptides 237
,,~
=t
0 /S+
NH
0
I I
NH N I S
bleomycin Az
which leads to the rapid conversion of monomeric G-actin
to polymeric F-actin and inhibition of the reverse (depolym-
erization) reaction. Phalloidin (9) administered interperito-
neally has an almost immediate effect, whereas amatoxins
do not cause death in less than 15 h regardless of the dose.
Phalloidins are not absorbed readily by the gastrointestinal
tract (Bresinsky and Besl, 1990).
A third group of peptides, the virotoxins, appear to be
similar in action to the phallotoxins (Bresinsky and Besl,
1990).
Pbytotoxius Produced by Bacteria or Fungi
As discussed previously (see Chapter 5), pathogenic bac-
teria and fungi synthesize a number of compounds that help
to break down host tissues and to weaken the host plant.
Similar phytotoxins, especially those produced by bacteria,
are peptides typically with molecular weights less than 600.
However, in contrast to the compounds of fungi, most bacte-
rial toxins exhibit an overall lack of specificity (Mitchell,
1981). In some cases, these phytotoxins are produced in con-
junction with phytotoxins frum other biosynthetic groups
of compounds. For example, in addition to the polyketide-
derived compounds involved in the attack on elm trees by
Ceratocystis uimi, phytotoxic glycoproteins are also released
(Harborne, 1988; Wood et aI., 1972).
Attack of the fungus Fusarium oxysporum on the tomato
appears to involve both fusarlc acid (10) (a pyridine deriva-
tive) and a small peptide, Iycomarasmin (11) (Fig. 14.4)
(Ballio, 1981; Harborne, 1988). The former compound is
linked to chelation of metal ions, whereas the peptide is
involved in water-permeability effects (Ballio, 1981).
Tabtoxin or wildfire toxin (12), produced by Pseudomo-
nas syringae pv. tabaci and related bacteria, on tobacco pro-
238 Peptides

duces light-dependent chlorosis in the plants (Ballio, 1981;
Mitchell, 1981). The peptide responsible possesses a i3-lac-
tam and is highly unstable. The active peptide is converted
to an inactive isomer, isotabtoxin (13), on standing (Ballio,
1981; Mitchell, 1981). A related compound, (2-serine)tab-
toxin (14), is produced along with tabtoxin in many in-
stances. Other types of Pseudomonas syringae produce simi-
lar compounds such as coronatine (15). This peptide is
responsible for chlorosis in a number of grasses (Mitchell,
1981).
A similar peptide toxin, rhizobitoxin (16), is produced by
the root-nodulating organism Rhizobium japonicum. Rhi-
zobitoxin causes chlorosis in the developing leaflets of
plants, such as soybean (Glycine max), which have nodules
colonized with these strains of Rhizobiumjaponicum (Mitch-
ell, 198 I). This compound is a irreversible inhibitor of ethyl-
ene production from methionine, as it blocks the conversion
of S-adenosylmethionine to I -aminocyclopropane- I -carbox-
ylic acid (Ballio, 1981).
Phaseolotoxin (17), a tripeptide, has been isolated from
cultures of Pseudomonas syringae pv. phaseolicola. This
toxin and related compounds which co-occur with it, irre-
versibly inhibit ornithine carbamoyltransferase and produce
chlorosis in the host (Ballio, 1981).
The toxins of many members of the fungal genus Al-
ternaria produce phytotoxins; of these, many [such as AM-
toxin I (18)] are peptides. The fungal pathogen Alternaria
mali on apples produce necrotic lesions on the leaves, shoots,
and fruits of susceptible cultivars (Natori et aI., 1981). Al-
ternaria kikuchiana, which causes black spot disease on the
Japanese pear (Pyrus serotina) produces phytotoxins which
are based on N-acetylphenylalanine and a C IO fatty acid
(Harborne, 1986).
Enniatins are peptides produced by Fusarium species. En-

alanin~ef ~ 'i~0
H" N~N
I! 0 OH

"" ~,l~" ~ "~"

H>Cl,-~o S
o
N
I H
tryptophan
0
hydroxyproline HNI ~k "~H
~ alanine

OH

!<
threonine
phalloidin (8)
(a phallotoxin)

~IH I! 0II i

>Ct
alanine 0
H" N~N
Nii ; H

~YPtOPhan
H, 0 '-"',
N /
HO ' 0 h ~ #

r
H NOS
~ I
hydroxyproline ~N-;CH
0
k
H 0
"-"'H alanine

I threonine
H OH

phalloin (6)

(a) (a phallotoxin)

Fig. 14.3 (a & b). Phallotoxins and amatoxins.

 rr
Peptide.~ 239

hydroxylated

~ --LJ--
OH OH tryptOPhan

""d:EN"' )cQ~'
a-amanitin (7) H 0 H glycine
(an amatoxin) I I °

H ° HI O">s, H 0 0 ~ isoleucine

r
hydroxyproline H ~
N", ,.~ ~ N
">"'H --"'N 'H
asparagine 0 ~ glycine
o NH2 cysteine
hydroxylated
tryptophan

~ i ~ if 'j

m ':."
glycine 0

H,. N-r\N~
~\,l:
""><-t. 0

O~ A _~ isoleucine

H ~N i I H7
r II
0 0
hydroxyproline ...., N............ I.~ H N,
""H -"'N~ H

o cysteine ~ glycine
asparagine 0 NHz amanullin (14)
(b)

Fig. 14.3. (continued)

niatin (19) (10-80 fLg/ml) reduces growth of wheat seed- selective advantage from opine synthesis by transformed
lings. Root elongation is inhibited more than leaf develop- plant cells (Tremblay et aI., 1987).
ment (Burmeister and Plattner, 1987).
Peptides from Blue-Green Algae
Opines A number of blue-green algae are known to produce
highly toxic compounds. When individuals of these organ-
Infection of susceptible plants with virulent cells of Agro-
isms occur in large numbers, as in algal blooms, they may
bacterium results in the development of crown gall tumors
produce severe poisoning problems in animals. The agents
and the synthesis of peptide metabolites called opines (Chil-
responsible belong to many diverse groups of compounds
ton et aJ., 1985) (Fig. 14.5). These compounds involve con-
(Moore, 1977, 1981); the toxin from Microcystis aeruginosa
densation of 2-oxo acids and basic amino acids such as L-
is a cyclic peptide. This compound is heat stable, dialyzes
arginine, L-histidine, and L-lysine (Luckner, 1990). The
slowly, and has an LDso intetperitoneally of 0.47 mg/kg in
genes of opine synthesis are carried by bacterial Ti or Ri
mice. Poisoning is rapid; symptoms appear in 15-45 min.
plasmids and are transferred to the plant cells in which they
One peptide from this organism, cyanoginosin-LR (20), has
are then expressed. The particular opines that are found in
been studied in some detail (Botes et aJ., 1984) (Fig. 14.6).
a given crown gall tumor correspond to those that can be
metabolized by the inciting bacteria. Further, opine synthesis
Siderophores
is a useful criterion for transfer of genetic material because
opines are unique products of transformed cells and are not A number of fungi, blue-green algae, and bacteria release
produced by free-living bacteria or nontransformed plant compounds into the environment that are highly effective
cells (Sederoff et aJ., 1986). Agrobacteria appear to gain a in chelating iron (also see Chapter 13). These organisms
240 Peptides

~(CH'hCH'

HO,C N

fusaric acid (10) coronatine (13)

CO,H
I (CH,hCHCH,", /
CO-NCH,
\
/CH2~H CH CHCH,
HO,C-CH- NH
I
NH
I kH bo
HOzC-CHz CHzCONHz
fO kH
Iycomarasmin (11) C,H,CH =C ):H'
\CH,-CO
o
II tentotoxin
H,N·1H.C.NH.~H.CO,H Alternaria tenuis, cotton chlorosis
CH, CH.OH
I I
o ~H, NH,
~C--C.OH
I I
NH-CH,

tabtoxin (12)

D-cys
/'
L-Ieu "- D-cys
\
D-Ieu _
/
L-val

malformin
(a) Aspergillus niger

Fig. 14.4 (a-b). Peptide phytotoxins.

apparently deplete iron from the surrounding medium to the
extent that competing organisms cannot survive. Several of
the compounds involved are peptides (Fig. 14.7) (Aaronson,
1981; Winkelmann et al., 1987).
Peptides from Higher Plants
Peptides in higher plants can be divided into two major
categories. Some have unique structures and functions,
whereas others are involved in the synlbesis or degradation
of proteins (Higgins and Payne, 1982). In this treatment,
emphasis will be given the former type. There are limited
data concerning peptides of either type from plants. A series
of peptides known as phytochelatins has been shown to che·
late heavy metals. A number of plants, including those of
certain members of the Celastraceae, Euphorbiaceae, and
Rharnnaceae, contain peptide alkaloids which are discussed
under Peptide and Macrolide alkaloids (Chapter 37). Anum·
ber of lectins or hemagglutinins are composed of peptide
units, but are discussed under Proteins below.
Several peptides can be absorbed intact by plants. The
three peptides DL·ala·DL·asp, DL·ala·DL·met, and DL·ala·
DL·leu are not hydrolyzed by the pitcher liquid of Ibe insec·
tivorous plant Sarracenia, but are taken up intact into leaves.
The mechanism of absorption is unknown (Higgins and
Payne, 1982). However, during the germination of barley
grains, peptides produced by breakdown of storage proteins
are actively transported by the scutellum (Higgins and
Payne, 1982).
Glutathione
Glutathione ('Y·glu·cys·gly) can occur in a reduced or an
oxidized form. The two are readily interconverted by the
enzyme glutathione reductase or by numerous redox re-
agents (Higgins and Payne, 1982). Both the peptide and the
 Peptide.s 241

CD3 CD3
"'-./
CH
O~ I
~C---C-O ",0
/ '-.... /,?
HN C

CH30O-CH'-CH'-CH''''''''"~H Hl""'CH3

- -:::?C, NH
0" /
HN _____ C..---c~
II ~O
AM-toxin I (19) CH,

~""OH
o CH
I'
CH, CH,OH
I
H,N-CH-CO-NH-CH-CO,H
I
serine tabtoxin (17) isolabloxin (16)

rhizobitoxin (14)

o
II ~H
HN-P(OH)-O~O,NH, NH-C-NH
I
(CH,h
I 2

I 1 3
CH (CH')4
I
H,N--CH---Co- NH-CH-CO --NH-CO,H

phaseolotoxin (15)

(b) (NO-phosphosulfamyl)ornithylanylhomoarginine

Fig. 14.4. (continued)

enzyme appear to be ubiquitous in plants and animals. Al-
though several possible functions in animals have been pro-
posed, the role is not as clear in plants. Glutathione is a key
compound in the ,,{-glutamyl cycle and may be involved in
the transport of amino acids and peptides. In the chloroplast,
glutathione may be involved in maintaining reducing condi-
tions and the stability of enzymes containing sulfhydryl
groups (Higgins and Payne, 1982).
y-Olutamyl Peptides
Although ,,{-glutamyl peptides are common in plants, they
are not found in animal cells. The majority are dipeptides,
although a number oftripeptides are found. Significant quan-
tities of "{-glutarnyl peptides occur, especially in storage or-
gans of plants. For example, 34% of the nonprotein amino
acid nitrogen of kidney bean seeds (Phaseolus vulgaris) is
present as "{-glutamyl-S-methyl-L-cysteine (Higgins and
Payne, 1982). Individual compounds of this type are dis-
cussed in Chapter 13.
Phytochelatins
Many plants respond to the presence of heavy metals
by the production of peptides that are rich in cysteine. The
presence of "{-glutamyllinkages indicates that these peptides
are not primary gene products. Glutathione or "{-glutamyl-
cysteine have been suggested as precursors (Gekeler et aI.,
1988). Many have the structure ,,{-glutamic acid-(cysteine)n-
glycine with n = 2-11. Those from several legumes have
the general structure (,,{-glutarnylcysteine)n-f\-alanine with n
= 2-7 (Grill et aI., 1986). Phytochelatins have been found
in several plants, including Anethum graveolens, Berberis
stolonifera, Catharanthus raseus, Dioscarea camposita, Fu-
maria parviflora, Galium mo/lugo, Glycine max, Malva sylv-
estris, Phaseolus aureus, Phaseolus multiflorus, Phaseolus
242 Pep/ides

D,L-succinamopine L,L-succinamopine L,L-succinamopine

ladam

H. n
~ __ ? O NH yCOH
' HO'VyCO,H
HO,c~ N A ~!'IH ~ H"NH
HOC V H,N N~ HN NH _ H,[
2 ~"""'C02H C02H 2 ~ ~"C02H

L,L-succinopine octopine nopaline

ladam

HO,C~CO'H H02C~C02H
o H 'NH
H , H --NH

H2N~C02H AX CO,H

succinamopine leucinopine

Fig. 14.5. Representative opines.

vulgaris, Rauvolfia serpentina, Rhazya stricta, Rosa canina,

Silene cucubalus. Solanum marginatum, and Thalictrum
dipterocarpum (Grill et aI., 1985, 1986).
A similar cadmium-binding complex of peptides is pro-
duced by the alga Chlorella fusea as well as other Phyto-
phyta (Gekeleret al., 1988). Phytochelatins have been identi-
fied in the roots of heavy-metal-sensitive Aeer
pseudoplatanus and resistant Silene cueubalus plants grown
in zinc-rich soil, whereas plants grown in the absence of this
metal lacked these peptides. Metal-binding phytochelatins
appear to be specifically induced in plants in heavy-metal-
enriched ecosystems (Grill et aI., 1988).

PROTEIl'IS

Proteins are found in all organisms, play many roles, and

vary widely in structure and properties. The enzyme ribulose
1,5-bisphosphate carboxylase (EC 4.1.1.39) is probably the
world's most abundant protein, as it is the major protein
present (up to 50%) in the leaves of plants (Ramshaw, 1982).
However, in the following discussion, only those proteins
with toxic or inhibitory properties to animals or fungi or
other noteworthy activity will be discussed. Several groups
of proteins from plants are known to be toxic to animals.
The most important group of these is called lectins or hemag-
glutinins. Many legume seeds also contain protease (or tryp-
cyanoginosin-LR (20) sin) inhibitors (Weder, 1981). Similar compounds are found
in plants of the Solanaceae (Ramshaw, 1982).
Fig. 14.6. Cyanoginosin-LR.
Phytohemoglobins
Plant hemoglobin is known to occur in eight families of
dicotyledonous plants. These farailies, the Betulaceae, Casu-
 Peptides 243

aerobactin [Aerobacter (Klebsiella) aerogenesJ

HH Hn HH
H,N(CH,J,N.C(CH,J,CONH(CH,J,N.C(CH,J,CONH(CH,J,N.CCHJ

desferal (Streptomyces pilosus)

IT fH iO,H HITI
CHJC.N(CH,JJNHIiCH'iCH'IiNH(CH,JJN.CCHJ

° OH °
(a) schizokinen (Bacillus megaterium) enterochelin (Escherichia coli) (b)

(c) ferrichrome (Ustilago sphaerogena)

Fig. 14.7 (a-c). Structures of several siderophores.

244 Peptides
arinaceae, Coriariaceae, Datiscaceae, Eleagnaceae, Faba-
ceae, Myricaceae, Rhamnaceae, Rosaceae, and Ulmaceae
(Landsmann et al., 1986), are not closely related; most of
the plants have a symbiotic relationship with nitrogen-fixing
bacteria or actinomycetes. The plant gene has a 4-exon-3-
intron structure, while in vertebrates exons 2 and 3 are fused,
forming a long internal exon (Kubitzki et al., 1991). In order
to account for the peculiar distribution of plant hemoglobin,
either the gene must be widespread, but only occasionally
expressed, or horizontal transfer of genetic material must
have occurred-possibly from vertetrates (Kubitzki et aI.,
1991). At present, neither possibility can be confirmed.
Lectins or HemaggIutinins
Lectins or hemagglutinins are well known among the nat-
urally occurring plant proteins with toxic effects in animals
(Liener, 1991; Lis and Sharon, 1981). This is a somewbat
heterogeneous collection of proteins that agglutinate cells
and exhibit antibody-like sugar-binding activity (Liener et
al., 1986; Ramshaw, 1982). Agglutination is inhibited by
sugars, oligosaccharides, glycosides, and glycoproteins. Pre-
cipitation occurs in the presence of glycoproteins and poly-
saccharides (Liener et al., 1986). Lectins are necessarily
multivalent; that is, they bind at least two sugar molecules
in order to cause precipitation. The sugar specificity of lec-
tins is usually dermed in terms of the monosaccharide(s}
that inhibit lectin-induced agglutination (Liener et al., 1986).
Lectins often constitute 6-11 % of the plant's total protein
(Liener, 1991).
These proteins occur in the seeds of many plants but are
especially common in the Fabaceae (Leguminosae) (more
than 600 species) and the Euphorbiaceae (lectins also occur
in other organisms such as fungi, bacteria, and animals). In
legnmes, lectins are usually found in the cotyledons (Liener,
1991). Well-known plant lectins are concanavalin A, from
jack beans (Canavalia ensiformis), favin, from the broad
bean (Vicia Jabal, and phasin, from the kidney bean
(P haseolus vulgaris) (Ramshaw, 1982). The toxicity of lec-
tins differs considerably (Liener, 1991; Liener et al., 1986).
Data for lectins are given in Liener et al. (l986) and Lis and
Sharon (1981).
The brilliant red black seeds of Abrus precatorius (preca-
tory bean) contain abrin, an extremely toxic protein (Ghosal
and Dutta, 1971). Seeds of this plant are commonly used in
the tropics to make necklaces and other jewelry. One seed,
if thoroughly masticated, is sufficient to cause death in a
child (Kingsbury, 1964). The lectins of this plant primarily
bind galactose and are similar in properties to those of ricin
(see below). The lectin has a molecular weight of 65,000
and is composed of dissimilar peptides.
Robinia pseudoacacia, the black locust (Fabaceae), is a
common cultivar in the United States and in Europe and
is commonly escaped from cultivation. The bark contains
several toxic proteins (Kingsbury, 1964). The seeds are also
known to contain a distinct lectin (Liener et aI., 1986).
Seeds of members of the Euphorbiaceae are also known to
be highly toxic (Anon., 1987; Griffiths et al., 1987). Protein
extracts of the seeds of Ricinus communis, castor bean (Eu-
phorbiaceae), contain proteins that are antigenic and aggluti-
nate defibrinated blood and red blood cells in vitro. As few
as two to four seeds of Ricinus communis can be deadly
and eight are almost always lethal (Ishiguro et al., 1971;
Kingsbury, 1964). Ricin is a dimeric protein with two differ-
ent peptide chains (63,000 MW). The chains have been puri-
fied and the amino acid sequence of both chains reported.
The A chain is capable of inactivating the 60 S subunit of
the ribosomes of eukaryotic cells resulting in inhibition of
protein synthesis. The B chain binds galactose and saccha-
rides containing nonreducing j3-galactosyl units and permits
entry into the cell by the toxic subunit (Liener et al., 1986).
A number of other agglutinins are found in seeds of this
plant.
The seeds of Aleurites [ordii, the tung nut (Euphor-
biaceae), formerly cultivated in the south central United
States, and presently cultivated in Argentina and China pro-
duce toxic proteins. There are many references to human
poisoning by this plant, as the seed is large and, to many,
appears edible. Press cake from the manufacture of tung
oil also is toxic and difficult to detoxify. Cocarcinogenic
diterpenes have been recently reported from this plant and
are undoubtedly responsible for part of the toxic activity
(Beutler et al., 1989). Plants of Jatropha curcas and J. mul-
tiftda, also from the Euphorbiaceae, contain toxic proteins,
sometimes called •• curcin. " Both species are planted widely
in the tropics.
Several members of the Loranthaceae (the mistletoe fam-
ily) have long been used as medicinal plants. Viscum album,
a European species, was used in this manner and there is
an extensive folklore associated with it. The toxic fraction
(sometimes called viscotoxin) is a mixture of several related
peptides which affect heart muscle (Ramshaw, 1982). One
of these, viscotoxin B, has 46 amino acids, a 9170 MW, and
an LD,o (mouse) of 0.78 mg/kg. Viscotoxin A has 46 amino
acids (Olson and Samuelsson, 1972; Samuelsson and Pet-
tersson, 1971; Sandberg and Samuelsson, 1961). Although
the froits of the southeastern American species, Phoraden-
dron villosum and P. flavescens (mistletoe), are also poison-
ous, they contain j3-phenethylamine and tyramine (see Chap-
ter 28).
Biological Activity of Lectins
The interactions of Rhizobium bacteria and plants of the
Fabaceae are highly specific. It is believed that lectins play
a major role in this specificity (Etzler, 1986, Liener, 1991;
Sharon and Lis, 1989). Several models have been proposed
to explain this interaction. The lectin appears to act as a
"glue" to hold the bacterium in place (Riidiger, 1984). It
appears that binding of host lectins may send a signal to the
bacterium that turns on a gene, which leads to the synthesis
of a specific polysaccharide on the bacterial cell wall that
serves as a receptor site for the lectin (Liener, 1991).
A mixture of lectins of Phytolacca americana, pokeweed

(Phytolaccaceae), is known to be highly mitogenic (pro-
motes mitotic cell divisions). Individual components of the
mixture have been isolated and their binding properties de-
termined (Liener et aI., 1986).
Another role of lectins is in the interactions of the plant
against insects and microbial pathogens (Etzler, 1986,
Liener, 1991; Sharon and Lis, 1989). The lectin from
PfUlseolus vulgaris has a lethal effect on the larvae of a
bruchid beetle, presumably because of the binding of the
lectin to epithelial cells lining the midgut of this insect. Such
binding inhibits uptake of nutrients (Liener, 1991). Soybean
lectin inhibits larval growth of Manduca sexta (Liener,
1991). A protein from the seeds of a wild variant of Phaseo-
Ius vulgaris is toxic to a bean weevil (Zabrotes subfascia-
tus), which is a common bean pest. Transfer of the allele
for the production of this lectin to nonresistant bean cultivars
and back-crossing resulted in plants with high levels of insect
resistance (Liener, 1991).
Lectins from wheat germ, potato, and soybean have been
shown to inhibit fungal growth (Liener, 1991).
The effect of lectins in the diets of humans has been
reviewed (Liener, 1991; Liener et al., 1986). Clearly, un-
cooked legume seeds should not be eaten. The effects of
cooking on lectins is not clear, but uncooked seeds contain-
ing these compounds should be considered toxic and inedible
under any conditions.
Proteinase InbIbitors
A number of proteinase inhibitors, often called trypsin
inhibitors, are known to occur in seeds of legumes (Ryan,
1981; Weder, 1981). These polypeptides often inhibit both
trypsin and chymotrypsin and block digestion of many leg-
ume seeds. Cooking deactivates most of these compounds.
Sweeteners
A number of peptides and proteins modify taste in hu-
mans and presumably in other animals (Ramshaw, 1982).
Aspartame (21) (Fig. 14.8), a purely synthetic dipeptide, is
widely used as a sweetening agent in many countries. Other
sweet-tasting compounds, such as those of serendipity ber-
ries (Dioscoreophyllum cumminsii, Menispermaceae), mira-
cle froit (Richardella dulcifera, formerly known as Synsepa-
lum dulcificum, Sapotaceae), and katemfe (TfUlumatococcus
danielli, Marantaceae) are proteinaceous. The sweet com-
fH,CO,H
H,NCHCONHCHCO,CH,
I
CH,C,H,
aspartame (21)
Fig. 14.8. A'partame.
Peptides 245
pound of serendipity froit, monellin, is 2500 times sweeter
than sucrose and has a molecular weight of 11 ,000. The
proteins from miracle froit cause sour substances to taste
sweet but have no inherent taste. These compounds are dena-
tured by heating, limiting their usefulness as sweetening
agents (Inglett, 1984). Thaumatin, a protein of 207 amino
acid residues, occurs in the West African shrub Thaumato-
coccus danielli (Marantaceae) and is about 5000 times swee-
ter than sucrose. It is used as a food additive in some coun-
tries, but high cost has limited its wider use. The genes
encoding thaumatin have been cloned and expressed in Esch-
erichia coli, but yields were disappointingly low. Expression
in SaccfUlromyces cerevisiae was better (McPherson and
Parish, 1987).
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BERny, J., Handbook of Antibiotic Compounds, Vols. 1-12, CRC
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CHILTON, W. S .• E. HOOD, and M. CHILTON, Absolute stereochemis-
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GRILL, E., W. GEKELER, E. WlNNACKER, and M. H. ZENK, Homo-
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15
Carbohydrates

Introduction other compounds as glycosides. Whereas a few sugars are

Simple Sugars primary metabolites and are Ubiquitous in plants (Fig. 15.1),
Simple Sugars-Secondary Metabolites many others are limited in distribution. Some sugars are
Nomenclature potent inhibitors of metabolism (Engel, 1992).
2-Deoxyhexoses Monosacchatides are polyhydroxy aldehydes (aldoses) or
6-Deoxyhexoses polyhydroxy ketones (ketoses). These monosacchatides usu-
Methoxy Sugars ally contain several chiral centers; those which have the same
Branched-Chain Sugars configuration as o-glyceraldehyde at the chiral C-atom
Sugar Carboxylic Acids farthrest from the carbonyl group belong to the o-series (0-
Amino Sugars glucose, o-fructose, etc.), whereas their counterparts belong
Biological Activity of Sugars to the L-series (L-rharnnose, L-fucose, etc.) (Engel, 1992;
Disacchatides and oligosacchatides Luckner, 1990). Monosacchatides exist as cyclic hemiace-
Sucrose tals (pyranoses and furanoses) rather than as open chain
OJigosacchatides forms by which they are frequently represented. The py-
Fructans ranose and furanose forms involve an additional, anomeric
Polysacchatides: Reserve and Structural Forms chiral center, represented by at- or 13-. The anomeric forms
Energy Storage Compounds Derived from Sugars of monosacchatides equilibrate in solution (Luckner, 1990).
Structural Carbohydrates The six-membered forms are best represented by chair con-
Callose formations; in general, several conformers of a sugar may
Pectins exist and can be interconverted.
Plant Gums There are several ways in which sugar structures are rep-
Algal Polysacchatides
resented. In some instances in this book, sugars are repre-
Chitin
sented in a chair-boat type of structure. However, many of
Biological Activity of Oligosacchatides and
the following figures include Fischer projections [in which
Polysacchatides
the aldehyde or keto group is at the top, and the penultimate
Sugar Alcohols
(from the bottom) OH group is on the right in o-sugars (R),
Polyols
the same as the relationship at the chiral carbon of ( + )-0-
Cyclitols
glyceraldehyde, and on the left in L-SUgars (S)], Haworth
L-Ascorbic Acid
Glycosides in Plants perspective formulas (El Khadem, 1988), and other repre-
Indigo-producing Glycosides sentations of sugars.
Lactone-forming Glycosides Solutions of aldoses at equilibrium contain mixtures of
Sugar Esters at least two (at and 13) furanoses and two (at and 13) pyranoses.
References Typically, the two pyranose forms predominate at equilib-
rium. The anomeric carbon is chiral (C-I of aldoses and C-
2 of ketoses). In the o-series, if the OH on the anomeric
Il'ITRODUCTION
carbon is to the right in a Fischer projection or below the
A large number of sugars or sacchatides are found in nature. plane of a Haworth perspective formula, the isomer is at and
These may occur singly (monosacchatides) or as dimeric, it is 13 if the OH is to the left or above. Conversely, in the
trimeric, oligomeric, or larger aggregates or combined with L-series, the at anomer has the OH at carbon 1 to the left or

247
248 Carbohydrates

above and the 13 anomer has this OH to the right or below
(El Khadem, 1988).
SJlIWLE SUGARS
o-Glucose (1), o-galactose (2), o-glucuronic acid (3), D-ga-
lacturonic acid (4), o-xylose (5), and L-arabinose (6) consti-
tute the major sugars of carbohydrates of higher plants (El
Khadem, 1988).
Monosaccharides are divided into two major groups de-
pending on whether their acyclic forms possess an aldehyde
or a keto group, that is, whether they are aldoses or ketoses.
Monosaccharides can also be grouped by the size of the ring
that they form, for example, furanoses or pyranoses. Both
aldoses and ketoses may be designated as to size, for exam-
ple, as aldopentoses or 2-hexuloses (El Khadem, 1988). Sug-
ars that possess a hemiacetal linkage may be easily oxidized
and are known as reducing sugars. All monosaccharides are
reducing, whereas many complex saccharides are nonre-
ducing.
Many other sugars are involved in primary metabolic
pathways such as the oxidative and reductive pentose cycle,
glycolysis, and photosynthesis.
Glucose, xylose, mannose, and arabinose often are associ-
ated with wall materials in plants (Fig. 15.1).
The Calvin cycle, associated with the photosynthetic as-
similation of CO2 , represents the principal source of phos-
phorylated sugars in plants. o-Fructose 6·phosphate acts as
the precursor of many of the monosaccharide moieties in
plants (Feingold and Avigad, 1980). Kinases capable of
phosphorylating o·glucose, o-fructose (8), o·mannose, and
o-glucosamine (9) at C-6 and L-arabinose, D·galactose, and
D-galacturonate at Col have been demonstrated in a large
number of plants (Feingold and Avigad, 1980).

CHO CHO
I I
CHO H-C-OH HO·C-H
I I I
H-C-OH H-C-OH H-C-OH
I I I
CH,OH CH,OH CH,OH

D-glyceraldebyde D-erythrose D-threose

CHO CHO CHO

CHO
I I I I
H-C-OH HO-C-H H-C-OH HQ-C-H
I I I I
H-C-OH H-C-OH HO·C-H HO-C-H
I I I I
H-C-OH H-C-OH H-C-OH H-C-OH
I I
I I CH,OH
CH,OH CH,OH CH,OH

D-ribose D-arabinose D-xylose D-Iyxose

CHO CHO CHO CHO

I I I I
H-C-OH HO'C-H H-C-OH HQ-C-H
I I I I
H-C-OH H-C-OH HO·C-H HO-C-H
I I I I
H-C-OH H-C-OH H-C-OH H-C-OH
I I I I
H-C-OH H-C-OH H-C-OH H-C-OH
I I I I
CH,.OH CH,.OH CH,.OH CH,·OH
D-allose D-altrose D-gJucose D-mannose
CHO CHO CHO CHO
I I I I
H-C-OH HO-C-H H-C-OH HO-C-H
I I I I
H-C-OH H-C-OH HO-C-H HO-C-H
I I I I
HO-C-H HO-C-H HO-C-H HO-C-H
I I I I
H-C-OH H-C-OH H-C-OH H-C-OH
I I I I
CH,·OH CH,·OH CH,·OH CH,.OH

(.) D-gulose D-idose D-galactose D-talose

Fig. 15.1 (a & c). Structures of some important primary monosaccharides.

 Carbohydrates 249

~
OH o
OHPH ~OH
HO 0
~OH
0
HO
HO ~:H~H 0 HO
HO H HO
HO
NH, H
OH OH OH

a-D-glucopyranose (1) a-D-galactopyranose (2) o:-D-mannopyranose (7) a-D-glucosamine (9)

CO,H 0 O~'=OlH HO 0 HOCHDo",--PH

~HHO
HO OHO
OH H ~CHlOH.I . ,
OHCH,OH
OH OH HO OH OHH

a-glucuronic acid. (3) ,,-gaIac!1lronic acid (4) ,,-D-fructopyranose (8) P-D-fructofuranose

"x::.. ';;-t.,0
HOCHYu°~OH
H
OH 0 H 0 CH,OH

H~H'H HOCH, HH<lu~HHDoH

OH H H OH HO OHOH
poD-ribose (10) ,,-D-xy)ose (5) a-D-ribulose

~HlOH

t---r
HX:°'6H<CHl OH C=O

H OH
HO-~-H
I
H-{;-OH
OH H
I
CH,OH
a-D-xylulose D-xylulose (open chain)
(b)

Fig. 15.1. (continued)

Many sugars occur in combined forms with nucleotides
(Feingold and Avigad, 1980). The amount of nucleotide sug-
ars is usually 10-25% of the pool of soluble nucleotides
extracted from plant tissues, but extraction and chromato-
graphic separation may lead to degradation of these nucleo-
tides. UDP-G1ucose usually predominates and is ubiquitous
in plants, but in seeds in which starch synthesis is intense, the
major nucleotide sugar is adenosine 5'-(a-D-glucopyranosyl
pyrophosphate) (ADP-glucose) (Feingold and Avigad,
1980). Techniques for analysis of nucleotide sugars have
been reviewed (Feingold and Barber, 1990).
Several epimeric pairs of monosaccharides are produced
by epimerization of nucleotide sugars (Luckner, 1990). For
example, UDP-D-glucose-4-epimerase converts UDP-D-glu-
cose to UDP-D-galactose. Enzymes that produce the other
epimers are also known. A C-2 epimerase may be involved
in the interconversion of D-glucose and o-mannose (Karr,
1976).
The reactions of monosaccharides and oligo saccharides
have been summarized (Dey, 1990; Gander, 1976).
Combined monosaccharides are widespread and occur in
all plants; free monosaccharides also are widespread, but
usually are not accumulated.
Techniques for the analysis of carbohydrates have been
reviewed (Churms, 1990; EI Khadem, 1988; Sturgeon,
1990).
SIMPLE SUGARS-SECONDAKY IllETABOLITES
Although most of the sugars discussed above are distributed
widely, a number of others are limited in distribution and
may be considered to be plant secondary compounds. A
number of unusual sugars are found in glycosides, especially
in cardiac glycosides and glycosidic Solanum alkaloids.
Other uncommon sugars are found in antibiotics produced
by bacteria and fungi.
Nomenclature
The trivial names of the common sugars, including a1-
doses with up to six carbon atoms and ketohexoses, are still
used (Fig. 15.1). These include the D- and L-forms of glycer-
aldehyde, erythrose, threose, ribose, arabinose, xylose, lyx-
ose, allose, altrose, glucose, mannose, gulose, idose, galac-
tose, and talose (El Khadem, 1988). The prefixes derived
250 Carbohydrates

from these names are used to designate the configuration of
a group of consecutive chiral carbon atoms to which other
groups are attached. The italicized prefix derived from the
name of the aldose with the same configuration is preceded
by the appropriate n or L symbol and followed by the root
denoting the total number of carbon atoms in the chain. Keto-
ses in which the carbonyl group contains C-2 are named by
prefixing one of these prefixes to a root denoting the total
number of carbon atoms in the chain and suffixing "ulose"
to make, for example, n-arabino-hexulose (n-fructose)
[however, the trivial names of the four n-hexuloses (n-fruc-
tose, n-psicose, n-sorbose, and n-tagatose) are accepted]. If
the carbonyl group is at a higher numbered position, the
appropriate number is used, for example, n-arabino-3-hexu-
lose (El Kbadem, 1988). Replacement of a hydroxy group
with a hydrogen yields deoxy sugars such as 6-deoxy-n-
galactose and 6-deoxY-L-mannose (which have the accepted
names of n-fucose and L-rhamnose). The names of deoxy
sugars may be used to name a product in which the hydroxyl
group of a sugar has been replaced by an amino group. For
example, n-glucosamine is named 2-amino-2-deoxy-n-glu-
cose. For more complex sugars, El Kbadem (1988) should
be consulted.
2·Deoxybexoses
2-Deoxy sugars may be formed by direct reduction at
the level of nucleotides by pyridine nucleotide-dependent
dehydrogenases in analogy to the biosynthesis of 2-deoxy-
n-ribose (11) [which should more correctly be named 2-
deoxy-n-erythro-pentose (El Kbadem, 1988)] from n-ribose
(10) (Luckner, 1990). (See Fig. 15.2.) Both n-ribose and 2-
deoxy-n-ribose are components of nucleic acids.
Among the 2-deoxy sugars found as the carbohydrate
portion of cardiac glycosides and other glycosides in plants
are n-cymarose (2,6-dideoxy-3-0-methyl-n-ribo-hexose)
(12), n-sarmentose (2,6-dideoxy-3-0-methyl-n-xylo-hex-
ose) (13), L-oleandrose (2,6-dideoxy-3-0-methyl-L-arabino-
hexose) (14), n-diginose (2,6-dideoxy-3-0-methyl-n-lyxo-
hexose) (15), n-digitoxose (2,6-dideoxy-n-ribo-hexose)
(16), and n-boivinose (2,6-dideoxy-n-xylo-hexose) (17)
(Courtois and Percheron, 1970).
6·Deoxyhex08es
A number of 6-deoxyhexoses also are widespread in
plants, but these compounds are especially common in car-
diac glycosides (Courtois and Percheron, 1970). These sug-
ars are formed from the corresponding hydroxylated mono-
saccharides (Luckner, 1990). Among the 6-deoxyhexoses
are L-acofriose (6-deoxy-3-0-methyl-L-mannose) (18), L-
acovenose (6-deoxy-3-0-methyl-L-talose) (19), n-allometh-
ylose (6-deoxy-n-allose) (20), L-altromethylose (6-deoxY-L-
altrose) (21), n-antiarose (6-deoxy-n-gulose) (22), n-boivi-
nose (2,6-dideoxy-n-xylo-hexose) (17), n-cymarose (2,6-di-

,
CH,OH
, CH,OH
,
CH,OH
,
c=o ,
c=o
,
CH,OH
c=o ,
I
c=o
HOC-H
,
H-C-OH

I
CH,OH
,
H-C-OH H-C-OH
, ,
H-C-OH
CH,OH CH,OH CH,OH

dihydroxyacetone D~erythrulose D-xylulose D-ribulose

,
CH,OH ,
CH,OH
, CH,OH
,
CH,OH

,
c=o ,
c=o ,
c=o ,
c=o
,
HOC-H ,
H-C-OH
,
HOC-H
,
H-C-OH

,
HOC-H HOC-H
, ,
H-C-OH
,
H-C-OH

,
H-C-OH ,
H-C-OH
,
H-C-OH
,
H-C-OH
CH,-OH CH,-OH CH,.OH CH,-OH

D~tagatose D-sorbose D-fructose D-psicose

CHO
, ,
CHO ,
CHO
,
CHO
HOC-H
, ,
H-C-OH HO·C-H
, ,
H-C-OH

,
H-C-OH
,
HOC-H ,
H-C-OH HOC-H
,
,
HOC-H
,
H-C-OH ,
H-C-OH HOC-H
,
,
HOC-H
,
H-C-OH ,
HOC-H
CH,-OH
,
H-C-OH
CH,-OH
CH,-OH CH,.OH

(c) L-glucose D-glucose L~galactose D-galactose

Fig. 15.1. (continued)
 Carbohydrates 251

NH2 reduced thioredoxin NU 2

O' O' (xN) ( OXidtz:~:~or~:OXin O' (x>

I INN ~ I I N

I'
O'-P-O-P-O~
tI
00 HHHH
ribonucleotide
reductase
O'-P-O-P-O~
II II
00 HHHH

OH OH OH H

adenosine diphosphate (ADP) 2'-deoxyadeoosine diphosphate (dADP)

H HHH HO~O
HOCHX-;;0';;j<0H HOCHx-;;0:t<0H
CH, OH
H H H OCH,H H

OH OH OH H CH, H
2,6-dideoxy-3-C-methyl-O-methyl-
D-ribose (10) 2-deoxy-D-ribose (11) L-ribo-hexose or L-c1adinose

CHO CHO CHO CHO

I I I I
CH, CH, CH, CH,
I I I I
H-C-OH H-C-OCH, H-C-OCOCH, CH,OC -H
I I I I
H-C-OH H-C-OH H-C-OH H-C-OH
I I I I
H-C-OH H-C-OH H-C-OH H-C-OH
I I I I
CH, CH, CH, CH,

D-digitoxose (16) D-cymarose (12) D-3-acetyl digitoxose D-sarmentose (13)

CHO CHO
I
CH,
,
CHO
,
CHO CHO
I I
CH, CH, CH, CH,
I
H-C-OCH,
I I I
I
H-~-OCH3
,
HO-C-H CH,-C-OCH,
I
HO·C-H
I
HOC-H
I
H-C-OH
, ,
H-C-OH H-C-OH
I
HO-C-H
HOC-H
I
H-C-OH
, ,
H-C-OH
H-C-OH
I
HO·C-H
I

CH, CH, CH, I

CH, CH,
L-oleandrose (14) D-diginose (15) D-boivinose (17) D-cladinose L-mycarose

Fig. 15.2. 2-Deoxyhexoses.

deoxy-3-0-methyl-D-ribo-hexose) (12), D-diginose (2,6-di- by the action of S-adenosyl-L-methionine-dependent methyl-

deoxy-3-0-methyl-D-lyxo-hexose) (15), D-digitalose (6-
deoxy-3-0-methyl-D-galactose) (23), D-digitoxose (2,6-di-
deoxY-D-ribo-hexose) (16), D-fucose (6-deoxY-L-galactose)
(25), L-fucose (6-deoxY-L-galactose) (24), L-oleandrose (2,6-
dideoxy-3-0-methyl-L-arabino-hexose) (26), D-quinovose
(6-deoxY-D-glucose) (27), L-rhamnose (6-deoxY-L-mannose)
(28), D-sarmentose (2,6-dideoxy-3-0-methyl-o-xylo-hex-
ose) (13), L-talomethylose (6-deoxY-L-talose) (29), D-theve-
tose (6-deoxy-4-0-methyl-D-glucose), L-thevetose (6-
deoxy-4-0-methyl-L-glucose) (30) (Fig. 15.3) (Courtois and
Percheron, 1970). D-Fucose (25) is a component of glycolip-
ids found in seeds of the Convolvulaceae.
lIfethoxy Sugars
Methoxy sugars arise by methoxylation of other sugars
(Fig. 15.2 and 15.3). For example, o-cymarose (12) arises
transferases (Luckner, 1990). Among the methoxy sugars
are o-cymarose (2,6-dideoxy-3-0-methyl-o-ribo-hexose)
(12), D-sarmentose (2,6-dideoxy-3-0-methyl-D-xylo-hex-
ose) (13), L-oleandrose (2,6-dideoxy- 3-0-methyl-L-arabino-
hexose) (14), D-diginose (2,6-dideoxy-3-0-methyl-o-lyxo-
hexose) (15), L-acofriose (6-deoxy-3-0-methyl-L-mannose)
(18), L-acovenose (6-deoxy-3-0-methyl-L-talose) (19), D-
digitalose (6-deoxy-3-0-methyl-D-galactose) (23), D-theve-
tose (6-deoxy-4-0-methyl-D-glucose), and L-thevetose (6-
deoxy-4-0-methyl-L-glucose) (30) (Courtois and Percheron,
1970).
Branched·Chain Sugars
The branched-chain sugar, apiose (31), was first isolated
from PetroseUnum hortense (parsley, Apiaceae) about 1900.
A similar sugar, hamamelose (32), was later isolated from
252 Carbohydrates

the bark of Hamamelis virginiana (witch hazel, Hamameli-
daceae). Although considered to be rare secondary metabo-
lites for many years, these sugars are now known to occur in
several species of plants (Beck and Hopf, 1990; Grisebach,
1980).
D-Apiose (31) is synthesized from D-glucuronic acid me-
tabolism in a reaction that involves loss of the carboxyl
group and C-3 of D-glucuronic acid. The enzyme which re-
quires NAD+ has been isolated (Grisebach, 1980).
D-Apiose (31) is widely distributed in the Apiaceae (Um-
belliferae). This sugar generally occurs in the D-erythro-fu-
ranose form as a component of glycosides such as apiin (33)
(Fig. 15.4). Apiose also occurs as a component of polysac-
charides, especially in aquatic monocotyledonous plants
(Grisebach, 1980). Relatively simple, specific methods for
screening for this sugar as a component of glycosides are
available (Grisebach, 1980).
D-Hamamelose (32) arises by rearrangement of fructose-
I ,6-bis(phosphate).
D-Hamamelose (32) and the corresponding polyol, D-ha-
mamelitol, are very widely distributed among plants. The
digalloyl ester of hamamelose has been isolated from witch
hazel, Castanea sativa (chestnut, Fagaceae), and red oak
(Quercus rubra, Fagaceae). Free hamamelose also occurs
in these plants. The overall pattern of distribution has been
reviewed (Grisebach, 1980).
Techniques for the analysis of branched-chain carbohy-
drates have been reviewed (Beck and Hopf, 1990; Sturgeon,
1990).
Sugar Carboxylic Acids
Aldose-derived carboxylic acids are synthesized in bacte-
ria, fungi, plants and animals (Fig. 15.5) (Luckner, 1990).

CHo. CHo. CHo. CHo.

I r r I
H-C-o.H HQ.C-H H-C-o.H CH,
I I I r
H-C-o.H H-C-o.H CH,o.C-H H-C-o.CH,
I r r r
HQ.C-H H-C-o.H H-C-o.H HQ.C-o.H
I I r r
Ho.C-H HQ.C-H H-C-o.H Ho.'C-H
I r I r
CH, CH, CH, CH,
D-thevetose (30) L-oleandrose (26)
L-rhamnose (28) L-fucose (24) 6-deoxy-3-0-D-glucose 2,6-dideoxy-3-0-methyl-
arabino-hexose
CHo. CHo. CHo. CHo.
I r r r
H-C-o.Co.CH, H-C-o.H H-C-o.H H-C-o.H
r r r I
CH,o.C-H Ho-C -H H-C-o.CH, H-C-o.CH,
I r r r
Ho.·C-H H-C-o.H Ho.·C-H H-C-o.H
I I r r
Ho.·C-H H-C-o.H HQ.C-H HQ.C-H
I I r r
CH, CH, CH, CH,
2-0-acetyl-L-vallarose D-quinovose (27) L-acofriose (18) L-acovenose (19)
6-deoxy-D-glucose 6-deoxy-3-0-methyl-L- 6-deoxy-3-0-methyl-L-
mannose talose
CHo. CHo. CHo.
CHo. CHo. I
I I r
I H-C-o.H
H-C-o.H H-C-o.H H-C-o.H H-C-o.H
I I I r I
H-C-o.H HQ.C-H H-C-o.H CH,Q.C-H H-C-o.H
I I I r I
H-C-o.H HQ.C-H Ho.C-H Ho.C-H H-C-o.H
I I I r I
H-C-o.H HQ.C-H H-C-o.H H-C-o.H Ho-C-H
I I r r I
CH, CH, CH, CH, CH,

D-aJlomethyJose (20) L-altromethyJose (21) D-antiarose (22) D-digitalose (23) L-talomethylose (29)
6-deoxy-D-allose 6-deoxy-L-altrose 6-deoxy-D-gulose 6-deoxy-3-0-methyl- 6-droxy-L-lalose
D-galactose

~~o.\. .o.H
Ho. ~o." H Ho.~o.H
~~ o.H H
~o.H
o.H H

a-L-rhamnopyranose (28) a·D-fucose (25) (t,-L·fucose (24)

Fig. 15.3. 6-Deoxyhexoses.

 Carbohydrates 253

CHO
CHO I
H~OH
""-- H - OH
I
C-
HOH'C~OOH
.L..-
HOH,CC-OH
I
CH,OHH ..." I H HOH,C "7 H-C-OH
H OH HOH,c-C-OH H H H-~-OH
OH OH
I
CH,OH OH OH
I
CH,OH

D-.piose (31) D-hamamelose (32)

H~O
H 0 H

CHO
H H,OH
~~~-
CH, H ~ ~O-UDP
OH OH OH OH

streptose UDP-D-apiose
OH

HO~OH
HO
0 0

H 0 0

~~;,;;'l H
H~~H
OH OH
apiin (33)

Fig. 15.4. Branched-chain sugars.

Several types of acids may be distinguished; some form lac-
tones readily. D-Glucuronic acid, a common component of
glycosides, can be derived from D-glucose 6-phosphate di-
rectly or via myo-inositol (Gander, 1976). UDP-D-Xylose
and UDP-L-arabinose are formed by decarboxylation of
UDP-D-glucuronic acid and UDP-D-galacturonic acid, re-
spectively (Luckner, 1990). Ribulose S-phosphate (34) is
formed by the action of a NADP-requiring dehydrogenase
on 6-phosphogluconic acid (35).
Amino Sugars
A number of unusual sugars are found in antibiotics
(Hanessian and Haskell, 1970; Sueader, 1985). Many of the
sugars contain amine, methoxyl, and methyl groups (Fig.
IS.6). Some antibiotics, mostly of bacterial or fungal origin,
such as steptomycin (36), consist primarily of sugar units
(Fig.IS.7).
Amino sugars are formed from the corresponding ketoses.
Ammonia or glutamine usually act as the amino donors
(Luckner, 1990).
N-Acetyl-D-glucosamine is the precursor of chitin in
fungi and animals. This sugar is also found in the cell walls
of bacteria (Luckner, 1990).
Biological Activity of Sugars
Many sugars and sugar-like molecules are accumulated
in plants. Most plant materials that contain S% or more mo-
nosaccharides or disaccharides taste noticeably sweet to hu-
mans. The sugars responsible usually are glucose (I), fruc-
tose (8), or sucrose (37) (Fig. IS.9). However, many sugars
have diverse taste properties to humans and, presumably,
other mammals. Some have sweet tastes, whereas others are
bitter. Although, specific functions for most sugars have not
been elucidated, several have pronounced physiological ac-
tivity.
A number of nitrogenous molecules with piperine rings
act as sugar mimics (Fig. IS.8) (Fellows, 1987; Fellows et
al., 1989). These compounds have been isolated from mi-
crobes of the genera Streptomyces and Bacillus, and from
the fungal genera Nectria, Rhizoctonia, and Metarrhizium.
Similar nitrogenous compounds also are known from M orus
(Moraceae), Omphalea (Euphorbiaceae), Derris, Loncho-
carpus, Swainsona, Astragalus, Oxytropis, Castanosper-
mum, Alexa, Angylocalyx, Xanthocercis (Fabaceae), and a
fern Arachnoides standishii (Fellows et al., 1989). The
larvae and adults of day-flying and brightly colored urania
moths that feed on Derris species in the larval stages con-
tain 2R,SR-dihydroxymethyl-3R,4R-dihydroxypyrrolidine
(DMDP) (Fellows et aI., 1989).
The glucose mimic, desoxynojirimycin (38) (from Morus,
mulberry, Moraceae), inhibits a-glucosidases in the mamma-
lian gut. A mannose analog, desoxymannojirimycin (39), in-
hibits mannosidases. Another alkaloid from Derris (Faba-
ceae) inhibits the action of invertase but does not prevent
hydrolysis of this disaccharide in the mammalian gut. In artifi-
cial diets with Locusta migratoria, 0.001 % of DMDP in the
254 Carbohydrates

CHo. Co.,H Co.2H

CHo. I
I I I
H-C-o.H H-C-o.H H-C-o.H H-C-o.H
I I I I
HOC-H Ho.-C-H HOC-H HOC-H
I I I I
H-C-o.H Ho.-C-H H-C-o.H H-C-o.H
I I I I
H-C-o.H H-C-o.H H-C-o.H H-C-o.H
I I I I
Co.2H Co.,H CH,.o.H Co.,H
D-galacturonic acid (4) D-glucaric acid
D-glucuronic acid (3) D-gluconic acid
CHo. CHo.
Co.2H
I CH,o.H I I

-
H-C-o.H I H-C-o.H HOC-H
I C=o. I I
Ho.·C-H I H-C-o.H Ho.-C-H
I H-C-o.H I I
H-C-o.H I Ho.-C-H H-C-o.H
I H-C-o.H 0.- I I
H-C-o.H 0.- H-C-o.H
I I I I H-C-o.H
CH,-o.-P-o.- CH,-o.-P-o.- I I
II Co.,H Co.,H
"
0. 0.
6-phosphogluconic acid (35) D-guluronic acid (52)
ribulose-5-phosphate (34) D-mannuronic acid (51)
OP NAD+-enzyme H+ ~

Ho.~<-
Ho.~ ~~ H_Ho.
~o.ft 0. _
Ho.~o. Ho.
o.P
o.H_
H 0. Ho. ~H o.H
0., o.H]( H
H c...
0 NADH-enzyme
D-glucose 6-phosphate H+

Ho.~P Co.,H 0.
Ho. o.HHo.~H
Ho. o.H __
Ho.~o.,~
Ho.~ H
o.Ho.H -- 0.
H o.Ho.H o.H

myo-inositol D-glucuronic acid

Fig. 15.5. Carboxylic acids derived from sugars (in part modified from Goodwin and Mercer, 1983; used with pennission of the copyright owner,
Pergamon Press, Oxford).

diet deters locust nymphs from feeding, although force-fed
nymphs showed no signs of poisoning at this level (Fellows,
1987; Fellows et al., 1986). Effects on other insects varied.
A more complex alkaloid, swainsonine (40) (from Swain-
sona species, Fabaceae), also inhibits a-mannosidase activ-
ity. A similar complex alkaloid, castanospennine (41) (from
Castanospermum austraie, Fabaceae) inhibits J3-glucosi-
dases [but not a-glucosidases as in (38)] (Fellows, 1987;
Fellows et aI., 1992).
Castanospennine, deoxynojirimycin (DN), and DMDP
reduce the infectivity of the HIVl and the Moloney murine
leukemia viruses (Fellows et al., 1989). These compounds
also have antitumor activity.
DlSACCHARIDES AI'ID OLiGOSACCHARIDES
Disaccharides and oligosaccharides are ubquitous in plants
and fungi. Several of these, [e.g., sucrose (37)] are among
the most important energy transfer compounds in plants,
whereas others appear to be esoteric secondary metabolites
(Pazur, 1970). a,a-Trebalose (a-n-glucopyranosyl a-n-glu-
copyranoside) (42) is common in fungi and insects, but ap-
parently rare in plants (Fig. 15.9). However, trehalose is
found in algae, fungi, and ferns (Kandler and Hopf, 1980).
Lactose (4-0-J3-n-galactopyranosyl-n-glucopyranose) is
common in mammary secretions of animals. Maltose (4-
O-a-n-glucopyranosyl-n-glucopyranose) (43) isa structural
component of two important n-glucans, starch and glycogen
(Greenwood, 1970; Pazur, 1970). In a similar manner, cello-
biose (44) is a part of the repeating units of cellulose and
certain other wall polysaccharides. Cellobiose (4-0-J3-n-glu-
copyranosyl-n-glucopyranose) also occurs as the carbohy-
drate constituent of many plant glycosides (cellobiosides)
(Pazur, 1970). Gentiobiose (6-0-J3-n-glucopyranosyl-n-glu-
copyranose) (45) and primeverose (6-0-J3-n-xylosyl-n-glu-
cose) (47) are components of many glycosides; the best
known of these are amygdalin, vicianin, and crocin. Lami-
narabiose (3-0-J3-n-glucopyranosyl-n-glucopyranose) (46)
 CHO CHO CHO
CHO
I I I I
H-C-NH, H-~-NHCOCH, H,N-C-H H-C-OH
I I CH" I
HGC-H H()'C-H HO-C-H ;N-C-H
I I I CH, I
H-C-OH H-C-OH H-C-OH H-C-OH
I I I I
H-C-OH H-C-OH H-C-OH H-C-OH
I I I I
CH,-OH CHrOH CHrOH CH,

n-glucosamine (9) N-acetyl-D-glucosamine (53) D-mannosamine D-mycaminose

-r:Jf""-......O~OH
H,N~H
H

kosugamine desosamine tolyposamine

2,4.diamino-2,3,4,6- 3-dimethylamino-3,4,6-trldeoxy- 4-amino-2,3,4,6-tetradeoxy·
tetradeoxy-D-arabino-hexose 8-D-xylo-bexose L-erythro-hexose

2-deoxy-2-methylamino- neosamine B 6-amino-6-deoxy· angolosamine

L-glucose 2,6-diamino-2,6-dideoxy- D-glucose 3-dimetbylamino-2,3,6-
L-idose trideoxy-D-xylo-hexose

neosamine C perosamine rhodosamine

kanosamine 2-dimethylamino-2,3,6-
3-amino-3-deoxy· 2,6-diamino-2,6- 4-amino-4,6-dideoxy-
D-glucose dideoxy-D-glucose D-mannose trideoxy-L-lyxo-hexose
(a)

HO~O, OH
HO~
H

digitoxose

digitoxose-digitoxose-digitoxose- 0

~ HO~OH
OH
o

~~
o HO 0 OH
H,N 0
00 H HO
HO H
H,N OH H NH,
OH NH, OH H
OH

kanosamine daunosamine perosamine D-gulosamine

(b)

Fig. 15.6 (a & b). Hexoses from antibiotics.

255
256 Carhohydrates

also occurs as a component of glycosides. These disaccha-
rides are rare as free sugars (Pazur, 1970). The structures,
properties, and distribution of a number of other disaccha-
rides have been reviewed (Dey and Dixon, 1985; Pazur,
1970). Techniques for analysis of disaccharides have been
reviewed (Avigad, 1990; El Khadem, 1988).
Sucrose
A major part of the CO2 assimilated in plants during the
operation of the photosynthetic carbon reduction cycle ap-
pears in sucrose (j3-D-fructofuranosyl a-D-glucopyranoside)
(37) (Fig. IS.9). In many plants, sucrose is the principal
or only common sugar to be translocated (Akazawa, 1976;
Akazawa and Okamoto, 1980; Hawker, 1985; Lucas and
Madore, 1988). Thus, sucrose is found in all plants and has
been reported from seeds, leaves, fruits, flowers, and roots
(Pazur, 1970). Honey consists largely of sucrose and its hy-
drolysis products glucose and fructose. Most commercial
sucrose is isolated from sugar cane and sugar beets. Sucrose
synthetase catalyzes the formation of sucrose from UDP-
glucose and D-fructose. This reaction is also reversible and
the reversal of the sucrose synthetase reaction appears to
be the principal mechanism of sucrose cleavage (Akazawa,
1976; Akazawa and Okamoto, 1980; Hawker, 1985; Lucas
and Madore, 1988). Invertase cleaves sucrose to yield D-
glucose and D-fructose. Both enzymes are common in plant
tissues (Feingold and Avigad, 1980).
Oligosaccharides
Oligosaccharides, compounds composed of several sugar
units (usually 2-10), are also widespread in plants (Dey,
1990; Pazur, 1970). At least SOO oligosaccharides are known
(Kandler and Hopf, 1980); most are comprised of a small
number of monosaccharide units (Pazur, 1970). Other oligo-
saccharides are formed as breakdown products of polysac-
charides. Raffinose [j3-D-fructofuranosyl O-a-D-galactopy-
ranosyl-(I - 6)-a-D-glucopyranoside] (49) and stachyose
[O-a-D-galactopyranosyl-(l - 6)-O-a-D-galactopyranosyl-
(I - 6)-O-a-D-glucopyranosyl-(1 - 2)-j3-D-fructofurano-
side] (48) are particularly common (Fig. IS.IO) (Goodwin
and Mercer, 1983; Kandler and Hopf, 1980); raffinose is
distributed almost as widely as sucrose, but is usually present
at only low concentrations (Dey, 1985; Pazur, 1970). How-
ever, raffinose is accumulated in cereal grains, sugar beets,
cottonseed, soybeans, and many other legumes. Stachyose
(48), usually associated with raffinose and sucrose, is found

NH,
2'6_diaminO_D_gluc~oe
0
HO
HO H HO
OH
NH
HNyNH
deoxystreptamine

"8.
H,N~NH,.o
HO~ H,N 0 °
HOH'Q<0
° streptose
H H H
D-ribose H
OH 0
OH 0
HO~
HO~~H HO0

HO
NHCH,

NH2 2,6-diamino-D-glucose 2-methylamino-L-gJucose

neomycin C streptomycin (36)

HO
~
NH'
00
0

OH
H
H~NH' OH
0
0
00
6·amino·D-glucose o~ 3-amino·D-glucose
HO~ NH,
H,N
deoxystreptamine

kanamycin A

Fig. 15.7. Carbohydrate antibiotics.

 Carbohydrates 257

HO ~°
HO
OHHO

OH
H HO ~
HO
OHHO
NH
HO 4
HO
0H NH

OH
OH
(X~D-mannose (7) desoxymannonojirimycln nojirimycin
DMJ (a maun..e mimic) (39)

r
~
OH
i----Y
NH HOCHQ0"---- HOCHl NH H

HO
H oH\ k:--~
HO HO CHlOH HO CHlOH
OH
OH H OH H
desoxynojirlmycin
poD-fructose (8) DMDP (4) (a fructose mimic)
DNJ (a glucose mimic) (38)

HO
HOCHVuNH~
H

W
HO'N:

" N c : r OH OH H

castanospermine (41) DABI (from Angylocalyx) swalnsonine (40)

Fig. 15.8. Nitrogenous compounds that mimic sugars.

in many genera of the Fabaceae and is a dominant constituent
of many plants in the Lamiaceae (Labiatae), the mint family
(Gander, 1976; Pazur, 1970). Melizitose [O-a-D-glucopyra-
nosyl-(1-3)-13-D-fructofuranosyl a-D-glucopyranoside]
(50) is present in the sweet exudations of many plants such
as the "honeydew" of limes and poplars and the manna of
Douglas fIr, Virginia pine, and larch (Pazur, 1970). Honey
sometimes contains this trisaccharide, which cannot serve
as food for bees, probably because they lack the enzymes
to degrade it (Pazur, 1970). The properties and distribution
of a number of other oligosaccharides have been reviewed
(Kandler and Hopf, 1980; Pazur, 1970).
Fructans
Fructans (or fructosans) are related both structurally and
metabolically to sucrose (Pollock and Chatterton, 1988).
Under some conditions, fructans can be the major site of
storage of fIxed carbon. Fructans are most important in the
Agavaceae, Asteraceae, Boraginaceae, Campanulaceae,
Goodeniaceae, Haemadoraceae, Irldaceae. Liliaceae,
Poaceae, and Stylidiaceae (Pollock and Chatterton, 1988;
Pontis and del Campillo, 1985). In some members of the
Asteraceae, Liliaceae, and Poaceae, more than 50% dry
weight of the tissues may be comprised of fructans (Pontis,
1990). In the Asteraceae, these compounds are usually accu-
mulated in underground storage structures, whereas in the
Poaceae, they are found throughout the plant.
In some plants, photosynthetic products are stored as po-
Iyfructosans. Inulin and other related fructosans with 13-1,2-
linkages are found in the roots and tubers of many members
of the Asteraceae and Campanulaceae (Akazawa, 1976;
Pontis and del Campillo, 1985). Inulin is rich in the tubers of
Helianthus tuberosus, the Jerusalem artichoke (Asteraceae).
This polyfructosan makes up more than 50% of the dry
weight of the tubers (Akazawa, 1976).
Methods for the analysis of fructans have been reviewed
(pontis, 1990).
POLYSACCHARIDES: RESERVE AI'ID
STRUCTURAL FORMS
Energy Storage Compounds Derived
from Sugars
Sugars often occur as part of large polymeric units.
Among these are cellulose and starches (Eastwood and Ed-
wards, 1991; Greenwood, 1970; Manners, 1985; Preiss and
Levi, 1980; Whistler et aI., 1984). Starch based on glucose
occurs in green algae and most other plants. Starch is an
"end product" of the phytosynthetic reduction of CO2 , This
assimilation starch is a transitory reserve carbohydrate that
disappears in the dark and is transported as sucrose through
the phloem to other tissues (Akazawa, 1976).
Starch consists of two chemically distinct polysaccharide
fractions, amylose (soluble in hot water) and amylopectin
(insoluble in hot water). Amylose is a linear polymer of a-
 Carbohydrates 259

H~O,
)~
H H~H ____ O, H

~
OHO
[O~

H~-----O'
HO
HO H

~
H
o 0 OH
O~
~
HO OH 0
o HO H o
OH HO

HO~H HOCHVO~
HO 0 H

HOCHVu°~
Ii W CH,OH
W
HOCH'K::0';;/,.

H W CH,OH
OH H
Ii
OH H
CH,OH

stachyose (48) OH H raffinose (49) melizitose (50)

Fig. 15.10. SbUctures of some common oligosaccharides.

I ,4-linked glucose with a helical conformation. The molecu-
lar weight ranges from 10,000 to 100,000. In amylopectins,
many chain segments with 20-25 glucose units are linked
to the main chain by a-I,6 bonds. These molecules are only
partially attacked by 13-amylases and phosphorylases. The
hydrolysis products are called dextrins. So-called de-
branching enzymes break down the a-I,6-linkages.
Starch synthetase catalyzes the stepwise transfer of the
glucose moiety from the nucleotide glucose molecule to the
nonreducing end of the accepting a-glucan molecule
(primer) by forming the linear a-I ,4-glucan amylose (Aka-
zawa, 1976; Preiss, 1988). The formation of a-I,6 bonds in
the glycogen molecule is known to be catalyzed by "branch-
ing enzyme" or amylo-(I,4->I,6)-translucosylase (Aka-
zawa, 1976; Manners, 1985; Preiss, 1988).
Alternatively, phosphorylases can catalyze the reversible
phosphorylation of a-glucan molecules and lead to the for-
mation of starch. Starch is broken down in plants by a-
amylases. Methods for the analysis of starch have been re-
viewed (Morrison and Karkalas, 1990).
structural Carbohydrates
Young plant cell walls are primarily made up of polysac-
charides and protein. Cells become more highly lignified as
they become older. The degree of modification is linked to
the function of the particular cell involved. Although the
composition of polysaccharides may vary in different plant
species, composition in a particular plant species is usually
constant from plant to plant. The amount and type of g1yco-
proteins present in the cell wall are usually characteristic for
different plants. The cell wall composition changes during
growth and development (Karr, 1976).
Cellulose, a 13-1 ,4-glucan, is synthesized by many organ-
isms from bacteria to higher plants (Aspinall, 1980; Colvin,
1980; Ward and Seib, 1970). This polymeric material occurs
in the cell wall and is packed in an ordered manner to form
compact aggregates called microfibrils (Baeic et ai., 1988).
The glucosyl donor in a number of cases appears to be GDP-
glucose (guanosine diphosphate-o-glucose), but there is
some controversy about the role of this compound as the
precursor (Karr, 1976). Cellulose is the most abundant or-
ganic compound.
Methods for the analysis of cellulose have been reviewed
(Franz and Blaschek, 1990).
Cellulose microfibrils are usually embedded in a continu-
ous phase of lignin, pectin, and hemicellulose; hemicellulose
usually predominates (Whistler and Richards, 1970). Most
of the hemicellulose is found mixed with cellulose in both
the primary and secondary cell walls. Hemicellulose is now
known not be a precursor to cellulose. In general, hemicellu-
loses are the cell wall polysaccharides other than cellulose
and pectin. These polymers are classified on the basis of the
type of sugar residues present. For example, o-xylan is made
up of o-xylose, o-mannan of o-mannose, and o-galactan of
o-galactose units (Whistler and Richards, 1970). In practice,
few hemicelluloses contain ouly one sugar, most contain
two to four. Furthermore most hemicelluloses have branched
structures. The major types of hemicellulose and their distri-
bution have been reviewed (Whistler and Richards, 1970).
Methods for the analysis of mannans have been reviewed
(Matheson, 1990).
Callose
Callose is a morphologically distinctive polysaccharide
that occurs in granular form deposited around sieve plates
and on the side of sieve-tube pores. Callose is a 13-1 ,3-linked
o-glucan with no detectable branching (Aspinall, 1980). In
higher plants, callose is deposited as a response to wounding
or infection by microorganisms (Baeic et ai., 1988).
260 Carbohydrates
Pectins
Pectin, a polymer rich in ,,-I ,4-linked o-galacturonic acid
residues, is important in plants as the material that glues
plant cell walls together (Aspinall, 1970, 1980). Although
o-galacturonic acid (4) is the main constituent of pectic sub-
stances, various proportions of other sugars are found, in-
cluding o-galactose (2), L-arabinose (6), o-xylose (5), and
L-rhamnose (28). In most instances, methylated sugars also
are present. An enzyme that converts UDP-o-galacturonic
acid to pectin has been isolated from mung beans (Karr,
1976). Extensive methyl esterification takes place after the
polygalacturonic acid molecule is assembled.
Many of the chemical properties and economic uses of
pectins have been reviewed (Aspinall, 1970, 1980; Fishman
and Jen, 1986). Most commercial pectins come from apple
pomace, citrus waste, and sugar beet pulp.
Techniques for the analysis of pectins have been reviewed
(O'Neill et al., 1990).
Plant Qums
A number of gum exudates from plants have a composi-
tion similar to pectins. These gums may form spontaneously
at sites of injury to the plant, or may be induced by deliberate
incisions; the actual site of formation of gums is not well
established (Joseleau and Ullmann, 1990). The most impor-
tant gum is gum arabic (or gum acacia) from Acacia senegal
and A. catechu (Fabacehe). The polysaccharides all contain
highly branched structures, usually based on o-g1ucutonic
(3) and/or o-galacturonic acids (4) (Aspinall, 1970). Many
gums contain L-arabinofuranose (6) residues attached to the
periphery of the molecules. Gum arabic contains L-arabinose
(6), o-galactose (2), L-rhamnose (28), and o-glucutonic acid
(3) in the ratio of3:3: I: I (Aspinall, 1970). Carob and guar
gum (from the seeds of Ceratonia siliqua and Cyamopsis
tetragonolobus, respectively) (Fabaceae) are characterized
by the presence of o-galacto-o-mannans (Reid, 1985).
Techniques for the analysis of plant gums have been re-
viewed (Stephen et al., 1990).
Algal Polysaccharides
Algae belong to three major groups: the Chlorophyceae
(green algae), the Phaeophyceae (brown algae), and the Rho-
dophyceae (ted algae). Polysaccharides are common in rep-
resentatives of each group (Percival, 1970; Percival and Mc-
Dowell, 1981, 1985). These polysaccharides often are
different from those of land plants, but some algae do synthe-
size cellulose and starch. Evidence has been advanced that
these polysaccharides are involved in mechanisms by which
the algae selectively absorb potassium and calcium from
seawater (Percival, 1970). For convenience, these com-
pounds are divided into three groups: structural carbohy-
drates, food reserves, and sulfated polysaccharides.
Many green algae (Chlorophyceae) contain starch which
can be fractionated into amylose and amylopectins. The
major polysaccharides, however, are polysaccharides in
wbich at least some of the hydroxyl groups of the sugars
are substituted by half ester groups. These compounds are
strong acids and exist as salts (Percival, 1979). Those of
Cladophora and Codium are often arabinogalactans [with 0-
galactose (2) and L-arabinose (6)]. Many species synthesize
comparatively simple xylans and mannans (percival, 1970,
1979).
Many red algae (Rhodophyceae) contain complex carbo-
hydrate molecules. These algae produce o-glucans, known
as f10ridean starch, as their food reserve material (Percival,
1970, 1979). This starch differs in that no amylose is present,
but it resembles amylopectins in many of its properties.
There is little evidence for starch in other red algae [e.g.,
Rhodymenia palmata (dulse)]. In this alga, the major poly-
saccharide is a water-soluble xylan made up of random 1,3-
and 1,4-linked units. Other 1,3-, 1,4-, and mixed 1,3- and
1,4-xylans have been isolated from a number of red algae
(Percival, 1970, 1979).
The major polysaccharides of most Rhodophyceae are
galactans consisting of 1,3-linked galactose units. Agar and
carrageenan are among these. Agars contain 0- and L-galac-
tose units, whereas carrageenans contain only o-galactose
(2) (percival, 1979). In each, some of the units are sulfated
and others OCCut as 3,6-anhydrogalactose. A carbohydrate
from Porphyra is known to have glucomannans with o-man-
nose (7) in a (3-1,4-linkage.
In the Phaeophyceae (brown algae), the food reserves are
laminarin, a water-soluble (3-o-(l-3)-linked o-g1ucan and a
sugar alcohol, mannitol. Laminarin contains 20-25 glucose
units (Percival, 1970, 1979).
The major polysaccharide of brown algae is alginic acid.
This polymer consists of unbranched chains of contiguous
(3-I,4-linked o-mannutonic acid (51) and blocks of contig-
uous ,,-1,4-linked L-guluronic acid (52) (Fig. 15.5) (Percival,
1970, 1979). Alginate is present as the salt of different met-
als, usually sodium and calcium. Calcium ions are important
in determination of gel strength.
A sulfated polysaccharide from brown algae is called
"fucan." This is a complex highly branched mixture, con-
taining fucose and other sugars and sugar acids (Percival,
1970, 1979).
Teclmiques for the analysis of algal polysaccharides have
been reviewed (Percival and McDowell, 1990).
Chitin
Chitin is a ubiquitous component of fungal cell walls,
being absent only from the Oomycetes and Trichomycetes
(Cabib, 1981). Chitin also makes up much of the wall mate-
rial of insects and crustaceans. This polysaccharide is com-
posed of (l-4)-(3-linked N-acetylglucosamine (53) (Fig.
15.6) units (Cabib, 1981).
Teclmiques for the analysis of chitin have been reviewed
(Lezika and Quesada-Allue, 1990).
BiolOgical Activity of Oligosaccharides and
Polysaccharides
These compounds probably are most important in the
diets of animals as sources of energy, but many other roles
also are known. As is true for simple saccharides, many
oligosaccharides possess sweet tastes (Pazut, 1970). Poly-

saccharides exhibit antitumor, immunological, anti-inflam-
matory, anticoagulant, hypoglycemic, and antiviral activities
(Srivastava and Kulshreshtha, 1989).
Humans, when awake, release 20-50 ml of flatus per hour
under nonnal conditions; the dry bean (Phaseolus vulgaris) is
the champion gas producer among common foods. Stachyose
(48), raffinose (49)(Fig. 15.10) (Dey, 1985), and sucrose (37)
are the major molecules that are fennented by Clostridium
perJringens to a mixture of carbon dioxide, hydrogen, and
other compounds (Murphy, 1968; Rockland, 1968).
Oligomers of N-acylated, N-acetylglucosamine (53) from
Rhizobium meliloti (nod factors) are involved in depolariza-
tion of root hair cells in alfalfa (Medicago sativa) at nanomo-
lar concentrations (Ehrhardt et aI., 1992). Other chemical
messengers are known to be involved in establishment of
nodulation in legnmes (see Chapter 11).
The structure of cell wall carbohydrates is important in
recognition of surfaces in plant-microbe interactions involv-
ing pathogens, mycorrhizal fungi, nitrogen-fixing bacteria,
and in other interactions. Cell recognition is the initial event
of cell-cell communication which elicits a defined biochem-
ical, physiological, or morphological response (Ralton et aI.,
1987). Many of these interactions involve proteins, often
those of the cell membrane, whereas others involve carbohy-
drates. Lectins bind to specific sugar moieties on plant sur-
faces (see Chapter 14) (Kauss, 1981; Schmidt and Bohlool,
1981; Sharon and Lis, 1990). Cell Walls often serve as
sources of secondary signal molecules. In instances where
the primary signal from one cell is an enzyme such as a
hydrolase or lyase, it may catalyze the release of fragments
from the cell wall of the target cell. These wall .fragments
may become involved in the recognition process by interact-
ing directly with a plasma membrane receptor (Ralton et aI.,
1987). Wall-bound lectins and agglutinins may bind these
secondary extracellular signals.
Many pathogens produce pectinases in the process of pen-
etrating tissues of the host plants (Collmer, 1987). Interac-
~
OH 0
HO
Ho~HOO 0 H o0h
O
HO OH 0 O~O
H HO
HOOH
HO~HOo
HO
Fig. 15.11. An active hepta-(3-glucoside alditol from an acid hydrolysate of Phthophthora megasperma cell walls.
Carbohydrates 261
tions between pathogenic fungi and their host plants indicate
that host cell wall fragments, often consisting of oligomeric
saccharides released by fungal enzymes, can elicit cyto-
plasmic changes. One well-studied mechanism of defense
involves the accumulation of phytoalexins at the site of in-
fection (Kogel and Beillman, 1992; Kosuge, 1981; Ralton et
aI., 1987). The presence of compounds produced by several
mechanisms, but usually by degradation of wall materials of
the host or of the pathogen, elicit fonnation of phytoalexins
(Ebel, 1986; Eilert, 1987; Kogel and Beillmann, 1992).
A glucan from yeast extract containing 3-, 6-, and 3,6-
linked glucosyl residues was shown to elicit fonnation of
glyceollin in soybeans (Glycine max, Fabaceae). The yeast-
derived elicitor stimulates accumulation of this isoflavone
when as little as 15 ng of the elicitor is applied to soybean
cotyledons (Hahn and Albersheirn, 1978).
A heat-labile endopolygalacturonase from culture fil-
trates of Rhizopus stolonifer elicited accumulation of the
phytoalexin casbene in castor bean (Ricinus communis).
This material releases heat-stable water-soluble cell wall
fragments from the host plant. These wall fragments contain
a high fraction of galacturonic acid or its methyl ester, indi-
cating their derivation from pectic polysaccharides (Ralton
et aI., 1987).
Solubilized polysaccharide fractions from Glycine max
(soy bean) cell walls elicit fonnation of phytoalexins in that
plant (Hahn et aI., 1981). These fragments are rich in galact-
uronic acid (4) and appear to come from the pectic materials
of the plant. A ~-glucosyl hydrolase from soy bean cell walls
has the ability to degrade the elicitor (Cline and Albersheim,
1981). Fractions from the soybean pathogen Phytophthora
megasperma var. sojae also serve as elicitors. The activity
is associated with the glucan fraction (Ayers et aI., 1976).
Only one of a series of eight hepta-~-glucoside alditols iso-
lated was capable of eliciting phytoalexin production (Fig.
15.11) (Ralton et aI., 1987).
Cell suspension cultures of parsley, PetroseUnum
0
O
OHk
0 0
OH OH~
0
H HO
HO
OH H,OH
262 Carbohydrates

crispum, accumulate coumarin phytoalexins when treated
with either a purified ,,-1,4-D-endopolygalacturonic acid
lyase from Erwinia carotovora or oligosaccharides solubi-
lized from parsley cell walls by endopolygalacturonic acid
lyase (Davis and Hahlbrock, 1987). The plant cell wall elici-
tor was found to act synergistically with the fungal glucan
elicitor in the induction of coumarin phytoalexins.
Aphids have flexible, stylet-like mouthparts adapted for
probing of plant tissues. By this means, the aphid must use
chemical cues from the plant to determine if the plant is a
suitable host (host plant quality), where the aphid is on the
plant, the location of the stylet within the plant tissues, and
the direction to probe to locate the plant phloem (Campbell
and Dreyer, 1990; Dreyer and Campbell, 1987). Aphids
avoid many of the toxic compounds stored in plant cells by
probing between the cell walls. These insects are able to
penetrate the intercellular spaces by producing a variety of
digestive enzymes which depolymerize the pectins and
hemicelluloses forming the intercellular-cell wall matrix.
Aphid-host plant compatibility is associated to the extent
that these enzymes depolymerize their respective substrates,
and a reduced rate of depolymerization is often associated
with host plant resistance. Differences in methoxylation,
acetylation, or neutral sugar composition in the matrix poly-
saccharides are often involved in this reduced depolymeriza-
tion. Further, specific breakdown products from depolymeri-
zation of the matrix polysaccharides provide cues that help
aphids to locate and or ingest materials from the phloem.
Some of these breakdown products also may act as elicitors
of plant hypersensitive reactions and phytoalexins (Camp-
bell and Dreyer, 1990; Dreyer and Campbell, 1987).
Other oligosaccharides, such as streptomycin (36) (Fig.
15.7) from Streptomyces griseus isolated from soil samples,
have potent antibiotic properties (Sneader, 1985). Strepto-
mycin was originally of great interest because of its activity
against Mycobacterium tuberculosis (Sneader, 1985).
SUGAR ALCOHOLS
Polyols
Although some representatives of this group are wide-
spread in plants, only about 35 structures have appeared in
the literature (Fig. 15.12). These compounds are derived by
the reduction of aldoses or ketoses with pyridine nucleotide-
dependent dehydrogenases (Luckner, 1990). Polyols corre-
sponding to C2 , C" C4 , Cs , C6 , and C7 are all known (Plou-
vier, 1963). Esters of ethylene glycol probably occurin small
amounts in many plants, and esters of glycerol (i.e., triglycer-
ides) are found in all plants (see Chapter 2). Compounds
with four and five carbons are common in many fungi. Sorbi-

CH,OH CH,OH CH,OH CH,OH

I I I
I H-C-OH H-C-OH
H-C-OH HO-C-H
I I
I I HO-C-H HOC-H
H-C-OH H-C-OH I
I
I I HO-C-H H-C-OH
CH,OH CH,OH I I
CH,-OH CH,OH
meso-erythritol (56) D·threitol L-arabinitol (57) meso-xylitol (58)

CH,OH CH,OH CH,OH

CHzOH
I I I I
H-C-OH HO-C-H H-C-OH
H-C-OH
I I I I
HO-C-H HOC-H
H-C-OH HO-C-H
I I
I I H-C-OH
H-C-OH HOC-H H-C-OH
I I
I I H-C-OH
H-C-OH H-C-OH H-C-OH
I I
I I CH,.OH
CH,.OH CH,.OH CH,.OH

meso-allitol (59) meso-galactitol (60) D-mannitol (55) D-sorbitol (54)

CH,OH CH,OH CH'-:=l

CH,~
HO-? -H I
I
H-C-OH
I
H-C-OH
I
I
H-?-OH I
HQ-C-H 0 HO-C-H HOC-H HO-C-H 0

H-?-OH I
I
H-C-OH
I
H-C-OH
I

I
H-?-OH I
H-C HO·C-H H-C-OH H-C
I I I I
CH,.OH CHrDH CH,-OH CH,.OH

1,5-anhydro-D.mannito) (61) L·iditol D-glucitol 1,5-anhydro·D-glucitol

Fig. 15.12. Polyols.

 Carbohydrate.~ 263

OH OH HO OH HO

~ OH
OH OH
+-
~ OH
OH +- ~o, OH OH
OH OH OH
L-chiro-inositol (71) myo-inositol (62) D-chiro-inositol (72)

I / \ \
CH,O HO ~OHCHoHO CH.O HO CH'~O
HO

~OH;)H 3 OH3~O --:H OH

~
OH
OH
OH OH
OHOH
OH
OH
D-(-)-bornesitol (65) sequoyitol (68) D-pinitol (63)

~
OH ~ ~
~H~
O~H
HO OCH,

OH
OH

scyllo-inositol (69)
OH

D-(+)-ononitol (67)
OH

L-(+)-bornesitol (66)

~OHJH
~ OH HO~OH
1 / D-I-O-methyl-muco-jnositol(70)
HO~OH
(a) myo-inositol (62) OH OH

H~
HO

HO~OH HO~
Yl
HO OH
OH OH OH
OH HO OH

myo-inositol (62) D-quercitol (73) D-pinitol (63)

'~~O"
HO OH
"O~o~" 03P~1
,)3~:"" OH OH

~PO;'
(b) sequoyitol (68) quebrachitol (64) phytic acid (74)

Fig. 15.13 (a & b). Cyclitols (modified from Loewus and Loewus, 1980; used with pennission of the copyright owner, Academic Press, Orlando, FL).
264 Carbohydrates
tol (54), a C6 polyol, is common in the Rosaceae, especially
in the Spiraeoideae, Maloideae, and the Amygdaloideae, but
seems to be lacking in other subfamilies. As much as 13.6%
of one red alga is composed of sorbitol. Mannitol (55), an-
other C6 polyol, is found in at least 50 families and is proba-
bly the most widely distributed polyol. Hamamelitol, the
polyol corresponding to hamamelose, is accumulated in
plants of the genus Primula (section Auricula) (Primulaceae)
(Grisebach, 1980).
Many polyols [such as meso-erythritol (56), 0- and L-
arabinitol (57), meso-xylitol (58), meso-allitol (59), meso-
galactitol (60), o-mannitol (55), 1,5-anbydro-o-mannitol
(61), and o-sorbitol (54)] taste sweet (Beck and Hopf, 1990).
CycHtols
A number of cyclic polyols also are known to occur (Fig.
15.13). myo-Inositol (62), widespread in animals, is a growth
factor in yeasts and a group B vitamin. This compound, one
of nine possible stereoisomers, is widespread in plants (six
other isomers also are naturally occurring). When plant cells
are incubated with radiolabeled myo-inositol, a large portion
of the label appears in the pentose and uronic acid residues
of the cell wall (Karr, 1976; Loewus and Loewus, 1980).
myo-Inositol serves as a precursor for o-glucuronic acid (3).
Furthermore, when glucose and other monosaccharides are
incorporated into cell walls, myo-inositol appears to be an
intermediate (Karr, 1976; Loewus and Loewus, 1980). Ana-
lytical techniques for the study of cyclitols and sugar alco-
hols (polyols) have been reviewed (Beck and Hopf, 1990;
Loewus, 1990).
The corresponding methyl ethers often are found in
H
HO i OH
?-+----r
~o~ H~oAo
OH OH
L-ascorbic acid (75)
C02H CH20H
H-t-OH H-~-OH
HO-C-H
I -
HO-C-H
I+-O
~02H I 80- C
L-(+)-tartaric acid (77) C0 H2
I i:. _ H
L-threonic acid
carbohydrate metabolism
---......
[C 3 -fragment]
Fig. 15.14. Oxidation of L-ascorbic acid (Loewus, 1980; modified and used with pennission of the copyright owner, Academic Press, Orlando,
higher plants (Loewus and Loewus, 1980). Nine of these
compounds occur commonly: 0-( +)- (63) and L-( - )-pinitol
(lo- and IL-3-0-methyl-chiro-inositol), L-( - )-quebrachitol
(lL-2-0-methyl-chiro-inositol) (64), 0-( - )- (65) and L-( + )-
bornesitol (66) (10- and IL-I-O-methyl-myo-inositol), 0-
(+ )-ononitol (l0-4-0-methyl-myo-inositol) (67), sequoyitol
(5-0-methyl-myo-inositol) (68), O-methyl-scyllo-inositol
(69), and 10-I-O-methyl-muco-inositol (70).
. Epimerization of myo-inositol (62) at C-I, C-2, or C-3
produces L-chiro- (71), scyllo-, (69), or o-chiro-inositol (72),
respectively (Fig. 15.13). Methylation at C-3, C-I, C-5, or
C-6 in the absence of epimerization gives 0-( - )-bornesitol
(65), L-( + )-bornesitol (66), sequoyitol (68), or 0-( + )-onon-
itol (67), respectively. All of these conversions occur in
plants (Loewus and Loewus, 1980). Methyltransferases that
convert inositol to 0- (65) or L-bornesitol (66) have been
characterized. An oxidoreductase that converts sequoyitol
(68) to o-pinitol (63) also has been studied. o-Pinitol (63)
is converted to o-I-O-methyl-muco-inositol (70) (presum-
ably by epimerization). A number of other epimerization
reactions are known to occur (Loewus and Loewus, 1980).
o-Quercitol (73) is common in members of the genus
Quercus, oaks, of the family Fagaceae. This cyclitol deriva-
tive is known from at least nine other families. o-Pinitol (63)
is known from six families of gymnosperms, in which it is
widespread, but it is also known from a number of angio-
sperms.
The hexakis-o-phosphate of myo-inositol, phytic acid
(74), occurs in most plants. It is recovered from most plants
as phytin, the calcium-magnesium salt. As much as 90% of
the organic phosphate of seeds may be stored in this form
(Loewus and Loewus, 1980). Three inositol dimethyl ethers
OH OH
H.
0H
HO H
3,6-anhydro-L-xylo-hexulono-
1,4·Jactone hydrate (76)
(dehydroascorbic acid)
C02H
o I
\ C02H
Ho-c'l Pelargonium crispum
oxalic acid
" I
---.J geranium CO,"
I
H- b H-C-OH
I
HO-C-H
HO _ I
I C02H
CH2-OH
L-(+)·lartaric acid (77)
L·ascorbic acid (75)
FL.).
 Carbohydrates 265

OH "o--R
HO~o O)H
OH 0 0
C:N
I I
(, /I /I A
UDPG(35) ~O-!;O-r:OON 0

!
H H
H H
glycosyl transferase OH OH

OH

OH ~N
HO~OR HO-~-OJ-o I NA.O
HO OH + I
OH I
OH ~
H H
H H
OH OH
(a)
a p-glycoside UDP

(b)
UDP-glucose dburrin

Fig. 15.lS (a & b). Synthesis of glycoside, by action of UDP-gluco,e.

are known: dambonitol (1,3-di-O-methyl-myo-inositol), 0-
(- )-liriodentritol (l-o-I,4-di-O-methyl-myo-inositol), and
(+ )-pinpollitol (lo-di-O-methyl-chiro-inositol). In view of
the amounts of these compounds encountered in plants, a
storage function is suggested (Loewus and Loewus, 1980).
Several C-methyl-branched inositols are known from
green, red, and brown algae (Plouvier, 1963). The biosyn-
thesis of these compounds does not proceed by C-methyla-
tion of inositols, but by cyclization of a I-deoxyheptulose
(Grisebach, 1980).
Pinitol (63) is a feeding stimulant for the larvae of the
butterfly, Eurema hecabe mandarina and also inhibits H eli-
coverpis zea larval growth in soybeans (Ley et aI., 1987).
L-ASCORBIC ACID
L-Ascorbic acid (75), vitamin C, is an important component
of many fruits and is important in human nutrition (Sneader,
1985). Methods for the determination of L-ascorbic acid have
been reviewed (Loewus, 1980, 1988). L-Ascorbic acid is
produced in actively growing plants. Although dry seeds
contain little, if any, ascorbic acid, upon germination there
is a rapid synthesis from carbohydrate reserves. Walnut hulls
(Juglans regia), rose hips (Rosa spp.), and the West Indian
cherry (Malpighia glabra, Malpighiaceae) all contain more
than 1% dry weight L-ascorbic acid (Loewus, 1980).
Labeling studies indicate that in the conversion of o-glu-
cose to L-ascorbic acid in plants, the carbon chain is con-
served. Although the steps of biosynthesis are not clear, they
involve oxidation at C-l, an internal oxidation of C-2 or C-
3, and epimerization at C-5 of glucose. One possible se-
quence is as follows: o-glucose is converted to o-glucosone,
which compound to L-sorbosone, which compound to L-
ascorbic acid (Loewus, 1988).
Ascorbic acid is oxidized by plants with ascorbate oxi-
dase tu yield dehydroascorbic acid (3,6-anhydro-L-xylo-hex-
ulono-l,4-lactone hydrate) (76) (Loewus, 1980, 1988). In
plants, ascorbic acid is rarely accumulated, but is usually
converted into tartaric (77) and oxalic (78) acids (Fig. 15.14).
Ascorbic acid is involved in removal of active oxygen
during photosynthesis, with activation and deactivation of
enzymes, mobilization of ferrous ion, growth regulation, and
the oxidation of organic compounds. One well-known exam-
266 Carbohydrale.s

HO 4
HO
0H

°
OH
H
O+H
CH,OH

CH,OCOCH'OH
HO
HO
~OH
°
OH
O-CH,

H+OH

~
[H'OH liIiosideC CH,OH
liIioside A HOHO 0 H

OH CHOH
H '
liIiosideB OH
OH

~
liIiOSideE
HO
HO ~ OH
HO
O-+CH,
H
HO

HO OH O+CH'
HO H
CH,OH CH,OCOCH,
liIiosideD
H
° CH,OCOCH,
HO
OH
oOH

~t"~~"
(104)

HO
]r ~
oH
OHH
H
H ~OH
OH

stachysoside A

HO

Fig. 15.16. Some unusual types of glycosides.

pie involves the activation of the glucosidase (myrosinase)
that hydrolyses the glucosinolate sinigrin to allyl isothiocya-
nate (Loewus, 1980, 1988).
GLYCOSIDES Il'I PLANTS
Many sugar molecules in plants occur as glycosides. Glyco-
sides have modified solubility properties, toxicity and trans-
port possibilities. Glucosides and galactosides are the most
common glycosides. Mannosides are known only from
algae. Diglycosides, especially those involving gentiobiose
[O-J3-o-glucopyranosyl-(l-6)-J3-glucose] (45), sophorose
(79), vicianose [O-a-L-arabinopyranosYl-(l-6)-J3-o-glu
cose] (81), rutinose (80), and primeverose (47) (Fig. 15.9)
are widespread (Courtois and Percheron, 1970; Dey and
Dixon, 1985). Glycosides involving oxygen, sulfur, nitro-
gen, and other atoms are known. In plants, most glycosides
are accompanied by enzymes capable of hydrolyzing them
(Nisizawa and Hashimoto, 1970).
In general, these compounds are derived via UDP-glucose
(UDPG) or a similar sugar nucleotide (Fig. 15.15). In gen-

~O.gIUCOSYI OH
° °
0-('~ 0-~
~N} \ ~N} ~N~N~
glucose
indican (82) indoxyl (83) indigo (84)

Fig. 15.17. Hydrolysis and oxidation of indican to produce indigo (modified from Courtois and Percheron. 1970; used with pennission of the copyright
owner, Academic Press, Orlando, FL).
 Carbohydrates 267

eral, inversion is observed when the glycoside is formed
(Dey and Dixon, 1985).
Glycosides are treated in the chapters that deal with the
aglycone portion of the molecule, but a few types, mostly
those of unclear origin, are described below. Other unusual
types include compounds such as glycerol glucosides from
Ulium longiflorum (Fig. 15.16) (Kaneda, 1990). Phenethyl
alcohol glycosides are widely distributed among plants and
have various types of biological activity. These glycosides
have been reported to be antibacterial, antifeedant, cytotoxic,
and enzyme-inhibitory activity against AMP phosphodies-
terase and 5-lipoxygenase (Nishimura et al., 1991).
Indigo-Producing Glycosides
Indican (3-hydroxyindole j3-o-glucoside) (82) occurs
mainly in the genera Indigo/era (Fabaceae),!satis (Brassica-
ceae), and Polygonum (Polygonaceae). When L_[5_3 Hjtryp_
tophan was adrnirtistered to young plants of !satis tinetoria
(woad) and Polygonum tinetorium, radioactively labeled in-
dican was isolated (Maier et al., 1990). In the woad plant,
roots may be the main site of biosynthesis. On hydrolysis,
indican yields o-glucose and indoxyl (83), which, on oxida-
tion in air, yields the insoluble dye indigo (84) (Fig. 15.17).
Lactone.Porming Glycosides
A number of low-molecular-weight glycosides that pro-
duce 5- or 6-membered lactones have been encountered in
several plant families, but are best known from members of
the Ranunculaceae and Liliaceae. These compounds often
occur at concentrations of 0.1 % or more dry weight in the
plants and are biologically active, having pronounced fungi-
toxic andlor allergenic properties (Hegnauer, 1973). These
lactones often produce intense irritation on human skin.
Nothing is known about the biosynthesis of this group of
compounds in plants. Many of these compounds can be de-
tected by Kedde' s reagent, antimony (III) chloride, and other
reagents for cardiac glycosides (which possess butenolide
or other lactone rings) (Fung et al., 1988).
The biting taste and blistering properties of many species
of the Ranunculaceae are well known. These properties are

rr OH

--
o:r-CH,-CH,-C-~H,

? ? 2HO (,0. O~o

~
I (-
gluiYI gluCjyl
o 0
I I )-ranuDculin (87)
CH,-C-CHrCH,-C=O
II
o
ranunculoside (86)
Ranunculaceae
anemonin (88)

OCH,

O£:\OH

n
nartheside (93), Liliaceae
o o

P~'" -
parasorboside (95) Rosaceae
OH H
parasorbic acid

c:f c\o
OH
~OH

0" -
o 0 mevaloside (94)
(a) Mespilus germanica, Rosaceae anhydromevalonic acid lactone

Fig. 15.18 (8 & c). Lactone-fanning glycosides and their hydrolysis products.
268 Carbohydrates

cSo o
a-methylene-y-
butyrolactone (91)
HO 0

HO~OH
tuliposide A (89)
a-methylene-r-hydroxy-
butyric acid

HO,
~ If
HO
A AO~OH
OH
0

tuliposide B (90)
OH

-
--............
HO~O
o
p-hydroxy-a-methylene-
y-butyrolactone (92)

HO 0

HO~OH
a-methylene-p,y-dihydroxy
(bJ butyric acid
Fig. 1S.18. (continued)

c," ,,,"~ru,, ~
O~C02H (~~O
o 0
0 0

Holygarna lactone (98) biglandulic acid (97) massoialactone (101)

Anacardiaceae Euphorbiaceae
Lauraceae

CH3(CH')~O
OAc
o
OAc OAc
hyptolide (99) argentilactone (100)
Lamiaceae Aristilochia sp.

C:~' o
(c) siphonidin (102) isosiphonidin (103)

Fig. 1S.18. (continued)


caused by protoanemonin (85), which is formed by a com-
plex set of reactions. The precursor ranunculoside (86) is
converted to ranunculin (87), hence to protoanemonin, and
subsequently by dimerization to anemonin (88) (Hegnauer,
1984; Nahrstedt, 1979). Protoanemonin, which arises by
cleavage of ranunculin by glucosidases found in the plant,
also has been isolated by steam distillation of plant material.
Protoanemonin spontaneously dimerizes to form anemonin
(Hegnauer, 1973). Both anemonin and protoanemonin have
antifungal properties (Misra and Dixit, 1980).
Protoanemonin (85) yielding compounds are known to
occur in the genera Anemone, Ceratophalus, Clematis,
Clematopsis, Helleborus, Hepatica, Knowltonia, Myosurus,
Pulsatilla, Ranunculus, and Trautvetteria (Hegnauer, 1973;
Ruijgrok, 1966). The results of numerous tests indicate that
these glycosides do not occur in Aconitum, Actaea, Adonis,
Anemonella, Anemonopsis, Aquilegia, Callianthemum, Cal-
tha, Cimifuga, Consolida, Coptis, Delphinium, Erantis, Hy-
drastis, lsopyrum, Leptopyrum, Nigella, Semiaquilegia,
Thalictrum, Trollius, and Zanthorhiza (Hegnauer, 1973).
Tuliposide A (89) is the ester of glucose with a-methyl-
ene-'Y-hydroxybutyric acid. This compound often is accom-
panied by the l3-hydroxyderivative, tuliposide B (90) (Fig.
IS.18) (Nahrstedt, 1979). The hydroxyacids released by en-
zymic or spontaneous hydrolysis of tuliposides lactonize to
form a-methylene-'Y-butyrolactones (91,92) (Slob et al.,
1975). The enzymes necessary to hydrolyze tuliposides often
co-occur with the glycosides (Slob et al., 1975). These com-
pounds have strong fungitoxic and allergenic properties. Tu-
liposide A is found in the bulbs, stems, leaves, and flowers
of cultivated tulips (Slob et al., 1975). The NMR spectra of
tuliposides have been reviewed (Tschesche et al., 1969).
TuJiposides are widespread in the genera Tulipa, Ery-
thronium, Gagea, Bomarea, and Alstroemeria (Liliaceae)
(Hegnauer, 1973; Siobetal., 1975). The genus Alstroemeria
is sometimes placed in the family Alstroemeriaceae, but re-
sembles the Liliaceae in the content of tuliposides. Tulipo-
side A (89) occurs in large amounts in tulips (Slob et al.,
1975).
Tuliposides appear to play a role in resistance of tulip
cultivars to various fungi (Tschesche et al., 1969). These
compounds serve as preformed defensive substances. Tulips
often are attacked by Fusarium species, especially at the end
of the growing season (Nahrstedt, 1979). These glycosides
apparently provide most of the resistance to Botrytis tulipae
in resistant lines. However, it is not the intact glycosides
themselves but their hydrolysis products that are antifungal.
The greatest amount of tuliposides in tulips occurs in the
stigmatic branches of the pistil-as much as 32% of the dry
weight or 32,000 ppm based on fresh weight (Nahrstedt,
1979). As little as 100 ppm is active in vitro.
Nartheside (a-methoxY-'Y-hydroxy-aa -butenolide) (93),
a glucoside that yields a-methoxy-aa-butenolide on hydrol-
ysis, occurs in Narthecium ossifragum and probably other
plants of this genus (Liliaceae) (Hegnauer, 1973).
Other unsaturated lactone glycosides are found in the Ro-
('arlm"'ydrltl(,.~ 269
saceae [parasorboside (95) in Sorbus), mevaloside (94) in
Mespillus germanica (Rosaceae) (Davies-Coleman and Riv-
ett, 1989; Tschesche et al., 1969), Holygama lactone in the
Anacardiaceae (98), biglandulic acid (97) in the Euphor-
biaceae, hyptolide (Hyptis pectinata) (99) in the Lamiaceae,
argentilactone (100) (Aristolochia argentina) in the Aristo-
lochiaceae, and massoia lactone (101) (Cryptocarya mas-
soia) in the Lauraceae (Davies-Coleman and Rivett, 1989;
Hegnauer, 1984; Nahrstedt, 1979).
Another butenolide, siphonidin (102) and its glucoside,
siphonoside, have been isolated from the leaves of Siphono-
don australe (Celastraceae) (Wagner and F1itsch, 1981;
Wagner et al., 1981). A new butenolide, isosiphonodin [3-
hydroxymethyl-2(SH)-furanonel (103) and a small amount
of siphonidin (102) were isolated from fifth-instar larvae of
Yponomeuta cagnagellus. The larvae of this moth feed on
the foliage of the spindle-tree, Euonymus europaeus (Celas-
traceae) (Fung et al., 1988).
Sugar Esters
The exudate of the glandular trichomes of Solanum ber-
thaultii are effective against aphids and similar insect pests.
One part of the defense involves the immobilization of the
insects in the exudate which hardens (Harbome, 1989). This
exudate proved to be a mixture of sucrose esters, of which
3,4-di-O-isobutyryl-6-0-caprylsucrose is a major compo-
nent. These compounds also appear to provide resistance to
potato blight (Harbome, 1989). A similar series of com-
pounds is found in the trichomes of other solanaceous plants
of the genera Datura, Lycopersicon, Nicotiana, and Petunia.
A series of esters of sucrose with E-p-coumaric acid (such
as 104) and acetate from Prunus maximowiczii proved to be
responsible for the very bitter taste of the fruits (Shimazaki
et al., 1991) (Fig. IS.18).
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16
Cyanogenic Glycosides and Cyanolipids
Introduction
Biosynthesis
Major Structural Types of Cyanogens
Cyanogens Derived from Phenylalanine
Cyanogens Derived from Tyrosine
Cyanogens Derived from Valine and Isoleucine
Cyanogens Glycosides Derived from Leucine
Cyanolipids
Cyanogenic Glucosides with a Cyclopentenoid Ring
Structure
Cyanogenic Compounds of Other Origins
Distribution
j3-Glycosidases
Biological Activity
Transport of Cyanogenic Glycosides
Cyanogenic Compounds as Defensive Substances
Cyanogenesis, Ants, and the Genus Acacia
Cyanogenesis in Millipedes and Insects
Biological Activity of Cyanide in Plants
Detoxication of Cyanide
Cyanogenesis in Crop Plants
Nitroglycosides
Nitrile Glucosides
Pseudocyanogenic Glycosides
Analytical Techniques
References
INTRODUCTION
The ability to produce cyanide or cyanogenesis has long
been recognized in plants. At least 2650 species, from more
than 550 genera, and 130 families possess the ability to make
cyanogenic glycosides (Hegnauer, 1986; Seigler, 1991).
Most reports of cyanogenesis are based on two simple, but
reasonably specific, color tests-the Guignard (alkaline pic-
ric acid) and the Feigl-Anger methods (Feigl and Anger,
1966; Seigler, 1991; Tantisewie et aI., 1969).
The actual cyanogens have been isolated and studied from
more than 475 species of plants (Seigler, 1991). Despite the
fact that this phenomenon is widespread, the structures of
only about 60 cyanogenic compounds have been published
(Nahrstedt, 1987a; Seigler, 1991). These compounds are gly-
cosides of Ci-hydroxynitriles or cyanohydrins with the excep-
tion of a few cyanogenic lipids (see below). The glycosides
are usually accompanied by a j3-glycosidase enzyme capable
of producing the corresponding cyanohydrin (aglycone) and
a sugar (Fig. 16.1). A second type of enzyme (hydroxynitrile
lyase) catalyzes the dissociation of the cyanohydrin to a car-
bonyl compound and hydrogen cyanide. Normally, the sub-
strate and enzymes are compartmentalized within the plant
and cyanide release does not occur unless the plant is dam-
aged (Conn, 1981, 1993; Poulton, 1988; Poulton and Li,
1994; Selmar, 1993).
In the family Sapindaceae (and possibly the related family
Hippocastanaceae), the Ci-hydroxynitrile is esterified with a
long-chain fatty acid (C 18 or C20 ) to produce cyanogenic
lipids (Fig. 16.2) (Mikolajczak, 1977).
Although many bacteria and fungi are cyanogenic, the
cyanogenic compounds usually are labile. Glycine is the pre-
cursor of hydrogen cyanide in many instances. Labeling
studies indicate that the C-N bond is not broken during the
biosynthesis of cyanide (Harris et al., 1987). In some cases,
cyanohydrins have been isolated, but these may result from
secondary reactions of hydrogen cyanide and other fungal
metabolites. The cyanohydrins of glyoxylic and pyruvic
acids have been reported from a snow mold fungus (Fig.
16.3) (Bunch and Knowles, 1980; Knowles, 1988; Tapper
and MacDonald, 1974).
Cyanogenic cyanohydrins and cyanogenic glycosides
also are known to occur in animals (Duffey et aI., 1977;
Nahrstedt and Davis, 1981).
The production of cyanide in many plants is extremely
273
274 Cyanogenic Glycosides and Cyanolipids

l3-glucosidase

Hu
dhurrin (15)

H .CN o

"0><0
+HCN
hydroxynitrile lyase

OH OH

4-hydroxymandelonitrile (3)

HOH~O~CN><U" OH 0 0
H
~

j
HO ~
cyanogenic RO OR f
diglycoside ~ ~YCOSidase

8-glycosidase eN H

:;~:~><O'"
HO
~ OH
H
/
n,g,::::-----
""><u a-cyanohydrin

~
cyanogenic monoglycoside

Fig.16.1. Catabolism of cyanogenic glycosides (Seigler, 1991; modified and used with the permission of the copyright owner, Academic Press,
Orlando, FL).

variable. All individuals of some species are cyanogenic;
populations of others contain plants that are cyanogenic
(ranging from very strong to weak) and plants that are not;
with other species, some populations are completely acyano-
genic, whereas others exhibit some cyanogenesis. The
expression of cyanogenesis often is influenced by stress and
other environmental factors. Nonetheless, the distribution of
cyanogenic glycosides is of systematic interest as certain
structural types of cyanogenic glycoside are associated with
specific groups of plants (Hegnauer, 1986; Saupe, 1981).
The presence of cyanogenic compounds in food and for-
age plants such as cassava and sorghum creates important
health problems in many tropical countries (Davis, 1991;
Nahrstedt, 1993; Wilson, 1987).
Methods for the isolation, purification, and characteriza-
tion of cyanogenic glycosides and related compounds have
been reviewed (Brimer, 1988; Brinker and Seigler, 1989,
1992; Nahrstedt, 1981; Seigler, 1991; Seigler and Brinker,
1993).
BIOSYNTHESIS
The aglycone portion of cyanogenic compounds is derived
from amino acids. To date, most cyanogenic compounds
come from a relatively small number of precursors: L-tyro-
sine, L-phenylalanine, valine, isoleucine, and L-leucine. Aca-
Iyphin (1) (Fig. 16.14) appears to be derived from nicotinic
acid. One series of cyanogens has aglycones that contain a
cyc1opentenoid ring and are derived from the nonprotein
amino acid, (2-cyc1opentenyl)glycine.
Much of biosynthetic work has been done with flax
(Linum usitatissimum), cherry laurel (Prunus lauroeerasus),
and sorghum (Sorghum bieolor). Introduction of labeled
 Cyanogenic Glycosides and Cyano/ipids 275

'X'
,
o
, ..Jl
NC H 0 CH,(CH')I7CH,

NC
':c' '
I
H
0
JL
CH,(CH')I7CH,

(----0 0
OH

_ (---0
OH
--y
H CN
0
_
Ho~00.
HO~O~O)lCH,(CH')I7CH' HO OH J--;0
OH (58) (59)

Fig. 16.2. Cyanolipids.

amino acid precursors into these plants results in extremely
high introduction of label (up to 25%). By double-labeling
experiments, it has been demonstrated that the C-N bond
is not broken during the biosynthetic process; all intermedi-
,tes in the pathway contain nitrogen. Recent work has been
facilitated by the development of particulate (microsomal)
fractions from Sorghum bicolor, Linum usitatissimum (flax),
and Triglochin maritima. In several instances, removal of
the seed coat is an obligatory step; preparations made with-
out this step usually are inactive (Koch et aI., 1992). One
similarity of all systems is that the product is produced with-
out the accumulation of any intermediate compounds. This
phenomenon was not consistent with the kinetic parameters
for the individual reaction steps. The enzymes of the path-
way are arranged in a way such that efficient flow of mole-
cules from one step to the other occurs (Conn, 1983; Cutler
and Conn, 1982; Dewick, 1984; Mf2IlIer and Poulton, 1993).
CO,H
CO,H
I I
HO-C-CN HQ-C-CN
I I
CH, H
pyruvic acid glyoxylic acid
cyanohydrin cyanobydrin
Fig. 16.3. Glyoxylic acid and pyruvic acid cyanohydrins.
Major intermediates include a hydroxyl amino acid, aldox-
ime, nitrile, and an a-hydroxynitrile (Fig. 16.4) (Halkier and
Mf2IlIer, 1990; Halkier et aI., 1988). These intermediates are
observed only at extremely low levels in the plants which
contain them. In the course of the biosynthetic studies, it
was observed that the proposed intermediates were incorpo-
rated at very different and inconsistent rates. These differ-
ences in rate were inconsistent with the order of incorpora-
tion of the different intermediates. A channeled process has
been proposed in which the compounds are not liberated
from the enzyme surface (Conn, 1981). Channeling provides
for the rapid and efficient flow of carbon and nitrogen atoms
and at the same time perhaps protects labile intermediates
from wasteful side reactions (Conn, 1981).
Many of the enzyme systems of the biosynthetic process
have now been studied. A microsomal fraction from etio-
lated sorghum seedlings converted L-tyrosine (2) into p-hy-
droxymandelonitrile (3) (Halkier and Mf2IlIer, 1991; Mf2IlIer
and Poulton, 1993). The particles required ouly NADPH in
addition to the substrate. N-Hydroxytyrosine (4) was shown
to be an intermediate in the synthesis of the aldoxime, and an
N-hydroxy1ating cytochrome P-450 was identified (Dewick,
1984; Halkier and Mf2IlIer, 1989, 1991; Halkier et aI., 1991).
The N-hydroxytyrosine (4) is converted to 2-nitro-3-(p-hy-
droxyphenyl)propionic acid (5), which is, in tum, converted
to 1-aci-nitro-2-(p-hydroxyphenyl)ethane (6). The last com-
pound appears to be the immediate precursor to (E)-p-hy-
276 Cyanogenic Glycosides and Cyano/ipids
droxyphenylacetaldehyde oxime (7). l-aci-Nitro-2-(p-hy-
droxyphenyl)ethane (6) exists in equilibrium with I-nitro-
2-(p-hydroxyphenyl)ethane (8) (Hallder and Ml'lller, 1989,
1990; Haikier et al., 1988, 1991). This nitro compound has
been isolated from culrures of cyanogenic plants, and similar
compounds are narurally occurring. In sorghum and in cas-
sava (see below), both the (E)-isomer (6) and (Z)"isomer
(9) of the oxime were accepted (Koch et aI., 1992). The
apparent NADPH and oxygen requirements for the oxime-
metabolizing enzyme appear to be the same as those for
the C-hydroxylating enzyme mentioned below. Using this
microsomal fraction, it has been demonstrated that the nitrile
(10) rather than the hydroxyaldoxime is involved in the syn-
thesis (Cutler and Conn, 1982; Dewick, 1984). A C-hydrox-
ylating cytochrome P-450 that converted the nitrile to the
hydroxynitrile was identified (Halkier and Ml'lller, 1991).
f3-Glucosyltransferases have been isolated and purified
from a few cyanogenic species. They have pH optima in the
range 6.5-9.0 and usually lack a requirement for metal ions
or cofactors. Although they have an absolute specificity for
UDP-glucose, they are less specific toward cyanohydrins
(Ml'lller and Poulton, 1993).
A microsomal system that catalyzes the in vitro synthesis
of the aglucones of the two cyanogenic glycosides linamarin
(11) and lotaustralin has been isolated from young seedlings
of cassava (Manihot esculenta, Euphorbiaceae) (Fig. 16.5).
Valine (12) and isoleucine were converted in the presence
ofNADPH to linamarin and lotaustralin in a process involv-
H,N
HO -oJ
-
~ CO,H
-HO
-o-FCO'H
V~
-
L-tyrosine (2) N-bydroxylyrosine (4)
!t
aci-t-nitro-2-p-hydroxyphenylethane
(6)
(E)-4'-bydroxypbenyl-
acetaldehyde oxlme (7)
HO~NO, l-nitro-2-(p-bydroxypbenyl)ethaoe
(8)
_ (o~o H~CN
HO~O I ~ __
00 00
....:;;
dhurrin (15)
Fig. 16.4. Biosynthesis of cyanogenic glycosides (Halkier et aI., 1991; modified and used with penmssion of author).
ing P-450 enzymes (Koch et al., 1992). As is true in
sorghum, nitro compounds [such as aci-1-nitro-2-methyl-
propane] (13) also appear to be intermediates in the synthetic
route. 2-Cyclopentenylglycine (14) also was converted to
cyanogenic glycosides with this enzyme system. The en-
zyme system is located in the cotyledons and their petioles;
after synthesis, linamarin and lotaustralin are transported
rapidly to other parts of the growing seedling (Koch et al.,
1992).
Hahlbrock and Conn (1970) isolated an enzyme system
from flax that catalyzed the glucosylation of a series of 2-
hydroxynitriles. This system exhibited maximum rates with
the acetone and methylethyiketone which would, on glyco-
sylation, yield linamarin (11) and lotaustralin, the cyanogens
of flax. This enzyme was inactive toward aromatic cyanohy-
drins. The enzyme glucosylated both the (R)- and (S)-forms
of the cyanohydrin of 2-butanone (Zilg and Conn, 1974). In
most cases, however, racemic mixtures of compounds are
not encountered in plants; this suggests that, in general, only
one optically active form of the cyanohydrin is glucosylated
by the enzyme. In contrast, when the corresponding glucosy-
lating enzyme from sorghum reacts with the cyanohydrin
[p-hydroxy-(R,S)-mandelonitrile (3)], only dhurrin (15) is
produced. When a soluble protein fraction containing the
UDP-glucosyl transferase was added to the cyanohydrin
from the microsomal preparation described above, the for-
mation of dhurrin occurs (Conn, 1981).
The biosynthesis of (R)-taxiphyllin (16) has been demon-
OH
--
HN/
2-nitro-3-(4'-hydroxyphenyl)
propionic acid (5)
HO~
yN
yH
'=I
H
(Z)-4'-hydroxyphenyl-
acetaldehyde oxime (9)
!
HO~
/" ~CN
p-hydroxypbenyJacetonitrile
HO ~~H (10)
~N
OH p-bydroxymaodelooitrlle (3)

~.0:H'+
Cn, CH,
--+
L-vallne (12) N·hydroxyvaline
(E)-2-methylpropanaloxime
HO" / C
CH'--~-
, C~
2-methylpropionitrile acetone cyanohydrin
Fig. 16.5. Biosynthesis of linamarin and lotaustralin (Koch et aI., 1992; modified and used with permission of the copyright owner, Academic Press,
Orlando, PL).
strated with a microsomal preparation from etiolated Tri-
glochin maritima. L-Tyrosine (2) was converted into p-hy-
droxyphenylacetonitrile (10) and p-hydroxymandelonitrile
(3) when the preparation was supplied with NADPH. When
UDP-glucose and a soluble fraction from the plant were
added, taxiphyllin was formed. Incubation of the glucosyl-
transferase fraction with p-hydroxy-(R ,s)-mandelonitrile
and UDP-glucose, produced taxiphyllin (16), but not (S)-
dhutrin (15) (Fig. 16.4) (Cutler and Conn, 1982; Dewick,
1984). It was necessary to remove the seed coats in order
to obtain an active microsomal fraction. In this case, p-hy-
droxyphenylacetonitrile did equilibrate with exogenous ma-
terial, although other intermediates were channeled (Cutler
and Conn, 1982; Dewick, 1984).
A similar series of compounds is converted into triglochi-
nin (17) (Fig. 16.10) in Trig/ochin maritima and Thalictrum
aquilegifolium (Ranunculaceae). 3,4-Dihydroxyphenylace-
tonitrile (18) also is incorporated (Fig. 16.10) (Cutler and
Conn, 1982; Dewick, 1984).
Treatment of racemic mandelonitrile with UDP-glucosyl
transferase from the fruits and leaves of black cherry, Prunus
serotina, produces only (R)-prunasin (19). These prepara-
tions did not convert prunasin to the diglycoside amygdalin
(20) (Dewick, 1984).
JllAJOR STRUCTURAL TYPES OF CYANOGENS
As mentioned above, most cyanogenic compounds are de-
rived from five amino acids. Other cyanogenic glycoside
are derived from the nonprotein amino acid cyclopentenyl
Cyanogenic GJycosides and Cyanolipids 277
(2-cyclopentenyl)glyclne (14)
--
aci-l-nitro-2-methylpropane (13) I-nitro-2-methyJpropane
~ glucosyl-O C=N
CU;-'><:H,
linamarln (11)
glycine and one probably from nicotinic acid (Seigler, 1991).
The known cyanogenic glycosides will be discussed (below)
in groups based on their probable biosynthetic origin. The
center bearing the nitrile group often is chiral. In many in-
stances, both (R)- and (S)-forms are known; occasionally,
both epimers occur in the same plant.
Cyanogens Derived from Phenylalanine
Several cyanogens are derived from L-phenylalanine (Fig.
16.6). Compounds derived from this precursor is found pri-
marily in the Rosidae and Asteridae (as defined by Cron-
quist). Among the compounds from this pathway, the best
known is amygdalin (20), which is widespread in seeds of
members of the Rosaceae such as apples, peaches, cherries,
and apricots. Phenylalanine-derived cyanogens include the
monoglucosides (R)-prunasin (19), prunasin-6-malonate
(21) (Nahrstedt et al., 1989), (S)-sambunigrin (22), and the
diglycosides (R)-amygdalin (20), (R)-Iucurnin (23), (S)-epi-
lucurnin (2-J3-primeverosyloxy-2-phenyl-2S-acetonitrile)
(24), (R)-vicianin (25), grayanin (26) (Shimomura et al.,
1987), prunasin 2'-glucoside (27) (Aritomi et al., 1985),
amydgalin 6"(4-hydroxybenzoate) (28), amygdalin 6"[4-hy-
droxy-(E)-cinnamatel (29) (Nahrstedt et aI, 1990), oxyan-
thin [2R-J3-D-apio-D-furanosyl-(1-6)-J3-D-glucopyranosy-
loxyphenylacetonitrile (30), and the 5"-benzoate of
oxyanthin (31) (Rockenbach et aI., 1992). Two complex gly-
cosides are also found in the froits of Anthemis cairica and
A. altissima. These compounds, Anthemis glycosides A and
B, epilucumin 4"-p-(J3-D-glucopyranosyloxy)-(E)-cinna-
mate (32), epilucumin 4"-p-(J3-primeverosyloxy)-(E)-cinna-
 HO
'
~
4'
H~.,.~CN
I
5'
OH

"
0 0:2 3
4
~5
,,(O~O
HO~
4' : ' »I Q
: """
C

//
4~,
HO 3' OH '~ HO OH I
, 3' 8 ~6

(R)·prunasin (19)
(S)-sambunigrin (22)

HO 0
14 13 10
H ICN
f
"~~o~,
12
HO
IS
~ j 11

" 17

..-,
grayanin (26)

o 0

HO
~O
'''~' H,~ .. ICN
.... 4

4' 0 0 2 3 ~5
HO ~
HO OH ,I
3' ""-:;:::::;6
7

(a) (R)-prunasin 6'-malonate (21)

~ :~~:>\),
HOH: 3" '''OOH O~,
0 :~"\
Ic~ 4~ ""
'I ~5
~::~"0:
6"
'7~ ,

00 • I •
HO 3' OH, HOHO 7)
..--;::::; 6 OH prunasin 2'-glucoside (2
(R)-amygdalin(20) 7 ~

}-o"" "0"" "on "~~:'~'.

H ~
~ 4"
" 1
HO OH /
.-::;:::::::.

"",," , '"" "::i A }-~ II';.

5" 0 "><oCN (S)-neoamygdalin
0' ,\,

HO:O~ / ~4' ~ ~OH'" 0

(R)-amygdalin6"(4-hydroxybenzoate)(28) HO~O" H , leN

><o,.

HO 3" OH ':\ ~O. O' 3 ~

(R)-amygdalin 6"(4-hydroxy-(E)·cinnamate) (29)
HO:n~
HO 3' OH
/
.--;::::.
(b)

Fig. 16.6 (a-c). Cyanogens derived from phenylalanine.

278
 Cyanogenic Glycosides and Cyanolipids 279

."~OH,,,
HO
0

3"
'"
OH
HO
o~",0 '
HO 3'
0

OH
H CN
»j' •

•
3

"
I
""-

""
~,

7
(R)-vicianln (25)

OO~~'><o'CN
HOH~O~'H~CN 3" OH HO~~ 3' "OOH 0 r ~
3" OH" 0 ~
HO
HO OH
0 1/
I
~ (R)-Iucumln (23)

_ . do~~~:~
.--:;::;

OHOH OH.V

" O~H~'CN.
HO ~ 3"
0."

HO
0 0 3 ~
r
oxyantbin S"-benzoate (31) ..&

OH OH HO OH" ....::::::'

(e) oxyantbin (30)

Fig.16.6 (continued)

mate (33) (Fig. 16.7), contain several sugar moieties as well
as p-hydroxycinnarnate residues (Nahrstedt, 1987a). Pm-
nasin and sambunigrin only differ in configuration at the
carbinol carbon. The families Asteraceae, Fabaceae, and Ro-
saceae are characterized by the production of these com-
pounds (but have other types of cyanogens as well) (Seigler
et aI., 1989). The diglycoside cyanogens are more restricted
in distribution. Amygdalin (20) is found primarily in fruits
of the Rosaceae, lucumin in seeds of the Sapotaceae, epilu-
cumin (24) and its derivatives only in the fruits of Anthemis

H('H~O
~

3",
0

OH
Hqj'O~O
6'.

~..::\.
3,.OH
_0 ~,¥
16 17

~ 11 ~~O:::\ ~0l))
_ ~.
. . .3 1 0 0
4" S"

3"
0

OHH ;o~O
q.o J' OH
H
•
eN

I ~
8 ....-:::;

Anthemis glycoside A (32)

6'. OH H 'CN
H~~o 4"'''0."o,'
~ ~
iii 17

11
~ .OHO
~o' r ~~, OH l'
3'. on 10 3" H<kO 3' OH •
.4 13
o .--::,

Anthemis glycoside B (33)

Fig. 16.7. Anthemis glycosides A and B.

280 Cyanogenic Glycosides and Cyanolipids

OH H ICN OH H~:'CN
Ho~~OHHO~ ~s
6' """ 6' / 4
o 0 ~ 0 0 OH
I
4 4'

8~~~( ~
(R}-holocalin (35) (S)-zierin (34)

4"

~ O~'IH><o./CN
"O

HOHO
~ ~ 0
OH 0 ~ OH
HO 2' fl 5
HO 3' OH I
~
zierin xyloside (36)

I
OH HO
~
6"

~o ~"O H~/CN4
14 13

HO 0 0 15 r; o
1"0 6'
HO
4'a OH 9
4"'2'"
0HO OH
~02
I' 1 ~ OH
16 17 5'" OH 3" H(lHO OH 8 '
o 3' --::::: 6

xeranthin (37)

Fig. 16.8, meta~Substituted cyanogenic glycosides.

cairica (Asteraceae) (Nahrstedt et aI., 1983), and vicianin donous plant of the genus Chloraphytum (Liliaceae). A dig-
(25) in seeds of Vicia (Fabaceae) and in Davallia (a fern) Iycoside of this group, zierinxyloside (36) [from the achenes
(prunasin also is found in ferns) (Seigler, 1991). of Xeranthemum cylindraceum (Asteraceae)] contains the
An unnamed 1,2-linked diglucoside (27) has been de- sugar primeverose, whereas an even more complex glyco-
scribed from Perilla Jrutescens var. acuta (Lamiaceae). side, xeranthin (37), has been isolated from this species (Fig,
The seeds of many Rosaceous species contain amygdalin 16.8) (Nahrstedt, 1987a).
(20) and a mixture of l3-g1ycosidases, often called emulsin.
This mixture preparation hydrolyzes both amygdalin and Cyanogens Derived from Tyrosine
prunasin (18) readily. The leaves of these plants usually con- The best known of this series is dhurrin (15), which may
tain only prunasin and the leaf enzymes hydrolyze prunasin make up to 30% of the dry weight of the leaves and coleop-
but not amygdalin (Poulton, 1983). Within seeds of Prunus tiles of etiolated sorghum seedlings (Halkier and M¢ller,
sera tina and Prunus domestica, the cyanogenic glycosides 1989; Saunders and Conn, 1977). Cyanogens derived from
amygdalin and prunasin are found in the cotyledonary paren- tyrosine [(S)-dhurrin, (R)-taxiphyllin (16), and triglochinin
chyma, whereas amydgalin and prunasin hydrolase are found (17) (probable) (Fig. 16.9) are widespread in nature, whereas
in protein bodies of the procambial cells (Poulton and Li, p-glucosyloxymandelonitrile (38) and proteacin (39) are less
1994; Swain et aI., 1992). The enzymology of cyanogenesis corrunon (Fig. 16.10). Tyrosine-derived glycosides are en-
of some Rosaceous fruits has been reviewed (Poulton, 1993). countered most commonly in monocotyledonous angio-
A eDNA clone of the flavoprotein (R)-( + )-mandeloni- sperms and in the Magnoliidae (sensu Cronquist), but are
trile lyase from Prunus sera tina has been made and a puta- found in many other plant families as well (Hegnauer, 1977;
tive Flavin Adenine Dinucleotide (FAD)-binding site was Saupe, 1981).
identified (Cheng and Poulton, 1993). Isotriglochinin (40), an isomer of triglochinin, and the
Although the biosynthetic origin has not been definitely methyl ester of triglochinin have been reported, but both
established for all meta-substituted cyanogens, (S)-zierin may be artifacts of isolation (Conn, 1981).
(34) is derived from phenylalanine (Fig. 16.8) (Nahrstedt, In addition to other cyanogenic glycosides such as p-
1992; Nahrstedt and Schwind, 1992). (R)-Holocalin (35) oc- glucosyloxymandelonitrile (38), Nandina domestica (Ber-
curs in the seeds of the legume, Halacalyx balansae. The beridaceae) contains a complex cyanohydrin, nandinin (41).
leaves of this same plant contain (R)-prunasin (19) (Nahr- This compound is the 4'-caffeoyl ester ofp-glycosyloxyman-
stedt, 1976). Holocalin is also known from a monocotyle- delonitrile (Olechno et al., 1984).
 Cyanogenic Glycosides and Cyalloiipids 281

OH
OH

0Qr
6 <' O~OHHO 8
0
o ~'S'6'
HO
0
3'
OH

8 3 -- 2' OH 2' OH
mm . m
5 CN
0
o 4 I

triglochinin (17)
isotriglochinin (40)

OH

"/.} ) < ~
'5'6'
,
6
0 ° 3' OR

3,4-dihydroxyphenylacetonitrile (18) HO OCH, M, 0" •

5 CN
4 1
o

triglochinin monomethyl ester

Fig. 16.9. Cyanogens derived by oxidative cleavage of tyrosine and 3,4-dihydroxy-phenylacetonitrile.

OH H~~CN (O~O H.. , ,eN> < o ,

.O"~ o 0
1 ~
~

OH
HOHO
~O ~
OH , I ~
OH
(S)·dhurdn (15) (R)-taxiphyllin (16)

("0
Ho~-\J'L
,,~".";;f:~;;)~~
U ~OH 0 OH
HO OH - CN 0 HO OH

p-glucosyloxymandelonitrile (38) (S)-proteacin (39)

nandinin (41)

Fig. 16.10. Cyanogens derived from tyrosine.

282 Cyanogenic Glymsidt's "lid CywlOlipids

~ O),[I.!OH:-·(-~O O~' ~'(-~O

.OH , , ,.OH

~CN
". CN I 3 OH
() 4' CN 6' 1
HOHO ,. HO ,
.,. OH ,~O~ ~O~O , ,
OH s" mf
s
linamarin (11) (S).epilotaustralin (43) (R)·lotaustralln (42)

~
" OH OH

O~, X HO~O~'
s~CN
~ ~

HO 0 , 'CN '" 0

HO '" OH'" " 0

HO
I'»A o 4 3 on 4' 0
l' 0 3
HO 3' OH HO
HO 3' OH
Ilnu,taOO (44)

~
' OH 0 ,":ollnu'taOO(45)

" "O~/"OH'
HO '1' " 5 OH
OH H OH 'CN~" 0

~
6' 0 4 ICN sarmentosin(47) 4" ~O
,. O~ HO 2' 5
5 H 3' 0 2
HOH 3' OH 0 3 OH , CN, CH,OH
isosarmentosin
sarmentosin epoxide (46)
Fig. 16.11. Cyanogens derived from valine and isoleucine.

In studies with etiolated sorghum seedlings, dhurrin (15)
was found to occur primarily in epidermal tissues, whereas
the corresponding f3-glucosidase occurred in the subtending
mesophyll tissues (Kojima et ai" 1979). The subcellular lo-
calization of dhurrin f3-glucosidase and hydroxynitrile lyase
in the mesophyll cells and a UDP-glucose: aldehyde cyano-
hydrin f3-glucosyl transferase in epidermal plastids of
Sorghum leaf blades have been examined (Thayer and Conn,
1981; Wurtele et aI., 1982).
Cyanogens Derived from Valine
and Isoleucine
The cyanophoric compounds linamarin (11) (R)-Iotaus-
tralin (42), (S)-epilotaustralin (43), linustatin (44), neolinus-
tatin (45), and sarmento sin epoxide (46) (probable) are de-
rived from valine and isoleucine (Fig. 16.11). The first two
compounds are widespread and probably are found in more
plant species than any other cyanogenic glycosides. Lina-
marin and lotaustralin almost always co-occur. These gluco-
sides are most commonly encountered in the Asteraceae,
Euphorbiaceae, Fabaceae, and Linaceae.
(S)-Epilotaustralin (43) was first found in Triticum mono·
coccum (Poaceae) and also occurs in Passiflora warmingii
(Olafsdottir et aI., 1989). As these (R)- and (S)-epimers are
difficult to distinguish and most previous studies did not
differentiate the two, (S)-epilotaustralin may be more wide-
spread than usually thought (Nahrstedt, 1987a). (R)-Lotaus·
tralin (42) occurs in Berberidopsis beckleri, considered to
be a primitive member of the Aacourtiaceae (Jaroszewski
et aI., 1987b).
The corresponding gentiobiosides, Iinustatin (44) and
neolinustatin (45), have been isolated from flax seed and
certain Passiflora species (Olafsdottir et aI., 1989; Smith et
aI., 1980; Spencer et aI., 1986).
Sarmentosin epoxide (46), from Sedum cepaea (Crassula-
ceae), contains an epoxide ring and is not a glycoside of
an a-hydroxynitrile. Upon opening of the epoxide ring, the
resulting cyanohydrin liberates cyanide spontaneously
(Nabrstedt, 1987a). This compound is related to the noncy-
anogenic nitrile, sarmentosin (47), from Sedum sarmen-
tosum.
Cyanogenic OIycosides Derived
from Leucine
Another cluster of compounds arises from leucine. (S)-
Proacacipetalin (48), (R)-epiproacacipetalin (49), (S)-proa-
caciberin (50), (S)-heterodendrin (51), (R)-epiheterodendrin
(52), 3-hydroxyheterodendrin (53), (S)-cardiospermin (54),
and the corresponding p-hydroxybenzoate, p-hydroxycinna-
mate, and sulfate are all known (Fig, 16.12). Of these glyco-
sides, proacacipetalin (48), epiproacacipetalin (49), and pro-
acaciberin (50) are known only from the genus Acacia. The
diglycoside, proacaciberin (50), which contains a vicianose
 Cyanogenic Glycosides and Cyano/ipids 283

OH
'
~
'
~
H'CN
OH H 'CN
4' 0 ~!5 4' 0 Y
"" , y ' 5
HOHO 0
H~O l' 0 2"
2' 2
3' OR
" OH 4
4

(S)-proacacipetalin (48) (R)-epiproacacipetalin (49)

OH

~
OH
~
' H'CN H 'CN

HO
o ~\ . HO 4' 0 ~'
. 4
HO 2' 0 2 HO 0,
OH 3' OR
5

(R}~epiheterodendrin (52)
(S)-heterodendrin (51)

HOHO
~
OH
o
H

0 Y O H H OHO
f
CN
5 0 !
~OH H

o y ' OSO,"
CN
5

OH OH
4 4

(S)-cardiospermin (54) (S)-cardiospermin sulfate

~ O~ ~(O~o
4'
'
'NyH OH
0
'CN
4

J H~~O~OH
HOHO l'

OH
3 OR I' 5 4
5

(a)
acacipetalin (56) sutherlandin (57)

OH
o
~
' H'CN
4' 5' 0 y ! 5
HOHO z' 0; 3 0
3' OR
4
14 13

J.-O'
(S)-cardiospermin 4-hydroxy-(E)-cinnamate (74)

H0
~
'
4
'
OH

0 o H y5 ! 0 6
'CN

\. jlOOH~OH
9

,
HO, HeN
O~!S
1211 6'

'OH 4'
4 HO l' 0
(S)-cardiospermin 4-hydroxybenzoate (55) HO 3' OH , OH

3-hydroxy-(S)-heterodendrin (53)

OR
Ls'/~
0 1" o~''oC~\
~ 0 " 5

4"
r::V
HO 3"
'OH
HOHO
4'

3'
2'
OH
4
(S)-proacaciberin (SO)

(b)

Fig. 16.12 (a & b). Cyanogens derived from leucine.

284 Cyanogenic Glycosides and Cyanolipids

unit, has been isolated from Acacia sieberiana (Brimer et Acacipetaiin (56) is probably an artifact of isolation (Et-
ai., 1981; Nartey et ai., 1981). Heterodendrin (51) and epi- tlinger et al., 1977).
heterodendrin (52) occur only in the Sapindaceae and in the Sutherlandin (57), a compound related by structure to the
Poaceae (grasses). Although cardiospermin is known only series of compounds derived from leucine, and in particular
from the Sapindaceae, the p-hydroxybenzoate (55) is known to certain cyanolipids, is weakly cyanogenic. This compound
only from Sorbaria arborea (Rosaceae: Spiraeoideae) co-occurs in Acacia sutherlandii with proacacipetalin and
(Nabrstedt, I 987a). the dimer of the two compounds (Swenson, 1986; Swenson

O Q
3 2
3 2
CN OH CN OH
4 1~'
5'
o 0 OH
4 ~'5'
5 HO 3'
o 0 OH
5 HO J'
2' OH 2' OH

tetraphyllin A (61)
deidaclin (60)

~
4'
HOHO
,OH
5'

3,OHNC
ON< l' 0
z

5
4
3
......-H

OH
~,OH
4'
HOHO
3
2'
,OHNC
0>0< l' 0
23

5
4
OH

tetraphyllin B (62) volkenin (61)

HOHo
~
4'
,OH

3'
0

OH
l' 0,

NC
>0< 23

1 4
H

080;
5

(a) tetraphyllin B sulfate (69)

HOHo
~
4'
,OH

3,OHNC
0 l' 0 N< 23

1 4
OH

H
5

epivolkenin (65) taraktophyllin (64)

~
,OH 23

HOHo
4,0

3'
2'
OH
0
0 ...
N~H
.....
- OH

HOi'IO~
.'
CH20H
~-./O, /0
~H
0
12 J
4
H

OH 3' OHNC sOH

(h) gynocardin (68) passisuberosin (70)

Fig. 16.13 (a-c). Cyanogens with a cyc1opentenoid ring structure.

 Cyanogenic Glycosides and Cyanolipids 285

!O<
1"0~' '_3 '" O~' '_3
4~~0 >0< ~~HO'"
'"
'" OH 0 .. 0 OH'" OH 00 OH
H0 3" 14 HO" , 14
"
OH 3' OH NC ,H OH 3' OH NC , H

6'·O·rhamnopyranosyJ taraktophyllin (66) 6'·O·rhamnopyranosyl epivolkenin (67)

~ >0<' H~'" >0<' ~

HO
"
CH'OHo 3 3" '''OH 'CH,OH o 3 0 ."

HORO
OH
o
Nt
l'
5
0

H
1"
0

HO
'" HOR~
6" 4'

3' OH
l' 0

NC
1
,
"
0

H
1"
2"
HO
3"

passitrifasciatin (73) passicapsin (12)

~\0II/0, 0.>0<'
3 O~
H~~ 1 4 'O~."
3' OH NC 5 H '''HO

(0) passibiOorln (71)

Fig. 16.13. (continued)

et al., 1987). As the dimeris found only in old dried material, and Spener, 1976). These compounds include deidaclin (60),
it may be an artifact. tetraphyllin A (61), tetraphyllin B (62), volkenin (epitetra-
phyllin B) (63), taraktophyllin (64) (probably same as passi-
CyanoJipids coriacin; see Seigler and Spencer, 1989), epivolkenin (65)
(possibly same as epipassicoriacin), the 6'-O-(a-L-rhamno-
Four cyanolipids occur in the seed oils of plants of the
pyranosides) of epivo1kenin and taraktophyllin (67, 66) (Jar-
Sapindaceae (Fig. 16.2) (Mikolajczak, 1977; Seigler, 1991),
oszewski etal., 1988), gynocardin (68), tetraphyllin B snlfate
although they also have been reported from the Hippocastan-
(69), passisuberosin (70), passibiflorin (71), passicapsin
caeae and Boraginaceae (Ahmad et al., 1978; Osman and
(72), and passitrifasciatin (73).
Ahmad, 1981). These lipids are derived from leucine. In
The structures of four of these compounds have been
two cyanolipids, a long-chain fatty acid is attached to an a-
established by x-ray crystallographic studies. Deidaclin has
hydroxynitri1e. Two other cyanolipids are apparent rear-
(IR)- (60), tetraphyllin A (61) has (IS)-, and tetraphyllin
rangement products and, although derived from the same
B (62) has (IS),(4S)-configuration (Nahrstedt, 1987a). The
precursors, are not cyanogenic.
structure of gynocardin (68) (from Pangium edule) was es-
Two glycosides, 3-[:l-n-glucopyranosyloxy-4-methyl-
tablished by x -ray crystal studies of the p-bromobenzenesul-
2(5H)-furanone (58) and 4-[:l-glucopyranosyloxy-3-hydrox-
fonyl derivative. By other methods, vo1kenin (epitetraphyllin
ymethylbutyronitril-2-ene (59), were isolated from the hem-
B) (63) has been shown to have a (lR),(4R)-configuration
olymph of adults of the bug, Leptocoris iso/ata (Heteropt-
(Jaroszewski and Olafsdottir, 1986; Jaroszewski et al.,
era). Th.( cyanogenic glycoside cardiospennin (54) was
1987a). The configurations of taraktophyllin (passicoria-
found in extracts of whole insects. The larvae contain one
cin?) (64) and epivolkenin (epicoriacin?) (65) also have been
of the glycosides, cardiospennin, and a mixture of cyanoli-
established (Jaroszewski et aI., 1987c).
pids. The frnit of the host plant, Allophylus cobbe (Sapinda-
These compounds occur in the families F1acourtiaceae
ceae) contains a similar mixture of cyanolipids (Braekman
(Spencer and Seigler, 1985b; Jaroszewski and Olafsdottir,
et al., 1982).
1987; Jaroszewski et al., 1988), Turneraceae (Spencer et aI.,
1985c), Passifloraceae (Olafsdottiret al., 1989), Malesherbi-
Cyanogenic mycosides with a
aceae (Spencer and Seigler, 1985a), and Achariaceae (Jensen
Cydopentenoid Ring Sbucture
and Nielsen, 1986). The two largest genera of the Passiflora-
A group of cyanogens that contain a cycIopentenoid ring ceae, Passiflora and Adenia, have different patterns of glyco-
structure (or related structure) are derived from (2-cycIopen- sides. Adenia species have mixtures of pairs of monohydrox-
tenyl)glycine, a nonprotein amino acid (Fig. 16.13) (Cramer ylated glucosides with diastereomeric aglucones [usually
 'DL
186 Cyanogenic Glycosides and Cyano/ipids
&
RO~O
" OR NC
4' 0 3
','
" ORRO
acalyphln (1)
nudiftorin
Trewio
Fig. 16.14. Acalyphin and related compounds.
tetraphyllin B (62) and volkenin (63), but in some species,
epivolkenin (65) and taraktophyllin (64)], and the nonhy-
droxylated compounds deidaclin (60) and tetraphyllin A (61)
(Olafsdottir et ai" 1989). Passiflora species contain a large
number of compounds, including cyclopentenoid glycosides
as well as those derived from valine and isoleucine. Among
these compounds are deidaclin (60), tetraphyllin A (61), tet-
raphyllin B (62), volkenin (63), epivolkenin (65), taraklo-
phyllin (64), passibiflorin (71), passicapsin (72), and passi-
trifasciatin (73) (Olafsdonir et aI., 1989). The presence of
cyclopentenoid cyanogenic glycosides has been reported
from the Caricaceae but should be confirmed (Spencer and
Seigler, 1984).
Cyanogenic Compounds of Other Origins
The compound acalypbin (1) from Acalypha indica (Eu-
phorbiaceae) appears to be derived from nicotinic acid me-
tabolism (Fig. 16.14) (Nahrstedt, 1987a).
DlSTRlBUI101'1
Cyanogenic compounds are found in all major plant groups
including ferns, gymnosperms, and both monocotyledonous
and dicotyledonous angiosperms. Cyanogenic compounds
occur in all major subgroups of dicotyledonous angiosperms.
The distribution of cyanogenic compounds in plants has been
reviewed (Saupe, 1981; Seigler, 1977, 1981a, 1981b). Fami-
lies in which cyanogenesis is most common are the Araceae,
Asteraceae, Euphorbiaceae, Fabaceae (Seigler et aI., 1989),
o
OCR
a~
4~,
S
7 0 N
I
0
,
N
CR, CR, CR,
ricinine malIorepine
Riel"us Mallotus
CX
, N
CH,
CN
ricinidine
Trewia
Flacourtiaceae, Malesherbiaceae, Papaveraceae, Passiflora-
ceae, Poaceae, Proteaceae, Ranunculaceae, Rosaceae, Sapin-
daceae, and Turneraceae. These compounds also are found
in bacteria, fungi, and animals.
There is much variation from plant to plant with regard
to content of cyanogenic compounds and the f3-glycosidases
necessary to hydrolyze them. In a number of taxa, only
1-3% of the individuals give positive cyanide tests done by
the Feigl-Anger method. In others, virtually all individuals
are cyanogenic (Aikman et aI., 1996).
In some genera, almost all species tested are cyanogenic.
For example, few species of the genera Prunus (Rosaceae)
or Passiflora (passifloraceae) are not cyanogenic. In other
families and genera, only a single species is cyanogenic.
Further, there may be pronounced variation during the grow-
ing season and in the development sequences of the plant
(Hegnauer, 1986).
At present, ferns are known only to produce phenylala-
nine-derived cyanogens such as prunasin (19) and vicianin
(25). Gymnosperms produce only taxiphyllin (16) (derived
from tyrosine). The Magnoliales and their close relatives
primarily produce cyanogens derived from tyrosine, as do
some monocotyledonous plants. There are several excep-
tions to this generality, however (Nahrstedt, 1987a).
The Euphorbiaceae consists offive subfamilies (Webster,
1975). In the Phyllanthoideae, cyanogens are derived pri-
marily from tyrosine, and, in the Crotonoideae, these com-
pounds are derived from valine/isoleucine. In the Acaly-
phoideae, acalyphin (1) appears to be closely related to the
series of four noncyanogenic 3-cyanopyridones isolated
from this group of plants (Fig. 16.14) (Nahrstedt, 1987a).

Although it has been thought previously that the Rosaceae
is relatively homogeneous with regard to cyanogenesis and
that the major compounds present are derived from phenylal-
anine, this now appears to be true only for the subfamilies
Maloideae and Amygdaloideae. Other members of the fam-
ily contain compounds such as the p-hydroxybenzoate (55)
and p-hydroxycinnamate (74) of (S)-cardiospermin (Fig.
16.12) and dhurrin (15).
The Fabaceae also are heterogeneous with regard to the
origin of cyanogenic glycosides (Nahrstedt, 1987a; Seigler
et al., 1989). The genus Acacia contains cyanogens derived
from the valine/isoleucine, leucine, and phenylalanine path-
ways. Phenylalanine-derived cyanogens are found mostly in
Australian acacias of subgenus Heterophyllum and subgenus
Aculeiferum. Valine/isoleucine and leucine-derived com-
pounds are primarily found in members of subgenus Acacia.
Members of the Flacourtiaceae, Passifloraceae, Turn-
eraceae, Malesherbiaceae, and Achariaceae, contain cyano-
genic compounds with cyclopentenoid rings. In many plants,
these cyanogens occur as complex mixtures often consisting
of epimeric, enantiomeric, and diastereomeric mixtures of
compounds, a situation uncommon with most types of sec-
ondary compound. In some members of these groups, how-
ever, other types of cyanogen also occur. Valine/isoleucine
and cyclopentenyl glycosides co-occur in some Passiflora
species (Spencer and Seigler, 1985e) and one isoleucine de-
rived cyanogen occurs in at least one member of the Flacour-
tiaceae (Jaroszewski et al., 1987b). The immature fruits of
Passiflora edulis contain prunasin (19), derived frum phe-
nylalanine (Spencer and Seigler, 1983). Leaves of Carica
papaya have been reported to contain prunasin (19) and
cyclopentenyl glycosides (Spencer and Seigler, 1984). I have
confirmed the presence of prunasin. This is of special inter-
est, as the plant also contains benzyl glucosinolate and repre-
sents one of the few plants to contain cyanogenic glycosides
and glucosinolates (Nahrstedt, 1987a).
Cyanogenesis in the Asteraceae also proves to be com-
plex. The pairs of epimers prunasin (19) and sambunigrin
(22), and holocalin (35) and zierin (34) are present in most
subfamilies. In the Calendulae, linamarin (11) and lotaus-
tralin (42) predominate. Recently, amygdalin (20), vicianin
(25), and prunasin (19) were isolared from the below ground
parts of Gerbera jamesonii hybrida (Nahrstedt, 1987a).
(l-GLYCOSIDASIlS
In most plants, cyanogenic glycosides are accompanied by
a corresponding !'I-glycosidase. One such enzyme system,
emulsin, from almond seeds, has fairly broad specificity and
has been widely studied. Most of these enzymes, however,
have more specific substrate requitements. The specificity of
enzymes from plants containing cyclopentenoid cyanogenic
glycosides has been reviewed (Spencer, 1987).
The !'I-glycosidases from plants containing diglycosides
also can differ in activity. For example, the enzymes from
Cyanogenic Glycosides and Cyano/ipids 287
Davallia trichomanoides and Vicia angustifolia hydrolyze
(R)-vicianin (25) and (R)-amygdalin (20) at the agly-
cone-disaccharide bond, whereas the enzymes of Prunus
serotina and Linum usitatissimum involve stepwise removal
of the sugars (Poulton, 1988).
In some instances, when an unnatural enzyme is added
to a substrate and the natural enzyme then added, no reaction
is observed. The nature of these effects is dependent on con-
centrations of enzymes and substrates as well as the order
of addition. Interactions of this type for cyclopentenoid cy-
anogenic glycosides and the corresponding enzyme system
have been reviewed (Spencer, 1987).
BIOLOGICAL ACTIVITY
Cyanogenic compounds sometimes represent a sizable pro-
portion of the plants total nitrogen and, in some cases, this
nitrogen becomes available upon germination of seeds as the
cyanogenic compounds are converted into other metabolites.
For example, the cyanolipids of Ungnadia speciosa (Sapin-
daceae) disappear rapidly upon germination of the seeds
(Selmar et al., 1990). In other instances, however, the cyano-
genic compounds are transferred to other parts of the plant.
Linamarin (11) in lima beans (Phaseolus lunatus) appears
to be transferred intact to the growing seedling (Clegg et aI.,
1979).
Transport of Cyanogenic Glycosides
Over 90% of the cyanogenic compounds of the seeds of
Hevea brasiliensis (primarily linamarin) are found in endos-
perm tissue (Selmar et al., 1988). The major glycoside was
linamarin (11). After storage, linustatin (44) and neolinus-
tatin (45) also were detectable (Selmar et al., 1991). During
germination of the seeds and development of the seedlings,
most of these compounds are converted into noncyanogenic
materials. No gaseous hydrogen cyanide is liberated during
the process. The !'I-glucosidase capable of cleaving the glu-
coside [principally linamarin, although some species of
Hevea contain small amounts of lotaustralin (42)] is wide-
spread in plant tissues. The greatest enzyme activity of !'I-
cyanoalanine synthase is found in young seedling tissues.
Thus, it appears that linamarin is transferred to the young
seedling tissues and metabolized there (Lieberei et al., 1985;
Selmar, 1993). An a-hydroxynitrile lyase also has been iso-
lated from Hevea brasiliensis leaves. The presence of this
enzyme greatly accelerates release of hydrogen cyanide (Sel-
mar et al., 1989).
Linamarin (11) is converted into the diglycoside linu-
statin (44) before transport from the endospermous tissues
(Selmar et al., 1988). Linustatin is not hydrolyzed by the
same !'I-glucosidase that hydrolyzes linamarin. This diglyco-
side is then transported to the seedling tissues where it is
hydrolyzed by a special !'I-glycosidase. The cyanide liberated
is utilized in a manner similar to that in many other plant
tissues (Selmar et al., 1988). Thus, in this example, glucosy-
288 Cyanogenic Glycosides and Cyano/ipids
lation is an essential step for the transport of cyanogenic
glycosides from the seed to the site in the developing plant
where they are metabolized.
Transport of linamarin (11) from the endosperm to the
cotyledons of Linum usitatissimum, flax, following germina-
tion has been observed. At the stage that the embryo is small,
almost all of the cyanogenic glycosides present are as lina-
marin and lotaustralin (42); after 1 week, only the diglyco-
sides linustatin (44) and neolinustatin (45) are present in
the large cotyledons. As apoplastic linamarase is present,
linustatin is a probable transport form (Selmar, 1993).
An apoplastic enzyme that rapidly hydrolyzes prunasin
(19) is found in Prunus seeds; this enzyme is incapable of
breaking down amygdalin (Poulton, 1988). However, it is
not established that this apoplastic enzyme is specific for
prunasin. Many apoplastic J3-glycosidases may be related to
the formation of lignin (Selmar, 1993). In a manner similar
to flax, the very young fruits contain only prunasin, but, after
development, the cotyledons contain amygdalin (20). Again,
it is probable that amygdalin is a transport form of cyano-
genic glycosides in this plant.
Cyanogenic Compounds as Defensive
Substances
Cyanogenic glycosides and their decomposition products
almost certainly playa role as defensive substances in plants
(Nahrstedt, 1992). However, the exact nature of these inter-
actions is complex. Hruska (1988) and Seigler (1991) (in
an improperly strong manner) have criticized many of the
classical papers concerning this role. Although many of
these studies should be reexamined in view of newer con-
cepts and with improved statistics, there is little question
that cyanogenic compounds and their decomposition prod-
ucts can play such a role.
One role of cyanogenic glycosides in plants is related to
their ability to produce toxic amounts of hydrogen cyanide
(Conn, 1981; Nahrstedt, 1985, 1992; Poulton, 1983), which
is extremely toxic to most organisms because it inhibits cyto-
chrome oxidase and other respiratory enzymes.
Many plants that contain cyanogenic glycosides are well
known from poisonous plant literature (see, for example,
Kingsbury, 1964; Nahrstedt, 1985; Poulton, 1983). Although
these effects may be due to cyanide [or unrelated compounds
in the plants (e.g., in Taxus species)], both cyanide and agly-
cones (aldehydes or ketones) resulting frum hydrolysis of
these compounds can be toxic to nonadapted animals, fungi,
and other organisms (Davis, 1991). Despite this toxicity,
most animals have the ability to detoxify limited amounts
of cyanide. Intact cyanogenic glycosides do not appear to
be highly protective against insects; these animals often are
effective in detoxification of cyanide (Bernays, 1983;
Hruska, 1988). Although it has been suggested that cyano-
genic glycosides serve as deterrents to herbivory (Jones,
1988; Nahrstedt, 1985), the glycosides themselves seem to
be relatively nontoxic to most organisms.
The presence of epiheterodendrin and a series of structur-
ally related nitriles are responsible for the susceptibility of
Hordeum vulgare to the pest Erysiphe gramini (Nahrstedt,
1992; Pourmohseni et al., 1993). These glycosides are im-
portant in the plant epidermis of compatible lines (those that
suffer attack), whereas incompatible lines lack these com-
pounds (Nahrstedt, 1992; Pourmohseni et al., 1993).
Purified dhurrin from sorghum seedlings was shown not
to be toxic to Locusta migratoria. The amount of cyanide
released was an effective plant defense and probably ac-
counts for most of the lack of palatibility of field-grown
sorghum to acridids in West Africa and India (Bernays,
1983). The mechanism of effectiveness of cyanide in many
plants appears to be related to the release rates during chew-
ing and not to the levels of cyanogenic glycosides present
(Bernays, 1983). Other work by this group indicates that
p-hydroxybenzaldehyde may be involved in acceptance of
sorghum plants by larvae (Nahrstedt, 1985, 1992).
Several cyanogenic glycosides serve as phagostimulants.
Amygdalin (20) serves as a phagostimulant for Malacosoma
americana, linamarin (11) and lotaustralin (42) from
Phaseolus vulgaris for Epilachna varivestis (this report
should be confirmed, as cyanide is rarely found in plants of
Phaseolus vulgaris) (Nayar and Fraenkel, 1963), and dhurrin
(15) from sorghum for Peregrinis maidis (Bernays, 1983).
However, in a study on highly cyanogenic black cherry (Pru-
nus seratina), insect feeding was only extensive when the
level of glycosides dropped well below the maximum
(Schroeder, 1978). Prunasin (19) from the peach, Prunus
persica, acted as an antifeedant for the oblique banded leaf
roller (Nahrstedt, 1985).
The moth Yponomeuta evonymellus does not respond be-
haviorally to prunasin (19) which occurs in its host plant.
Other species of this genus, however, are both sensitive ane
deterred (Stadler, 1984).
In Hevea brasiliensis (Euphorbiaceae, natural rubber)
(and other Hevea species), mechanical injury leads to evolu-
tion of hydrogen cyanide. Infection with the fungal pathogen
Microcyclus ulei leads to the production of a phytoalexin,
scopoletin (Giesemann et al., 1986) (see Chapter 8). This
attack also results in a decrease of cyanogenic compounds,
and hydrogen cyanide can be detected in the leaves. In sus-
ceptible clones of the plant, the amount of cyanide liberated
is much greater than in resistant clones. The increased
amount of cyanide produced in highly cyanogenic plants
appears to result in inhibition of the formation of scopoletin.
In this instance, cyanogenesis does not lead to greater, but
reduced, resistance to the pathogen (Lieberei, 1986, 1988;
Lieberei et al., 1989). In general, lines of Hevea brasiliensis
with both large amounts of cyanogenic glycosides and 13-
glucosidases are the most susceptible to the South American
leaf blight (Microcyclus ulei) (Davis, 1991; Lieberei, 1988;
Selmar, 1993).
Intact cyanogenic glycosides appear to be relatively non-
toxic to mammals when injected. These compounds are ex-
creted rapidly via the urine (Nahrstedt, 1987a); they are not
especially toxic when taken orally unless the corresponding

/3-glycosidase is consumed at the same time (Nahrstedt,
1987a; Poulton, 1983).
Both cyanogenic and acyanogenic phenotypes of Lotus
corniculatus occur. Cyanogenic forms contain linamarin
(11) and lotaustralin (42), whereas acyanogenic plants may
lack either the cyanogenic glycosides, the /3-glucosidase, or
both. In general, snails preferentially graze on acyanogenic
forms (Jones, 1972, 1988). However, the relationship be-
tween cyanogenesis and herbivory by slugs on Lotus corni-
culatus and Trifolium repens appears to be complex (Dirzo
and Harper, 1982; Horrill and Richards, 1986; Kakes, 1987).
In Lotus corniculatus, the presence of tannins (also consid-
ered to have antiherbivore properties) is strongly negatively
correlated with the presence of cyanide (Ross and Jones,
1983).
Cyanolipids (Fig. 16.2) have been shown to be toxic in
the diet of Callosobruchus maculatus at both the 1% and
5% level; they do not appear to be particularly toxic to house-
flies.
Cyanogenesis, Ants, and the Genus Acacia
Among the American species of Acacia, a number are
characteristically inhabited by ants. Among these are Acacia
cornigera, A. hindsii, and A. chiapensis. The ants live in
swollen stipular spines and eat foliar nectaries and special
structures known as Beltian bodies that are born at the tips
of the leaves. The ants receive most of their nutrition in this
manner, as well as provide the plant with protection against
insect, plant, and other animal infringement. Many of these
Acacia species cannot survive without the ants. Most of the
ants (usually of the genus Pseudomyrmex) cannot survive
in the absence of host Acacia plants. Leaves of A. chiapensis
and A. tarnesiana proved toxic to southern army worms,
Prodenia eridania, raised on Phaseolus vulgaris, whereas
those of A. cornigera did not. Amygdalin (20) added to the
diet was also toxic. No alkaloids were present in the leaves
of these tbree species, Rehr et al. (1973) concluded that non-
ant Acacia species produce cyanogenic defense compounds,
whereas ant acacias do not. They reckoned A. chiapensis
(which produces cyanogenic glycosides) to be a case margin-
ally adapted to ant mutualisms. More recent evidence, how-
ever, shows that three common ant acacias, Acacia hinds;;,
A. globulifera, and A. chiapensis, are often strongly cyano-
genic (Seigler and Ebinger, 1987).
Cyanogenesis in JlliIUpedes and Insects
Compounds capable of releasing cyanide are found in
a number of millipedes and insects (Duffey et aI., 1977;
Nahrstedt, 1985, 1988). Both millipedes and beetles of the
Cbrysomelidae and Cicindelinae possess the ability to pro-
duce mandelonitrile (Nahrstedt, 1988). Interestingly, one of
these, Paropsis atomaris, contains both (R)-mandelonitrile,
a small amount of pronasin (19), and a /3-glucosidase capable
of splitting the pronasin (Nahrstedt, 1988).
The larval secretion of the mountain ash sawfly, Prisot-
Cyanogenic Glycosides and CyanoJipids 289
phora geniculata (Hymenoptera: Tenthredinidae), which
feeds on Sorbus (Rosaceae), contains benzaldehyde and
mandelonitrile (Duffield et al., 1990).
The larvae of Zygaena species contain linamarin (11) and
lotaustralin (42). These insects feed on Lotus corniculatus
(which contains linamarin and lotaustralin). The moths ap-
pear to synthesize the cyanogenic glycosides de novo and
synthesize them even when the moths are fed on an artificial
diet. All stages of the insects appear to be able to synthesize
these two glycosides (Nahrstedt, 1987b, 1992). Zygaena lar-
vae also contain both /3-glucosidases and a-hydroxynitrile
lyases needed to release cyanide from the glycosides (Miiller
and Nahrstedt, 1990).
Nahrstedt has shown that moths of the genus Acraea and
Heliconius also contain these two glycosides even when fed
on species of Passiflora that contain cyclopentenoid cyano-
gens (Davis, 1991; Nahrstedt and Davis, 1981; Nahrstedt,
1987a, 1987b). However, all stages of Acraea horta, which
feeds on the flacourtiaceous plant Kiggelaria africana, con-
tain gynocardin (68)-the cyanogenic glycoside produced
by the host plant (Raubenheimer, 1989).
The larvae and imagines of Leptocoris isolata (Hemipt-
era) feed on fruits of Allophylus cobbe that contain cyanoli-
pids. These insects contain cardiospermin (54) as well as an
isomeric nitrile (Braekman et al., 1982).
Biological Activity of Cyanide in Plants
Small amounts of cyanide reversibly inhibit nitrate re-
ductase in plants. Furtbermore, in experiments in which mea-
surements of this inhibition was used as a bioassay, it was
possible to demonstrate the presence of very small amounts
of cyanide in a number of plants not previously known to
have cyanide (Vennesland et aI., 1981).
Because 1 mole of cyanide is produced for each mole
of ethylene generated from ACC (l-amino-cyclopropane-1-
carboxylic acid) (see Chapter 13), all plants must contain
small amounts of cyanide (Peiser et al., 1984). However, due
to a concomitant increase in the amount of /3-cyanoalanine
synthase, the ability to detoxify cyanide in the tissues is
much higher (Manning, 1988).
Flowering in the short-day plant, Lemna paucicostata,
could be induced under continuous light by introduction of
2-5 iJM cyanide into culture media (Tanaka et al., 1983).
Detoxication of Cyanide
Plants convert HCN into asparagine (75) and /3-cyano-
alanine (76) (Fig. 16.15). When HI'CN is introduced in
plants, the label is incorporated into the amide carbon of
asparagine (Davis, 1991). This suggests that the cyanogenic
compounds are being synthesized and catabolized, and the
HCN produced in the intact plant is subsequently incorpo-
rated into asparagine by the action of /3-cyanoalanine syn-
thase and /3-cyanoalanine hydrolase. /3-Cyanoalanine syn-
thase has been shown to occur in many plants (Conn, 1981;
Harborne, 1989; Nahrstedt, 1992).
290 Cyanogenic Glycosides and Cyanolipids
HCN H,S
--
~ONH,
- H,O ,Hz
,HNH, -
COOH
HzO
cysteine 3-cyanoalanlne (76) asparagine aspartJcacld
(75)
Fig. 16.15. Conversion of HCN to ~-cyanoalanine and asparagine
(modified from Conn, 1979b; used with pennission of the copyright
owner, Academic Press, Orlando, FL).
Most organisms have the ability to detoxify cyanide. One
system that appears to be common in mammals involves the
enzyme rhodanese (thiosulfate sulfur transferase) and at least
two other sulfur-containing enzymes (Davis, 1991). This en-
zyme catalyzes the reaction of cyanide and thiosulfate to
produce thiocyanate and sulfite. In animal tissues, the sulfur
of cysteine is utilized. The thiocyanate generated is elimi-
nated slowly and is responsible for many of the chronic ef-
fects of cyanide poisoning (Conn, 1979a; Davis, 1991).
Many other organisms contain the enzyme (3-cyanoalanine
synthase which converts hydrogen cyanide and cysteine or
serine into (3-cyanoalanine (Nahrstedt, 1985). Many fungi
convert hydrogen cyanide and water into formamide, which
is relatively nontoxic (Hanis et aI., 1987). Reaction with
nitrogenase enzyme also can account for the removal of
small amounts of hydrogen cyanide in many plants. A num-
ber of bacteria contain a "cyanide oxygenase" system capa-
ble of converting hydrogen cyanide into carbon dioxide and
ammonia (Hanis et aI., 1987).
CYAI'IOOEI'IESIS 11'1 CROP PLANTS
Many plants of economic importance are cyanogenic: ap-
ples, peaches, almonds, apricots, plums, cherries, macada-
mia nuts, forage grasses, corn, sorghum, bamboo shoots,
cassava, sugar cane, flax and lima beans. Of these, most
human poisoning problems arise from cassava and, proba-
bly, the majority of animal poisoning cases from Sorghum
species (Davis, 1991).
Cassava, Manihot esculenta, is the major starchy food for
over 300 million people in many tropical countries of the
world. Plants with 20 mg HCNIl 00 g fresh weight are usu-
ally considered toxic (Kingsbury, 1964). Many cultivars of
cassava exceed this value. Methods of detoxication have
been developed by the American Indians who consume the
tuberous root of this plant. These involve grating or grinding
the plant, pressing the ground material to remove liquid con-
taining hydrogen cyanide and glycosides (and inadvertently
mixing the (3-glucosidase and substrate), storing the product,
and cooking. If the ptoduct is pressed and stored for a period
of time (often as long as overnight) and then cooked, the
NH, cyanohydrin is decomposed and any free cyanide remaining
is eliminated (Nahrstedt, 1993).
~OOH Leaves of Manihot esculenta often contain 1-2% Iina-
~Hz
,HNH,
COOH
marin (11) and 10taustraIin (42). Although leaves with low
cyanide-releasing ability are preferred, the acceptability of
cassava leaves for the herbivore Zonocereus variegatus de-
pends on both the physiological state of the leaves and the
insect larva, and whether other foods are available to them
(Bernays et aI., 1977).
(79) Cattle and other livestock are frequently poisoned when
allowed to eat Sorghum seedlings or material that has been
stressed (by drought, inundation, frost, etc.) and allowed to
resume growth (Boyd et aI., 1938; Willaman and West,
1916).
NlTROOLYCOSIDES
Nitro acids, alcohols, and their glycosides have been re-
ported from plants in a number of plant families (Seigler,
1991). There are two main types: those derived from aro-
matic precursors and aliphatic precursors.
The pathways to cyanogenic glycosides, nitro com-
pounds, and glucosinolates in higher plants seem to be
closely linked (Conn, 1988; Hosel et aI., 1985) (also see
Chapter 17). For example, (3-phenylnitroethane (77) has
been reported as the peppery and fragrant principle of edible
fruits of Dennettia tripetala (Anoonaceae) (Okogun and
Ekong, 1969). Cell suspension cultores of Eschscholtzia cal-
ifornica produce low levels of HCN, ptesumably due to cy-
anogenic glycosides. However, the source of the HCN does
not appear to be triglochinin (17) or dhurrin (15) which are
ptoduced by the intact plant. Additionally, microsomal frac-
tions from stressed cell cultores of this plant catalyze the
formation of 1-(4'-hydroxyphenyl)-2-nitroethane (8) from L-
tyrosine (2) (Fig. 16.16). A glucosyltransferase that glucosy-
lates the compound is also found in these cultores.
A number of esters of 3-nitropropionic acid (78) occur
in the genera Astragalus, Coronilla, Indigo/era (Fabaceae),
Heteropteris, Hiptage (Malpighiaceae), Viola (Violaceae),
and Corynocarpus (Corynocarpaceae) (Fig. 16.17).
3-Nitroptopionic acid (78) is derived from aspartic acid
(Fig. 16.15) in the fungus Penicillium atrovenetum, but both
oxygen atoms of the nitro group are derived from molecular
oxygen (Fig. 16.17) (Baxter and Greenwood, 1986). Further,
the carbon-nitrogen bond of aspartic acid is preserved dur-
ing the formation of 3-nitropropionic acid (Baxter et aI.,
1985). In Lathyrus sativa, however, asparagine (75) gave the
highest rate of incorporation into the isoxazolinone moiety
of the heterocyclic amino acid (3-(isoxazolin-5-on-2-yl)-L-
alanine (Randoux et aI., 1991).
Other compounds [e.g., miserotoxin (80)] involve 3-ni-
tropropanol moieties. These compounds are poisonous to
livestock (Stermitz and Yost, 1978) and to several insects
and other animals (Byers et aI., 1986). 3-Nitropropionic acid
(78) is toxic to the hrochid Callosobruchus maculatus at
 Cyanogenic Glycosides and Cyanolipids 291

4'~NO
~l '
HO~NO'
5' 6' 5' 6'

1-(4'hydroxypbenyl)·2-nitroethane (8)
I-phenyl-2-nitroethane (77)
OH

HO~O~"
O~ IA ,
~",,,
OH
- ( J - - ! ' ,"
,'" OH
HO
HO 3"
0

OR
~
5' -
NO,
HOHO
5,,00 f' NO
_ I 2
3" OR 5'

1-(4'hydroxyphenyl)·2-nitroethane 1-(4'hydroxyphenyl)·2·nitroethane
primeveroside
glucoside

Fig. 16.16. Aromatic nitro compounds.

0.1 % when incorporated into artificial diets (Janzen et a!.,
1977). However, another insect, Sparganothis sulfureana,
feeds on Coronilla varia, crownvetch, a plant containing 3-
nitropropionate derivatives, and seems to be relatively insen-
sitive to the effects of these compounds. Hiptagin (81) and
three other nitro derivatives of glucose occur in the root of
Lotus pedunculatus and appear to be responsible for resis-
tance of the root to the grass grab Costelytra zealandica
(Harborne, 1989).
The eggs of many species of chrysomelid beetles contain
isoxazolinone glucosides. One of these compounds which
contains a nitropropionate residue is highly deterrent to feed-
ing of ants on the eggs (Fig. 16.18) (Pasteels et aI., 1986).
The defensive glands of other chrysomelid beetles possess

HO~NO' HO~NO,

3·nitropropionic acid (78) 3-nitro-l-propanol

o
o II ~NO, 0 0

~
---.[J./ '-../ O~NO, O~NO,

HOHO 0 OH HO Ao.. ( - - - ; 0 HO Ao.. ( - : OH

~O~~ ;O~
NO-,~O OH J ~NO, OH

o
coronarian cibarian 6~(3-nitropropanoyl)-j3~D-glucopyranose

o
O~NO,

NoV'rr-~
o
HO
0 OH

o OH

(a) 4,6-di(3-nitropropanoyl)-a-D-glucopyranose 4,6-di(3~nitropropanoyl)-j3-D-glucopyranose

Fig. 16.17 (a-c). Esters of 3-nitropropionic acid from plants.

292 Cyanogemc
. G/ycosides and Cyanolipids

~NO, ~O~NO'
o
~ o
0 0

O~NO'NO-'~O
' g O~NO'
HO H

HOHO 0
NO.2~O
o

karakin coronillin

corollin corynocarpin

o
O~NO,
~/'..'-../~NO, ./',.
o -....v 0
II ~
~~N00
0

./',.
o
II
NO, ~OO
r--./
H

~ ;O~ \\~
0 "'- ( - -;:- 0, /NO, 00H
NO, If
NO,~ o 0 NO 0 0
o ,

hiptagin (81) 2 3 4 6-tetra(3-nltropropanoyl)-

(b)
, , , a-D-glucopyranose

~
.' ORo
80R O "
0,

'V 'v"
' l
A ,NO, rr:o, ,. o~. A
HO~.
,. OR 0 0' 'V
•
A
'No,
• OR HORO " • OR
mfseroIoxIb{88)

Fig. 16.17. (continued)

 Cyanogenic G/ycosides and Cyanolipids 293

legumes such as the soy bean, Glycine max, the winged bean,
Psophocarpus tetragonolobus, and Erythrina species are
known to produce nitric oxide, nitrous oxide, and possibly
other nitrogen oxides (Betting, 1909; Dean and Harper,
1986; Weehuisen, 1907).
(82) (83)

l'IITRILE GLYCOSIDES

Fig. 16.18. lsoxazolinone glucosides from chrysomelid beetle eggs and
defensive glands.
defensive glands that contain d '-isoxazolin-5-one gluco-
sides 1 (82) and 2 (83). The first of these compounds also
is known from Pisurn sativum and Lathyrus odoratus (Ran-
doux et al., 1991). In the plants, d 3-isoxazolin-5-one and
UDP-glucose were precursors of the fIrst glucoside,
whereas, in the insect, labeled aspartic acid was incorporated
into both glucosides (Randoux et al., 1991).
Both picrate and Feigl-Anger paper may give positive
tests when 3-nitropropionic acid and related compounds are
present (Seigler et al., 1989).
Although the origin is not known with certainty, several
Another series of noncyanogenic nitrile glycosides, with
structural similarities to intermediates in cyanogenic glyco-
side biosynthesis are found in members of the AquifoJiaceae,
Boraginaceae, Crassulaceae, Menispermaceae, Fabaceae,
Ranunculaceae, and Simmondsiaceae (Fig. 16.19) (Seigler,
1991).
PSEUDOCYAl'IOGEI'IIC GLYCOSIDES
Glycosides based on a methyl azoxymethanol structure
occur in cycads. These glycosides are found in most mem-
bers of this gymnospermous family, along with an enzyme
that effects hydrolysis of the compounds to release methyl

8HC5I:~O~:
I
H~'CN
8,
I
0 HO"
~OH
" ~OH
OH

7 • 5
H " OH
7
I : 6
H
....""'H

menisdaurin dasycarponin
H- OH H OH OH

H~'CN
8H~I'~O~:
5' OH
I O~O~OH HO~
I : I :
8 3
H :&' OH H l' OR
7 Ii """H 7 Ii ""'H

>fl
OH bauhinin H OH OH lithospennoside
(a) H OCH,

'CN~,
H~'CN
I~
'S , OH
HO
H ,
I,
5' OH
0 0 OH
o 0 OH HO
HO
I
8 3
/8 4 "OH
~ H " OH H 7 5 H
7 {; \: H CH,O •
H
OH H OCH,
H OH

(b) llex warburgii glucoside simmondsin

Fig. 16.19 (a & b). Nitrile glycosides.

294 Cyanogenic Glycosides and Cyanolipids
HO
-_\ .-0. O/N~N/CH3
HO~~
HO OH tI
o
cycasin (84)
Fig. 16.20. Pseudocyanogenic glycosides.
azoxymethanol and glucose (or other sugars). Normally, this
group of glycosides does not produce cyanide. Only when
treated with base do pseudocyanogenic glycosides liberate
nitrogen, formic acid, HCN, and glucose.
Several of these plants are used as human food sources
in Oceania and many are eaten by animals in many areas of
the South Pacific and in Australia. A form of amyotrophic
lateral sclerosis (ALS or Lou Gehrig's disease) used to be
endemic among the Chamorros of Guam and is linked to
the presence of an unusual amino acid ,,-amino-i3-propionic
acid or i3-N-methylarnino-L-alanine found in this cycad
(Fowler, 1987; Spencer et al., 1987) (see Chapter 13).
Methyl azoxymethanol has been shown to be carcinogenic
(Hirono, 1972). Cycasin (84) reduces the litter size in rats
if consumed prior to mating (Fig. 16.20).
The hairstreak butterfly, Eumaeus atala, endemic to Flor-
ida, has brilliant waming coloration. The larvae are red and
yellow, the adults red and black. This insect is a specialist
on the cycad Zamia floridalUl, the young leaves of which
contain 0.2% cycasin by dry weight, and the insect accumu-
lates cycasin (Harborne, 1989).
A1'IALl'11CAL TECIII'IIQUES
For qualitative (presence-absence) or semiquantitative deter-
minations of cyanide, the easiest and most reliable method
is a simple test with either Feigl-Anger or sodium picrate
paper. The reactions on which these tests are based as well
as other methods for detection of cyanogenic glycosides are
described by Hegnauer (1986).
Sodium picrate paper is prepared by dipping filter paper
into an aqueous solution of 0.5% picric acid and 5%
Na2C03, then allowing the paper to dry. The paper may be
stored dry but should be moistened just before use (Guig-
nard, 1906a,b; Horwitz, 1980; Kingsbury, 1964). The detec-
tion limit of picrate paper with plant samples is
0.001-0.002% HCN by weight, which corresponds to about
0.01-0.02% prunasin (Brinker and Seigler, 1989; Hegnauer,
1986).
Feigl-Anger paper is made by mixing equal volumes of
solutions of tetrabase [4,4'-tetramethyldiaminodiphenyl-
methanel and copper ethylacetoacetate (Brinker and Seigler,
1989, 1992; Tantisewie et al., 1969). Feigl-Anger paper is
somewhat more sensitive than picrate paper (Nahrstedt,
1980).
These qualitative methods are very useful for screening
large numbers of samples because they are simple, fairly
specific, and require no equipment other than vials and corks.
These qualitative methods also are useful for monitoring
separations of cyanogenic compounds from TLC plates or
chromatography paper during isolation and purification.
Methods for the quantification of cyanide in plant tissues
involve hydrolysis of the cyanogenic glycosides and release
of HCN, which is trapped in a basic solution and determined
colorimetrically (Brinker and Seigler, 1989) by the method
of Lambert et al. (1975) which can detect as little as 5 J.l.g
HCN (Lambert et al., 1975).
Methods for the quantification of particular cyanogenic
glycosides have been reviewed (Brimer, 1988; Brimer and
Dalgaard, 1984; Nahrstedt et al., 1981).
Emulsin, the i3-glycosidase from almonds, has been used
for many qualitative and quantitative cyanide determina-
tions. This commercially available enzyme will hydrolyze
several cyanogenic compounds (some very slowly), al-
though it is inactive against others (Conn, 1993). Snail or
snail gut acetone powder has also been used to hydrolyze
many cyanogenic glycosides (Brimer et al., 1983). This com-
plex mixture of enzymes (i3-glucosidase, i3-glucuronidase,
sulfatase, and i3-D-mannosidase) is also commercially avail-
able. This enzyme is active against a broad spectrum of cy-
anogenic glycosides. In contrast, most other i3-glycosidases
have relatively specific substrate requirements (Fan and
Conn, 1985; Gross et al., 1982; Hosel and Conn, 1982; Hosel
and Nahrstedt, 1975; Hosel et al., 1987; Spencer, 1987).
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17
Glucosinolates
Introduction
Biosynthesis
Distribution
Utilization of Glucosinolate Data in Systematic Studies
Biological Activity
Properties of Glucosinolates
Properties of the Hydrolysis Products
Goitrigenic Derivatives in Crop Plants
Glucosinolates as AIIomones and Kairomones
Glucosinolates and Oviposition by Insects
Long-Distance Attraction
Glucosinolates and Plant Disease Resistance
Glucosinolates and AIlelopathy
References
INTRODUCTION
Glucosinolates produce hydrolysis products responsible for
the pungent taste of mustard, horseradish, and other bras sica-
ceous plants. These glycosides occur in several important
crop plants and in several common weedy species (Ettlinger
and Kjaer, 1968; Louda and Mole, 1991; Tapper and Reay,
1973). Approximately 100 compounds of this type have been
described (Poulton and M¢IIer, 1993; Reed et al., 1988);
some representative compounds are illustrated in Fig. 17.1.
A semisystematic nomenclature for glucosinolates exists
along with many of the earlier trivial names (Larsen, 1981).
Virtually all species of the mustard family (Brassicaceae or
Cruciferae) contain glucosinolates and the greatest variety
of glucosinolate structures is found in this family. Many
of the species of this family are fast-growing, early-season
herbaceous C3 plants (Louda and Mole, 1991). Typical
amounts present are from 0.1 % to 0.6% dry weight (Bernays,
1983). The content of glucosinolates in seeds usually is much
higher than that of vegetative tissues. In general, young tis-
300
sues are richer in glucosinolates than older tissues (Louda
and Mole, 1991).
In many properties, these compounds resemble the cyano-
genic glycosides, to which they are biosynthetically related.
Glucosinolates are derived from many of the same amino
acids as the cyanogens, although some amino acids serve as
a precursor for one group but not for the other. Glucosino-
lates that correspond to alanine, valine, leucine, isoleucine,
phenylalanine, tyrosine, and tryptophan are known (Larsen,
1981). In contrast to the cyanogenic glycosides, however,
the distribution of glucosinolates is restricted to a smaIl num-
ber of families, many of which are related.
Glucosinolates are water-soluble, polar compounds that
possess a common structural moiety, described correctly for
the first time in 1956 by Ettlinger and Lundeen. Glucosino-
lates occur in plants as salts, and most have been isolated
as the potassium salt because of the predominance of potas-
sium in plant cells. These compounds may also occur in
association with positively charged organic compounds and
proteins in plants. Some [e.g., sinalbin (1)] occur as salts
of sinapine (2), a quaternary ammonium base composed of
choline esterified with 3,5-dimethoxy-4-hydroxycinnamic
acid (Larsen, 1981). Although leaves usually contain only
about 0.1 % dry weight, as much as 10% dry weight glucosi-
nolates may be stored in seeds. This requires a large amount
of ionic material to counterbalance the negatively charged
glucosinolates.
As is true for cyanogens, special i3-glucosidases, often
called myrosinases or thioglucosidases (BC 3.2.3.1), co-
occur and catalyze hydrolysis of glucosinolates (Fig. 17.2)
(Poulton and M¢Iler, 1993). A number of isozymes of these
enzymes occur, and some fonns of myrosinase are activated
by ascorbate. Although these enzymes show some specific-
ity, all known glucosinolates are substrates for these en-
zymes (Larsen, 1981; Poulton and M¢IIer, 1993). All cruci-
fer organs contain myrosinase.
On disruption of the tissues, myrosinases and glucosino-
 Glucosinolates 301

-
N'OSO,K +

~
CR,=CRC R,-{ OR
N'OS6'K+ OR
S~OR I S~OR
:r
OR

o-n
RO "" OR
sinigrin (15)
glucotropaeolin (6) sinalbin (1)
benzyl glucosinolate
- +
N'OSO'K OR

:r S~OR
I
""
OR

gluconasturtiin (12) progoitrin (21)

e=:rr<
glucocochlearin

~N-OSO;K+ OR N.OSO;K+ OR

/ \~OR ?"
I I
S~OR
OR
OR '" NR
benzyl isothiocyanate (32)
glucoputranjavin from glucotropaeolin
glucobrassicin (3)

OCR,

RO~o~£i(CR,J, sinapine(2)
methyl isothiocyanate
from glucocapparin

(a) OCR,

- + - +

~~~OR
UN)' OR
~~OR
UN ) OR
I I _
OCH3 neoglucobrassicin (4) S03 sulfoglucobrassicin (5)
o
t
/S~N=C=S
sulforaphene (33) sulforaphane (17)
N-OSO;K+

~S~O
RO~ ' ~N=C=S
~OR
OR
o
t
OR
2-hydroxy-3-butenylglucosinolate (16) allylisothiocyanate (26)

hirsutin (34)
o arabin (35)

t
8-methylsulfonyloctyl isothiosyanate 9-methylsulfonylnonyl isothiocyaniate
o
t cammelinin (36)
/S~N=C=S

(b) /S ~N=C = S 10-methylsulfonyldecyl isothiocyanate

Fig. 17.1 (a & b). Some representative glucosinolates.
302 Gfucos;noJates
~'NXH
~ V
• • CO,H
9' I H ~
:::,.. NH,
myrosinase or
tbioglucosidase
an isothlocyanate
+ glucose + HS04"
pH 3-6, Fe++
glucosinolate _ _ _ _ _ _
or nitrile factor
Fig. 17.2. Hydrolysis of glucosinolates by myrosinase (modified from Haslam, 1974).
lates are brougbt together, resulting in the release of isothio·
cyanates through a combination of thioglucoside bond hy·
drolysis and spontaneous rearrangement of the aglycone
(Fig. 17.2). Most evidence favors a subcellular compartmen-
talization for these compounds and enzymes (Poulton and
M~ller, 1993). Isothiocyanates (mustard oils) are pungent-
smelling substances with a sharp taste. Under other condi-
tions, glucosinolate hydrolysis produces thiocyanates and
nitriles (Cole, 1976; Louda and Mole, 1991). There is some
debate about the participation of enzymes in the conversion
of isothiocyanates to thiocyanates.
In order to isolate glucosinolates, the co-occurring f3·thi-
oglucosidases must be inactivated as quickly as possible.
Plant material is usually extracted with boiling 70% alcohol.
Methods for paper, thin-layer (nC), and ion-exchange
chromatography have been described (Larsen, 198 I). Many
analytical methods involve hydrolysis of the glucosinolate
followed by identification of the hydrolysis products. Iso-
thiocyanates can be determined by gas chromatography or,
as derivatives, by nc. Methods for the isolation, purifica-
tion, and characterization of glucosinolates by nuclear mag-
netic resonance (NMR) and mass spectrometry have been
reviewed (Betz and Page, 1990; Bodnaryk, 199 I; Louda and
Mole, 1991; Olsson et aI., 1977; Schraudolf, 1989).
The distribution of sinapine (2) (3,5-dimethoxy-4-hy-
droxycinnamoylcholine) and aromatic choline esters in
many genera of the Brassicaceae have been surveyed
(Bouchereau et aI., 199 I). These compounds were analyzed
by high-performance liquid chromatography (HPLC).
Indole glucosinolates are especially sensitive; many re-
ports present erroneous data because these compounds are
destroyed in isolation procedures (Slominski and Campbell,
~N'OS03K+
V .. \S~OH
__ OH
"y. CO,H
OH
gJuconasturtiin (12)
isomerase? ~S-C=N
a thiocyanate
.--,~
a nitrile
1987). Indolyl glucosinolates predominate in the foliage of
many crucifers, contrary to earlier reports (fraynier and
Truscott, 1991). These compounds occur widely in the
Brassicaceae and also have been reported from the genus
Capparis (Capparidaceae) (Schraudolf, 1989). They are
probably found in most other glucosinolate-containing fami-
lies. Indole glucosinolates can be analyzed by HPLC of the
desulfo-derivatives followed by mass spectrometry (Goetz
and Schraudolf, 1983).
BIOSl'Nl'HESIS
Radiotracer studies have demonstrated that L-amino acids
are the direct precursors of the known glucosinolates (poul-
ton and M~lIer, 1993). Although glucosinolates that corre-
spond to alanine, valine, leucine, isoleucine, phenylalanine,
tyrosine, and tryptophan are known (Larsen, 1981), the bio-
synthesis of only a few specific compounds has been investi-
gated. None of the intermediates has been properly estab-
lished, and the participating enzymes have neither been
isolated or characterized as components of crude prepara-
tions (Poulton and M~lIer, 1993). It is generally assumed that
these steps are catalyzed by microsomal systems analgous to
those of cyanogenic glycoside biosynthesis, but the apparent
biosynthetic similarity has never been established (Poulton
and M~lIer, 1993).
Isotopically labeled amino acids have been administered
to excised plant parts. As is troe for cyanogenic glycosides,
incorporation of administered amino acid precursors into
glucosinolates is often extremely high (up to 40%) (Larsen,
1981). In one study, plants were fed amino acids, and biosyn-
 Glucosinolotes 303

o v
H
~COlH a1COZ- ~COlH o
HNHl - - . "'" I N -0 ~+-o-
II
II
N+
H/ 'OH
o '0-
L~pheDylalanine
+ ~
N~hydroxy~L~phenylalanine

m
(10)
(11)

~HRS_~H ~~H
"'"
I
SRH
--
N~
~O
V
~-O:- ~+-O- ..- 0
I
NOH V I
OH OH phenylacetaldoxlme (7)

+
()!
I
~ lJ..
SH UDP UDP-glucose
~S-glUCOSYI -.V..
PAPS PAP

V
~S-gIUCOSYI
"'" NOH
thiohydroxirnic acid (8)
NOH

desulfoglucosinolate (9)
V NOSO,

PAPS := 3t~phosphoadenosine~S'~phosphosulfate glucotropaeolin (6)

(benzylglucosinolate)

Fig. 17.3. Proposed mechanism for the biosynthesis of benzylglucosinolate (glucotropaeolin) (modified from Poulton and M~ner. 1993).

thetic intermediates different from those normally present
in the plants examined_ Neglible amounts of "unnatural"
glucosinolates were formed when the amino acids were pro-
vided as precursors, but high levels resulted from feeding
the intermediate compounds_ This finding suggests that high
enzyme specificity occurs for the side-chain structure of the
precursor amino acids, but not for the intermediate com-
pounds (Reed et al_, 1988). L-Phenylalanine fed to nastur-
tium plants (Tropaeolum majus) leads to the formation of
glucotropaeolin (6) (Fig. 17.3). Phenylacetothiohydroximate
(8) has been established as an intermediate and is subse-
quently glucosylated to form desulfobenzylglucosinolate (9)
by transglycosylation with UDP-glucose. Feeding doubly
labeled 14C!lsN amino acids produces glucosinolates with
essentially unaltered ratios of isotopes. Thus, the biosyn-
thesis occurs without cleavage of the carbon-nitrogen bond
(Poulton and Mf/lller, 1993).
The conversion of amino acids to thiohydroximic acids
constitutes the first part of the biosynthesis of glucosinolates.
An early step probably involves N-hydroxylation of the
amino acid. This reaction is most likely catalyzed by a cyto-
chrome P-450-dependent monooxygenase. An a-nitrocar-
boxylic acid (10) may serve as an intermediate (Fig. 17.3)
(Poulton and Mf/lller, 1993). Such an intermediate has been
demonstrated to be an intermediate in the biosynthesis of
cyanogenic glycosides and may represent the branch point
between the two pathways instead of the oxime (7) previ-
ously suggested. N-Hydroxyamino acids are easily con-
verted to the corresponding amines; the reaction is stimu-
lated by flavin mononucleotide (FMN) and requires
molecular oxygen. Although oximes are easily converted to
glucosinolates, they may not be true intermediates in the
pathway. The introduction of the thioglucosidic sulfur atom
of glucosinolates may take place by addition of a thiol to
the aci-nitro compound.
Corresponding nitro compounds are known from several
plants [e.g., I-nitro-2-phenylethane (11)] occurs in extracts
of Tropaeolum majus (Tropaeolaceae). Radiotracer feeding
studies have shown that this compound is incorporated into
the glucosinolate (6) and that I-nitro-2-phenylethane can be
derived from the aldoxime (7). Feeding of2-nitrobenzaldox-
ime to Brassica species leads to the accumulation of the
non-naturally occurring 2-nitrophenylglucosinolate (Groot-
wassink et al., 1990).
Several of the putative intermediates contain a C-N
double bond, presenting the possibility of geometrical iso-
mers. The actoal configuration of these intermediates has
not been examined but is assumed to be the same as observed
in the final glucosinolate (Poulton and Mf/lller, 1993). L-CyS-
teine may serve as an efficient source of the sulfur atom in
the thioglucoside moiety.
S-Glucosylation of thiohydroximates catalyzed by UDP-
G:thiohydroximate glucosyltransferases (BC 2.4.1.-) is
thought to be the penultimate stage in glucosinolate biosyn-
thesis (poulton and Mf/lller, 1993).
The last enzyme of the sequence, sulfation of desulfoglu-
cosinolates, is catalyzed by 3'-phosphoadenosine-5'-phos-
phosulfate (PAPS) : desulfoglucosinolate sulfotranserases
(BC 2.8.2.-) (Fig. 17.4) (Poulton and Mf/lller, 1993; Un-
derhill, 1980).
Many other glucosinolates appear to arise by modifica-
tion of glucosinolates formed from protein amino acids at
the glucosinolate stage or are derived from nonprotein amino
acids (Larsen, 1981).
An unusual feature of the biochemistry of glucosinolates
is the occurrence of homologs of the aglycones which differ
304 Glucosinolates
~CO,H
V H NH,------+
()!C0T-
vC
malonyl-eoA
T"'"v0-()
OH
o:? I CO,H o:?
"" CO,H
CO,
NHOH
~CO'H_ ~H ~ ~S.glUCOSYI
lJ lJ
-
H OH NOSO;
~s.gIUC"YI
glucobarbariu
Fig. 17.4. Proposed biosynthesis of gluconasturtiin and glucobarbarin (modified from Geissman and Crout. 1969),
by one methylene group. In the case of 2-phenylethylglucos-
inolate (gluconasturtiin) (12) in watercress (Nasturtium offi-
cinalis and Rorippa nasturtium-aquaticum), both L-phenyl-
alanine and acetate (methyl labeled) were readily
incorporated into the compound with loss of their carboxyl
groups (Figs. 17.2 and 17.4). Degradation studies showed
that the methyl group of the acetate provided the thiohydrox-
imate carbon, whereas the remaining C6 -C2 fragment came
from phenylalanine. Furthermore, labeling studies indicated
that the amino nitrogen of phenylalanine was preserved in
the formation of glucotropaeolin (Haslam, 1974).
Homomethionine (14) is the precursor of allylglucosino-
late (sinigrin) (15). The allyl group is derived by loss of
the terminal sulfur function from 3-(methylsulfinyl)propyl
glucosinolate (13) (Dewick, 1984).
Feeding experiments with 3H_ and 14C-Iabeled precursors
in leaves of horseradish (Armoracia lapathifolia) demon-
strated the stereospecific removal of the 4-pro-S-hydrogen
of homomethionine during the biosynthesis of sinigrin. The
fate of the 5-hydrogens has also been established by 2H_
NMR (Fig. 17.5) (Dewick, 1984). An overall anti process
is involved. Mutants of Arabidopsis thaliana which lack the
ability to extend the carbon chain of methionine beyond the
homomethionine stage have been reported (Davin et aI.,
1988).
DISTRlBUDOI'l
Glucosinolates occur primarily in II plant families. One
cluster of these families, the order Capparales (including
the Brassicaceae, Capparidaceae, Moringaceae, Resedaceae,
-
OH
~CO'H
V CO,H
0
HNH,
CO,H ~
CO,H_
NHOH NOSO;
·lJ
gluconasturtiin (12)
• sulfotr&nsferase
and Tovariaceae) is conceded by most to be closely related.
The Papaveraceae and Fumariaceae, which some previously
placed with this group of families, do not have glucosino-
lates. Most systematists today remove these two families
because of a body of both chemical and morphological data.
The Limnanthaceae and Tropaeolaceae (Cronquist places
these in his Geraniales) do possess glucosinolates. Most tax-
onomists do not consider these families related to the first
group of families, but do consider them related to each other.
Dahlgren transferred the Limnanthacene and Tropaeolacene
to the same group as the Brassicaceae and then, subsequently
removed them (Dahlgren, 1983; Dahlgren et al., 1981).
Glucosinolates are found in several other families that
are not particularly related to each other nor are they proba-
bly closely related to the first two groups of families. Among
these are the Caricaceae (possibly related to the Brassica-
ceae), the Euphorbiaceae (Putranjiva roxburghii and the
genus Drypetes), the Gyrostemonaceae, Bretschneideraceae,
Bataceae, Sterculiaceae, Plantaginaceae, and Salvadoraceae
(Boufford et al., 1989; Louda and Mole, 1991).
Vtillzation of Olucosinolate Data
in Systematic Studies
Problems with generic delimitation and evolutionary
trends in the family Brassicaceae are complex (AI-Shehbaz,
1973). Glucosinolates, however, often exhibit species-spe-
cific arrays of compounds that are of value for the study of
systematics and evolutionary studies in this group (Chew,
1988).
The genus Thelypodium has been treated in several ways
by taxonomists, but has been studied in a multidisciplinary

NH,
CH3S~ CO,H -+
homomethionine (14)
,......,..
r
CHS~~
..."
O·
S·glurosyl
NOSO,'
~
H'Hd
..
CHrS 5 H.
4 Co,H
Ii H
Fig. 17.5. Biosyntbetic steps in the synthesis of sinigrin (Dewick, 1984; modified and used with pennission of the copyright owner, the Royal Society
of Chemistty, Cambridge),
manner by Al-Shehbaz (1973). The hydrolysis products of
glucosinolates of the taxa of interest were examined by paper
chromatography after conversion to the thioureas and oxa-
zolidine-2-thiones (Ettlinger and Thompson, 1962; Ettlinger
et al., 1966). The isothiocyanates derived from hydrolysis
were determined by gas chromatography. A variety of glu-
cosinolates (17 in all) were found in Thelypodium species.
Both seeds and vegetative material of most species were
investigated. With the exception of a few species, the quanti-
tative as well as the qualitative patterns of glucosinolates in
Thelypodium were species-specific. The exceptions were
five species with 2-hydroxy-3·butenyl glucosinolate (16)
and T. eucosmum and T. paniculatum that were chemically
indistinguishable. Almost no quantitative or qualitative dif-
ferences in glucosinolates were found between the plants of
a given population. Although these data were useful at the
specific level, they did not provide significant taxonomic
information concerning the relationships of the genera in the
tribe Thelypodieae (Stanleya, Thelypodium, Thelypodiopsis,
Caulanthus, Streptanthus, and Streptanthella) (Al-Shehbaz,
1973).
The genus Cakile is found in both the Old World and
New World. Many variants of taxa of this genus were de-
scribed and relationships were poorly understood until Cak·
ile was monographed by Rodman (1974). In addition to stud-
ies of the anatomy, morphology, and cytology, the
glucosinolate composition of plants of the genus was exam·
ined. Glucosinolates were isolated from seeds, hydrolyzed,
and converted to the thiocyanates and oxazolidine-2-thiones.
Analysis was similar to that above. The two morphologically
distinct seeds of fruits of Cakile species did not differ in
Glucosinolates 305
NOSO~
CH,S I
~s.g1urosYI
(13) \
/"
NOSO;
~s.gIUCOSYI
sinigrin (15)
-- 8,J . . . .,rso,
NH,
'S~glucosyl
Hb
composition. Further, there seemed to be little variation
within populations of a particular species. Although the qual-
itative pattern of greenhouse-grown plants was almost iden-
tical to that of wild plants, some quantitative differences
were observed. The glucosinolates were found to be stable
under a number of environmental conditions and consis-
tently present in popUlations of each taxon. Single plants
usually contained the full complement of compounds found
in mass collections. Distinctive qualitative and quantitative
patterns were found for most of the taxa studied. Intraspe-
cific variation which correlated with morphologically recog-
nized subspecies was found in Cakile edentula, C. maritima,
and C. laneeolata. Geographic variation was not closely
linked to morphological variation in Atlantic coast C. eden·
tula ssp. edentula and in Pacific coast C. edentula where it
appeared to be clinal (Rodman, 1974).
As indicated above, the glucosinolate complement of
many species appears to differ. Analysis of the hydrolysis
products of Draba euneifolium and D. platyearpa suggested
that these two taxa were distinct (Hartman et al., 1975).
Recent evidence indicates that insect infestations can dra-
matically alter both glucosinolate concentration and compo·
sition in Brassiea napus (Koritsas et al., 1989).
BIOLOGICAL ACTIVITY
Properties of Glucosinolates
Many of our common vegetables come from families
such as the Brassicaceae that possess glucosinolates. These
J06 (;llIc(lsi"ola'('.~
plants are edible and nutritious and the glucosinolates (and
their derivatives) seem to have little adverse physiological
effect in humans. Some of the vegetables rich in glucosino-
lates are mustard greens (Brossicajuncea), broccoli, brussel
spmuts. cabbage, cauliflower, kale, kohlrabi, collards (all
Brossica olerocea), horseradish (Armoracea lapathifolia),
radish (Raphanus sativa), rutabaga (Brassica campestr;s),
turnip (Brossica rapa), a numberofiess well-known vegeta-
ble cultivars (especially in China) (Hill et aI., 1987), and the
oilseed crop plants crambe (Crambe abyssinica) and rape
and canola (Brassica napus). However, no mammals are
known to specialize on crucifers and excess consumption
produces numerous problems (Louda and Mole, 1991).
Nonetheless, many small mammals occasionally rely on cru-
cifer seeds as a major part of their diet.
Indoles in vegetables of the genus Brassica inhibit carci-
nogenesis in experimental animals. These compounds arise
from enzymatic hydrolysis of glucobrassicin (3) (Fig. 17.1).
However, consumption of these compounds under other con-
ditions enhances carcinogenic activity (Beier and Nigg,
1992). Consumption of cruciferous vegetables is linked to
a decreased incidence of colo-rectal tumors in humans (Beier
and Nigg, 1992; Cassady et al., 1990). A key compound
responsible for the activity of broccoli is sulforaphane (17)
[( - )-I-isothiocyanoato-(4R)-(methylsulfinyl)butanel (Fig.
17.1) (Zhang et al., 1992).
Nonetheless, glucosinolates and their derivatives are bio-
logically active and have pronounced effects when con-
sumed in excess or when encountered by certain other organ-
isms. Numerous instances of animal poisonings occur
because of these plants. Detoxification of the pressed or ex-
tracted seed meals of rape and crambe are important pro-
cesses because of the large quantities that are used as feed
supplements for livestock and poultry (VanEtten and
Tookey, 1978).
R~-OSO;K+ OH
-
R--<-OS03 K
\ HO~OH
S~0---h
OH
~N:C:S
oV
HO~H
HO OH
4(a-L-rbanmosyloxy)benzyl isothiocyanate (IS)
Fig. 17.6. Hydrolysis of glucosinolates (Dewick, 1984; modified and used with pennission of the copyright owner, the Royal Society of Chemistry,
Cambridge).
Froperties of the Hydrolysis Froducts
The intact glucosides are probably not the active agents,
but rather the isothiocyanates, thiocyanates, and nitrile deriv-
atives derived from them. The initial hydrolysis products
are thiohydroximate O-sulfonates, which are followed by
rearrangements to give isothiocyanates, and, under some
conditions, nitriles and thiocyanates are also formed (De-
wick, 1984). In contrast to the intact glucosinolates, most of
the hydrolysiS products are relatively volatile (Fig. 17.6).
Isothiocyanates and thiocyanates are quite reactive chem-
ically; they react with water, alcohols, amines, and a variety
of other functional groups, either free or on macromolecules
(Larsen, 1981).
4(a-L-Rhamnosyloxy)benzyl isothiocyanate (18) has
been identified as an active antimicrobial agent from seeds
of Moringa oleifera and M. stenopetala (Eilert et al., 1981).
The seeds contain 8-10% of this compound, which inhibited
a broad range of bacteria and fungi in cultures at concentra-
tions of about 40 f.Lmol/L (Eilert et aI., 1981).
Enzymic hydrolysis of3-indolylmethylglucosinolate (20)
from fresh herbage of Brassica species leads to the formation
of 3-indoleacetonitrile (19), a compound with known auxin
activity (Tapper and Reay, 1973).
In many references, it is not clear whether the hydrolysis
products or the intact glucosinolates are involved. The hy-
drolysis products are volatile, whereas the glucosinolates are
not. Nonetheless, both types of compound can and do have
biological activity. Some hydrolysis products of glucosino-
lates that stimulate or attract herbivorous insects have been
tabulated (Stiidler, 1992).
Goitrigenic Derivatives in Crop Plants
Consumption of plant materials containing glucosinolates
and their hydrolysis products are known to produce goiter
in animals (Beier and Nigg, 1992). The presence of glucosi-
--
• + RNCS + So,"
--
RCN+S+SOi''"
S'
RSCN+SO,"
3-jndoleacetonitrile (19)

l-cyano-2-hydroxy·3,4-epithiobutanes
Rz Rt
t
\1
CHrCH-C-CH,----( OH
- S~OH
OH
R. =OK, R, = K, epi-progoitrin (22)
"'"
R, = OH, R, = H, (S)
l-cyano-l-bydroxy-3-butenes
goitrins
(SR)-S-vinyloxazolidine-2-tbione
Fig. 17.7. Secondarily derived hydrolysis products (modified from VanEtten and Tookey, 1979; used with pennission of the copyright owner,
Academic Press, Orlando, FL).
nolates is especially important in two oilseed plants,
Brassica napus (rapeseed) and Crambe abyssinica (crambe).
As the presscake from these seeds is produced in quantity
as a by-product of oil isolation, it represents a significant
economic and waste problem. In general, rapeseed meal may
be fed at no more than 10-15% of the total diet because
consumption of larger quantities of glucosinolates leads to
vesication of mouth and throat tissues (VanEtten and
Tookey, 1978, 1979). Rapeseed contains (2R)-hydroxy-3-
butenylglucosinolate (progoitrin) (21) and crambe contains
the corresponding (2S)-compound (epi-progoitrin) (22) (Fig.
17.7). In efforts to detoxify the meal, itis often heated. Heat
treatment of these seed meals produces a somewhat different
complement of compounds than those naturally formed. In
this case, secondarily derived compounds are formed from
glucosinolate hydrolysis products that are even more toxic
than the original glucosinolates. One of these compounds,
(S)-5-vinyloxazolidine-2-thione (goitrin) (23) prevents up-
take of iodine and leads to the formation of goiter in livestock
fed this meal.
Glucosinolates as A1lomones and
Kairomones
The presence of glucosinolates in plant tissues inhibits
feeding by most non-coadapted insects and mammals (Ber-
Glucosinolates 307
N.OSo.K+
R, = H, R, = OH, progoitrin (21)
/
R, = H, R, = OH, (R)
(5S)-5-vinyloxazolidine-2-thione (23)
nays, 1983; Louda and Mole, 1991). On the other hand,
insects that normally feed on plants containing these sub-
stances may require their presence for continued feeding
(Renwick, 1988). Not all glucosinolates serve equally well
in any particular case (Louda and Mole, 1991). Glucosino-
lates and their hydrolysis products that stimulate or attract
herbivorous insects have been tabulated (Stiidler, 1992).
Butterflies of the genus Papilio normally do not feed on
plants that contain glucosinolates. Glucosinolates are toxic
to the black swallowtail (Papilio polyxenes) when larvae of
this insect eat celery leaves that have been infiltrated with
potassium allylglucosinolate (sinigrin) (Fig. 17.1) (15) at a
concentration of 0.1 % fresh weight (Chew, 1988; David and
Gardiner, 1966).
Insects that normally feed on brassicaceous plants, such
as cabbage butterflies of the genus Pieris, can consume these
glucosinolates without obvious effect. The presence of glu-
cosinolates is required for normal feeding by the insects.
Verschaffelt (1910) was able to induce larvae of Pieris
brassicae (cabbage butterfly) and P. rapae to eat plant mate-
rials they normally reject by applying potassium allylglucos-
inolate to the surface of the leaves. The larvae of Pieris
brassicae will eat artificial diets when potassium allylglu-
cosinolate (sinigrin) or other glucosinolates are added (Ren-
wick, 1988). Once they have eaten this diet, the larvae
will starve before they will eat a diet without glucosinolates.
308 GJucosinoiates

- +
J N-OSO,K _ +
N-OSO,K
f
HO~OH ~.~~OH
CH,\ OH '-...
S
~u-------h 'I' S HO 0 OH
OH 0
OH

glucocapparin (24) glucoiberin (25)

~NH ~NH
~N) I
SASCH
'
~N} SASCH,
OCH,
(27) (28)

~NH ~N
~N) I
OASCH
' ~NH~S)lSCH'
OCH,
(29) (30)

~>-SCH'
~NHJ::O
(31)

Fig. 17.8. Some biologically active glucosinolates.

Glucocapparin (24) and glucoiberin (25) (Fig. 17.8) serve
as feeding stimulants for Pieris brassicae larvae and are
active at about 10-6 M concentration in the diet, whereas
all other glucosinolates tested were active only at 10-4 M_
When potassium allylglucosinolate (sinigrin) and linseed oil
were added to the diet, normal growth resulted. illterestingly,
glucocapparin and glucoiberin, the two most effective com-
pounds, do not occur in cabbage or other Brassica species,
but do occur in the alternate food host Tropaeolum majus.
The flea beetle Phyllotreta cruciferae has a narrow host
range, feeding only from plants in the families Brassicaceae,
Capparidaceae, and Tropaeolaceae. ill the laboratory, the in-
sect fed on plants of these families and the Limnanthaceae.
All of these plants contain glucosinolates. Field experiments
showed that allyl isothiocyanate (26) (Fig. 17.1) is a power-
ful attractant for adults of both Phyllotreta cruciferae and
P. striolata (Feeny et aI., 1970).
Seedlings of Sinapis alba (mustard) have high concentra-
tions of sinalbin (1) (20 mM in cotyledons and 10 mM in
leaves) and are resistant even to the attacks of flea beetles
and the bertha army worm, Mamestra corifigurata (Bodn-
aryk, 1991). The resistance that sinalbin confers appears to
be critical for the survival of the crop under feeding pressure
of the flea beetle in the field.
For the diamondback moth, Plutella xylostella (syn. A.
maculipennis) (another crucifer-feeding insect), (2R)-hy-
droxy-3-butenylglucosinolate (progoitrin) (21) was more ef-
fective than other glucosinolates in inducing feeding on arti-
ficial diets.
The cabbage aphid, Brevicoryne brassicae, is highly spe-
cific in its feeding behavior to cruciferous plants, although
it can be induced to feed on other plants when g1ucosinolates
are added exogenously. These aphids use the presence of
potassium allylglucosinolate (sinigrin) to detect an appropri-
ate host plant. The insects land and test the plant; if potas-
sium allylglucosinolate (sinigrin) is lacking, they continue
searching for an appropriate host plant (Harborne, 1982).
Glucosinolates and Oviposition by Insects
Oviposition frequently involves a complex series of stim-
uli, many of which are chemical. Further, because many
larvae are relatively immobile, selection of the host plant
effectively occurs when the gravid female selects a site for
oviposition (Renwick, 1988). However, many factors other

than glucosinolates are involved in host selection (Chew,
1988). For instance, nutrient availability is also related to
the selection of Brassica nigra plants for oviposition by fe-
males of Pieris rapae (Wolfson, 1980). Orientation of this
insect also is based on color of the host plant. In instances
where stimulatory cabbage extracts were obscured from
sight by placing them in cups (with holes punched in the
cups), there was no preference for these extracts (Renwick,
1988).
Some glucosinolates and glucosinolate hydrolysis prod-
ucts that are involved in oviposition by insects have been
tabulated (Stiidler, 1992).
Glucosinolates can induce oviposition by the cabbage
butterfly. Gravid females of Pieris brassicae oviposit on
filter paper or on Vida faba, if it is first treated with potas-
sium allylglucosinolate (sinigrin) (15). It has been suggested,
however, that the natural stimulant is glucobrassicin (3-indo-
lymethyl glucosinolate) (3) (Traynier and Truscott, 1991).
This compound elicited oviposition at threshold concentra-
tions as low as 10-6 M. Sinigrin is active at 10-2 M. The
markedly greater potency of glucobrassicin is consistent
with known glucosinolate profiles of crucifers which show
indolyl glucosinolates predominant in foliage (Traynier and
Truscott, 1991).
In studies in which the oviposition stimulants for Pieris
rapae from nasturtium, mustard, and cabbage were fraction-
ated, the most attractive fractions from the three plants were
distinct; these studies indicate that the insect responds to a
different complement of compounds in different crucifers
(Renwick,1988).
In another study, females of Pieris rapae oviposited on
plants of Cardamine cordifolia in one field, but did not ovi-
posit on plants of this species in an adjacent area, even
though both the butterfly and the plants were present (Chew,
1977). When cabbage plants were sprayed with a butanol
extract of Erysimum cheiranthoides, a wild crucifer normally
rejected by ovipositing Pieris rapae because of the presence
of cardenolides in the foliage, oviposition by gravid females
was greatly reduced (Dimock and Renwick, 1991). This in-
sect does not oviposit on many other species of crucifers.
These results confirm that a combination of attractant and
deterrent effects are involved in oviposition behavior. Repel-
lent compounds may include cardenolides, alkaloids, and
cucurbitacins (Renwick, 1988).
Allyl isothiocyanate (26) is the principal volatile compo-
nent produced by damaged cabbage. This compound is at-
tractive to the cabbage root fly [Delia (Erioischia) brassi-
cae) (Finch, 1978; Wallbank and Wheatley, 1976). Antennal
receptors proved sensitive to allyl isothiocyanate, whereas
the tarsal receptors of females were sensitive only to the
corresponding glucosinolate (Louda and Mole, 1991). The
insect will lay eggs when provided with allyl isothiocyanate
or the corresponding glycoside, allyl glucosinolate (15).
Allyl isothiocyanate is involved in attraction of the mus-
tard beetle, Phaedon cochleariae, to its host plants (Tanton,
1977).
G/ucosinolates 309
The host range of the diamondback moth, Plutella xylos-
tella, appears to be correlated with the presence of glucosino-
lates in the host plants, but the role of stimulants and attrac-
tants in oviposition seem to be important. Extracts of
Brassica oleracea (cabbage), B.juncea (mustard), and Erysi-
mum cheiranthoides stimulated oviposition by gravid fe-
males on bean plants. Extracts of Erysimum cheiranthoides,
Tropaeolum majus, and Capsella bursa-pastoris which de-
terred oviposition by the cabbage butterfly Pieris rapae,
were not deterrent to Plutella xylostella (Renwick and
Radke, 1990).
Long-Distance Attraction
Although there is a common view that isothiocyanates
are important odor components of intact brassicaceous
plants, field levels are extremely low and are usually below
the level of detection of the usual analytical techniques. The
principal vapor component of turnip and radish is hexenyl
acetate (see Chapter 2). Even in the case of disrupted tissue
of cauliflower, turnip, radish, and wallflower (Alyssum), the
principal component was Z-hex-3-enyl acetate (Wallbank
and Wheatley, 1976). These data suggest that "green leaf
volatiles" may be involved in the attraction of many species
of insects to cruciferous plants.
QIucosinolates and Plant Disease
Resistance
Glucosinolates via their hydrolysis products are among
the most powerful antibiotic substances known from higher
plants (Louda and Mole, 1991). In cultivated Brassica spe-
cies, there is a correlation between the content of glucosino-
lates (isothiocyanates) and disease resistance (Chew, 1988;
Greenhalgh and Mitchell, 1976). Wild populations of
Brassica species typically have higher levels of glucosino-
lates and are usually more disease resistant. Selective breed-
ing for milder flavored individuals has been a contributory
factor to the general lack of resistance of modem varieties to
powdery mildew and other pests (Greenhalgh and Mitchell,
1976).
A series of antifungal sulfur-containing indole derivatives
(27-31), which appear to be related to glucobrassicin (3), are
produced as phytoalexins in Raphanus sativus and Brassica
campeslris in response to the fungus Leptosphaeria macu-
lans (Devys et aI., 1990; Barbome, 1989) (Fig. 17.8).
QIucosinolates and AUelopatby
A number of cruciferous plants inhibit the growth of com-
peting vegetation; several glucosinolates and their hydroly-
sis products have been isolated and demonstrated to possess
herbicidal or growth-inhibiting activity. Others inhibit seed
germination.
Benzyl isothiocyanate (32) (Fig. 17.1) from Carica pa-
paya seeds strongly inhibited germination of the seeds of
Abutilon theophrasti (velvet leaf, Malvaceae) at 4 X 10-4
M (Wolf et aI., 1984).
310 Glucosinolates
Sulforaphene (4-methylsulfinyl-3-butenyl isothiocya-
nate) (33) has an EDso of approximately 2 X 10-4 M against
the seedlings of velvetleat (Abutilon theophrasti, Malva-
ceae) (Brinker and Spencer, 1993).
A series of isothiocyanates from Rorippa indica inhibit
lettuce hypocotyl and root growth at 0.1 mM. The corre-
sponding glucosinolates hirsutin (34), arabin (35), and cam-
melinin (36) were isolated. The isothiocyanates appear to be
responsible for most of the aUelopathic activity of this weed
(Yamane et aI., 1992).
This phenomenon may involve incompatibility of brassi-
caceous plants with mycorrhizal fungi (Chew, 1988). How-
ever, these authors concluded that rather than producing
compounds harmful to the mycorrhizal fungi, plants of the
Brassicaceae fail to produce compounds stimulatory to the
fungi.
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18
Introduction to Terpenes

Introduction General procedures for the isolation, purification and

The Isoprene Rule characterization of various types of terpenes have been re-
Biosynthesis of the Cs Unit viewed (Banthorpe, 1991; GersheD20n and Croteau, 1991).
Stereochemical Features of Mevalonic Acid
Isopentenyl Pyrophosphate and Dimethylallyl
Pyrophosphate
Hemiterpenes THE ISOPREl'IE RULE
Chromenes, Benzofurans, Benzopyrans, and Precocenes
Polyterpenes Early studies indicated that terpenes were composed of five
Biosynthesis carbon units. By 1860, isoprene, a compound with the empir-
Biological Activity ical formula CsH., could be derived by pyrolysis of turpen-
Natural Rubber tine and rubber. Further, isoprene could be transformed into
Hevea brasiliensis a C IOH'6 compound that subsequently decomposed back to
Guayule the original five-carbon unit. Wallach recognized that ter-
Gutla Percha penes could be subdivided into several groups: hemiter-
Chicle penes, true terpenes, sesquiterpenes, and diterpenes. In 1887,
Dolichoprenols he proposed that monoterpenes (true terpenes) as well as
Prenylated Proteins other terpenoids were composed of isoprene units, a concept
Similar Five-Carbon Units Not Derived from Mevalonate that became known as the isoprene rule (Wallach, 1887).
References The structure of isoprene was not solved until much later
(Spurgeon and Porter, 1981).
In the 1920s, Ruzicka and co-workers systematically
studied the stroctures of many sesquiterpenes and a diter-
Il'ITKODVCTlOI'l pene, abietic acid (1959, 1973). The correct structure of cho-
lesterol was published by Wieland and Dane (1932) and by
Terpenes are the largest and most diverse group of plant others. Structures of other terpenoids, such as vitamin A,
secondary compounds; at least 15,000 terpenoids have been were solved in the 1930s. The empirical isoprene rule was
described, and thousands more are undoubtedly awaiting dis- useful for making assigrunents of structure, but the results
covery (Gershenzon and Croteau, 1991). Terpenes typically were not satisfactory in all cases. A "biogenetic isoprene
are made up of units of five carbons, Cs , C lO , CIS, ClO, C25 , rule" later was proposed by Ruzicka to explain the origin
C30 , and C40 structures (Fig. 18.1), that generally occur free of compounds formed from an aliphatic precursor made up
but may be modified, or derivatized as esters and glycosides, of isoprene units, but involving subsequent rearrangements
or attached to proteins. Terpenes are common in most plants (Banthorpe, 1991; Ruzicka, 1953, 1959, 1973).
and fungi, but they rarely accumulate in bacteria (Bell and The development and utilization of radioactively labeled
Charlwood, 1980; Poulter and Rilling, 1981). Steroids in compounds was a major step in the study of the biosynthesis
mammals are products of terpenoid metabolism. of terpenoids.

312

--op~ tc~~~~~-
\P: ~c:
WP I
~OPP
PPO~
A \
DMAPP
.f \ a monoterpe~ne
geranyl ~~;PhOSPhate
FPP--+
¢
~
;~?P~ ~
Hl
__
Opp
+GGPP / geranylgeraoyJ
*
presqualene pyrophospbate
tetraterpenes (carotenoids) C40
Fig. 18.1. Structural types of terpenes.
610SYNfHESIS OF TIlE C5 UNIT
Although a number of C s precursor units for terpene had
been proposed over the years, studies in the 1950s indicated
that a six-carbon compound, from brewer's yeast solubles,
mevalonic acid (MVA) (1), could support growth of an ace-
tate-requiring mutant strain of bacteria when acetate was
omitted from the growth medium. Subsequent feeding stud-
ies indicated that mevalonic acid was incorporated into cho-
lesterol with loss of carbon dioxide. Most of the steps of
these basic pathways of terpenoid biosynthesis have been
worked out during the last 25 years, largely with yeast or
mammalian liver extracts.
The first step in the formation of mevalonic acid involves
the formation of acetoacetyl-CoA (2) from acetyl-CoA (Fig.
18.2). The enzyme responsible for this conversion, acetoace-
tyl-CoA thiolase (AACT, E.C.2.3.1.9) recently has been ob-
served in plastid preparations from the plants Parthenium
argentatum andPhaseolus radiatus (Bachet aI., 1990). Con-
version of acetoacetyl-CoA to (3R)-3-hydroxy-3-methylglu-
taryl coenzyme A (j3-hydroxy-j3-methylglutaryl coenzyme
A, HMO-CoA) (3) is catalyzed by HMO-CoA synthase (3-
hydroxy-3-methylglutaryl-CoA synthetase; j3-hydroxy-j3-
methylglutaryl-CoA synthase, E.C.4.1.3.5). This enzyme
has been isolated from a number of plant sources, among
them orange peel and sweetpotato root tissue. 3-Hydroxy-3-
Introduction to Terpenes 313
-+ WP \
(E,E)-famesyl pyrophosphate
!
I a sesquiterpene
~ I ~ OPP FPP
a diterpeoe
" pyropbosphate
GGPP
~WP
sesterterpenes (e2S)
methylglutaryl-CoA synthetase is first acetylated by acetyl-
CoA to give an acetyl-enzyme complex. This complex then
condenses with acetoacetyl-CoA to yield a covalent deriva-
tive between HMO-CoA and the enzyme that is hydrolyzed
to produce HMO-CoA and the free enzyme (Bach et aI.,
1990; Beale and MacMillan, 1988; Qureshi and Porter,
1981).
Next, hydroxymethylglutaryl-CoA reductase (HMO-
CoA reductase, j3-hydroxy-j3-methylglutaryl coenzyme A
reductase; E.C. 1. 1. 1.34) reduces 3-hydroxy-3-methylglu-
taryl-CoA (3) to (R)-mevalonic acid (MYA) (1) in a two-
step process (Fig. 18.3) (Bach et aI., 1990; Beale and Mac-
Millan, 1988; Harrison, 1988; Qureshi and Porter, 1981).
This enzyme is widely considered to be the key regulatory
enzyme in the biosynthesis of cholesterol in humans and has
been the target of many medically oriented studies; although
plant HMOR has been less intensively studied, techniques
for the solubilization, purification and characterization of
this enzyme have been developed (Bach et aI., 1990).
j3-Hydroxy-j3-methylglutaryl coenzyme A reductase
(HMO-CoA reductase) is widespread in bacteria, yeasts,
higher plants, insects, and mammals and is present in all
tissues that synthesize isoprenoid compounds. In mammals,
this enzyme is localized in the endoplasmic reticulum; in
yeasts, in the mitochondrial matrix; and, in plants, both chlo-
roplasts and cytoplasm have HMO-CoA reductase activity
314

.-\ '-r
Introduction to Terpenes

bound
o
H
NH,
0)
H
1
alB'X'AJ -
XI~
s"

(3)
HH
"R'

pyridine nucleotide *corresponds to carbon 5

of mevalonic acid (1)

.-< ~
HAIRH Hi

~X
\1 CS/
X A "R' /N --

NH,

. X (IY
o H) H H H

I I

H)/H ) __
( A N"R'

H H H

Y
1

mevalonic acid (1)

Fig. 18.2. Mechanism of action of HMG-CoA reductase (modified from Qureshi and Porter. 1981).

(Bach et aI., 1990; Reddy and Das, 1987; Schulze·Siebert
etal., 1987; Schultz and Schulze-Siebert, 1989). The enzyme
is largely membrane bound (Bach et aI., 1990). HMG-CoA
reductase from radish seedlings has a molecular weight of
about 180,000, made up of units of about 45,000. A eDNA
encoding an entire radish HMGR protein has been cloned
and sequenced. This eDNA encodes a monomeric unit of
about 63,000 molecular weight that may represent an unpro-
cessed form of the enzyme (Back et al., 1990). HMG-CoA
reductase from Arabidopsis rhaliana is a protein with 592
amino acids and a molecular weight of 63,605 (Monfar et
al., 1990). This protein from potato tubers has a molecular
weight of 110,000 and subunits of 55,000 (Beale and Mac-
Millan, 1988). Factors involved in the regulation of HMG-
CoA reductase in plants have been reviewed (Gershenzon
and Croteau, 1990).
The subcellular compartmentation of terpenoid metabo-
lism is a matter of controversy. Chloroplasts seem to contain
the entire terpenoid biosynthetic pathway and appear to be
autonomous in regard to terpene biosynthesis. Carotenoid.
and the side chains of chlorophyll are synthesized in the
chloroplasts. Sterols are synthesized in the cytoplasm (Gers-
henzon and Croteau, 1990).
Stereochemical Features of iIIevalonic Acid
The mevalonic acid molecule (1) has three prochiral
methylene carbon atoms (and six prochiral hydrogen atoms)
(Fig. 18.2). Replacement of any one of these hydrogen atoms
with a tritium or deuterium atom will produce a new chiral
center. In strncture 1 (Fig. 18.2), HR indicates a proton that
will confer the (R)-configuration on the center bearing the

o H~
~
j
CH,
-CH,COSCoA
HMG·CoA
synthetase
H
~
OH
~,~~
·0.,' SCoA
HO
Fig.lS.3. Biosynthesis of mevalonic acid (Qureshi et al., 1976: modified and used with pennission of the copyright owner, the American Chemical
Society, Washington, DC).
proton if replaced by an isotope of hydrogen, This proton
is referred to as a pro·(R) proton, Replacement of the Hs'
proton ipro·(S)] similarly produces the (S)·configuration at
the new chiral center.
Isopentenyl Pyrophosphate and
Dimethylallyl Pyrophosphate
The mevalonic acid molecule (1) possesses a chiral center
(bearing hydroxyl and methyl) at C·3, Only the (3R)-enanti-
orner is used in isoprene synthesis, The fate of each of the
six possible (3R)-monotritiated species of MVA has been
determined in subsequent reactions of this important precur-
sor. These reactions are highly stereospecific (Cori, 1983;
Mann, 1987),
The conversion of mevalonate (1) to isopentenyl pyro-
phosphate (IPP) (4) involves two consecutive phosphoryla-
tions at position 5 by successive action of mevalonate kinase
(EC 2,7.4.2) and a decarboxylation and dehydration of the
tertiary alcohol group by mevalonate 5-pyrophosphate de-
carboxylase (EC 4,1.1.33) (Fig, 18.4) (Crotean & Jolinson,
1985; Gershenzon and Croteau, 1990), One mole of ATP
is required for each phosphorylation reaction, Mevalonate
kinase converts mevalonic acid to (5R)-phosphomevalonate
(5), The second phosphorylation is catalyzed by phospho-
mevalonate kinase, The subsequent decarboxylation and de-
hydration is mediated by the enzyme mevalonate diphos-
phate decarboxylase (di- or pyrophosphomevalonate
decarboxylase; EC 4_1.1.3.3); this enzyme requires Mg2+ or
Mn 2+ and ATP for activity (Beale and MacMillan, 1988;
Harrison, 1988), All three of these enzymes are found in a
number of plants,
The product of this reaction, isopentenyl pyrophosphate
Introduction to Terpenes 315
acetoacetyl-CoA
thiolase
kCH,COSCOA
CH,) (2)
-CH,COSCoA
HMG·CoA
>..
~ \.f,~OH COSCoA reductase
.O~ NADPH
3S-3-hydroxy-3-methylgIutaryl CoA (3)
NADPH
(3R)-mevalonic acid (1)
(IPP) (4), is then isomerized to dimethylallyl pyrophosphate
(DMAPP) (6), via the addition of a proton and abstraction
of the pro-(R)-hydrogen from C-2 (originally the 4-pro-(S)-
hydrogen of MVA) (Fig, 18.4), Mechanistic studies indicate
that the oxygen from C-3 of mevalonate 5-diphophosphate
ends up in inorganic phosphate, These and other data require
a mechanism in which there is a direct enzyme-mediated
reaction between the oxygen at C-3 and ATP rather than an
initial transfer of phosphate from ATP to the enzyme and
then to mevalonate 5-diphosphate (Beale and MacMillan,
1988),
IPP and DMAPP are interconverted by isopentenyl-di-
phosphate D-isomerase (isopentenyl pyrophosphate: dimeth·
ylallyl pyrophosphate isomerase; isopentenyl pyrophosphate
~3-~2-isomerase; EC 5.3.3.2), This enzyme has been iso-
lated from a number of plant sources, such as pumpkin.
orange peel, and pine seedlings, Isopenenyl-diphosphate D-
isomerase (from the fungus Claviceps) has a molecular
weight of 35,000, a requirement for Mg2+, and an pH opti-
mum of 6,0-85, and it is inhibited by geranyl and famesyl
diphosphate,
Lynen and co-workers (1959) were the first to realize that
dimethylallyl pyrophosphate (6) corresponds to Ruzicka's
"active isoprene" and that this compound (and homologous
allylic pyrophosphates) is involved in repetitive condensa-
tions with isopentenyl pyrophosphate (4) (Poulter and Rill-
ing, 1981),
HElIUTEKPEl'IES
Because DMAPP is such a potent electrophile, it is not sur-
prising that the 3,3-dimethylallyl group is present in many
secondary metabolites that derive the major part of their
316 Introduction to Telpenes

H ~H
~
mevalonate H H phosphomevalonate H H
~HOl t HOl
op kinase OPP
kinase
H H H H H H H H

mevalonic acid (1) mevalonic acid S·phosphate mevalonic acid

5·pyropbosphate (5)

~
OH~

-
f" C../ 0 0

:0 3 'O-~-O-~-OH
ATP

I
O·
I
O·
.CO,

mevalonic acid S.pyrophosphate

~ O-~-O-~-OH ~='H=R==..,,:::: k
o 0

H
I
H+
4I
H
3'
H. Hs
Y !... . . "o-LO-~-OH
O·
I I
O·
isomerase /3
H O· O·

isopentenyl pyrophosphate (4) dimethylallyl pyrophosphate (6)

DMAPP
IPP

Fig. 18.4. Origin and stereochemistry of isopentenyl pyrophosphate and dimethylallyl pyrophosphate fonnation.

skeleton from non-mevalonate-derived pathways (Fig. 18.5). Cbromenes. Benzofurans. Benzopyrans.

These reactions are catalyzed by a number of prenyltransfer-
ases. Products of C" N-, and O-alkylation are common, and
the dimethylallyl group is invariably located at sites that
were nucleophilic before alkylation, such as methylenes and
phenolic oxygen atoms.
Humulone (7), from Humulus lupulus (Cannabaceae), is
partly responsible for the bitter flavor in beer. About 35 ppm
of hop-derived substances contibute a specific bitter taste
and hoppy flavor to beer. Hops also contribute for the micro-
biological stability and the stability of foam of beer (De
Keukeleire, 1991). However, the activity comes not from the
native hop compounds, but from' 'iso-a<-acids" produced by
boiling the wort-containing hops (De Keukeleire et ai., 1992;
Bondeel et al., 1987).
Lysergic acid (8) occurs in ergot. The diethylamide (not
naturally occurring) is known as LSD. This topic is discussed
in more detail in Chapter 35.
Hemiterpene units are also incorporated into furanocoum-
arins, some anthraquinones rotenoids, and other isoflavonoid
derivatives. Often, the hemiterpene unit is further metabo-
lized and may not be easily recognized. The presence of
intermediates sometimes serves as an indicator of mevalo-
nate precursors in these pathways (see Chapter 9).
and Precocenes
Most of the naturally occurring chromenes and benzofu-
rans (about 200 compounds) occur in the family Asteraceae
(Fig. 18.6) (Proksch and Rodriguez, 1983). These com-
pounds are often cytotoxic and insecticidal. Both chromenes
and benzofurans appear to be formed from dimethylallyl
pyrophosphate and an acetate-derived polyketide precursor.
The terpenoid chemistry of at least 14 species of the genus
Encelia (Asteraceae) has been examined. Most species of
this genus are characterized by two distinct classes of terpe-
noids: sesquiterpene lactones and benzpyransibenzofurans
(Isman et al., 1990). Analysis of the chromenes and related
compounds of Encelia ventorum showed the presence of a
number of chromenes, benzopyran and benzofuran deriva-
tives, several of which were insecticidal. Encecalin (9) was
moderately toxic to frrst-instar larvae of milkweed bugs and
has an LCso of 1.4 and 11.8 ....g/cm 2 (residue contact on
glass surfaces) against the variegated cutworm (Peridromia
saucia) and the migratory grasshopper (Melanop/us sangui-
nipes, Acrididae), respectively. Encecalin also exhibits anti-
feedant properties against several species of noctuid caterpil-
lars (Isman, 1989). Others (e.g., compound 10) were feeding
deterrents to Helicoverpa zea. The benzofuran (11) from
 Introduction to Telpenes 317

o NH ~O 0 Ha02C
HN0 0 I OH ~ NCH,

o HO ~
~ I ~
"" NH

echinulin (a fungal antibiotic) humulone (7) lysergic acid (S)

HO

OCH,
OCH,
OCH, rotenone OCHJ

o o
~OH
y\,~o-\-
OCH3 CH J

lunacrine isobalfouridine

CH'OvSQ
OCHJ skimmianine dictamnine

~ HO""OO
"" -cCCl""
~ "" - r.=(X)1 I
I HO
0
""
000
I
"""00

Fig. 18.5. Hemiterpene-derived secondary metabolites.

Flourensia dentata and F. ilicifolia was toxic to milkweed
bugs and highly phototoxic (Harborne, 1986; Proksch et al.,
1983; Rodriguez, 1983). In general, benzofurans are not in-
secticidal, but antagonize or reduce the toxicity of encecalin
to at least three species of insects (Isman, 1989).
Both eupatoriochromene and encecalin (9), from yellow
starthistle (Centaurea solstitialis L., Asteraceae), retard seed
germination and reduce radicle and hypocotyl growth of
weed and crop plant seedlings (Merrill, 1989).
Compounds with similar structure have been implicated
in cases of livestock and human poisoning by Eupatorium
rugosum, white snakeroot, in the eastern United States
(Beier and Norman, 1990; Beier et al., 1987). This plant-
poisoning syndrome was once a major problem and was
considered an illness, often called "milk sickness" (Beier
and Norman, 1990; Kingsbury, 1964). The lipophilic com-
pounds of white snakeroot are excreted by lactating ani-
mals, usually cattle. In the southwestern United States,
where white snakeroot does not grow, another species,
lsocoma wright;; (syn. Haplopappus heterophy/lus), has
been implicated (Beier and Norman, 1990; Beier and Nigg,
1992; Kingsbury, 1964).
Although a ketone, tremetone (12), has been proposed to
be the compound responsible, this compound failed to pro-
duce symptoms of the disease in test animals. Two inactive
fractions from Eupatorium rugosum were converted to ac-
tive agents by treatment with cytochrome P-450 enzymes
(Beier and Norman, 1990). The exact structores of the active
compounds have not been established.
Other representatives of this group of compounds (such as
compounds 13 and 14) from Ageratum houstonianum have
antijuvenile hormone activity and cause precocious produc-
tion of adult insects. Because of these properties, the com-
pounds are called precocenes. Female insects that are ex-
posed to these compounds never reach sexual maturity.
External application of the compounds to second-instar lar-
vae of the milkweed bug, Oncopeltus fasciatus, causes the
nymphs to molt to normal third- and fourth-instar larvae and
then to precocious, sterile adults (Proksch and Rodriguez,
1983, 1984; Rodriguez, 1983).
318 Introduction to Tnpenes
o
~ ~
CH3-0~O+
encecalin (9)
o o
c:Xo-<
o
~
CH3-0~O--\-
precocene 1 (13)
Fig. 18.6. Chromenes, benzopyrans, benzofurans, and precocenes.
Precocenes induce precocious metamorphosis by causing
irreversible changes in the development of the corpus alla-
tum, a vital honnone-producing gland in insects_ Treatment
with juvenile honnone (produced by the corpus allatum)
temporarily reverses the effects of precocenes (Bowers,
1988, 1991, 1992). Precocenes first are absorbed in the insect
fat body. The use of this group ofhemiterpenes for insectici-
dal purposes is limited, however, because of the specificity
of action. Many insects are able to detoxify and excrete pre-
cocenes rapidly (Bowers, 1988, 1991). When precocene 2
(14) was fed to the grasshopper, Me/anop/us sanguinipes,
it was converted to the 2-hydroxymethyl derivative and a
demethylated product. These oxidized products are less toxic
than the parental compounds and are more readily excreted
(Harbome, 1989).
POLYTERPENES
At least 2000 species (mostly of angiospennous plants, but
including some ferns and fungi) contain polyisoprene, al-
though the amount is small in most cases. Usually the poly-
isoprene produced is all Z-isomer (rubber) and only a few
o
HO~O~
//
(10)
o O~
~nU
CH3-0~O~
(11)
o
~
precocene 2 (14) tremetone (12)
species produce the all E-isomer (gutta percha) (Tanaka,
1991).
Usually, either the Z- or E-isomer, but not both, is pro-
duced in any species with the major exception of chicle
(Achras sapota, Sapotaceae). Rubber occurs in the fonn of
latex as minute particles which are accumulated in special-
ized cells or in vessels known as laticifers.
NMR spectroscopy is of value for the detennination of
the structure of polyisoprenes. Gel-pennealion chromatogra-
phy is a fast and reproducible method of detennining the
molecular-mass distribution of natural rubber (Tanaka,
1991).
Biosynthesis
Rubber fonnation takes place in the latex vessels and all
intennediates of the pathway occur there. The latex of H evea
and many other plants consists of multinucleate protoplasm
in extensively anastomosed duct systems of laticifers
(Loomis and Croteau, 1980). Electron microscopy oflatici-
fers from several plants families has shown that latex is a
highly specialized cytoplasm containing typical structures
such as nuclei and mitochondria, endoplasmic reticulum, and
ribosomes, as well as polyisoprene and resin particles. Latic-

ifers also contain lutoid particles, which have been character-
ized as vacuoles containing compartmentalized hydrolytic
enzymes (Loomis and Croteau, 1980).
A number of studies of the systems have examined the
production of mevalonic acid in latex and latex products
(Archer, 1980). HMG-CoA reductase is the rate-limiting
enzyme in rubber biosynthesis (Bach et ai., 1990). Meva-
lonic acid (1) and isopentenyl pyrophosphate (4) are effi-
ciently incorporated into latex in substantial yield into
rubber in latex of Hevea (Archer and Audley, 1973; Cor-
nish, 1993).
The biosynthesis of rubber may be divided into three
steps: (I) initiation, which requires an allylic diphosphate
molecule, (2) elongation, in which IPP units are added to
a Z-I,4-polyisoprene chain, and (3) termination, in which
the polymer is released from the rubber transferase enzyme
(Cornish, 1993). In plants, the elongation of Z-I,4-polyiso-
prene (natural rubber) requires a small E-allylic diphos-
phate initiator (less than or equal to C 20 ). Farnesyl pyro-
phosphate (FPP) is an effective initiator of polyisoprene
biosynthesis (Light et ai., 1989); further, because only one
molecule of FPP is needed for each molecule of rubber
formed, small traces of this substance that are inadvertently
present complicate biosynthetic studies. The E-allylic di-
phosphates are hydrophilic cytosolic compounds, whereas
Z-I,4-polyisoprene is hydrophobic and compartmentalized
in subcellular rubber particles. A soluble E-prenyl transfer-
ase from the latex of H evea brasiliensis serves as a farnesyl
diphosphate synthase and plays no direct role in elongation
of Z-I,4-polyisoprene (Cornish, 1993). Because the hydro-
phobic rubber molecule is produced inside a rubber particle
but is formed from hydrophilic precursors from the cyto-
plasm, the polymerization reaction must take place at the
particle surface.
The Z-I,4-prenyl transferase is associated with rubber
particles in Hevea brasiliensis and other rubber-producing
plants. This enzyme is membrane bound (Cornish, 1993).
This enzyme requires Mg2+ or Mn2+, but will not synthesize
rubber unless a second component of the system, an allylic
diphosphate, is present (Fig. 18.7).
,
~opp ~opp
+ 2 '::::""
to a molecular weight of about 500,000 to 1,000,000
Fig. 18.7. Proposed origin of Z-polyprene compounds.
Introduction to Terpenes 319
Biological Activity
Once rubber is formed, it is not subject to remetabolism
by the plant and it is unlikely that rubber serves as a food
reserve. Latex helps to seal wounds and its sticky properties
help to protect the plant from insect attack.
Natural Rubber
Commercial rubber has been isolated from Castilla elas-
tica (Moraceae), Manihot glaziovii (Euphorbiaceae), Lan-
dolphia spp. (Apocynaceae), Taraxacum kok-saghyz (As-
teraceae), Hevea brasiliensis (Euphorbiaceae), and
Parthenium argentatum (guaynle, Asteraceae). Despite in-
tense interest in finding other rubber sources, virtually all
commercial natural rubber comes from Hevea brasiliensis
or closely related species (Euphorbiaceae) (Rogers, 1981).
The search for alternate rubber sources is especially im-
portant as Hevea species are highly susceptible 10 certain
fungal diseases (principally Microcyclus ulei). The preva-
lence of these diseases in Latin America prevents cultivation
of Hevea in large plantations (Latin America accounted for
less than 1% of world rubber production in 1977; Rogers,
1981). Although plants of Hevea are cultivated on planta-
tions in Southeast Asia and it is known that these plants are
susceptible to the fungi, the pathogenic agents have not been
introduced into that part of the world. If any of these patho-
gens were to be inadvertently introduced, major changes in
the economies of several rubber-producing and rubber-con-
suming nations wonld occur. Partly because of the demand
for radial tires, natural rubber still accounts for about one-
third of the world's rubber usage (Rogers, 1981).
Hevea brasiliensis
In Hevea brasiliensis, rubber is largely formed and stored
in the bark, in rings of latex vessels interspersed with the
sieve tubes of the secondary phloem of the trunk, branches,
or roots. Laticifers also are present in the leaves, flowers,
__
R~ I ~
Opp
opp
n
320 Introduction to TeJpenes

and fruit. In the cortex, the latex vessels run at a slight angle
to the longitudinal axis of the trunk or branches and originate
from longitudinally contiguous rows of cells, from which
the cross-walls are resorbed. Anastomoses between adjacent
vessels in each ring allow the latex to drain from a large area
of the cortex on tapping, but there are few or no connections
between the rings. Hevea is particularly useful as a source
of rubber, as the latex can be drained from a large area of
bark when the vessels are cut. The rubber regenerates rapidly
and rubber trees can be tapped on alternate days, yielding a
constant or increasing amount of rubber for a period of 30
or more years (Benedict, 1983).
H evea latex is a suspension in which rubber particles are
stabilized by an adsorbed film of phospholipids and proteins;
triglycerides together with l3-sitosterol and related com-
pounds are the principal constituents of the neutral lipids of
the rubber phase.
Hevea synthesizes both rubber and low-molecular-weight
E-compounds such as triterpenes from the same precursors
in the latex (Light and Dennis, 1989).
Guayule
As observed above, there has been much interest in find-
ing a nontropical rubber source. So far, one of the most
promising candidates is guayule, Partheniurn argentaturn
(Asteraceae). This plant, which grows in the northern part
of Mexico and the southwestern United States, has long been
known to produce latex. Although there is some minor pro-
duction in Mexico, guayule rubber is not currently produced
in the United States.
Guayule rubber is found in individual thin-walled cells
throughout the plant with the exception of the leaves (Rubis
et aI., 1981).
Gutta Percba
Gutta percha or gutta is all E-polyisoprene. The biosyn-
thesis of gutta does not seem to have been investigated. The
molecular weight of this polymeric material is usually lower

tiglicacid (15) angelic acid (16)

heliosupine senecionine
(heliotridine + angelic (retronecine +
and echimidinic acids) senecic acid)
Boraginaceae Asteraceae

ri"'""K
o

Xll
NC H 0 (CH2)18CH, NC H 0 (CHil18CH,

NZ ro~ (CHil18CH,

HI~')l.
0 (CH2)18CH,

Fig. 18.8. TigHe and angelic acids and other five-carbon nonterpenoid compounds from plants.

than that of natural rubber. The all E-double-bond system
results in a product with much different physical properties
than those of natural rubber. Gutta tends to be thennoplastic
or hard at ordinary temperatures. Plants that produce gutta
are known from the Celastraceae, Eucomiaceae, Euphor-
biaceae, Garryaceae, Poaceae, and Sapotaceae. Two species
dominate as commercial sources: Palaquium gutta and Mi-
musops balala (both Sapotaceae). The latex does not flow
as does that of Hevea and the isolation procedures are de-
structive to the trees. Gutta percha has largely been replaced
by synthetics (Loomis and Croteau, 1980).
Chicle, a mixture of 2- and E-isomers of polyisoprene is
isolated from Manilkara (Achras) sapota (Sapotaceae). The
biosynthesis of this material does not appear to have been
examined. There is little doubt that there are two stereospe-
cific enzyme systems metabolizing IFP in chicle latex, one
producing rubber (2) and the other yielding gutta (Charl-
wood and Banthorpe, 1978). Chicle is one of the few known
examples where a mixture of the two structures occurs (Ar-
cher and Audley, 1973). Chicle, which is commonly used
in chewing gum, has been partially replaced by synthetic
substitutes (Loomis and Croteau, 1980).
DOLICHOPRENOLS
Dolichoprenols (C80 to C IOS ) are derived from 2 elongation
of E,E-famesyl pyrophosphate and are universal components
of eukaryotic cells. These compounds function in glycosyl
transfer reactions (Waechter and Lennarz, 1976).
PREl'IYLATED FROTEIl'IS
Recent evidence indicates that various prenyl groups can be
attached to proteins. Both famesyl and geranylgeranyl
groups have been isolated from proteins (Epstein et al.,
1990).
Cellular ras genes encode a family of proteins tenned
p21ras. These, in turn, can acquire the ability to transform
cells through structural mutations that alter the ability of the
protein to bind or hydrolyze guanidine triphosphate (GTP).
Altered ras genes are the most frequently identified onco-
genes in human tumors (Casey et al., 1989). Processing of
these ras proteins involves the addition of a famesyl moiety,
near a carboxy-tenninal cysteine, followed by proteolytic
processing. Famesylation may be important for membrane
association and transfonning ability of ras proteins (Casey
et aI., 1989).
Introduction to Terpenes 321
SIMILAR. FIVE·CARBON Vl'IITS NOT DERIVED
FROM MEVALONATE
Some commonly encountered five-carbon units are not de-
rived from mevalonic acid. These moieties are found in such
diverse groups as pyrrolizidine alkaloids and cyanolipids.
Tiglic (15) and angelic (16) acids and their derivatives are
widespread (Buckles et al., 1955). These compounds are
derived in plants from leucine (Fig. 18.8).
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MERRILL, G. B., Eupatoriochromene and encecalin, plant growth
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POULTER, C. D. and H. C. RILLING, Prenyl transferases and iso-
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19
Monoterpenes

Introduction (Charlwood and Charlwood, 1991a). Monoterpenes are also

Biosynthesis present in fungi and some bacteria. Many monoterpenes also
Formation of Geranyl Pyrophosphate occur in animals, particularly in insects (Nahrstedt, 1982).
Interconversion of GPP and NPP Monoterpenes are often partially responsible for the essence
Studies with Labled Precursors of Monoterpenes or odor of piants and are the major odoriferous compounds
Acyclic Monoterpenes of many flowers and fruits. The heartwood of many trees,
Cyclic Monoterpenes especially conifers, is rich in terpenoid materials. In general,
Secondary Transfonnations sapwood of trees contains few terpenoids, but can saturate
Catabolism of Monoterpenes with resin in response to wounding (Croteau and Johnson,
Compounds Derived by Alkylation with Geranyl-OPP 1985).
Monoterpene-Derived Compounds of Marijuana The volatile fractions of many plants are isolated by steam
Hydroquinone Derivatives in Cordia Species distillation, distillation, or by solvent extraction (Banthorpe,
Chemosystematic Use of Monoterpene Chemical Data 1991). The resulting volatile compounds that make up the
Chemosystematic Study of Citrus Species essence or aroma of plants are called essential oils. Although
Chemosystematic Study of Gymnospenns essential oils are comprised of many types of compounds,
Chemosystematic Studies in Mints monoterpenes are major among them. These oils may also
Biological Activity contain metabolically modified fatty acids, aldehydes, hy-
Monoterpenes as Allomones, Kairomones, and drocarbons, esters, phenylpropanoid compounds, acetylenic
Synomones compounds, volatile alcohols, volatile alkaloids, phenylpro-
Allomones panoids, and other shikimic acid derivatives.
Allomones Produced by Arthropods, Especially Insects About 1000 monoterpenes, belonging to about 38 differ-
Kairomones ent skeletal types, are known (Fig. 19.1) (Charlwood and
Aggregation Pheromones
Charlwood, 1991a; Gershenzon and Croteau, 1991; Har-
Trail-Marking Pheromones
borne, 1982). These compounds usually occur free, but
Alarm Pheromones
sometimes occur as glycosides, especially in the iridoid se-
Synomones
ries. Essential oils are usually associated with specialized
Allelopathy
storage structures in plants. These lipophilic materials are
Uses of Monoterpenes by Hnmans
Medicinal Uses of Monoterpenes frequently found in secretory canals, cavities, glandular tri-
Flavors chomes, or in special oil cells (Croteau, 1981; Croteau and
Insect repellents Johnson, 1984; Gershenzon and Croteau, 1991; Johnson and
Irregular Monoterpenes Croteau, 1987; Rodriguez et aI., 1984). Monoterpenes are
References usually synthesized in the epithelial cells lining the ducts or
cavities in which they are eventually sequestered (Croteau
and Johnson, 1985). The production of monoterpenes often
INTRODUCTION
occurs in nonphotosynthetic tissues and is highly dependent
Monoterpenes are widespread in plants. These C IO com- on imported carbohydrates for both carbon and energy (Cro-
pounds occur in algae, bryophytes, ferns, gymnospenns, and teau and Johnson, 1985).
both monocotyledonous and dicotyledonous angiospenns Essential oil components appear isolated from the rest of

324
 MonOlelpenes 325

~ ~ 2 22
~ ~"~1'mcri
p-cymene (81) sabinene (22) tbujeue (23) camphene (IS)
«-pheUandrene (79)

~l!e~200~
'~: ~~ 4'-~:~~
£" "1
Hnalool (6) thymol l,8-dneole (10) borny. acetate (77) plperitone

$" crt (tt

2 25:
(a) earvooe (48) thujone (ll) camphor {33} fencbone verbenone (65)

Eft { 00

~~OO2" 2 $00
a-fenebene E. or B-oclmene (47) terplnoleoe (12) «-terpinene dtnmellol (7)

5
geraniol (4) nerol (5) I,B-cineole (10) ascaridol (87) borneol (32)

oo-0~-?J ~~':(
~I°IPP
~ ~ CO,H

(b) p-thujaplicin (49) p-thujapUcinoi (46) tbujic aeld (SO) fenchyl acetate Iinaly. pyrophosphate (8)

Fig. 19.1 (a & b). Representative monoterpenes.

326 Monoterpenes
the plant; there is evidence that despite reports of tnrnover
in cuttings, there is a lack of rapid tnrnover of monoterpenes
in intact plants (Mihaliak et ai., 1991).
Most essential oils are complex mixtnres involving from
a few to several hundred compounds. The techniques for
collecting floral fragrances and other similar mixtnres of
essential oils have been reviewed (Charlwood and Charl-
wood, 1991a; Gershenzon and Croteau, 1990, 1991; Hills
and Schutzman, 1990). Extraction with supercriticalliquids
and headspace trapping are useful to avoid decomposition
of essential oil components.
General chromatographic techniques for monoterpenes
have been reviewed (Banthorpe, 1991; Charlwood and
Charlwood, 1991a; Coscia, 1984; Gershenzon and Croteau,
1991). As most monoterpenes are volatile and relatively non-
reactive, capillary gas chromatography (GC) and mass spec-
trometry are most widely used techniques for investigation
of essential oils (Banthorpe, 1991; Charlwood and Charl-
wood, 1991a; Hills and Schutzman, 1990; Shibamoto, 1981).
However, because monoterpenes usually contain 10 carbon
compounds, many have identical parent ions and similar
fragmentation patterns. Nuclear magnetic resonance (NMR)
techniques also are quite useful in determining structnres of
these compounds (Atta-ur-Rahman and Ahmad, 1992;
Charlwood and Charlwood, 199Ia).
BIOSYNTHESIS
In contrast to some other plant metabolites, most species of
monoterpene-producing plants do not produce and accumu-
late monoterpenes in tissue cultnre (Charlwood and Charl-
wood, 1991b). This lack of monoterpene synthesis may be
associated with special requirements for compartmentaliza-
tion. However, a few such cultnres do produce monoter-
penes. Callus cultnres of Perilla Jrutescens produce up to
2 mg of volatile oil per gram fresh weight of tissue. The
composition of the oil is similar to that of the parent plant.
In other plants, such as Jasminum officinale and Rosa da-
mascena, the enzymes of biosynthesis have been demon-
strated to be present, although there is no accumulation of
monoterpenes (Beale and MacMillan, 1988; Ellis, 1988).
Cell-free extracts of callus or suspension cultnres of several
species that did not accumulate monoterpenes were shown
to convert mevalonate and isopentenyl pyrophosphate into
geranyl, neryl, and farnesyl pyrophosphates at rates much
greater than those of the parental plant (Beale and MacMil-
lan, 1988).
Cells thought to be involved in monoterpene synthesis
typically possess an abundance of nonpigmented plastids
known as leucoplasts that lack an organized system of thyla-
koids and have few other internal membranes. Leucoblasts
frequently have been observed to contain droplets of lipid-
like material. Monoterpene-synthesizing secretory cells also
contain a well-developed network of smooth endoplasmic
reticulum that may be involved in monoterpene biosynthesis
(Gershenzon and Croteau, 1990).
Regnlation of monoterpene biosynthesis is controlled by
many factors. Morphological differentiation of the plant is
of paramount importance. Monoterpene formation occurs
only in cells of specialized secretory structures during the
relatively brief periods when these cells are metabolically
active (Gershenzon and Croteau, 1990). Feeding stndies with
isotopically labeled precursors have demonstrated that the
site of monoterpene formation is physiologically isolated
from the mainstream of plant metabolism, suggesting that
monoterpene biosynthesis is subject to control by the avail-
ability of assimilate. Cellular compartmentation and regula-
tion at the enzyme level are likely involved in overall regula-
tion of monoterpene biosynthesis but have been inadequately
stndied. HMG-CoA reductase appears to catalyze a key regu-
latory step in the biosynthesis of all plant terpenoids, includ-
ing monoterpenes (Gershenzon and Croteau, 1990).
Biosynthetic reactions leading to the formation of monot-
erpenes largely involve formation of geranyl pyrophosphate
(GPP), cyclization of GPP to one of a number of skeletal
types, and secondary transformations of the initial cyclic
product (Gershenzon and Croteau, 1990).
Formation of OeranyI Pyrophosphate
Monoterpenes are the product of the union of two acti-
vated Cs units, the biological equivalents of isoprene (Fig.
19.2). The reaction is catalyzed by prenyltransferases (BC
2.5.1.1) that effect condensation of sopentenyl pyro-
phosphate (IPP) with an allylic pyrophosphate, such as
dimethylallyl pyrophosphate (DMAPP), giving an ally-
lic pyrophosphate with five additional carbon atoms.
Prenyltransferases catalyze the first committed step to the
isoprenoid pathway (Gershenzon and Croteau, 1990). Mo-
noterpene biosynthesis requires a specific prenyl transferase,
geranyl pyrophosphate synthetase, that occurs in cells near
the specialized storage sites of monoterpenes. Such a geranyl
pyrophosphate synthase, that synthesizes geranyl pyrophos-
phate (3) as the sole (>95%) product from dimethylallyl
pyrophosphate (1) and isopentenyl pyrophosphate (2), has
been isolated from the leaves of sage (Salvia officinalis,
Lamiaceae) (Croteau, 1987; Croteau and Puckett, \989). In
contrast to farnesyl pyrophosphate synthetase, geranyl pyro-
phosphate synthetase is restricted in distribution within the
plant (Croteau, 1981, 1987; Croteau and Johnson, 1985; Cro-
teau and Purkett, 1989).
DMAPP (1) is an excellent aikylating agent. Although it
would appear to suffer nucleophilic attack at C-1 with loss
of pyrophosphate, a good leaving group, ionization provides
the C-1 cation generally regarded as the active electrophile.
Inversion of the center of DMAPP-bearing pyrophosphate
occurs; Mg2+ appears to be involved in the condensation. In
cell-free extracts of Tanacetum vulgare (Asteraceae), the
pro-(4R)-hydrogen of MVA [the pro-(2S)-hydrogen of IPPl
and both tritium atoms from [5-3 H21MVA (C-1 of IPP) are
retained in geraniol (4) (Banthorpe et al., 1978a).
The stereochemistry is well established, and many ques-
tions concerning the overall mechanism of the condensation
 MonOferpenes 327

-0
.
JlXA 3
.
PH, 0
II
O-P-O-P-OH
0
11 __

4 I I
0- O·
mevalonic acid

y
mevalonic acid 5-pyrophosphate

~
# 2
o
II
0
II -HR oo
II
o-i-o-i-
H 3 .,' O-P-O-P-OH -----"- 3~ 1\
4~. I I ~
Isomerase 2 OH
H HR HS 0- 0-
H 0- 0-

isopentenyJ pyrophosphate (2)

dimethylallyl pyrophosphate (1)
IPP
(a) DMAPP

(1)

OPP

(b) E-geranyl pyrophosphate (3)

Fig. 19.2 (a & b). Biosynthesis of geranyl pyrophosphate.

have now been resolved (Connforth et a!., 1966). Pamesyl-
pyrophosphate synthetase (BC 2.5.1.1) is the key enzyme in
the biosynthetic pathways for several classes of terpenes.
This enzyme catalyzes 1'-4 condensation between IPP and
DMAPP, or geranyl pyrophosphate, polymerizations that
constitute the major building steps of terpenoid biosynthesis
(Pig. 19.3) (Poulter and Rilling, 1978; Poulter et al., 1978,
1981). The condensation reaction may be subdivided into
three phases: ionization, condensation, and elimination. Ioni-
zation of the pyrophosphate group of DMAPP to generate
the allylic cation is the first step of condensation of IPP.
Studies by Poulter and co-workers indicate that cleavage
of the carbon-oxygen bond of geranyl pyrophosphate is a
discrete step, yielding a geranyl cation-pyrophosphate ion
pair and that this reactive species subsequently alkylates the
double bond in IPP (presumably the same is true for
DMAPP). These workers concluded that ionization and con-
densation are not concerted (Poulter et a!., 1981). Studies
with [1-180]geranyl pyrophosphate indicate that exchange
of oxygen does not occur during the reaction and that a
highly structured ion pair exists (Mash et al., 1981).
The fonnation of a 2,3-E- or 2,3-Z-double bond is a con-
sequence of the syn- or anti-conformation of the double
bonds of the precursors (Cori, 1983). Most, if not all, mono-
terpenes appear to arise from GPP (geranyl pyrophosphate)
(with a 2,3-E-double bond) and most of the numerous ter-
penes in nature are based on the E-configuration mentioned
above. Loss of the pro-S-proton to fonn compounds of Z-
confonnation (mostly polyisoprenoids) occurs in some
plants (e.g., Hevea brasiliensis) (Cori, 1983) (see Chapter
18).
Interconversion of OPP and l'IPP
Neryl pyrophosphate (NPP) (with a 2-Z-double bond)
also has been suggested as a product of the reaction of IPP
and DMAPP. Tracer studies show that the pro-(4S)-hydro-
gen of mevalonic acid [the pro-(2R)-hydrogen of IPP] is lost
in both the fonnation of geraniol (4) and nerol (5). This
evidence is in accord either with the prior fonnation of gem-
nyl-OPP and subsequent conversion to neryl-OPP (see
below), or with the presence of two transferases which cata-
328 Monoterpenes
~.~~. --
:8·
-----+-
OPI'"
Fig, 19.3. Proposed cationic mechanism for monoterpene biosynthesis.
Iyze the simultaneous fonnation of geranyl-OPP and neryl-
OPP. There is some evidence in support of each hypothesis
(Banthorpe and Modawi, 1978b).
Nerol (5) and related compounds with a 2-Z double bond
occur in many plants. Although GPP is a precursor to many
other groups of terpenoid compounds and is highly reactive
in biological systems, despite earlier reports, neither neryl
and linalyl pyrophosphates serve as intennediates in monot-
erpene biosynthesis (Croteau, 1984). Present evidence sug-
gests that geranyl pyrophosphate (GPP) is the preferred pre-
cursor of most compounds of this series (Croteau, 1984).
Enzymes in cell-free systems from carrot (Daucus carota,
Apiaceae) and peppermint (Mentha piperita, Lamiaceae)
catalyze the reversible fonnation of nerol and neryl phos-
phate from geraniol and geranyl phosphate, respectively.
Geranyl phosphate appears to have been isomerized directly
to the neryl derivative without the intervention of an alde-
hyde intennediate. The presence of a flavin, thiol, and light
was required for the reaction (Croteau, 1984).
Studies with Labeled Precursors
of Monoterpenes
Often as little as O.DJ-OJ % incorporation is observed in
attempts to introduce labeled MYA into monoterpenes in
-...~H
/ ' .. + "--H :8·
OPI'"
~.
l OP~H
'~
H -.. H
~ H H
H H H8'·
OPI'"
whole plants (Loomis and Croteau, 1980). In cell-free sys-
tems, somewhat greater incorporation of label is observed,
although the levels are still less than those observed for many
other secondary metabolites. Increased rates of incorporation
of biosynthetic precursors for monoterpenes in Tanacetum
vulgare (Asteraceae) in vivo occurred during the plant's dor-
mant phase. Rates 75 times greater than those of the growing
phase were observed (Banthorpe et al., 1977b). This may
partially explain the low incorporations in some stodies.
In any case, studies with specifically labeled precursors
indicate that MYA is an obligate precursor of monoterpenes
(Pig. 19.4). Incorporation of CO2 and glucose is much better
(Charlwood and Banthorpe, 1978), but the large number of
products obtained complicates analysis. It seems probable
that MYA (often introduced as the 8-lactone) is not trans-
ported efficiently to the site at which monoterpene biosyn-
thesis occurs.
The high rate of incorporation of MYA into geraniol (4)
and nerol (5) and their ~-D-glucosides in flower petals of
Rosa dilecta (up to 22%) represents an exception to the usu-
ally low rates of incorporation which are observed (Charl-
wood and Banthorpe, 1978).
CuriOUSly, when complete degradation of labeled monot-
erpenes has been carried out, in many studies, label from

MVA or from l4C02 resides almost entirely in the portion
of the molecule derived from isopentenyl pyrophosphate
(IPP) (2) but is not significantly present in the portion of
the molecule derived from dimethylallyl pyrophosphate
(DMAPP) (1). This appears to be a general phenomenon. It
is likely that a pool of DMAPP exists and labeled IPP reacts
with this pool of inactive DMAPP before significant isomer-
ization can occur. The amount of labeled DMAPP produced
is probably small with regard to the pool size, and the amount
oflabel introduced would be slight. The source of this endog-
enous DMAPP is not known, although it is probably due to
the fact that the equilibrium of the isomerase favors DMAPP
over IPP, and the next step in the pathway, the prenyltransf-
erase, is a relatively slow step, allowing buildup of DMAPP.
Such a pool may be observed only when incorporation times
are brief, or when incorporation rates of exogenous precur-
sors are low, as is frequently the case with monoterpenes.
Acyclic Monoterpenes
Acyclic, monocyclic, and bicyclic monoterpenes are
found in many plants, fungi, and certain insects, but rarely
in other animals. Acyclic compounds are derived from both
geranyl-OPP and from neryl-OPP, whereas cyclic species
are almost always derived from geranyl-OPP.
Cyclic Monoterpenes
The cyclization of geranyl-OPP (3) to produce monocy-
clic and bicyclic monoterpenes proceeds via enzyme-bound
intermediates that are probably similar to those postulated as
intermediates in Wagner-Meerwein rearrangements. These
reactions (catalyzed by strong acid) result in the formation
of many types of monoterpenes when compounds similar to
the precursors of cyclic monoterpenes are used as reactants.
These enzymes, called monoterpene cyclases, largely deter-
-0 ~lOH •
,
OH
-+PPO~I
[2_ 14Clmevalonic acid
6 -~D~oD
~ ~
(+)-sabinene (+)-Z-sabinol
Fig. 19.4.
Monoterpenes 329
mine the basic character of the monoterpene end products
(Gershenzon and Croteau, 1990). Monoterpene cyclases are
key regulatory enzymes in the synthesis of monoterpenes.
Intermediates are seldom isolated and, usually, do not appear
to be released during synthesis. Multiple cyclases, each pro-
ducing a different skeletal arrangement from the same acy-
clic precursor, often occur in higher plants; single cyclases
which synthesize a limited variety of skeletal types also are
known (Croteau, 1987).
A hypothetical biogenetic scheme was proposed by Ruz-
icka and co-workers (1953) that explains the origin of many
structural types of monoterpene. The final structures are the
result of an initial cyclization followed by chemical modifi-
cation, skeletal rearrangements, and functional group intro-
duction (Fig. 19.5). A carbocation or ion pair is formed from
the allylic substrate. The positive charge developed adds to
a double bond and a new carbocation is developed. The final
product is formed through regiospecific and stereospecific
elimination of a proton. Other intramolecular additions, hy-
dride shifts, and skeletal rearrangements must occur before
the final proton elimination in the biosynthesis of bicyclic
monoterpenes.
The formation of the cyclohexanoid ring from an acyclic
precursor requires a syn- or Z-conformation either in the
ground state or in the activated complex. On a basis of this
argument, formerly it was thought that NPP, the Z-isomer of
GPP, was the most likely precursor of cyclic monoterpenes.
However, it is now known that GPP is the preferred precur-
sor. Recent studies with cell-free systems indicate that GPP
can be converted into cyclic products without detectable con-
version into any other acyclic intermediates (Croteau, 1984,
1987; Johnson and Croteau, 1987).
Geranyl pyrophosphate is cyclized without preliminary
conversion to NPP or linalyl pyrophosphate (LPP) (8). An
isomerase system is not involved (Croteau, 1984). This im
.~opp
I
.- +
.2"'~
I
+'
:
-+
. .
~
.~.
(+ )-3-thujone
Labeling of monoterpenes.
330 Monoterpenes

plies a multistep cyclization process whereby the cyclase
itself converts GPP into a bound intermediate stereochemi-
cally suitable for cyclization. The mechanism of cyclization
appears to involve initial ionization of the pyrophosphate
moiety, in which a divalent ion appears to assist, followed
by stereospecific syn-isomerization to a linalyl intermediate
with rotation about the C-2-C-3 single bond and subsequent
cyclization of the cisoid rotamer in the anti-endo conforma-
tion. The chiral a-terpinyl cation so produced may then
undergo electrophilic addition to the remaining double bond
as well as hydride shifts and rearrangements to provide the
various other cationic cyclic products (Croteau, 1988; John-
son and Croteau, 1987).
Partial purification of the d-bomyl pyrophosphate cyclase
from sage leaves (Salvia ojJicinalis, Lamiaceae) and removal
of containing phosphatases and pyrophosphatases allowed
the demonstration that geranyl pyrophosphate (3) was pre-
ferred to neryl pyrophosphate (9) as substrate (Croteau,
1984) (Fig. 19.6). Cyclization of(IR)- and (lS)-[l-3H]gera-
nyl pyrophosphate and neryl pyrophosphate by partially pu-
rified d- or (+ )-bornyl pyrophosphate synthase (a cyclase
from Salvia ojJieinalis) was investigated, as the C-l of gera-
nyl pyrophosphate should exhibit net retention of configura-
tion, whereas neryl pyrophosphate should exhibit net inver-
sion of configuration. The bornyl pyrophosphate obtained
from each precursor was converted to camphor and the tri-
tium label was located by selective exchange of the exo- and
endo-a-hydrogens by established techniques. Tritium was
in the predicted position in all cases (Fig. 19.6). With 1- or
( - )-bornyl pyrophosphate cyclase (from Tanaeetum vul-
gare), exactly the opposite results were obtained. These re-
sults establish the rotation of the C-2-C-3 bond and net

~'
r<!- ~
~_~w ~ pyrophosphate
(-)-3R-LPP ~ (3) + / (+)-3S-LPP

+opp~ _ opp+

~~~/~
~~
>-0- h
T-wr:ne~
t
~
PPO- ~ ~
lJ ~
(+)-a-plnene (14) (-)-a-pinene

t+.t
+ -y
PPo-

~-:CfY
myrcene (17)

~~1r,-~-. I j

~;£~ ~ ~
(+)-sablnene (22)
OPP
(+)-bornyl
pyrophosphate
(-)-endo-rencbol (-)-bornyl pyrophosphate (-)-camphene (15)

Fig. 19.5. Wagner-Meerwein rearrangements of geranyl-OPP (modified from Croteau, 1987; used with permission of the copyright owner, the
American Chemical Society, Washington. DC).

Fig. 19.6. A model for the cyclization of GPP and NPP to d- or (+)- and /- or (- )-bomyl pyrophosphate based on studies with lR- and IS-labeled
precursors (Croteau, 1984; modified and used with pemrission of the copyright owner, Marcel Dekker, Inc., New York).
inversion of configuration at C-l of geranyl pyrophosphate,
and the lack of rotation and net retention of configuration
in neryl pyrophosphate. The detailed mechanism by which
geranyl pyrophosphate is cyclized and the relationship to the
cyclization of neryl pyrophosphate (9) and linalyl pyrophos-
phate (8) is an important question related to monoterpene
biosynthesis (Beale and MacMillan, 1988; Croteau, 1984;
Croteau and Johnson, 1985).
Cyclase preparations have been obtained which catalyze
the cyclization of geranyl pyrophosphate to essentially all
major structural classes of monoterpenes. These cyclases are
membrane bound in the synthesizing cells, but are readily
solubilized (Charlwood and Charlwood, 1991a; Croteau,
1987).
A cell-free system from Salvia officinalis (Lamiaceae)
that synthesizes 1,8-cineole (10), Iimonene (11), terpinolene
(12), and a-terpineol (13) from GPP (NPP also serves as a
precursor) has been established. These cyclic monoterpenes
were formed by independent routes from the precursor and
not as free intermediates of a common reaction sequence
(Loomis and Croteau, 1980). Fractionation of the soluble
preparation allowed separation of 1,8-cineole, a-terpineol,
and limonene cyclase activities. Thus, a series of competing,
but distinct, cyclases exist in relatively crude preparations
with the ability to synthesize cyclic monoterpenes in this
plant. A single protein seemed to be involved in the forma-
tion of 1,8-cineole (10) from an acyclic precursor and there
was no evidence for any free intermediates between GPP
and 1,8-cineole. It is possible that some sort of channeled
process occurs that precludes entry of exogenous precursors
to the enzyme of the cell-free system or release of intermedi-
Monoterpenes 331
ates (Charlwood and Banthorpe, 1978; Croteau and Karp,
1977). A number of cyclases including 1,8-cineole, 'Y-terpi-
nene, endo-fenchol, bornyl pyrophosphate, and d- and I-pi-
nene cyclases have been isolated, purified, and partially
characterized from this system. Most of these produce a sin-
gle product from the acyclic precursor.
In a subsequent examination of the cyclases that formed
(+ )- and ( - )-pinene, cyclase I, 96,000 MW, converted ger-
anyl pyrophosphate to (+ )-a-pinene (d-a-pinene) (14), but
produced smaller amounts of ( + )- or d-camphene (15) and
( + )- or d-limonene (11) as side products (Johnson and Cro-
teau, 1987). Cyclase II, 55,000 MW, transformed geranyl
pyrophosphate into (- )-(3-pinene (l-(3-pinene) (16) along
with smaller amounts of I-a- or ( - )-a-pinene, (-)- or 1-
camphene, (-)- or I-limonene, and myrcene (17) as copro-
ducts (Fig. 19.7) (Croteau, 1984; Johnson and Croteau,
1987). Extensive purification of each enzyme and differen-
tial inactivation studies ensured that each set of stereochemi-
cally related products was synthesized by a single, distinct
enzyme.
Involvement of tight ion pairs in monoterpene cycliza-
tions is indicated by the absence ofPa-P(3 interchange (i.e.,
the two ends of the pyrophosphate group are not inter-
changed during the reaction) and lack of I·O-isotope ex-
change of the pyrophosphate moiety. These factors establish
a remarkably tight restriction on the motion of the transiently
generated pyrophosphate anion with regard to its cationic
terpenyl reaction partner (Johnson and Croteau, 1987).
A mixture of (3R)-[8,9- 14Cjlinalyl diphosphate and
(IE,3RS)-[I-'Hdlinalyl diphosphate was incubated with the
two cyclase preparations. The borneol from the Tanacetum
332 Monoterpenes
Ce
(+~-pinene (16)
ee--p
(+)-a-pinene (14)
pinene n CYcla~ finene I cyclase
t~r~~~2
~~/.~. ~ ,~, ~ i~
_0" / I'
Ce (+p-pinene (16)
~ ~=cfJ
Fig. 19.7. Formation of (+ )~a.·pinene and (- )-~-pinene (modified from Croteau and Johnson, 1985; used with pennission of the copyright owner,
Academic Press, Orlando. FL).
vulgare system had a 3H: I'C ratio of 31 : 1, indicating an
almost exclusive use of the (3S)-enantiomer, whereas the
borneol of the Salvia ojJicinalis system had a ratio of 4: I,
indicating a preference for the (3R)-enantiomer. (3R)-Lina-
Iyl pyrophosphate (18) preferentially gave rise to the (+ )-
olefms (generated by cyclase I), and (3S)-linalyl pyrophos-
phate (19) preferentially gave rise to the ( - )-olefins (gener-
ated by cyclase II) (Fig. 19.8) (Beale and MacMillan, 1988;
Johnson and Croteau, 1987).
Preparations from Mentha piperita (peppennint, La-
miaceae) convert the acyclic precursors geranyl and neryl
pyrophosphate into limonene (11). The bulk of the cyclase
activity is in the soluble-enzyme fraction (Croteau, 1984).
In stodies with a geranyl pyrophosphate: (- )-endo-fen-
chol cyclase from fennel (Foeniculum vulgare, Apiaceae),
(3R)-linalyl pyrophosphate (18) had a Km lower than that
obtained with geranyl pyrophosphate (3) and a relative ve-
locity nearly three times higher. These results suggest that
the isomerization step is rate limiting (Johnson and Croteau,
1987).
~ (-l-a-pinene
ll(
(-)-camphene
(I-camphene)
At least 20 cyclases have been isolated, and as many
as 50 may exist. Most catalyze the fonnation of olefinic
compounds, but a few involve oxygenated products (Chari-
wood and Charlwood, 1991a).
Secondary Transformations
Although a relatively small number of cyclases must de-
termine the basic structural character of the monoterpenes
produced, the great variety of derivatives of each structural
type encountered suggests that numerous enzymes must be
involved in the secondary transfonnations of the parent
cyclic compounds (Croteau, 1984). As a group, the enzymes
catalyzing secondary transfonnations are not well studied.
The fonnation of oxygenated derivatives usually involves
oxygenation of the parental hydrocarbons. The essential oil
of Artemisia absinthum contains d-sabinyl acetate (42%)
(20), d-3-thujone (32%) (21), d-sabinene (12%) (22), and
l-a-thujene (3%) (23). Sabinene, fonned by cyclization of
geranyl pyrophosphate with a soluble enzyme, is the key
cyclic precursor of 3-thujone and other C-3-oxygenated
 0 yt
Monotelpenes 333

0pp 10pp
tansy -----.

I -- I opp
geranyl OPP (3) (+)-(3S)-linalyl OPP (19)
(-)-bornyIOPP

(-)-(3R)-linalyl OPP (18)

~ (+)-bornyIOPP
OPP

Fig. 19.8. Biosynthesis of bomanes (Croteau, 1987; modified and used with pennission of the copyright owner, Copyright 1987, the American
Chemical Society, Washington, DC).

compounds of this structural group (Croteau, 1984)_ Under

aerobic conditions, geraniol is incorporated into thujane de-
rivatives_ Sabinene is fIrst converted to cis-sabinol (24) by
a membranous, NADPHl02 , P-450-dependent mixed-func-
tion oxidase (Croteau and Johnson, 1985; Gershenzon and
Croteau, 1990)_ Under conditions where oxygen is limiting,

ot) --
most of the labeled geraniol precursor was incorporated into d~sabinene (22) d-cis-sablnol (24) d~cis..sabIDyl acetate (20)
sabinene_ d-[1O-3H1Sabinene was incorporated into both d-
sabinyl acetate (20) and d-3-thujone (21) (Croteau, 1984)_
These data support a pathway based on the intermediacy of
+-
d-sabinene (Fig_ 19_9), but not a-thujene (23), a-terpineol
(13), and terpinen-4-ol (25), as had been previously sug-
gested (Croteau, 1984)_
~
d-3-thuJone (21) d-sablnone 1-3-isothujone (51)
Evidence for conjugate reduction as a key step in monot-
erpene biosynthesis has been obtained from studies of the
oxygenated monoterpenes of Mentha piperita (Fig_ 19_10)
(Croteau, 1984)_ The pathway from isopiperitenone to the
menthol esters was deduced largely by time-course studies
and direct feeding experiments_ Other evidence supports the
intermediacy of I-Iimonene (11) as the fIrst cyclization prod-
uct of GPP in this plant. This is followed by the allylic
a-thuJene (23) (-)-trans-isopiperitenol (34) (-)-trans-carveol (35)
oxidation of the olefin and subsequent isomerization and
reduction of the double bonds of isopiperitenone to the men-
thones (such as 26)_ Furthermore, stereospecifIc dehydro-
genases responsible for the synthesis of I-menthol (27) and
d-neomenthol (28) have been isolated (Croteau, 1984)_
( + )-Pulegone (29) arises from ( - )-isopiperetinone (30)
via (+ )-cis-isopulegone (31) in leaf disks and enzyme
preparations of Mentha piperita_ The enzyme responsible (-)-perillyl aleobol (36)
for the reduction of the enone double bond had a molecular
Fig. 19.9. Proposed pathway for the biosynthesis of C-3-oxygenated
weight of 60,000 (Croteau and Venkatachalam, 1986)_ thujane monoterpenes from sabinene (modified from Croteau, 1984;
In sage, geranyl pyrophosphate (3) is converted to ( + )- modified and used with pennission of the copyright owner, Marcel
bomyl pyrophosphate, which is subsequently hydrolyzed by Dekker, Inc., New York).
334 Monoterpenes

geranyl OPP (3) I·limonene (11) isopiperitenol I·isopiperitenone (30) d·cis·isopulegone (31)

d·isomenthol d.isomenthone d·pulegone (29) I-menthone (26)

60H
A
d-neoisomenthol d-neomenthol (28) I-menthol (27)

Fig. 19.10. Origin of oxygenated monoterpenes in Mentha species (Croteau, 1984; modified and used with permission of the copyright owner, Marcel
Dekker, Inc .• New York).

Avo ~o\
ttJ -lV O
-
tG -glUCOSYl

o -..
O·glucosyl
transported to roots

camphor (33) 1,2-campholide

transported

to rhizome

6=
I-menthone (26) d-neomenthol (28) d-neomenthyl glucoside

modified J3-oxidation

/ .+te

A
. 0 acyl lipids

PhytosterOI:;n rh;zome

d-neomenthol (28) I-menthone (26) /-3,4-menthone lactone (37)

Fig. 19.11. Catabolism of monoterpenes (Croteau, 1988; modified and used with permission of the copyright owner, Elsevier Science, Amsterdam).

o~
~
lloJlAoJ,o
bergamottln (38)
FIg. 19.12. Bergamotin.
a distinct pyrophosphatase to ( + )-borneol (32), followed by
the NAD-dependent dehydrogenation to ( + )-camphor (33)
(Croteau and Johnson, 1985; Gershenzon and Croteau,
1990).
The enzymes responsible for the hydroxylation of monot-
erpenes such as ( - )-limonene (11) from peppermint (Men-
tha piperita), spearmint (Mentha spicata), and perilla (Per-
illa Jrutescens) have been isolated and characterized (Karp
et al., 1987, 1990). Microsomal preparations from the epider-
mal oil glands of these plants catalyze the NADPH and Oz-
dependent allylic hydroxylation of (- )-(4S)-limonene (the
major olefinic constituent of each of the three species) at C-
3, C-6, and C-7, respectively, to produce ( - )-trans-isopiper-
itenol (34), ( - )-trans-carveol (35), and ( - )-perillyl alcohol
(36) (Fig. 19.9) (Karp et al., 1990). These transformations
are the key steps in the biosynthesis of oxygenated monoter-
penes in the respective species. The enzymes appear to be
geranyl OPP (3) olivetol
Al(fi).tetrabydrocannibinol cannabidiol R=H (42)
(41) cannabidiolic acid R=COzH (44) cannabinolic acid R=COzH (45)
Fig. 19.13. Proposed biosynthesis of 1l 1-tetrahydroc8IUlabinol.
Monoterpenes 335
cytochrome PA50-dependent mixed-function oxygenases
(Karp et al., 1990). The three limonene hydroxylases exhib-
ited a requirement for O2 and a reduced pyridine nucleotide.
Although there have been many previous suggestions that
the enzymes involved in the secondary transformations of
monoterpenes are relatively nonspecific, most of the work
cited above suggests that these enzymes are quite specific
(Croteau, 1984; Karp et al., 1990).
Catabolism of Monoterpenes
The content of monoterpenes in peppermint after flower-
ing is 35-50% less than in younger plants. This decrease
begins when flower buds appear. The ratio of ( - )-menthone
(26) to menthol (27) decreases. UDP-glucose reacts with
( + )-neomenthol (28) in the presence of ( + )-neomenthyl
glucosyl transferase (a soluble enzyme with 46,000 MW) to
form ( + )-neomenthyl glycoside, which is transferred to the
roots. There the glycoside is hydrolyzed to neomenthol, oxi-
dized to menthone, and subsequently converted to 1-3,4-
menthone lactone (37) (Fig. 19.11) (Croteau, 1988; Gershen-
zon et al., 1989).
Compounds Derived by Alkylation with
(ieranyl·OPF
Geranyl pyrophosphate is a potent alkylating agent that
reacts with compounds like DMAPP to produce compouods
similar to hemiterpenes such as bergamotin (38) (Fig. 19.12)
t55
I
" ---
HOHI
HO" C,Hll
-+
CsHu
a1.tetrahydrocannibinol
(40)
cannibinol R=H (43)
336 Monoterpenes
and with isopentenyl pyrophosphate to produce FPP and then
sesquiterpenes (Geissman and Crout, 1969).
Geranylhydroquinone (39) (Fig. 19.14), a compound re-
sponsible for photodermatitis from Plulcelia crenulata, ap-
pears to be derived in a similar manner (Rodriguez, 1983).
lIIonoterpene-Derived Compounds
oflllarijuana
Cannabis sativa (Cannabaceae) has been used as a drug
plant for millenia. The plant also is important as a fiber and
oilseed crop in some countries and is widely cultivated for
that purpose as well as for drug purposes. It is estimated
that 200-300 million people use marihuana, hashish, bhang,
daga, and so forth. The major psychoactive component is
(- )-A-1-tetrahydrocannabinol (A-1-THC) (40) (Kajima
and Piraux, 1982) (Fig. 19.13).
Varying amounts of Al(6)_THC (41) (also psychoactive),
cannabidiol (42, R = H), cannibinol (43, R = H), cannabidi-
olic acid (44 R = C02H), and cannabinolic acid (45, R =
C02H) co-occur in most plants of the species.
Labeling studies have not been overly successful because
of poor incorporation of precursors, but it appears that gera-
cymopol
cordiachromes allioqulnols
Fig. 19.14. Geranylhydroquinone and the proposed biosynthesis of related compounds from Cordia alliodora (Manners and Jurd, 1977; modified and
used with pennission of the copyright owner, the Royal Chemical Society, Cambridge).
nyl pyrophosphate and olivetol are major precursors (Kajima
and Piraux, 1982; Crombie, 1986) (Fig. 19.13).
Hydroquinone Derivatives in Cordia
Species
A series of hydroquinone terpenoids in Cordia alliodora
(Boraginaceae) are derived from a geranylphenol precursor
(Fig. 19.14). The presence of a number of compounds de-
rived from this pathway in this species suggests that a simple
reaction of the phenolic nucleus is followed by cyclization,
rearrangement, and subsequent oxidation (Manners and
Jurd, 1977).
ClmlIIOSYSTElIIADC USB OF 1II01'l0TERPBNB
ClmmCAL DATA
The analysis of volatile monoterpenes has been of considera-
ble value for the resolution of systematic problems at the
generic, specific, and infraspecific level (Adams, 1977; Heg-
nauer, 1978; Irving and Adams, 1973; von Rudloff, 1975),
but is oflimited value for the resolution of phyletic problems
~ OH
geranylbydroquinone (39)
PhaeeUa crenulata
,ry0-l~.A
HO~- - ,
cordiaebromenes
CH,OH
cardiols

at the family level and above. In several, if not most cases,
a few genes appear to be involved in the control of the struc-
tnre and amount of monoterpenes produced. The comple-
ment of monoterpenes for many plants is often unique, but
the individual compounds are widely distributed and the
pathways leading to them are found in many unrelated taxa
of plants. Further, plant-tu-plant, populational, and specific
variation often is sufficient to pose problems in utilization
of monoterpenes as characters for systematic stndies and
must be evaluated in any study of this type. Under some
circumstances, stressful environments cause enhanced allo-
cation of fixed carbon into essential oils (Ross and Som-
brero, 1991).
Although the value of specific compounds and pathways
is of limited phylogenetic value, it is clear that certain groups
of plants accumulate monoterpenes and possess the morpho-
logical features for storing them. Monoterpenes often are
found in gymnosperms (Coniferopsida), the Annoniflorae
(order Annonales), Apiaceae, Araliaceae, Asteraceae, Cyp-
eraceae, Euphorbiaceae, Geraniaceae, Juglandaceae, La-
miaceae, Myrtaceae, Orchidaceae, Pittosporaceae, Rosa-
ceae, Rutales (Anacardiaceae, Burseraceae, Meliaceae,
Rutaceae, and Simaroubaceae), Verbenaceae, and Zingiber-
aceae. These volatile compounds are encountered, but occur
sporadically or in small amounts, in many other families
(Gibbs, 1974; Hegnauer, 1962-1986).
The accumulation of large amounts of monoterpenes in
the Annonales, but not in the Berberidales, Nelumbonales,
and Nympheales, supports segregation of that order. An
overall unity of the superorder is demonstrated by the pres-
ence of benzylisoquinoline alkaloids throughout (Seigler,
1977).
Dahlgren (1977) placed the Pittosporaceae in his Arali-
iflorae, in agreement with chemical data previously reviewed
by Hegnauer (1969). Additionally, Dahlgren segregated the
Araliaceae and Apiaceae from the Comiflorae and placed
them in his Araliiflorae along with the Pittosporaceae. Both
the Araliaceae and Apiaceae lack the iridoid monoterpenes
commonly found in the Corniflorae.
Hegnauer (1969, 1978) has pointed out that the Hippuri-
daceae differs from the Haloragidaceae and Gunneraceae in
chemistry and morphology and most Closely resembles the
Bignoniaceae. The Verbenaceae and Lamiaceae are qnite
similar chemically; both accumulate many types of mono-,
sesqui-, and diterpenes and both contain iridoid monoter-
penes. These two families are chemically distinct from the
Boraginaceae and Hydrophyllaceae, but they are placed in
the same superorder by Thorne (1976).
Cbemosystematic Study of Citrus Species
Monoterpenes from a series of Citrus species and certain
closely related genera have been studied [mostly by Scora
and coworkers (1970)]. The essential oils of rinds of 4 Citrus
parents, 2 Pondrus parents, and 17 hybrids were examined
and found to contain principally limonene (11) and myrcene
MonOlerpenes 337
(17). Linalool (6) was variable during fruit development.
Less limonene occurred in hybrids.
Hybrids of diploid and tetraploid Citrus species exhibited
essential oil composition that varied widely from those of
the parental stock. In many cases, the tetraploid and diploid
parents contributed almost equally in terms of essential oil
composition, despite the fact that two-thirds of the chromo-
somal material was from the tetraploid parent. The trends
observed in leaf oil composition often did not coincide with
those of the rind oil (Scora et al., 1970).
Chemosystematic Study of Gymnosperms
The use of essential oils for chemosystematic stndy of
North American conifers has been reviewed and many of the
problems of sample collection, analysis, and interpretation
of data discussed (von Rudloff, 1975). In addition, specific
treatments of Abies, Chamaecyparis, Juniperus, Picea,
Pinus, Pseudotsuga, Thuja, and Tsuga are summarized.
Sampling of these coniferous trees was found to be most
reproducible during the dormant period from fall through
winter.
Among members of the genus Picea (spruces), examples
are found in which there is so little variation that no signifi-
cant measure of introgression can be made, some in which
the degree of variation is sufficient to study both intraspecific
and interspecific problems and others in which tree-tu-tree
variation is so large that systematic studies are impractical
with this type of character. Picea mariana and P. rubens
(black and red spruce, respectively) exhibit little intrapopula-
tional or interpopulational variation in essential oil composi-
tion. These species vary only slightly throughout their
ranges, and the complement of monoterpenes in the two
species is quite similar. This confirms the close relationship
that has been proposed for these species. Picea breweriana
is similar to black and red spruces in monoterpene composi-
tion and less so to white, Sitka, blue, and Engelmann spruces.
The northwest complex of white (Picea glauca), Sitka (P.
sitchensis), and Engelmann spruces (P. engelmannii) has
several regions where the species overlap and hybridization
is reported to occur in all of these. This is especially true
for white and Engelmann spruce. Although the essential oil
composition for Picea glauca is relatively constant over
most of the range of the species, in areas of proximity to P.
engelmannii much more variation is observed, suggesting
that introgression occurs. The essential oil composition of
blue spruce (P. pungens) resembles that of Picea glauca.
The ranges of the two species do not overlap. Chemical
evidence suggests, however, that blue spruce and Engelmann
spruce do hybridize in some areas (von Rudloff, 1975).
Over 50 species and varieties of the genus Pinus occur
in North America. These have previously been studied by
Mirov and were reviewed by von Rudloff in addition to his
own studies on Canadian members of the genus. An espe-
cially large difference was noted in the essential oils of Pinus
ponderosa and P. jeffreyi. The essential oil of the latter con-
sists of n-heptane. Hybrids of the two species can easily be
338 Monoterpenes
recognized by chemical analysis. Differences in essential
oil composition between P. banksiana Gack pine) and P.
contorta var. latifolia (lodgepole pine) were large enough
to permit studies of introgression in populations in Alberta.
This phenomenon was also observed in the composition of
the leaf oils (von Rudloff, 1975).
The species Pseudotsuga menziesii (Douglas fir) consists
of a coastal and an inland taxon. These meet in British Co-
lumbia and many intermediate plants exist. The two taxa
also have distinct essential oil composition from leaf oil and
cortical oleoresins. Samples from the Cascades of southern
British Columbia and northern Washington are intermediate
between the coastal and the inland taxa (von Rudloff, 1975).
Many systematic aspects of the genus Abies (firs) are
difficult to understand. It is probable that hybridization and
introgression have played a role in this. The essential oil
composition of eastern and western balsam fir (Abies balsa-
mea) in Canada was found to differ. In addition, where A.
balsamea and A. lasiocarpa (alpine fir) meet or overlap, the
essential oil of balsam fir assumes many of the features of
alpine fir oil. The wide distribution of these characters in
populations of balsam fir in Saskatchewan and Manitoba
suggests that this is an ancient phenomenon. Many other
troe firs show variation in areas where overlap of species is
thought to occur (von Rudloff, 1975).
An extensive survey of the essential oils from populations
of Juniperus virginiana from Texas to Ontario indicates that
elinal variation occurs. Further, the proposed introgression
between J. virginiana and J. ashei which had been thought
to occur widely in Texas in areas of overlap between the
two species does not appear to exist, based on analysis of
the essential oils. This was also confirmed by analysis of
micromorphological characters (von Rudloff, 1975).
In species of the Pinaceae, three general trends concern-
ing the inheritance of essential oils in relation to hybridiza-
tion are observed. In F, hybrids, essential oils often are com-
positionally intermediate between those of the parents.
Although they are commonly not exactly intermediate, F,
hybrids rarely possess oils with composition outside the
range of the two parental species. In other instances, a weak
linkage between morphological characters of the plant and
essential oil composition has been observed in some popula-
tions of conifers. In general, however, there is no necessary
correlation of essential oil composition and the various mor-
phological features of plants, and in backcrosses, plants re-
sembling one parent morphologically resemble the other in
essential oil chemistry. The variation observed has been use-
ful in determination of the presence of hybridization and
backcrossing in populations of mixed parentage (von Rud-
loff, 1975).
In studies of Cupressus sargentii and C. macnabiana in
California, Lawrence and co-workers (1975) noted that the
essential oil composition of the two parental types was rela-
tively constant and differed in a number of features. In a
population where the ranges of the two species overlapped,
trees which could be identified as typical C. "macnabiana"
and "pure C. sargentii" were selected. In 25 out of 35 trees,
the terpenoid composition identified the tree as either C.
sargentii or C. macnabiana. Of these trees, 12 were identi-
fied as C. sargentii and 13 as C. macnabiana or a ratio of
about 1 : 1 of pure genotypes. Ten trees could be identified as
intermediate and hybrids. The complexity of this population
suggests that extensive hybridization had been occurring for
some period of time (Lawrence et aI., 1975).
The composition of essential oils of Juniperus scopu-
lorum (Cupressaceae) was shown to differ between young
leaves and mature leaves. In general, hydrocarbon terpenoids
were higher in concentration in new leaves, and oxygenated
compounds were higher in old leaves. This pattern has also
been observed in a number of other gymnosperms. The
amount of variation in young leaves was less than in older
leaves with regard to essential oil content.
Oil samples from Juniperus scopulorum trees taken at
different times of the day differed significantly in composi-
tion. Oxygenated terpenes and sesquiterpenes tended to in-
crease during the day, whereas sabinene (22) decreased until
late evening and increased during early morning. Diurnal
variation was much less in winter than in summer (Adams,
1979; Adams and Hagerman, 1976, 1977).
Analysis of populations of Juniperus ashei throughout
Texas for areas of population differentiation and possible
hybridization with J. virginiana and J. pinchotii by both
morphological and essential oil features failed to detect evi-
dence of hybridization (Adams, 1975; Adams and Tumer,
1970).
Chemosystematic studies in lIfints
Irving and Adams (1973) found that essential oil compo-
nents of Hedeoma drummondii and H. reverchonii var. re-
verchonii (Lamiaceae) were additive or complementary in
F, hybrids of the two species. In F2 hybrids, plants were
intermediate in chemistry, some of which resembled each
parent, and a few with novel chemistry were observed (irv-
ing and Adams, 1973).
BIOLOGICAL ACTIVITY
Most monoterpenes are cytotoxic to plant and animal tissues,
causing a drastic reduction in the number of intact mitochon-
dria and Golgi bodies, impairing respiration, and photosyn-
thesis, and decreasing cell membrane permeability (Charl-
wood and Charlwood, 199Ia). At the same time, they are
volatile and many serve as chemical messages for insects
and other animals. Furthermore most monoterpenes serve as
signals of relatively short duration, making them especially
useful for synomones and alarm pheromones. Several types
of semiochemical functions of monoterpenes are described
below.
 Monoterpenes 339

lIIonoterpenes as A11omones. Kairomones.
and Synomones
Essential oils are comprised of complex mixtures of ter-
penes, phenylpropanoid-derived compounds, and a number
of esters, alcohols, aldehydes, ketones, acids, and hydrocar-
bons derived from fatty acid metabolism. The constituent
compounds usually are of low to medium molecular weight
and not highly oxygenated (Fig. 19.15). Many of these vola-
tile compounds are involved in interactions with animals and
are major components of the "taste" and "odor" of plants.
Many monoterpenes are biologically active (Fig. 19.15)
(Herout, 1970; Seigler, 1983) and representatives of this
group of compounds are toxic to a large number of organ-
isms. For example, thujaplicinol (46) (Fig. 19.1) is a useful
antibacterial adenyltransferase inhibitor (Croteau and John-
son, 1985). Among the biologically active terpenoids, mo-
noterpenes and sesquiterpenes predominate.
Biotic stresses can have a significant effect on plant terpe-
noid levels. Herbivory often induces increased concentra-
tions of defensive substances in many species of plants. For
example, bark beetle feeding and the presence of their fungal
symbionts causes increased accumulation of terpene-con-
taining resin in a locallzed area surrounding the site of attack
(Gershenzon and Croteau, 1991).
Ironically, terpenes serve both as major deterrents to feed-
ing and as attractants for animals (Hedin et al., 1974). Vola-
tile compounds are often involved in long-distance interac-
tions and are especially important as attractants and
repellents (Kogan, 1975).
A11omones
Monoterpenes serve as a solvent that permits other resin
constituents (particularly diterpenes) to flow into wounds,
an important defense of plants against insect, fungal, and
bacterial attack. Changes in the composition of secondarily
formed resins have been correlated with an increase in anti-
fungal and insect-repellent properties. Biological effects also
are highly dependent on the enantiomeric composition of

limonene (11) nerol (60)' geraniaJ (61)· citronellal (62)

(e
a-pinene (14)
\ (57)
0\ 0.0 (58) (59)

methyl chaviool (56) carvone (48) canooe oxide (80) E.limonene oxide (78)

2
a phenylpropanoid

a;-phellandrene (79) borny. acetate (77) n-phellandrene (63) 2-terpinolene (64)

•citral (mixture of geranial and neral)

Fig. 19.15. Some biologically active monoterpenes.

340 Monoterpenes
terpenoid mixtures (Croteau and Johnson, 1985). For exam-
ple, (+ )-limonene (11) (common in Citrus oils) strongly
inhibits germination and sperm tube growth of Diplodea
pinea, a pathogen of pines. ( - )-Limonene, which occurs in
many Pinus species, was relatively nontoxic.
Volatile monoterpenes are common components of the
"taste" and "odor" of plants. A significant proportion of
herbivorous insects are "specific" (monophagous or oli-
gophagous), feeding on plants of a few genera or a single
family (Bernays and Graham, 1988; Jermy, 1984). This
choice often is determined by the ptesence of plant second-
ary compounds, among which monoterpenes are important.
Most insects do not eat most plants; in part, this is because
of the presence of allomones or compounds that benefit the
emitting organism. In general, a successful herbivore is
adapted to the secondary compounds of a particular plant.
\3-0cimene (47) is a repellent to the leaf culter ant Alta
cephalotes in both field and laboratory experiments (Har-
borne, 1987). Experiments with the aphid Cavariella aego-
pod;;, which feeds on umbellifer species in summer, indicate
that the aphid can be captured in traps baited with carvone
(48), but are repelled by linalool (6) (Chapman et al., 1981;
Harborne, 1987). Carvone occurs in the essential oils of sev-
eral plants of the Apiaceae.
A number of monoterpenes and methyl esters of fatty
acids were evaluated for their repellent and attractant proper-
ties toward Ips, Dendroctonus, and Hylurgops species. Al-
though activity was observed in the laboratory, none of the
compounds tested were active in field tests (Seigler, 1983).
The wood of western red cedar (Thuja plicata) is re-
nowned for its ability to withstand insect attack in tim-
berstands and as lumber. This may be attributed to the mo-
noterpenes that it contains. \3-Thujaplicin (49) is toxic to
larvae of the old house borer (Hylotrupes bajulus), a com-
mon pest in Europe. Both oc- and \3-thujaplicin showed low
activity against the termite Reticulothermes Jlavipes. Inter-
estingly, methyl thujate (52) (thujic acid, 50) was much more
active. This compound is active against a number of other
insects. (+ )-3-Thujone (21) and (- )-3-isothujone (51),
which make up most of the leaf essential oil of this plant
(80-90%), are feeding deterrents to the white pine weevil
(Pissodes strobil (Alfaro et al., 1981).
Bay leaves (Laurus nobilis, Lauraceae) and cineole (10),
geraniol (4), and piperidine (which occur in bay leaves) pos-
sess repellent properties tuward cockroaches (Verma and
Meloan, 1981).
Female Caribbean fruit flies, Anastrepha suspensa, lay
their eggs readily in ripe grapefruit, but do not oviposit in
immature grapefruit or in ripe or immature oranges because
of the presence of linalool (6). This compound is toxic to
the eggs and larvae of the insect. Limonene (11), found in
sour oranges (Citrus aurantium), is toxic tu adult bean wee-
vils (Callosobruchus phasecoli), but highly attractive to
male Mediterranean fruit flies (Jacobson, 1982).
Two monoterpenes, citra! (sic) and geraniol (4) inhibited
reproduction of the root-rot nematode by 52% and 86%,
ochtodene (54) cbondrocole A (55) dtondrocole C
Fig. 19.16. Monoterpenes from algae.
respectively, when applied as l00-mglml soil drenches
(Chitwood, 1992).
Few mammals appear to be able to adapt tu large quan-
tities of monoterpenes in the diet, but have an aversion to
terpenoid odors and plants rich in terpenoid constituents
(Harborne, 1991).
The leaves of the California bay laurel (Umbellularia
cali/ornica, Lauraceae), sometimes used as a spice, contain
0.5-4% of an irritating oil of which 40-60% is umbellulone
(53). The vapors of this compound produce severe headache,
skin irritation, and, in some cases, unconsciousness. This
plant is one of several avoided by deer. Essential oils inhibit
microbial activity in ruminants and disrupt digestive pro-
cesses (MacGregor et al., 1974; Buttery et al., 1974).
Several species of algae produce halogenated secondary
metabolites. For instance, the red alga Ochtodes secundira-
mea, which is highly resistant to herbivory, produces ochto-
dene (54) and chondrocole A (55) (Fig. 19.16). Octodene
was highly repellent toward marine fishes, but only the unre-
solved monoterpene mixture from the plant was deterrent to
herbivorous amphipods (panl et al., 1987).
Cymopol, a terpenoid bromohydroquinone frum the
green alga Cymopolia barbata, significantly reduced feeding
by reef fishes in feeding trials, but significantly stimulated
feeding by an herbivorous sea urchin species of the genus
Diadema (Fig. 19.16) (Hay et al., 1987).
AlIomones Froduced by Arthropods.
Especially Insects
Monoterpenes are encountered commonly in a number
of insects (Nahrstedt, 1982). Many of these compounds are
identical to those found in plants and, in any given case,
it may be difficult to decide whether the compounds are
sequestered from plants in the diet, synthesized de novo by
the insect, or produced by symbiotic gut microorganisms.
The lower terpenoids are relatively nonspecific toxicants
produced in the defensive secretions of many insects (Fig.
19.17) (Herout, 1970; Harborne, 1982). These compounds
are volatile and this may be important in the mechanism of
action. The vapors often have an irritating action.
Larvae of the sawfly, Neodiprion setifer (Hymenoptera)
discharge an oily effluent when disturbed. This material is
identical in composition to the resin of the host plant Pinus
sylvestris and the larvae appear to sequester the resin from
the plant. Some of the components are oc- and \3-pinene (14

~ Ce
myrcene (17) a-pinene (14)
p~ ~
resin compound resin compound
(e
~-plnene (16) car-3-ene (71)
~oo ~~ ~ H
~~--
(+)-eis-verbenol (74) Ipsdienol (75)
Fig. 19.17. Biologically active compounds from arthropods.
and 16) and a number of diterpenes. The diterpenes appear
to act as a fixative for the more volatile components (Eisner
et aI., 1974).
A number of monoterpenes are used as defensive com-
pounds by the walking stick insect Anisomorpha bupresti-
odes and the ant Acanthomyops daviger. The compounds
are apparently synthesized within the insect. Other allomonal
compounds (57-59) produced by ants are probably terpene
derived. ex-Pinene (14) is used by some tennites for defense.
Kairomones
In other instances, compounds called kairomones are re-
leased by plants (or other organisms) and benefit the receiv-
ing organism. A number of these compounds serve as both
repellent and attractant substances; most kairomones proba-
bly originated as allomones. In any instance, it is possible
for a compound to be an allomone with regard to many
insects and a kairomone to others. More than 4000 com-
pounds have been evaluated for their ability to attract several
kinds of insects (Wright, 1966). Plant volatiles are only one
factor in the attraction of animals to plants. Visual cues may
also be extremely important (Stfuller, 1983).
Essential oils are involved in the feeding response of sev-
eral Papilio species to members of the Apiaceae (Feeny et
al., 1983). Many species of butterflies that feed on the Apia-
Monoterpenes 341
-
in vivo
~"
verbenone (65)
beetle pheromone
0
0
exo-brevicomin (72) frontalin (73)
beetle pheromone
I ~ OH
(-)-Ipsenol (76)
ceae locate the plants by the presence of methyl chavicol
(56) andlorcarvone (48) (Fig. 19.17). If filter paper is soaked
with these compounds, the insects will eat it (Herout, 1970).
A number of factors control the feeding preferences of
most animals. In the case of the silkworm, Bombyx mori,
which feeds almost exclusively on the mulberries Morus
alba and M. nigra, a range of factors is involved. Most of
the olfactory components are monoterpenes such as citra! [a
mixture of neral (60) and geranial (61)] linalool (6), and
linalylacetate. Bombyx larvae are sensitive to the monoter-
pene mixtures when they get within 3 cm of a leaf.
Upon infestation ofliroa bean leaves (Phaseolus lunatus)
with two-spotted spider mites (Tetranychus urticae), induc-
tion of (E)-j3-ocimene (47) and a homomonoterpene, E-4,8-
diroethyl-l,3,7-nonatriene, occurs. A homosesquiterpene,
(3E, 7E)-4,8,12-trimethyl-l,3,7,l1-tridecatetraene also has
been observed (Dicke et al., 1990). These compounds attract
another mite, Phytoseiulus persimilis, which is a predator of
the two-spotted spider mite, a phenomenon known as indi-
rect defense (Dicke et al., 1990; Takabayashi et al., 1991).
When uninfested leaves are placed on moist cotton that had
previously come into contact with leaves that had been in-
fested (but had the mites removed), production of these com-
pounds again occurred, providing evidence that induction
of these kairomones occurs (Takabayashi et al., 1991). The
342 Monoterpenes
homomonoterpene appears to arise by cleavage of a sesqui-
terpene (Gabler et a!., 1991).
Aggregation Pheromones
Many of the monoterpenes found in essential oils of
plants also occur as aggregation pheromonal substances in
insects. Examples of some compounds found both in plants
and insects are the monoterpenes citronellal (62), citronellol
(7), geraniol (4), myrcene (17), citral [a mixture of geranial
and neral (60, 61)], l3-phellandrene (63), limonene (11), 2-
terpinolene (64), a-pinene (14), l3-pinene (16), 1,8-cineole
(10), and verbenone (65).
The male cotton boll weevil (Anthonomus grandis) is
attracted to the cotton plant by a number of monoterpenes
and sesquiterpenes, among them are a-pinene (14),limonene
(11), and caryophyllene (66) (Fig. 19.18). The boll weevil
then produces a series of metabolites that attract both male
and female individuals. Although these terpenes can come
from the plant, the beetles can also synthesize the com-
pounds de novo. At least four (67-70) have been isolated
and characterized (Vanderwel and Oehlschlager, 1987).
In some cases, the production of monoterpene aggrega-
tion pheromones by insects is quite complex. The production
of pheromones by bark beetles (mostly of the genera Den-
droctonus, Ips, and Scolytus) has been reviewed (Gershen-
zan and Croteau, 1991; Vanderwel and Oehlschlager, 1987).
Death of the host tree usually follows successful colonization
(Johnson and Croteau, 1987). Tree mortality is usually nec-
essary if the beetles are to survive because excavation of
egg galleries and subsequent larval development can only
take place after host defensive reactions have stopped. Pi-
oneer beetles may encounter constitutive (preformed) resin
on initial attack. This often leads to emission of pheromonal
substances. Mass attack usually leads to rapid depletion of
limonene (11) a-pinene (14)
(68)
(67)
Fig. 19.18. Proposed biosynthesis of attractive compounds from cotton for the male boll weevil and bon weevil metabolites (Vanderwel and
Oehlschlager, 1987; modified and used with pennission of the copyright owner, Academic Press. Orlando, Fl.).
the constitutive resin. Healthy trees respond by a hypersensi-
tive response; that is, the cells around the area of attack die
and deprive the pathogen of nutrients and compartmentalize
the attack. In addition, adjacent wood parenchyma differen-
tiates and secretes a secondary resin into the wound site.
Bark beetles respond by trying to clear the wound site or
abandoning attack. Fungal growth is also inhibited by the
secondary resinosis. Elicitors from the fungi may modify
the monoterpene content of the resin (Johnson and Croteau,
1987).
The terpenoid fraction of many conifers consists of
20-50% volatile monoterpenes and sesquiterpenes and
50-80% nonvolatile diterpene acids. In general, there is little
variation in the diterpene fraction among trees of a particular
species, although the monoterpene fraction often varies
greatly. Alterations in the monoterpene content often deter-
mine whether attack by bark beetles will occur and be suc-
cessful. The monoterpenes may be attractants, repellents, or
toxins of not only the insects, but also the pathogenic fungi
involved in these systems. The conversion of geranyl pyro-
phosphate to the parent compounds of the various cyclic
types is catalyzed by monoterpene cyclases (see the subsec-
tion biosynthesis, above).
The effect of enantiomeric monoterpenes on bark beetle
activity is very significant. In some cases, as little as 2-5%
of an enantiomeric product will completely inhibit the effect
of the active form and greatly upset the normal pheromonal
system of the insect. Fungi are also sensitive to these effects.
For example, (+ )-a-pinene (14) is three times more inhibi-
tory than (- )-a-pinene against the blue stain fungus, Cerat-
ocystis spp. The differential expression of the cyclases re-
sponsible for coproduction of enantiomeric monoterpenes
may determine the highly selective resistance response coni-
fers exhibit toward bark beetles and their fungal symbionts
(Johnson and Croteau, 1987).
caryophyllene (66)
(69) (70)

In the case of the Western pine beetle (Dendroctonus
brevicomis) and the ponderosa pine (Pinus ponderosa), uti-
lization of terpenes involves several stages. The oleoresin
of pine bark is rich in volatile terpenes and traces of the
vapor exude from the tree, especially if it has been damaged
(Wood, 1982). The tree contains (3-myrcene (17), (3-pinene
(16), and 3-carene (71) (Fig. 19.17). The female beetles are
attracted to the tree and begin to feed. Once the females
are established, they begin to attract males for reproductive
purposes. The females employ a mixture of three compo-
nents: myrcene (17), which is sequestered from the oleoresin
and used directly, and two bicyclic compounds, exo-brevi-
comin (72) and frontalin (73), which appear to be synthe-
sized de novo by the insect. Brevicomin and frontaIin proba-
bly are products of fatty acid metabolism. The males,
attracted by the pheromone, arrive at the site, copulate with
the females, and a new generation of beetles emerge. The
female beetles appear to control the sex ratio by varying the
proportions of the sex pheromone mixture exuded at any
given period of time. If the mixture contains all three compo-
nents, a I: 1 mixture of males and females are attracted,
whereas if frontaIin is omitted, the ratio changes to 2: 1 in
favor of the males. When the area of infestation reaches its
optimum size, there is only food for the existing beetles.
The female then stops pheromone prodUction and begins to
form a male repellent, verbenone (65). This compound repels
males and keeps them from reaching the infestation site.
Verbenone is formed from one of the major bark terpenes,
a-pinene (14). The addition of myrcene (17) to the fron-
talin-brevicomin mixture doubles the effectiveness of the
attractant. Furthermore, myrcene is essential and cannot be
substituted by the closely related compound limonene (11).
A mixture of frontalin and 3-carene (71) is highly attractive
to females, but not to males (Fig. 19.19) (Harborne, 1982;
Wood, 1982). Production of verbenone (65) inhibits coloni-
zation by the bark beetles Ips paraconfusus, and the produc-
tion of ( + )-ipsdienol (75) inhibits colonization by Ips pini
(Harhorne, 1986).
Many of the monoterpenes from host trees are toxic to
the beetles that feed on the trees. The ability to oxidize these
compounds may have originated as a detuxification mecha-
nism and, secondarily, been selected for reproductive pur-
poses (Vanderwel and Oehlschlager, 1987). Investigation of
the stereochemistty of these oxidation and hydration re.ac-
tions indicates that most are highly specific.
A bacterium has been isolated from the gut of Ips confu-
sus that can oxidize a-pinene (14) to verbenol (74), whereas
a symbiotic fungus of Dendroctonus has been shown to fur-
ther oxidize verbenol to verbenone (65) (Fig. 19.19). The
male of the insect Ips paraconfusus, which feeds on Pinus
ponderosa, produces a frass which contains terpenoid-de-
rived compounds ipsdienol, ipsenol (76), and cis-verbenol
(74) (Wood, 1982). This frass attracts both male and female
insects to the tree. It is quite possible that microorganisms
playa major role in the survival of the beetle on a success-
fully colonized tree (Harborne, 1982; Wood, 1982). Produc-
Monoterpenes 343
tion of ( + )-ipsdienol by the males of Ips paraconfusus in-
hibits colonization by two other species of bark beetles, Ips
pini and Dendroctonus brevicomis (Harborne, 1986).
In the related species, Dendroctonus frontalis, the com-
pound frontalin (73) is primarily attractive to male bees and
the female does not release a female attractant. The first
males to arrive ingest resin and synthesize and release a male
inhibitor, verbenone (65). It seems quite likely that the male
beetles have the ability to convert a-pinene into verbenone.
Parasitoids and predators of many of these bark beetles
are attracted to the monoterpenes and derived substances.
In this way, these insects locate their insect hosts (Wood,
1982).
Bornyl acetate (77) and verbenyl acetate mimic the activ-
ity of the American cockroach sex pheromone (Bowers,
1985).
Honey bee swarm attractants include geraniol (4) and
(E)-citral (neral ?), monoterpenes that are found in the Naso-
nov glands of living honey bees (Pickett, 1991).
Trail.Marking Pheromones
Trail markers are used almost exclusively by social in-
sects, such as bees, ants, and termites. An insect that has
located a new source of food returns to the nest, marking his
trail by releasing these substances. At the nest, recruitment
is initiated by perception of these trail pheromones. Some
representative trail pheromones are presented in Fig. 17c.
Alarm Pheromones
Many insects produce volatile compounds that are deliv-
ered from the mandibular or anal glands or from the sting
apparatus. Production of these compounds is often related
to the production of defensive compounds. Alarm is commu-
nicated to other members of the society by diffusion of the
compound into the air (Harborne, 1982).
Wasps of the genus Vespa spray venom containing an
alarm substance, whereas honey bees leave traces of isoamyl
acetate at the sting site which induced other bees to sting at
the same location. In some insects, the same compound may
serve for both alarm and defense. This is true of formic
acid produced by the genus Formica. Most of these alarm
compounds have a relatively simple structure. Essential oil
components including citronellol (7), citral (a mixture of
neral and geranial) (60, 61), a-pinene (14), terpinolene (12),
and Iimonene (11) have been implicated in various examples
studied (Fig. 19.19). Ants use neral (61) and geranial (60)
as alarm signals.
Synomones
Synomones are compounds that are involved in interac-
tions that are of net benefit to both the producer and the
receiver. The role of monoterpenes in pollination has been
reviewed (Vogel, 1983).
The pollination of orchids (Orchidaceae) involves many
species-specific interactions and exhibits many interesting
344 Monoterpenes

and benzyl acetate is used (Dodson et aI., 1969). Although

most bees are attracted to many of the pure compounds,
fewer are attracted to mixtures in almost all cases.
The complement of volatile substances produced by most
species of orchids is highly specific and this specificity ap-
pears to preclude hybridization in many cases (Hills et aI.,
1972). Although some species of orchids are pollinated by
geraniol (4) geranial (60) '" geranic acid several species of euglossine bees, most are pollinated by a

A Am. A_
single species of bee (Ackennan, 1983).
There is controversy about the exact role of the odorifer-
ous compounds collected by the male bees, but it is likely

~~OH ~ ~
that they are involved in attraction of other euglossine bees
or converted into sexual (aggregation) pheromones. It has
been suggested that males use the compounds and various
aspects of behavior to attract other males. This makes a small
nerol(5) neral(61) '" nerolieacid swarm of bees, and the females are attracted. This is similar
'" a mixture of geranial and neral is called citral to lek behavior in birds (Harborne, 1982, 1989).
Although the orchids are visited only by euglossine bees,
Fig. 19.19. AIann pheromones.
the bees are known tu visit flowers of plants of other families
with similar chemistry (Williams and Dodson, 1972). Al-
though the bees have undoubtedly been important in deter-
types of evolutionary problems. The color, shape, and odor
mining the course of evolution in the orchids, facturs in
of the flower are all important. Orchids are pollinated var-
addition to those associated with the orchids have been im-
iously by butterflies, moths, flies, mosquitos, birds, and bats,
portant in the evolution of the bees (Ackennan, 1983).
but most commonly, by bees.
In orchids pollinated by five species of Eulaema and three
Several species of orchids are pollinated by eUglossine
species of Euglossa in Panama, carvone oxide (80) is the
bees (Dodson et aI., 1969; Hills, 1989; Williams and Whit-
dominant volatile compound in II of 12 plants pollinated.
ten, 1983). In one example, pollination appears to involve
Although 11 of these plants are orchids, Dalechampia
a relatively simple monoterpene. The essential oil comple-
spathulata (Euphorbiaceae) also produces carvone oxide and
ment of Stanhopea pulla, which consisted mostly of E-Iimo-
is pollinated by the same bees (Harborne, 1987, 1989).
nene oxide (78) (Fig. 19.17), 1,8-cineole (10), and an uniden-
One of the important monoterpenes in bark beetle-coni-
tified monoterpene, varies both quantitatively and
fer interactions, ipsdienol (see above), is also a major compo-
qualitatively depending on the time of day. Maximum fra-
nent of several tropical orchid species and is attractive to a
grance production occurs early in the morning. The euglos-
number bees of the genus Euglossa (Whitten et al., 1988).
sine bee involved responds to E-Iimonene oxide (78) in mix-
Many Ophrys species (Orchidaceae) are pollinated by
tures of E- and Z-limonene oxide (Fig. 19.17) (Hills, 1989).
bees of the genera Andrena and Colletes. Pseudocopnlation
In other instances, the parameters that detennine pollina-
and the presence of highly specific flower scents are in-
tion are complex. Many of these orchids attract only the
volved in this process. Linalool (6), citronellol (7), citronel-
male bee. When a flower is placed in an opaque container,
lal (62), geraniol (4), and geranial (61) occur in the scents
the bees still find it, indicating that the bees use odor and
of Ophrys species (Harborne, 1989). In Ophrys lutea var.
not vision to locate the flowers. Even when the flower was
lutea, famesol (a sesquiterpene), geraniol (4), and geranial
removed, the bees continued to be attracted to the container.
are primarily responsible for release of odor-guided mating
Most of the orchid species produce a combination of 7-10
behavior at the O. lutea labellum and are general attractants
compounds. Among these are d-carvone (48), l,8-cineole
for many species of Andrena (Harborne, 1987, 1989). For
(10), eugenol, bornyl acetate (77), anethole, geraniol (4),
discussion of other Ophrys-bee interactions, see Chapter 21.
methyl cinnamate, methyl salicylate, myrcene (17), vanillin,
and indole. In pure fonn, 1,8-cineole, methyl salicylate, eu-
genol, methyl cinnamate, bornyl acetate, a-phellandrene
(79), myrcene (17), piperonal, indole, vanillin, and benzyl ALLELOPA'DIY
acetate serve as attractants. Neither a- or j3-pinene nor oci-
mene (47) are attractive to the bees tested. Combinations of As previously discussed (see Chapter 8), many plant second-
these compounds (in proportions similar to those found in ary compounds are involved in plant-plant chemical warfare
various orchid species) lead to greater specificity of attrac- called allelopathy. Terpenoids often are involved in interac-
tion. For example, when a-pinene (14) is added to a mixture tions of this nature (Fig. 19.20). Many monoterpenes inhibit
of l,8-cineole (10) and benzyl acetate in the proportions gennination of seeds and growth of seedlings. Exposure of
found in the orchid Stanhopea tricorn is, fewer bees of two plants to the monoterpene vapors produces developmental
species are attracted than when a mixture of only l,8-cineole and physiological changes of several types (Fischer, 1986,

£0 S:
1,8·cio..l. (10) camphor (33)
1
0
Ihuj.oe (21) (+ ).puleg.o. (29)
piquer.1 A (82)
Fig. 19.20. Terpenes involved in a1lelopathy.
1990; Vaughn and Spencer, 1993a, 1993b). Among the most
active monoterpenes are a-pinene (14), (3-pinene (16), cam-
phene (15), limonene (11), a-phellandrene (79), p-cymene
(81), 1,8-cineole (10), borneol (32), pulegone (29), and cam-
phor (33). In a comparison of many structural types of mo-
noterpenes, the greatest phytotoxic effects were observed
with cyclic a,(3-unsaturated ketones (Fischer, 1990). Several
volatile monoterpenes were effective in inhibiting sprouting
of potato tubers; 1,4·cineole, 1,8-cineole (10), and fenchone
were among the most effective (Vaughan and Spencer, 1991,
1993b).
Pioneering plants of disturbed habitats often produce ac-
tive monoterpenes. ( + )-PuJegone (29) was four times, and
( + )- and ( - )-camphor two times more toxic to seeds and
seedlings of Raphanus sativus (Brassicaceae) than HCN
(Asplund, 1968). The Mexican plant Piqueria trinervia (As-
teraceae) produced monoterpene diols, piquerol A (82) and
B (83), that strongly inhibited root and stem growth of com-
peting plants at 50-200 ppm.
One of the best known studies of allelopathy was done
in the California chaparral, in an area where two of the most
important shrubs are Salvia leucophylla and Artemisia cali·
fornica. Bare zones of soil from 1 to 2 m in width surround
each shrub. Beyond the bare zones are areas of stunted
growth where a few herbs show limited development. Muller
and Chou (1972) have postulated that these zones are pro-
Monoterpenes 345
2
a-pinene (14) p·pio.o. (16) camphene (15)
H£CH3COO£
0 u
o
0 u
0
:::...1
:::... :::...
epievodone (85) calimintbone (86) p-cymene (S1)
piquer.1 B (83) p-menthane--3,S-cis-dlol (84)
duced by the effects of monoterpenes liberated from the
plants. These workers carefully eliminated other factors such
as shade, lack of water, nutrient conditions, the slope of
the ground, root competition, herbivory, and water·soluble
compounds. However, other factors may playa significant
role in the creation of these bare zones. Small rodents that
consumed seeds and shoots also are implicated (Bartholo-
mew, 1970).
The allelopathic activity present is associated with vola-
tile, lipophilic compounds. Monoterpenes occur in high con-
centrations in the leaves and a vapor cloud hangs around the
plants. A similar complement of monoterpenes occurs in the
soil surrounding the plants. These terpenes remain in the dry
soil until rain encourages the growth of microorganisms that
degrade them. Fires, which periodically sweep through the
chaparral, decompose the compounds. These monoterpenes
can be transported into plant cells through the waxy coatings
of seeds or roots. Componnds from the plants have a signifi-
cant effect on the germination of seeds of annuals that grow
in the adjacent grassland areas (Muller and Chou, 1972).
The most effective toxins of Salvia leucophylla are a-
and (3-pinene (14 and 16) and camphene (15) (Fig. 19.20).
Those of Artemisia californica are 1,8-cineole (10) and cam-
phor (33).
In the allelopathic effects of Eucalyptus camaldulensis,
cineole (10) and a·pinene (14) proved to be the most active
346 Monoterpenes
compounds (del Moral and Muller, 1970). The major allelo-
pathic monoterpene from Eucalyptus citriodora proved to
be p-menthane-3,8-cis-diol (84). The ( + )-cis-enantiomer in-
hibited germination and hypocotyl growth of several test
species but showed no effect on E. citriodora (Cutler, 1992;
Fischer, 1990).
In a sand hill area of Florida, monoterpenes from Con-
radina canescens and Calamintha ashei (both Lamiaceae)
are important in inhibition of competing vegetation. Satu-
rated aqueous solutions of monoterpenes from Conradina
canescens inhibited germination and radical growth of two
native grasses (Weidenhameret al., 1993; Williamson et al.,
1989). The triterpene ursolic acid appears to increase toxicity
of the monoterpenes, probably by enhancing the solubility
of the monoterpenes in water. However, monoterpenes are
sufficiently soluble in water to exhibit biological activity
(Weidenhamer et al., 1993). A mixture of the monoterpenes
epievodone (85) and caliminthone (86) and the sesquiterpene
caryophyllene oxide (from Calamintha ashei) totally inhib-
ited germination of little bluestem (Schizachyrium scopa-
rium), but had only minor effects on lettuce (Fischer, 1990;
Fischer et al., 1988). This fmding is of importance because
lettuce seeds have often been used as an assay system for
phytotoxic compounds.
USES OF JIIOI'lOTERPEl'IES BY IIUJIIAl'IS
Many monoterpenes have antimicrobial activity. This prop-
erty is linked to many human uses of monoterpenes, includ-
ing medicinal and food uses (Beier and Nigg, 1992). The
odor-taste properties of many are considered desirable and
are used for flavorings and perfumery ingredients. 1,8-Cine-
ole (10) is commonly used as a flavoring and an antioxidant
in foodstuffs (Charlwood and Charlwood, 199Ia).
JIIedicinai Uses of JIIonoterpenes
Monoterpenes and other volatile terpenes have a number
of widespread medicinal uses (Beier and Nigg, 1992; Dnke,
1992 and references cited therein). Compounds such as cam-
phor and menthol are used as "counterirritants" or "cool·
ing," analgesic, and antiitching agents and as components
of liniments.
Many monoterpenes have been used for anthelminthics.
Arnong these are sabinol, cadinol (a sesquiterpene), pinene,
ascaridole (87), p-cymene (81), citronellol (7), caryophyl-
lene (a sesquiterpene), limonene (11), phellandrene, cadi-
nene (a sesquiterpene), camphor (33), pyrethrin, carvone
(48), linalool (6),linalyl alcohol, tagelone, thymol (88), and
1,8-cineole (eucalyptol) (10).
Paeoniae radix, prepared from the roots of Paeonia lac-
tif/ora, is an antispasmodic, analgesic, mitigative, and astrin-
gent drug. A series of monoterpene glycosides appear to be
responsible for much of the activity. For example, paeon-
iflorin, a monoterpene glycoside isolated from this medicinal
preparation, effects vasodilation of coronary vessels and the
femoral vascular bed (Hikino, 1985).
Flavors
Man has long used plant materials as spices and herbs.
More recently, essential oils have been substituted for many
purposes. The chemistry of most of these materials is com-
plex, but in a few fruit or plant flavors, a single compound
is responsible for most of the characteristic properties. Those
of apple, peach, coconut, and pear are largely single-compo-
nent flavors. Others, such as banana, are comprised of rela-
tively simple mixtures. Many others, such as apricot, are
more complex. The flavors of black currants, strawberries,
coffee, and chocolate have not been successfully reproduced;
the last two have yielded over 700 components on analysis.
Trace components are often important and may contribute
more significantly to the flavor than major ones. In lemon,
for example, limonene (11) makes up about 70% of the oil,
but it is the content of citra!, a mixture of geranial (61) and
neral (60) (less than 5% of the oil), that produces the lemon
flavor. An even more effective example is that of cucumber
smell produced by nona-2,6-dienal. This substance has an
odor threshold of 0.0001 ppm (Harborne, 1982).
Thujone (21), a major component of wormwood, Artemi-
sia absinthum, was once a major flavoring of the liquor ab-
sinthe (Arnold, 1989; Harborne, 1991). At doses of 30 mg/kg
of body weight, thujone produces convulsions associated
with lesions of the cerebral cortex. Thujone is also a major
constituent of cedar leaf oil (Thuja occidentalis) and an im-
portant component of sage (Salvia officinalis) (Alfaro,
1981).
Insect Repellents
Oil of citronella (the essential oil of Andropogon nardus,
Poaceae) has long been used as a mosquito repellent. This
oil is mostly composed of geraniol with lesser amounts of
citronellol (7), citronellal (62), and borneol (32). Other es-
sential oils also have been used to repel insects (Levin, 1973;
Seigler, 1983).
IRREGULAR JIIOI'lOTERPEl'IES
A number of monoterpenes do not fit the "isoprene rnle"
and are called irregular monoterpenes. There are three major
structoral types of irregular monoterpenes: the chrysan-
themyl (89), artemisyl (90), and santolinyl (91) skeletons
(Charlwood and Banthorpe, 1978; Charlwood and Charl-
wood, 1991a). These compounds are found primarily in the
Asteraceae (they are especially well known from the genus
Artemisia), although a few are found in the Apiaceae and
Lamiaceae (Poulter, 1990). As two skeletal types often occur
in the same plant, it is reasonable to suspect that a common
biosynthetic pathway exists and it is possible that the three
types arise from a common catiouic species (Fig. 19.21).
 MonOlerpenes 347

bond opens between

-_-
bond opens between
santolinyl b" ' /

~M lavandulyl

bond opens between

<a)
~--~ artemisyl rothrockyl

~~hr~(89)J~
artemisyl skeleton (90)
santollnyl skeleton (91) lavandulyl skeleton

it1: --
rothrockyl skeleton
rolbrockene\

PPO~ PPO
1
+
1
1
HO

~Hb.J I
~ """ " -
H,.110
h

/ lavandulyl skeleton

_H~_H~
HOCH, H HO,C H
chrysantbemyl skeleton chrysanthem.yl alcohol (92) chrysantbemic acid (93)

OH

~ H
'</
/
~'X:"""""'fOH
....,...

santoUna alcohol yomogi alcohol

4+ ~
~';x' ..<;>-, /_:'X:" ~ /~'X:" ~ /
'V'" "0"+'," to.;'1 r "I '</

artemisia alcohol
.'</

artemisia ketone
(95) (94)
<b) artemisyl skeletons

Fig. 19.21 (a & b). Proposed biosynthesis of irregular monoterpenes (modified from Epstein and Poulter, 1973; used with permission of the copyright
owner, Elsevier Science Ltd., The Boulevard Langford Lane, Kidlington OXS 1GB, UK).
348 Monoterpenes
Fig. 19.22. Pyrethrins and related compounds.
It is of interest that in some nonenzymatic stodies, a small
percentage of head:to-head condensation products are ob-
served. Chrysanthemyl alcohol (92) is an analog of presqua-
lene alcohol and prephytoene (see Chapters 23 and 26), but
the fissions postolated to lead to the irregular monoterpenes
have no counterparts for the higher classes (Charlwood and
Charlwood, 1991a).
Label from (3R,4R)[4- 3 H]mevalonic' acid but not from
(3R,4S)[4-3 H]mevalonic acid was incorporated into chrysan-
themic acid (93). Chrysanthemyl alcohol is an intermediate
in the biosynthesis of chrysanthemic acid (Pattenden et al.,
1975).
Artemisia ketone (94), derived from IPP and DMAPP in
Santolina chamaecyparissus, is asymmetrically labeled; that
is, the label from IPP is incorporated at much greater levels
than that from DMAPP (Allen et al., 1977). A dehydrogen-
ase system rather than a mixed-function oxidase (MFO) sys-
tem based on cytochrome P-450 appears to be involved in
formation of artemisia ketone.
In cell-free extracts of Artemisia annua and Santolina
chamaecyparissus, chrysanthemyl alcohol and its pyrophos-
phate are incorporated into artemisia ketone and alcohol.
Artemisia alcohol (95) is converted into artemisia ketone
(94) and trans-chrysanthemic acid in the preparation from
S. chamaecyparissus (Banthorpe et al., 1977a), IPP and
DMAPP are incorporated into irregular monoterpenes
whereas geranyl and neryl-OPP are not. An enzymatic sulf-
hydryl group is involved.
Pyrethrins (such as 96 and 97, Fig. 19.21 and 19.22) are
of special interest because of their insecticidal properties
and ecomonic importance (Mabry and Gill, 1979). These
compounds are isolated from the genus Chrysanthemum
(sometimes segregated as species of Pyrethrum, or trans-
ferred to the genus Tanacetum). Several species are culti-
vated and the flowers harvested and extracted with lipid sol-
vents (such as petroleum ether) to yield a crude pyrethrin
fraction.
In general, these compounds have relatively low mamma-
lian toxicity but are highly toxic to insects. Pyrethrins are
especially useful because they have good "knockdown"
chrysanthemlc acid (93)
properties. These compounds also are highly toxic to fish.
Pyrethrins interfere with the sodium channel, upset sodium
and potassium balance, and cause rapid, recurrent excite-
ment of nerve endings followed by paralysis, Pyrethrins are
rapidly decomposed by polysubstrate monooxygenase
(PSMO) [mixed-function oxidase (MFO)] enzymes. Syner-
gists are often used to slow detoxication and make the insec-
ticidal preparations more effective. Pyrethrins account for
about one-third of world's insecticide use (Pickett, 1988).
A number of synthetic insecticides have been modeled
on the structores of natorally occurring pyrethrins. Several
of these are less biodegradable than pyrethrins and avoid
the problem of too rapid decomposition. In addition, these
synthetic derivatives have better knockdown and toxicity
properties.
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20
Iridoid Monoterpenes
Introduction
Biosynthesis
Fonnation of Deoxyloganic Acid from Geraniol
Fonnation of 8-epi-Deoxyloganin and Related Iridoids
Iridoids Derived from 10-Hydroxycitronellol
Conversion of Loganin to Secologanin
Secologanin as a Precursor for Indole Alkaloids
Distribution of Iridoid Monoterpenes
Biological Activity
Medicinal Uses of Iridoid Compounds
References
II'ffKODUCTIOI'I
At least 500 compounds (-300 iridoid glucosides, 100 sec-
oiridoid glucosides, and 100 nonglycosidic iridoids) (Bow-
ers, 1991; Croteau, 1981; Inouye, 1991; Inouye and Uesato,
1986), derived from a specialized monoterpenoid pathway
and usually characterized by a 5-membered carbocyclic ring
fused to a 6-membered heterocyclic ring containing an acetal
linkage, are known (Fig, 20.1). Although the tenn iridoid is
based on iridomynnecin (1) and iridodial (2), two monoter-
penes that occur in the defensive secretions of ants of the
genus lridomyrmex, most compounds of "iridoid" structure
are found in plants. These compounds are frequently in-
volved in plant-insect interactions and are sequestered,
sometimes after modification, and apparently synthesized
independently by some insects (Rimpler, 1991). In contrast
to other monoterpenes, iridoid monoterpenes in plants are
usually not associated with specialized oil glands or other
such structures, and occur in all plant parts, typically as
water-soluble glycosides, sometimes comprising several
percent of the dry weight of the plant (Bowers, 1991; Ster-
mitz, 1988). In some instances, up to 22-25% of plant mate-
rials may consist of iridoid compounds.
Some suspension cultures produce iridoid monoterpenes,
but many fail to produce the same complement of com-
pounds found in the parental plants (Ellis, 1988). However,
various cultures from Gardenia jasminoides (Rubiaceae)
and Valeriana and related genera (Valerianaceae) produce
a similar complement of iridoid monoterpenes to the parent
plants. Cultures of Fedia cornucopiae and Valerianella 10-
custa (both Valerianaceae) produce greater amounts of iri-
doids than do the roots of the parental plants. Transfonned
hairy root cultures of Valerianella discoidea produce essen-
tially the same valpotriates as the original plant (Charlwood
and Charlwood, 1991). Indole alkaloids are produced in a
number of plant cell cultures, indicating that iridoid monot-
erpene biosynthesis must be occurring (Ellis, 1988).
Iridoid monoterpenes can be purified by chromatography
on a variety of substrates; general chromatographic tech-
niques have been reviewed (Bowers, 1991; Coscia, 1984;
Inouye, 1991; Junior, 1990). Thin-layer chromatography
(TI..C) (Bowers, 1991; Inouye, 1991; Junior, 1990; van der
Sluis, 1985) and high-perfonnance liquid chromatography
(HPLC) (Foerster et aI., 1984; Inouye, 1991; Junior, 1990)
have proven especially useful for the separation and purifica-
tion of iridoid compounds. Other physical properties and
spectral data, such as the optical rotation, melting point, ul-
traviolet, 'H- and l3C-spectral measurements are valuable
for detennination of structure (Boros and Stennitz, 1990;
El-Naggar and Beal, 1980). A number of known compounds
have been studied by 13C_NMR (nuclear magnetic reso-
nance) spectroscopy; the characteristic shifts observed are
useful in detennination of substitution patterns and stereo-
chemistry (Boros and Stennitz, 1990; Chaudhury et aI.,
1980; Damtogt et aI., 1981). Mass-spectral measurements
also are valuable for characterization of iridoid monoter-
penes (Junior, 1990). The plant sources of many iridoid mo-
noterpenes also are indicated in these references.
Monoterpene and indole alkaloids are frequently derived
from iridoid monoterpene precursors (Inouye, 1991).
353
 q:
354 Iridoid Monoterpenes

CHO

H CHO ~

iridodial (2) aetinidine (45) iridomyrmecin (I)

1R
OH lIC0 2CH3

oo~
OH

oct) ~
~
~ 6 4~ 3
HO 7 H O-glucosyl
~ 0 • 1 0 -
O-glucosyl 10 H O-glu_yl CH,O,C :::,... 0
HO H O-glucosyl

unedoslde aucubio (19) loganio (6)

w<t
the major alkal0?Jld from
Valeriana o.fjicinalis

H j
~ I~
~~ ~
CHO

g)'CH'
o H CHO
o I
nepetalaetone (29) dolicbodial (27) Il....ytanthine dolicbolaetone (28) :::,...
(a) OH

Fig. 28.1 (a & b). Some naturally occuning iridoid compounds.

BIOSYNTHESIS at positions 3 and 11 is involved and the product is epi-deoxylo-

The biosynthesis of iridoid monoterpenes is complex and
much work was required to establish the precursors and path-
ways leading to iridoid monoterpenes. Label from mevalonic
acid, in contrast to other monoterpenes, is incorporated into
the entire molecule. Incorporation stodies in this group of
compounds often are complicated by the presence of side
branches to the main pathways that allow incorporation of
nonobligatory precursors (Inouye, 1991). In most situations,
dialdehydes may exist in equilibrium with the corresponding
dihydropyran forms. These dihydropyran forms are impor-
tant for the formation of many of the known glycosides.
Although glycosides at other positions also are known, the
glycosides of dihydropyran forms usually are !3-D-glucopyr-
anosides (Jensen, 1991).
There seem to be at least three routes to iridoid com-
pounds (Bowers, 1991; Jensen, 1991):
Route 1 derives from lO-hydroxygeraniol (3), via iridodial (2)
and iridotrial (4), and culminates in deoxyloganic acid (5) (Fig.
20.2). Scrambling of label between positions 3 and II occurs.
Deoxyloganic acid is converted to loganin (6) and, fmally, to
secoiridoids (Jensen, 1991).
Route 2 also involves lO-hydroxygeraniol (3) as a major precur-
sor, but proceeds via the intermediacy of epi-iridodial (7) and
epi-iridotrial (8) (Fig. 20.3). In some plants, scrambling oflabel
ganic acid (20), in a manner paralleling the first route ofbiosyn-
thesis. In other examples, the pathway is identical up to epi-
iridotrial (8), where glucosylation takes place, followed by oxi-
dation of C-1I to the carboxyl stage (Jensen, 1991).
Route 3 begins with lO-hydroxycitronellol (9), but also involves
the intermediacy of iridodial (2) (Fig. 20.4) (Jensen, 1991).
Thus, contrary to earlier expectations, various routes lead-
ing to the iridane skeleton in the biosynthesis of iridoids and
secoiridoids are not identical (Inouye and Uesato, 1986).
Formation of Deoxyloganic: Acid
li'om Geraniol
Iridodial (2) has been established to be a major intermedi-
ate in the biosynthesis of indole alkaloids in Rauvolfia ser-
pentina (Inouye and Uesato, 1986). Subsequently, the con-
version of lO-oxogeranial (10) to iridodial (2) was
demonstrated. Geraniol (11), lO-hydroxygeraniol (3), and
iridodial (2) (and, in some instances, nerol and lO-hydrox-
ynerol) are efficient precursors of deoxyloganic acid (5) and
loganin (6) (Fig. 20.2) (Balsevich, 1985; Balsevich and
Kurz, 1983; Inouye, 1991; Jensen, 1991). In the formation
of loganin in Catharanthus roseus, the first intermediate
seems to be 10-hydroxygeraniol (3); 9-hydroxygeraniol is
not incorporated well. ColO hydroxylation of geraniol (and
 too
Iridoid Monoterpenes 3SS

= cop, o 0

W COlCH.

0;R~0~.:." ;D.:.
?' "'"
R, H 0
Rz O-glucosyl
o
foliamenthin ~ secoJoganin (18) sweroside R=CHzOH, R=OH, monotropein
R=OH, R=CHzOH, gardenoside (26)
I H O-g1ucosy)
HO~HO : O-CO
iH"",
HO~O~CH'
~ ~ 0

~b o CH,sCOO H O-g1ucosy)

O-g1u..sy) IH O-g1ucosy)
oleuropln hydrangenoside A paederoside (48)

O·g1ucoay)

ipecoside
O-g1ucosy)

(b) vincoside

Fig. 20.1. (continued)

nerol) is accomplished by a cytochrome P-450-mediated
system.
Although the exact mechanism of ring closure is not
known, that proposed by Escher et aI. (1970) and Battersby
et aI. (1970) is reasonable in view of other studies (Fig.
20.5). In formation of the cyclopentane ring ofioganin, posi-
tions C-9 and C-lO of geraniol (C-3 and C-11 of loganin)
become equivalent (Beale and MacMillan, 1988).
The conversion of 10-oxogeraniai (10) (and lO-oxoneral)
to iridodial (2) has been demonstrated; a novel monoterpene
cyclase from Rauvolfia serpentina that catalyzes formation
of iridodial has been partially purified and characterized
(Uesato et aI., 1987). NADPH accelerates the cyclization.
The molecular weight of the cyclase and its subunit are
118,000 and 28,700, respectively (Uesato et aI., 1987).
Scrambling of radioactive label between positions 3 and
11 in deoxyloganic acid (5) indicates that iridotrial (4) [not
iridodial glucoside (12)] is an intermediate in the formation
of deoxyloganic acid (5) (Fig. 20.3) (Jensen, 1991).
In certain other iridoid monoterpenes, positions 3 and 1 I
do not become equivalent. In Deutzia crenata (Saxifraga·
ceae), lO-hydroxygeraniol (3), iridodial (2), and its glucoside
also are converted to deutzioside (13) (Fig. 20.2). When
iridodial glucoside was used as the precursor, no scrambling
of label was observed (Jensen, 1991). In old plants of Ver-
bena officinalis, introduction of 2- 14C-Iabeled mevalonic
acid resulted in the formation of iridoid compounds and the
production of verbenalin (comin) (14), in which no scram-
bling was observed (Fig. 20.6). Presumably, the pathway
involved iridodial glucoside (12) and iridotrial glucoside
(15) (Fig. 20.2) (Jensen, 1991).
Both [1-3H]IO-hydroxygeraniol (3) and [1O-3H]iridodiai
(2) are incorporated into vindoline (17) in Catharanthus ro-
seus and secologanin (18) in Lonicera morrowii (Caprifolia-
ceae), whereas (R,S)-[1O-3H]hydroxycitroneIIol (9) was not.
Thus, the cyclization pathway involving conversion of 10-
oxogeranial (10) (and lO-oxoneral) is common, not only in
plants producing iridoid glycosides but also in plants produc-
356 lridoid Monole/penes

~
~HO
---+ ~+~
HO eHO
eHO

0
lO HH

H
"'"

0
O-glucosyl
geraniol (11) 10-hydroxycitronellol (9) deutzioside (13)

~~ ~
~
HO
OH
----+
~!
~
#
eHO
eHO
----+
<;=CeHO

eHO
--..
yO"'" <;Q"'"
H
O--+-
H
eHO

O-glucosyl O-glucosyl

10-hydroxygeraniol (3)10-oxogeranial (10) iridodial (2) iridodial glucoside (12) iridotrial glucoside (15)

~ 1 11
l
,
OH eHO eHO
CHO _ ?-glucosyI

~ ~ eHo
~
HO
OH----..
9' eHO
-----.
~eHo ~
eHO
10 HO
~'_<=pf
~
H
• #
C0 2 H
0

iridotrial (4) deoxyloganic acid (5)

Fig. 20.2. Biosynthesis of deoxyloganic acid (Jensen, 1991; modified and used with pennission of the copyright owner, Oxford University Press,
Oxford).

~~q:~ro-q5
HO ~ ! HO ! HO
10-hydroxygeraniol (3) 8-ep;-iridodial (7) 8-epi-iridotrial (8)

OH

~
~

\ 0 -

HO H O-glucosyl H
O-glucosyl
geniposidic acid (37) deoxygeniposidic acid aucubin (19) epi-deoxyloganic acid (20)

WOH
OH >=pH
CO,eH,
Plantago major
Scrophularia racemOSQ

, ~ ~ Ho_~H'
o ;
i H
o
.
° :>r+-r~
~ HO! H
O-glucosyJ ! O-gJucosyl O-glucosyl
antirrhinoside (23) ipolamiide (21) lamiide (22)
Anti"hinum majus Hebenstretia dentala Hebenstretia dentola

Fig. 20.3. Biosynthesis of epi-deoxyloganic acid (Jensen, 1991; modified and used with pennission of the copyright owner, Oxford University Press,
Oxford).
 Iridoid Monoterpenes 357

~0¢if-~

HO
OH?
~

HO
OH

---+- H C~
CHO

H CHO
CHO

l()..hydroxygeraniol (3) l()"hydroxycltrolellol (9) irldodlal (2) dollehodlal (27)

WC;_~O~~H
0:0
H
H
0
OH
H
0
0

~~ ir°"-~~'
~0~H3
teuerein (30) +
10 0
nepetalactone (29)

y¢~
photocltralA dolleholaetone (28)

Fig. 10.4. Biosynthesis of nonglycosidic iridoid monoterpenes derived from lO-hydroxycitronellol (Inouye and Uesato, 1986; Jensen, 1991; modified
and used with pennission of the copyright owner, Springer-Verlag, Vienna).

OH_~:O_~CHO__
~ ~
I7 geraniol (11) H+
9' OH

10
10-oxogeraniai (10) iridodlaI(2)

OHC
~~HO---
H

""" OH
HO

O-glucosyl
HO
-yp H
CO'CH3

"""
0=
HO'" 7

O-glucosyl
H
w~
,
l! ~.gl:COSYI
'.-6'3
4
COCH
11 2 3

IridotrlaI(4) )oganin (6)

Fig. 20.5. Proposed cyclization of iridoid monoterpenes (modified from Escher et aI., 1970; used with pennission of the copyright owner, the Royal
Society of Chemistry, London).
 t;:,. t
358 lridoid Monoterpenes

•
,t~
•
IOH
-+
OH_
CHO
CHO
10 --+
I'
3
9' CHO
, 1

q:'
OH
, 10 CHO
geraniol (11) 10-hydroxygeraniol (3) 10-oxogeranial (10)

10 10 • O-glucosyl 10 • O-glucosyl

~-
CHO Ho.".. q;l,
';,I,: 0
v;;y, s..H
/tCH: ; -
H 7 U J
H CHO - -
•
10 CHO 11 C02H U C02CHJ
iridodial(2) iridotrial(4) deoxyloganic acid (5) loganin (6)

¢6' O-g1ucosyl

secologanin (18) vindoline (17) verbenaJln (14)

(cornin)

Fig. 20.6. Biosynthesis of secologanin and the indole alkaloid vindoline (modified from Inouye and Uesato. 1986; used with pennission of the
copyright owner, Springer~Verlag, Vienna).

ing secoiridoid glucosides and indole alkaloids (Fig. 20.6)
(Inouye, 1991; Inouye and Uesato, 1986; Uesato et al.,
1986).
Formation of 8.epJ.Deoxyloganin and
Related lridoids
A second series of iridoid monoterpenes is derived from
the epimeric series of precursors (Figs. 20.3 and 20.7). Intro-
duction of [9- 13C]-IO-hydroxygeraniol (3) in Plantago
major gives incorporation into aucubin (19) with scrambling
of label. Furthermore, 8-epi-iridodial (7) and 8-epi-iridotrial
(8) and the corresponding glucosides were all incorporated
with scrambling of the label at C-1I (Fig. 20.7) (Jensen,
1991). Because both glycosides are incorporated with scram-
bling of label, hydrolysis must occur prior to incorporation.
In addition, 8-epi-deoxyloganic acid (20) is a precursor for
ipolamiide (21) and lamiide (22) in Rebenstretia dentata
(Globulariaceae), for aucubin (19) in Scrophularia racemosa
(Scrophulariaceae), and for antirrhinoside (23) in Antirrhi-
num rnajus (Scrophulariaceae) (Fig. 20.3) (Inouye and
Uesato, 1986).
Gardenia jasminoides (Rubiaceae) cell cultures incorpo-
rated epi-iridotrial (8) and 7,8-dehydroiridotrial glucosides.
8-epi-Iridodial (7) and boschnaloside (24) are readily incor-
porated into tarennoside (25) and gardenoside (26), but epi-
deoxy10ganin was not a precursor (Fig. 20.7) (Inouye and
Uesato, 1986; Jensen, 1991).
lridoids Derived from lO.Hydroxydtronellol
The biosynthesis of some nonglycosidic iridoids such as
dolichodial (27), dolicholactone (28), and nepetaIactone (29)
involve pathways somewhat different from those of glyco-
sidic iridoids and secoiridoids (Inouye and Uesato, 1986;
Jensen, 1991). (S)-( - )-Citronellol and (S)-( - )-IO-hydrox-
ycitronellol (9), but not lO-hydroxygeraniol (3) nor other
2,3-unsaturated analogs, can serve as intermediates for doli-
chodial (27), dolicholactone (28), and teucrein (30) in Teu-
crium rnarum (Lamiaceae), and for nepetaIactone (29) and
dihydronepetaIactone (31) in Nepeta cataria (Lamiaceae)
(Fig. 20.4) (Inouye and Uesato, 1986).
Conversion of Loganin to Secologanin
Loganin (6) is a key intermediate in the biosynthetic path-
way leading to other iridoid monoterpenes as well as com-
plex indole alkaloids. Many of these additional compounds
are derived by conversion of this bicyclic iridoid monoter-
pene into secologanin (18). The mechanism by which ring
cleavage occurs to yield secologanin is not well understood,
but apparently the cleavage happens after oxidation of the

..
~
,;::--
HO
OH
-- «-=~ro --
I !
lO·hydroxygeraniol (3) epi-iridodial (7)
'CHO
\P
CHO
__ 5Q
~
~.
0
O·glucosyl
HO H 01llucooyl
tarrenoslde (25)
Fig. 20.7. Iridoid monoterpenes derived from 8-epi-deoxyloganin (Jensen, 1991; modified and used with pennission of the copyright owner, Oxford
University Press. Oxford),
methyl group and fonnation of a phosphate ester (Fig. 20.8)
(Inouye, 1991).
Some evidence supports the idea that distinct biosynthetic
pathways lead to iridoid g1ycosides and to secoiridoids.
Equal labeling of positions C-3 and C-lI is observed in
secoiridoids and in indole alkaloids.
Secologanin (18) is, in torn, the parent of a group of
compounds called secoiridoids of which gentiopicroside
(32) and sweroside (33) are representative members. These
compounds arise in the sequence sweroside, swertiamarin
(34), and gentiopicroside (32) (Fig. 20.8) (Inouye and
Vesato, 1986). When [4R-4- 3HJ-, [4S-4- 3HJ-, or [2S-2-3H]
mevalonic acid (MYA) together with [2_14C]MYA were ad-
ministered to Swertia caroliniensis (Gentianaceae) and the
products loganic acid (35) and gentiopicroside (32) were
studied by degradation, it was found that both C-4 pro-R
hydrogens of two molecules of MYA were retained in 10-
ganic acid, whereas only one remained in gentiopicroside
(Fig. 20.8); neither of the two C-4 pro-S hydrogens was
present in either compound. Both of the C-2 pro-R hydro-
gens of MYA were found at C-3 and C-7 in loganic acid
(35); one pro-S hydrogen was at C-3, whereas the other was
essentially eliminated from the hydroxylated C-7 position.
Gentiopicroside (32) from [2S-3H2 , 2_14C]MYA incorpora-
tion had the same 'H! 14C ratio as loganic acid (Inouye and
Vesato, 1986). Randomization of label from [2- 14CJMVA
between C-3 and C-lI usually was observed in iridoid and
secoiridoid g1ycosides and in indole alkaloids (Inouye and
Vesato, 1986).
/ridoid Monoterpenes 359
HO
!
CHO
--~ q)
HO~I~COOYI s O-glucosyl
~
A
boscbnaloslde (24)
H
,
HO~6
HO'" O·glucooyl
gardenoside (26)
SecologllDin as a Frecursor for Indole
Alkaloids
Secologanin undergoes condensation with tryptamine in
some groups of plants to yield strictosidine (isovincoside)
(36), the immediate precursor of indole alkaloids.
DIS1RIBUI'IOI'l OF IRIDom JIIOI'lOTERPEl'IES
Although not all steps of the biosynthesis of iridoid monoter-
penes have been examined in detail, the probable pathways
leading to this group of compounds appear to be lengthy
and complicated. Thus, their distribution should be limited
and it seems improbable that iridoid monoterpenes would
have arisen often in the course of evolution. The distribution
of iridoid mouoterpenes among higher plants is restricted
to about 50 families, most of which belong to Wettstein's
Tubiflorae (Gershenzon and Mabry, 1983). The families that
possess these compounds belong primarily to two major
groups as viewed by most phylogenists. Dahlgren observed
that the presence of iridoid compounds is strongly correlated
with the presence of certain significant morphological fea-
tures (Dahlgren et al., 1981). The placement of a number of
families in these groups and removal of others has been
discussed by Dahlgren and reviewed concisely by Gershen-
zon and Mabry (1983). A number of families such as the
Escalloniaceae, Grossulariaceae, Hydrangeaceae, and Saxi-
fragaceae were thought to be closely related to the Cornaceae
360 lridoid Monoterpenes

HO
.A.. _
J 1 ~OlH
HO,'
W •

10
8

H
ll
C:CH3

1
",'

0..........

O·glucosyl
H_ 0
V
5Q~01CH3
H
"":::

0 ----.

O.glucosyl
CI(r0':?

H3COOC~
H

0
O·glucosyl
----...

mevalonic acid :J

Q&
loganin (6) secologanin (18)
10

~O_gIUCOSYI OH H

1f.·-
o !~ 0 O.glUCOSYI,

~~~
o o
o r
HO::r:v

oo-g5
gentioplcroslde (32) swertiamarln (34) sweroside (33) secologanic acid

O-glucosyl
O-glucosyl

loganic acid (35)

Fig. 20.8. Proposed formation of secologanin and related compounds (modified from Inouye and Uesato, 1986; modified and used with pennission of
the copyright owner, Springer-Verlag, Vienna).

(Bate-Smith et al., 1975), whereas there does not appear to
be a close relationship of the Comaceae to the Apiaceae
(Umbelliferae) and the Araliaceae with which they are
placed by many phylogenists. The Apiaceae and Araliaceae
completely lack iridoid compounds. The presence of alka-
loids in the Icacinaceae and the Nyssaceae based on an iri-
doid monoterpene structure suggests that these plants also
may be related to the Comaceae.
Dahlgren felt that because of the combination of charac-
ters above, these groups should be combined with the other
iridoid producing families (Gershenzon and Mabry, 1983).
Many of the iridoid compounds of the Comaceae and related
families are shared with the Rubiaceae, Dipsacaceae, and
other families, suggesting a link between the two groups.
Dahlgren and co-workers (1981) transferred the family Fou-
quieraceae to the Comiflorae because it was the only family
in the Solaniflorae that contained iridoid monoterpenes (Jen-
sen and Nielsen, 1982).
Most of the plants concemed were in the superorders
Ericanae, Comanae, Loasanae, Gentiananae, and Lamiana-
nae, but a few other sources have been reported (Jensen,
1991). In a reevaluation of the application of chemical evi-
dence to the systematics of this group of plants, Jensen ob-
served that data based on the biosynthetic pathways provide
a sounder basis for these placements. Based on present infor-
mation, the presence of secoiridoids and of compounds de-
carboxylated at C-11 is mutually exclusive. Most of the iri-
doid compounds found in the Comanae (orders Comales,
Eucommiales, and Dipsacales), Loasanae (Loasales), and
Gentianananae (Gentialales, Goodeniales, and Oleales) are
synthesized by the biosynthetic route involving formation
of secoiridoids (Jensen, 1991). Those of the Lamianae (La-
miales and Hippuridales) are synthesized by a second route
(see the subsection biosynthesis, above) involving decarbox-
ylation at C-l1. Data related to the Ericanae and other iri-
doid-containing taxa are not as easily interpretable. In a few
instances, compounds such as geniposidic acid (37) are inter-
mediates in both routes of biosynthesis. More detailed inves-
tigation of these biosynthetic pathways will be needed to
establish relationships more clearly (Jensen, 1991).
Plants in the Comanae, Gentiananae, and Loasanae, in
general, contain both normal iridoid monoterpenes and sec-
oiridoids. Plants in the Lamianae contain not only many
normal iridoid monoterpenes but also those in which C-l1
is decarboxylated. They lack secoiridoids. Plants of the Eri-
canae do not exhibit a clear pattem. Iridoid compounds with
8-J3-stereochemistry were assumed to derive from pathways
associated with secoiridoid biosynthesis, whereas those with
8-a-stereochemistry were associated with the route involv-
ing C-l1 decarboxylation (Jensen, 1991). Some exceptions

exist: Decarboxylated iridoids also are found in the Aucuba-
ceae, Eucommiaceae, and Garryaceae (Cornanae), as well
as in the Ericanae. Secoiridoid structures are known from
the Cornanae, Gentiananae, and Loasanae, but also from the
Sarraceniaceae and Stylidiaceae (Ericanae) (Jensen, 1991).
The Cornanae include the ComaIes (Adoxaceae, Alangia-
ceae, Aralidiaceae, Aucubaceae, Cornaceae, Curtisiaceae,
Davidiaceae, Escalloniaceae, Garryaceae, Griselinaceae,
Hydrangiaceae, Icacinaceae, Mastixiaceae, Menyanthaceae,
Montiniaceae, Montiniaceae, Nyssaceae, Sambucaceae,
Stylidiaceae, Symp10caceae, Torricelliaceae, and Vibuma-
ceae), Dipsacales (Calyceraceae, Caprifoliaceae, Dipsaca-
ceae, Moringaceae, Triplostegiaceae, and Valerianaceae),
Loasales (Loasaceae), Goodeniales (Goodeniaceae), and
Oleales (Oleaceae) (Jensen, 1991).
The order Gentianales (Apocynaceae, Gentianaceae, Lo-
ganiaceae, Rubiaceae, and Theligonaceae) contains normal
iridoid monotetpenes and secoiridoids, as well as iridoid-
derived alkaloids in families other than the Asclepiadaceae.
Multiple types of alkaloids are found in the Apocynaceae
(indole and steroidal types), the Loganiaceae, and Rubiaceae
(emetine, quinine, and indole types).
The iridoid families that constitute the Lamianae, include
the Lamiales [which includes the Acanthaceae, Bigno-
niaceae, Buddlejaceae (possibly misplaced here), CaIIitrica-
ceae, G1obulariaceae, Lamiaceae, Lentibulariaceae, Marty-
niaceae, Myoporaceae, Pedaliaceae, Plantaginaceae,
Retziaceae, Scrophulariaceae (including Orobanchaceae),
Selaginaceae, Stilbaceae, and Verbenaceae), and the Hippur-
idales (Hippuridaceae) (Jensen, 1991; Jensen et al., 1988).
The relatively large family Gesneriaceae apparently lacks
iridoids. lridoids are found in the Thunbergiaceae, but not
in the Mendonciaceae (Jensen et al., 1988), both sometimes
merged with the Acanthaceae. In general, members of the
Larniaceae that accumulate iridoid monoterpenes do not ac-
cumulate normal monotetpenes and vice versa (Waterman
and Gray, 1987).
Among the iridoid-containing families of the Ericanae
are the Ericales (Actinidiaceae, Epacridaceae, Ericaceae,
Monotropaceae, and Pyrolaceae), the Stylidiales (Stylidia-
ceae), Sarraceniales (Sarraceniaceae), and Fouquieriales
(Fouquieriaceae) (Jensen, 1991).
lridoid monotetpenes also are found in several other
groups of plants not considered closely related to the above
by most systematists or phylogenists [for example, the Daph-
niphyllaceae, Eucommiaceae, Hamamelidaceae, Malpighia-
ceae (Sainty et al., 1981), Meliaceae (however, see Jensen,
1991), and Sarraceniaceae.
BIOLOGICAL ACTIVITY
Many iridoid monoterpenes possess biological activity, al-
though the role of these compounds in biological interactions
has not been stodied as much as many or other groups of
secondary metabolites.
Iridoid Monoterpenes 361
The iridoid glycosides geniposide (38) and geniposidic
acid (37) and their aglycones have have been shown to in-
hibit growth of wheat embryos (Cameron et al., 1984).
The iridoid glycoside plumieride (39) [from Plumeria ob-
tusifolia (Apocynaceae)] has been demonstrated to have
plant growth-inhibiting activity. Although gibberellin-stim-
ulated growth was inhibited, there was no effect on indole-
acetic acid (lAA)-stimulated growth (Adam et al., 1979).
lridoid monotetpenes are involved in a number of
plant-animal interactions (Bowers, 1988, 1991; Rimpler,
1991). Many insects sequester iridoid monotetpenes in a
variety of tissues, including all stages of the insect and the
silk produced. Uptake of iridoids may be selective or nonse-
lective; they may be modified before or after uptake. These
compounds also are excreted in the frass in many instances
(Rimpler, 1991).
Many iridoids can act as antifeedants. To mammals, iri-
doids often have an intensely bitter taste. Growth rates of
generalist feeders such as Spodoptera eridiana are reduced
with iridoid-containing diets (Rimpler, 1991). In contrast,
Lymantria dispar, the gypsy moth, tolerates the "taste" of
iridoid glycosides and excretes catalposide unchanged in the
frass (Harborne, 1989). Nonetheless, this insect grows and
survives less well on diets containing iridoids than on iri-
doid-free control diets (Rimpler, 1991). The vapors of many
volatile iridoid monotetpenes repel insects such as ants and
beetles.
Moths and butterflies that sequester iridoid compounds
are unpalatable to birds that might be potential predators.
Adults of Euphydryas phaeton that fed on Chelone glabra
(Scrophulariaceae) during larval development are emetic to
birds that eat a piece of the butterfly (Rimpler, 1991).
The compounds iridomyrmecin (1) and iridodial (2) serve
as defensive compounds in ants of the genus Iridomyrmex.
Nepetalactone (29), from Nepeta cataria, Lamiaceae, is in-
secticidal. Eisner (1964) demonstrated that this compound
is repellent to 17 out of 24 insect species studied. NepetaIac-
tone also has been reported to have hallucinogenic properties
in humans. NepetaIactone and a similar compound, boschni-
alactone (40) from Boschniakia rossica (Orobanchaceae),
have attractive activity toward cats (Herout, 1970) (Fig.
20.9). These compounds occur free, in contrast to most iri-
doid compounds.
Xylomollin (41), a secoiridoid isolated from the bitter
unripe fruit of Xylocarpus moluccensis (or more likely X.
granatum) (Meliaceae), is an effective deterrent to feeding
by the African army worm, Spodoptera exempta at the 100-
ppm level in leaf disks and strongly inhibits respiration in
rat liver mitochondria (Kubo and Nakanishi, 1977; Mabry
and Gill, 1979; Nakanishi, 1977; Nakane et al., 1978). How-
ever, there is some doubt about the source of this compound;
reinvestigation failed to reveal the reported compounds (Jen-
sen, 1991).
The interaction of the catalpa sphinx moth and Catalpa
is very complex and involves a mixture of at least 15 iridoids,
including cataIpol (42) and catalposide (43) in the feeding
362 lridoid Monoterpenes

attraction system (Bowers and Puttick, 1986; Harborne,
1982; Nayar and Fraenkel, 1963).
Catalpa speciosa, Bignoniaceae, a tree native to the
south-central United States, is pollinated by bumblebees,
carpenter bees, and some moths. In contrast to many other
flowers, those of catalpa attract few nectar thieves. This is
surprising, as the flowers contain a large amount of sugar
compared to other bee-pollinated flowers, and catalpa trees
produce a large floral display. In Michigan (outside of the
native range of the plant), ants that visited the extrafloral
nectaries and a small butterfly (Poanes hobomok) that fed
on nectar of catalpa flowers consumed less (compared to
sugar solution) and developed behavioral abnormalities. The
iridoid glycosides catalpol (42) and catalposide (43) were
present in the nectars of both flowers and extrafloral nectar-
ies of Catalpa speciosa (Stephenson, 1981, 1982).
Plants of Actinidia polygama (Actinidiaceae) have an ex-
citatory effect on cats and other Felidae. This plant is also
used in folk medicine in Japan. Several iridoid monoterpenes
have been isolated [iridomynnecin (1), isoiridomynnecin
(44), dihydronepetalactone (31), isodihydronepetalactone
and neonepetalactone, actinidine (45) and actinidiolide, and
dihydroactinidiolidel. Cats (Felidae) responded to the pres-
ence of these compounds (Inouye, 1991). In addition, male
adults of lacewings (Chrysopa septempunctata, Chrysopi-
dae) also are attracted strongly to the leaves and fruits of
this plant. Furthermore extracts of the plant proved to be
attractive. When these extracts were chromatographed
(TLC), the active zone on thin-layer plates could be deter-
mined by observing the pattern of bites of the adult males
on the plates. Adult males responded to 10-6 ,.M of neoma-
tatabiol (46) and isoneomatatabiol (47), 10-3 ,.M of mata-
tabiol and dehydroiridodiol, and 1 ,.M of iridodiol, 5-hy-
droxymatatabiether, 7 -hydroxydihydromatatadiether, and
allomatatabiol.
Jridomynnecin (1) and isoiridomyrmecin (44) are used
by ants such as Iridomyrmex humilis, I. nitidis, and Doli-
choderus scabridus as defensive compounds. These lactones
also were found in Aphis polygama. Thus, the structures of
the lacewing attractants correspond to the reduced forms of
the defensive compounds of ants (Sakan et al., 1970).
Although many aphids (the major insect pests of northern

yO q:r··W-Ml
~ o I OH

nepetaiaeione (29) bosclml.lactone (40) xylomollin (41) neomatatabiol (46)

:~~ catalpol (42)

HO...... O-glucosyl
isoiridomyrmecin (44)

M~ -'~ ;+<
~ LJ:?. ".. rn~~
!

isoneomatatabiol (47) iridomyrmecin (1) dihydronepetalactone (31) pnederoside (48)

~'<:::~
i O_gl':"y~

~ ~
COZH
H COzCH,
'<:::
~ 0 ~ '<::: ~ 0
~ 0
H '\'\ 0
HO H O-glucosyl
O-gluc:osyl H
CH,COO HO O-glucosyl HO H O-glucosyl

(a) asperuloside geniposide (38) genoposidic acid (37) 6-0-glucosylaucubin (49)

Fig. 20.9 (a & b). Biologically active iridoid monoteIpenes.

 W
~ ~
o
HO
COZCHJ
~
0
H H
O.glucosyl O·gluoosyl
cy
iridodial glucoside (12) loganln(6)
HO
(4aS,7S,7aR)·nepetaJactol (2)
COZCHJ
a?
~ OH
o H.
o o H ~
(b) plumlerlde (39) allamandln (50)
Fig. 20.9. (continued)
European agriculture) reproduce asexually during the sum-
mer, at certain times of the year, the male aphid locates the
female by means of sex attractant pheromones. The phero-
mones for the vetch aphid Megoura viciae are nepetalactone
(29) and iridodial (nepetalactol) (2). Neither of these com-
pounds is known to occur in the host plant Vicia laba (Daw-
son et al., 1987, 1990; Pickett, 1991). Iridodial (nepetalactol)
alone is the pheromone of the greenbug, Schizaphis grami-
num. Again, this iridoid does not occur in the host plant
(Dawson et al., 1988). These compounds are closely related
to known lacewing attractants and may act as kairomones
in enabling lacewings to locate populations of aphids when
aphids are scarce (Pickett, 1988). Other aphids that produce
iridoid sex pheromones are the black bean aphid, Aphis
labae, the pea aphid, Arcthosiphon pisum, and the peach-
potato aphid, Myzus persicae (Dawson et al., 1990).
The damson-hop aphid Phorodon humuli, a pest resistant
to all registered insecticides in England, must produce sexual
forms to leave hops (Humulus lupulus) for its primary host
(Prunus spp.) when the hops are harvested. A single active
compound similar to nepetalactol, but presently unidentified,
serves as a sexual pheromone (pickett, 1991).
The aphid Acyrsiphon nipponicus secretes paederoside
(48) from the host plant, Paederia scandens (Rubiaceae).
This secretion apparently protects the aphid from the lady-
bird beetle Harmonia axyridis (Harbome, 1989; Nishida and
Fukami, 1989).
A number of methylcyc1opentanoid monoterpenes are
lridoid Monoterpenes 363
q) H
CO,H
~
o
CHJCOO
roOHH
~
0
H H O.glucosyl
O·glucosyl
deoxyloganic acid (5) lamioside
(4aS,7S,7aR).nepetalactone (29)
CO'CH~H l O H
~
o
0
o 0 H
O.glucosyl
scabroside
found in the larval secretions of chrysomelid beetles of the
tribe Chrysomelini (Fig. 20.10) (Rowell-Rabier and Pasteels,
1986). These iridoids appear to be synthesized by the insects
and do not come from the host plants. The host plants include
Alnus, Rumex, Ranunculus, Brassica, Nasturtium, Salix, and
Juglans (Pasteels et al., 1982). Eggs and newly hatched lar-
vae are not protected by these compounds (Rowell-Rabier
and Pasteels, 1986).
Iridoid glycosides appear to be feeding stimulants for
checkerspot butterflies (Euphydryas) and butterflies of the
genus Anartia. These butterflies are restricted to iridoid gly-
coside-containing plants (Bowers, 1988, 1991). Larvae of
E. cynthia sequester iridoid compounds from the host plant
Plantago lanceolata (Harborne, 1989). Two of these com-
pounds, aucubin (19) and catalpol (42) occur in the host
plant, whereas the third, 6-0-glucosylaucubin (49), probably
is formed by conjugation within the insect (Harborne, 1989).
Larvae of E. chalcedona were attracted to and ate much
more of diets containing known iridoid monoterpenes or
plants that contained them than diets that lacked them. These
compounds seem to playa major role in host-plant specific-
ity in these insects (Bowers, 1983, 1988). Individuals of
Euphydryas anicia sequester iridoids from Besseya alpina,
B. plantaginea, and Castilleja integra (Gardner and Ster-
mitz, 1988; Stermitz et al., 1986b). The ratio of iridoids in
the insects often differs from that of the host plants. Catalpol
esters are hydrolyzed by the insect that sequesters the result-
ant catalpol and excretes the acid. A similar situation prevails
364 lridoid MonoteJpenes
~
<x~
H
CHO
"'H
~~CHO
chrysomelidial epichrysomelidial
Cy Co
H 0
plagiolactone epiplagiolactone
Fig. 20.10. Methylcyc}opentanoid monoterpenes from larval secretions of Chrysomelini.
in the interactions of the buckeye butterfly, Junonia coenia
(Nymphalidae) and plants of the families Acanthaceae,
Plantaginaceae, Scrophulariaceae, and Verbenaceae (all iri-
doid-containing families) (Bowers, 1984).
Many species of Castilleja (Scrophulariaceae) contain iri-
doid monoterpenes (Arslanian et al., 1985) as well as pyrrol-
izidine, quinolizidine, and monoterpene iridoid alkaloids
(Stermitz et al., 1986a). Both pyrrolizidine and quinolizidine
alkaloids appear to be taken from the hosts of these hemipar-
asitic plants (see Chapter 30). The larvae of Platyptilia pica
(Pterophoridae) excrete but do not sequester iridoids. The
adult moths contained rhexifoline, an iridoid monoterpene
alkaloid (Stermitz et al., 1986a).
The iridoid glycoside catalpol (42) is sequestered by lar-
vae of Meris alticola feeding on Penstemon virgatus, and
Neoterpes graefiaria on P. barbatus. The larvae have similar
larval patterns, but the adults, which contain little of the
iridoids, are cryptic (Stermitz et al., 1988). Antirrhinoside
(23) is sequestered by the larvae of the highly aposematic
larvae of the moth Meris paradoxa and two moth species
of Lepipolys that feed on Maurandya antirrhinijlora (Scro-
phulariaceae) (Boros et al., 1991). These larvae accumulate
from 3% to 11 % dry weight of the glycoside. Adults do not
contain antirrhinoside and are cryptic (Boros et aI., 1991).
JllEDiCIl'IAL USES OF IRIDOID COl'll"OVNDS
Valerian consists of the dried rhizome and roots of Valeriana
officinalis (Valerianaceae). Valeriana wallichii and V. edulis
also serve as commercial sources of the drug. Species from
related genera also are known to contain the active princi-
ples. Valerian has been used as a calmative in nervousness
and hysteria for at least 1000 years. A series of water-soluble
glycosides, collectively called valepotriates, are responsible
for the mild tranquilizing activity. These preparations are
widely available in Europe (Charlwood and Charlwood,
1991; Tyler et al., 1981).
Ct~o
Hr
HCHO
H
plagiodial
cy
0
H i 0
i
gastrolactone
Gentian (the dried rhizome and roots of Gentiana lutea,
Gentianaeeae) has long been used as a bitter touic in treat-
ment of anorexia and dyspepsia. This preparation contains
about 2% gentiopicrin. These products are also used to pre-
pare alcoholic beverages (Tyler et al., 1981).
An iridoid glycoside, allarnandin (SO), with antileukemic
properties has been isolated from AI/amanda cathartica
(Apocynaceae) (Kupchan et aI., 1974).
A number of the pharmacological activities of iridoids
are due to the aglycone, because the activity appears only
after treatment with [:I-glucosidase, or only when the pure
aglycone is tested (Stermitz, 1988).
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Jridoid Monoterpenes 365
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21
Sesquiterpenes

Introduction Il'fI'KODvcnON
Biosynthesis
Biosynthesis of (E, E)-Farnesyl Pyrophosphate Sesquiterpenes are the most numerous of all terpenoid com-
Interconversion of 2-E-6-E- and 2-Z-6-E-Farnesyl pounds. The approximately 5000 known compounds of this
Pyrophosphate type mostly can be grouped into about 30 major skeletal
Acyclic Sesquiterpenes types, but at least 200 less common skeletal types are known
Cyciization of Acyclic Precursors (Fig. 21.1). The distribution of sesquiterpenes in plants is
The Origin of Major Groups of Cyclic Sesquiterpenes essentially the same as monoterpenes. Sesquiterpene hydro-
Biological Activity carbons are common essential oil components. Although
AIlelopathy only a few fungi accumulate monoterpenes, many accumu-
Medicinal Properties late sesquiterpenes. Abscisic acid, a plant growth-regulating
Fungal Pheromones or Chemotactic Agents compound, is synthesized as a sesquiterpene in fungi. De-
<'Iant-Fungal Interactions spite the fact that this compound often is considered a sesqui-
Phytoalexins terpene, in higher plants abscisic acid is derived from the
Phytotoxins
breakdown of xanthophylls and should be considered as a
Plant-Animal Interactions
tetraterpene derivative (see Chapter 26).
Plant allomones
In the sesquiterpene series, a-, mono-, bi-, trio, and tet-
Kairomones
racyclic compounds are known (Fraga, 1991). Of these, bi-
Synomones
cyclic and tricyclic compounds predominate. Most sesquiter-
Insect semiochemicals
penes occur free, although glycosides of this series are
Allomones or Defensive Compounds in Insects
known (Wong et al., 1991).
Insect pheromones
Insect Juvenile Hormones and Plant Juvenile Hormone Basically, the same phylogenetic conclusions that can be
Mimics derived from studies of the structural types and distribution
Essential Oil Components of monoterpenes are true for sesquiterpenes. Despite their
Sweeteners diversity, these compounds have proved to be of liruited
Picrotoxins value in establishing the phylogeny of higher plants.
Sesquiterpene Lactones Sesquiterpenes are catabolized by poorly understood
Biogenesis pathways (Loomis and Croteau, 1980).
Chemosystematic Studies Involving Sesquiterpene Techuiques for the isolation and purification of sesquiter-
Lactones penes include extraction, followed by various types of chro-
Biological Activity matography (Baerheim Svendsen and Scheffer, 1985; Cos-
Plant Growth Regulator Activity cia, 1984; Fraga, 1991). Mass spectrometry and nuclear
Allelopathic Effects magnetic resonance (NMR) spectroscopy are the most com-
Plant AIlomones monly used methods for characterization of sesquiterpenes.
Chemotactic Agents from Parasitic Plants Accumulation of sesquiterpenes is associated with spe-
Medicinal Uses cialized secretory structures, and even though both monoter-
References penes and sesquiterpenes may be synthesized within oil

367
368 Sesqu;terpenes

~OH
~ 9J1
'"
0
I h i h' "
; 6 ;0S 0
",OH yjy""
A HO

emmotinA S-elemene
7-hydroxyealamenene furanoeudesma-l,3-diene

drimenol cedrol guaiol ex-copaene (58)

longirolene (22) P-santalol p-caryophyllene (11) germncrene D (67)

1 •

~~o
:,..

12 o 0 HO ~

P~
costunolide (119) germaerene A y-lirlodenolide , 0
epox/de (20)
H

HO~"" ,,,p ~
goYazeOSOvlide(l20)
...
"-._",, , :,..

....
o _""...,,"" :,.. ""

gynomitr-8(12)·en.9-ex-ol (1) gymnomitr-8(12)-enone (2) patchonlol (14)

humulene (10)

Fig. 21.1. Representative sesquiterpenes.

glands, accessibility of the sites of synthesis to the precursor
molecules differ (Banthorpe and Charlwood, 1980; Croteau
and Johnson, 1984; Loomis and Croteau, 1980). In Pinus
pinaster needles, synthesis of sesquiterpenes occurred for
the length of the needle, whereas monoterpenes were ouly
synthesized at the base of young needles (Croteau and John-
son, 1985). Rates of incorporation of exogenous precursors
often are low, but the use of specifically labeled precursors
and degradation studies indicates that sesquiterpenes are la-
beled by mevalonic acid (MYA), isopentenyl pyrophosphate
(IPP), dimethylaliyl pyrophosphate (DMAPP), and geranyl
pyrophosphate (GPP) (Loomis and Croteau, 1980).
Most evidence supports synthesis of sesquiterpenes in
the cytosol/microsomal compartment of plant cells (Threlfall
and Whitehead, 1991). The endoplasmic reticulum appears
to be the site ofFPP synthase (prenyltransferase) and sesqui-
terpene cyclase activities, although several studies show that
key biosynthetic enzymes are operationally soluble (Gers-
henzon and Croteau, 1990).
Production of sesquiterpenes in cell cultures has been
of value for study of biosynthesis (Ellis, 1988); in several
instances, the amount of products was enhanced by challeng-
ing the culture with fungal pathogens. In general, however,
the levels of sesquiterpenes produced in culture is low
(Charlwood and Charlwood, 1991). Bryophytes are unique
in that terpenoids are stored in intracellular oil bodies. In
Calypogeia granulata, both gametophytic cells and suspen-
sion cultures contain dark blue bodies in which the trinorses-
quiterpene, 1,4-dimethylazulene, accumulates (Charlwood
and Charlwood, 1991). The main components of the oil from
cultures of Reboulia hemisphaerica are gymnomitr-8(12)-
en-9a-ol (1) and gymnomitr-8(l2)-en-9-one (2). Differen-
 Sesquiterpenes 369

tiated cultures of liverworts have proven to be useful for the
accumulation of sufficient material for study (Charlwood
and Charlwood, 1991).
A number of alkaloids that possess sesquiterpene skele-
tons are discussed under Sesquiterpene Alkaloids in Chapter
36.
BIOSYNI'HESIS
Sesquiterpenes are derived from a IS-carbon intermediate,
farnesyl pyrophosphate (3), which is assembled by head-to-
tail fusion of isoprene units (Cane, 1990). Biogenetic paths
to most of the important structural types of sesquiterpenes
have been proposed, but few have been studied in detail.
The diversity of sesquiterpenes is much greater than that
of monoterpenes, but also exceeds that of diterpenes and
triterpenes. This situation presumably reflects the much
greater conformational flexibility of the 10- or II-membered
rings as compared with that of 6-membered rings in the last
two classes.
Biosynthesis of (E.E)-Farnesyl
Pyrophosphate
Each of the known skeletal types is derived from (E,E)-
farnesyl pyrophosphate (FPP) (3), formed by union of a mol-
ecule of isopentenyl pyrophosphate (IPP) and dimethylallyl
pyrophosphate (DMAPP) to produce an enzyme-bound gera-
nyl pyrophosphate. That intermediate, in tum, reacts with
another unit of isopentenyl pyrophosphate (Fig. 21.2) (Cane,
1985, 1990; Croteau, 1987; Croteau and Johnson, 1985).
Geranyl pyrophosphate normally does not accumulate dur-
ing this process. The reaction occurs with net inversion of
configuration (Cane, 1990).
A prenyl transferase, FPP-synthetase (BC 2.5.1.1), from
extracts of germinating castor bean seedlings, has been
highly purified; both forms obtained synthesized all E-farne-
syl pyrophosphate (porter and Spurgeon, 1981). FPP synthe-
tases also have been demonstrated from Gossypium hirsutum
and from Pisum sativum (Croteau and Johnson, 1985). E,E-
Farnesyl pyrophosphate synthetase is proposed to employ
a stepwise ionization-condensation mechanism involving a
rigid pyrophosphate-carbonium ion pair as an intermediate
(Poulter et al., 1981).
The stereochemistry is well established, and many ques-
tions concerning the overall mechanism of the condensation
have now been resolved. Farnesyl pyrophosphate synthetase
(EC 2.5.1.1) is the key enzyme in the biosynthetic pathways
for several classes of terpenes. This enzyme catalyzes 1'-4
condensation between IPP and DMAPP, or geranyl pyro-
phosphate, polymerizations that constitute the major build-
ing steps of terpenoid biosynthesis (Fig. 21.2) (Poulter and
Rilling, 1978; Poulter et al., 1978, 1981). The condensation

OH
~ OH_ H~

,
Ho,e HO,Cr>4.X'7 ~ B /-J
OH'" ) ( "'-./ 'OPP -+ OPP
,~ ,~
mevalonic acid IPP

~
APP

A)(!'s
:::,... + J
~OPP
inversion
--+ "" lis B,,~
OPP
OPP
DMAPP B"HR ""
IPP

I"... I".. I"..

~OPP
Hs Us

GPP
R I .y

OPP

(E,E)-farnesyJ pyrophosphate (3)

Fig. 21.2. Formation of (E,E)-farnesyJ pyrophosphate.

370 SesquUerpenes
reaction may be subdivided into three phases: ionization,
condensation, and elimination. Ionization of the pyrophos-
phate group of DMAPP and activation of the allylic moiety
is the first step of both hydrolysis and condensation of IPP.
Studies by Poulter and co-workers indicate that cleavage
of the carbon-oxygen bond of geranyl pyrophosphate is a
discrete step, yielding a geranyl cation-pyrophosphate ion
pair and that this reactive species subsequently alkylates the
double bond in IPP. These workers concluded that ionization
and condensation are not concerted (Poulter et al., 1981).
Studies with [1- 18 01geranyl pyrophosphate indicate that ex-
change of oxygen does not occnr dnriog the reaction, and
that a highly structured ion pair exists (Mash et al., 1981).
The biosynthesis of sesquiterpenes in plants appears to
be isolated from that of either monoterpenes or diterpenes. A
prenyl transferase isolated from pumpkin (Cucurbita pepo,
Cucnrbitaceae) converts Cs units into FPP, but not into gera-
nylgeranyl pyrophosphate (the precnrsor to diterpenes). An-
other enzyme from the same source forms C20 terpenoids
from Cs units, but does not accumulate lower homologs (also
see Chapters 19 and 22). However, because famesyl pyro-
phosphate synthetase is a branch-point metabolite for the
synthesis of sesquiterpenes, triterpenes, and sterols, this en-
zyme is ubiquitous in plants (Croteau and Johnson, 1985).
Asynunetric labeling of sesquiterpenes by labeled meva-
lonic acid or other precnrsors, presnrnably caused by an en-
dogenous pool of DMAPP, has been reported for a few ses-
qniterpenes. Label primarily is introduced into the portions
of the molecules derived from IPP (Charlwood and Banth-
orpe, 1978).
The formation of 2-E-6-E-famesyl pyrophosphate (3)
from (4S)- and (4R)-[4-3Htl-MVA in systems from Pinus
and from Citrus species, is accompanied by loss of the pro-
4S hydrogen and retention of the pro-4R hydrogen (the pro-
4S proton of mevalonic acid becomes the pro-2R proton of
isopentenyl pyrophosphate). The possibility of interconver-
sion of 2-E-6-E-famesyl (2-trans-6-trans-famesyl) (3) and
2-Z-6-E-famesyl (2-cis-6-trans-famesyl) (4) pyrophosphate
has been ruled out in these systems.
Interconversion of 2-.8-6-.8- and 2-Z,6-.8-
FarnesylPyropbospbate
Both 2-E-6-E-famesyl (2-trans-6-trans-famesyl) (3) and
2-Z-6-E-famesyl (2-cis-6-trans-famesyl) (4) pyrophosphate
have been suggested as intermediates for various types of
cyclic systems (Fig. 21.3), but, at present, there are no unam-
biguous examples of conversion of 2-E- to 2-Z-famesyl py-
rophosphate. The direct conversion of the 2-E compound to
cyclic intermediates without intermediacy of the 2-Z com-
pound has been suggested. This may possibly occnr because
of the conformational flexibility of the lO-carbon ring
(Banthorpe and Charlwood, 1980; Loomis and Croteau,
1980). The status of a 2-Z-famesyl pyrophosphate synthetase
is uncertain (Croteau and Johnson, 1985).
The isomerization of E,E-famesol to Z,E-famesol by an
enzyme system from Andrographis paniculata (Acantha-
ceae) tissue culture leads to loss of the pro-S hydrogen atom
from C-l of Z,E-famesol (6) (Fig. 21.3).
Acyclic Sesquiterpenes
Most acyclic sesquiterpenes are derived from famesol
and nerolidol (7) or from the corresponding pyrophosphate
esters. Although the number of acyclic sesquiterpenes is rela-
tively small, Z- and E-famesol (5 and 6), nerolidol (7), and
the corresponding olefins are relatively common in essential
oils. The famesenes and a few other compounds, such as 13-
sinesal (8), are derived in a straightforward manner, but most
acyclic sesquiterpenes are more complex in origin (Fig.
21.4).
Cyclization of Acyclic Precursors
Cyclases transform 2-E-6-E-famesyl pyrophosphate into
cyclic sesquiterpenes via ionization and electrophilic attack
of the resultant allylic cation on either the central or distal
double bonds (Cane, 1990). The stereochemistry of bond
scission, of ring closure, and of the migration of hydrogens
and alkyl groups involves overall anti stereochemistry. Such
stereochemistry probably is observed because the cyclase
acts as a template for the acyclic precnrsor, allowing it to
adopt the conformation from which the series of stereospe-
cific transformations proceed with greatest facility (Cane,
1990; Loomis and Croteau, 1980). The central theme of the
biosynthetic hypotheses for sesquiterpene biosynthesis is an
intramolecular attack by electrons of either the central or
distal double bond of the famesyl molecule on the carbon
bearing the pyrophosphate (Cane, 1985; Croteau, 1987; Cro-
teau and Johnson, 1985). Orbital aligument also is an impor-
tant consideration in sesquiterpene cyclizations that are initi-
ated by double-bond protonation rather than pyrophosphate
ionization. Enzymatically controlled initial intramolecular
attack governed by either electronic or steric effects pro-
duces a monocyclic system. Subsequent 1,2- and 1,3-hydride
shifts, oxidations, cyclizations, and reductions lead to the
observed diversity of structures. Predictable cationic inter-
mediates are useful for explaining the lines of compounds
that arise from various points in the biosynthesis (Fig. 21.5)
(Cane, 1990; Loomis and Croteau, 1980; RUcker, 1973).
The first step in the enzymatic formation of sesquiter-
penes is the ionization of 2-E-6-E-famesyl pyrophosphate
(3) to the corresponding transoid allylic cation-pyrophos-
phate anion pair. This ion pair can undergo several transfor-
mations. Nucleophilic attack on the back face of the allylic
cation by the neighboring 10,11 double bond will result in
net anti displacement of the pyrosphate moiety from C-l
and formation of a new C-C bond (Cane, 1990). On the
other hand, collapse of the ion pair will either regenerate
the starting material or the transoid conformer of nerolidol
pyrophosphate (9) by a net suprafacial allylic rearrangement.
The tertiary allylic pyrophosphate ester can undergo simple
rotation about the newly generated 2,3 single bond followed
by reionization to the corresponding cisoid allylic cat-

Q 'R.
Andrographis paniculata
ceJl free e)[tract
(5)
Andrographisptmicu/sla
ceJlfreeexh'ad
Fig. 21.3. Isomerization of 2-E-6-E-famesol and 2-Z-6-E-famesol (modified from Mackie and Overton, 1977; used with pennission of the copyright
owner, European Journal of Biochemistry Zurich).
ion-pyrophosphate anion pair. The nature of the products
eventually formed are a function of the stereochemistry and
conformation of the intermediates (Cane, 1990). Cyclases
may serve as the rate-controlling enzymes in sesquiterpene
biosynthesis.
In order for cyclization of the intermediates to occur, the
1T-orbitals of the relevant double bonds must be properly
aligned to achieve the required geometry for interaction.
This condition is met only if the individual double bonds of
the allylic substrate are mutually perpendicular to a common
plane. Further, C-l to C-4 and the attached methyl group,
C-IS, are constrained to a common plane, as are C-S to C-
8 andC-14, and C9 to C-13. To cyclize, C-l must be brought
to within bonding distance of either the central or distal dou-
ble bond with displacement of pyrophosphate from C-l of
famesyl pyrophosphate occurring with net anti stereochem-
istry (Cane, 1990). For those cases which require the inter-
mediacy of an nerolidol pyrosphate-like intermediate, the
allylic displacement of the pyrophosphate moiety will take
place in an anti sense from a cisoid confonnation (Cane,
1990).
Sesquiterpenes 371
R
I OH (5)
H,
(3)
Opp
(4)
Opp
The cyclases isolated to date are operationally soluble
proteins in the molecular weight range of 40,000-100,000.
Several are monomers, whereas at least two are homodimers.
The enzymes are moderately lipophilic and require no cofac-
tor other than a divalent metal ion, Mg2+ usually being pre-
. ferred. The role of these enzymes appears to be to bind the
substrate in a conformation appropriate for cyclization and
to catalyze the ionization of the allylic pyrophosphate ester
(Cane, 1990).
Two of the most common sesquiterpenes, humulene (10)
and J3-caryophyllene (11), were synthesized by a soluble
enzyme preparation from leaves of sage (Sa/via ojficinalis,
Lamiaceae). Partial purification of the extracts allowed reso-
lution of the two cyclizing activities. Both cyclases had mo-
lecular weights of S8,000 and depended on the presence of
a divalent cation; Mg2+ was preferred (Cane, 1990).
The origin of eremophilane sesquiterpenes by migration
of a methyl group from C-IO to C-S in an eudesmane inter-
mediate has been postulated to reconcile the apparent devia-
tion of eremophilanes from the isoprene rule (Cane, 1990).
( - )-Aristolochene (12), an eremophilane-type sesquiter-
372 Sesquiterpenes

R I -;?

farnesyl pyrophosphate (3)

opp

nerolidol (7) p-sinesal (8)

davanone ipomeamarone (38)

o
freelingyne

Fig. 21.4. Representative acyclic sesquiterpenes.

pene has been isolated from several plants; among these
are Aristolochia indica (Aristolochiaceae) and Bixa orellana
(Bixaceae), as well as in the defensive secretions of soldiers
of the termite Synfermes na. According to the proposed
mechanism, cyclization of farnesyl pyrophosphate by elec-
trophilic attack at C-1O of the distal double bond, followed
by loss of a proton from one of the two adjacent methyl
groups will generate the known sesquiterpene germacrene
A (13). The latter intermediate can undergo further cycliza-
tion by protonation at C-I and attack of the resultant cation
on the 4,5 double bond to form the bicyclic eudesmane cat-
ion, which can rearrange by sequential 1,2-hydride and
methyl migrations to yield ( - )-aristolochene (12, Fig. 21.6).
The reaction is catalyzed by a single enzyme, with no evi-
dence for the release of free intermediates (Cane, 1990).
In tobacco and in potato cell cultures, the levels of cy-
c1ases are increased by treatment with fungal elicitors; at the
same time, the level of squalene synthase activity declines
(Gershenzon and Croteau, 1990; Loomis and Croteau, 1980).
The 5-epi-aristolochene cyclase is involved in the formation

12

13
15

opp

/
~-\rb-8 neroJidyl pyrophosphate (9)

:if
farnesyl pyrophosphate (3)

~-~/
Fig. 21.5. Isomerization of E,E~famesyl pyrophosphate to the corresponding alllylic cation-pyrophosphate ion pair, and subsequent modifications
(modified from Cane, 1990; used with permission of the copyright owner, Copyright 1990, American Chemical Society, Washington, DC),
 Sesquiterpenes 373

__
H+

" --+-

-H

11
farnesyl pyrophosphate (3) germacrene A (13)
H

~ --+-

~
13

eudesmane cation (-)-arisotolochene (12)

Fig. 21.6. Biosynthesis of ( - )-aristolochene (modified from Cane, 1990; used with pennission of the copyright owner, Copyright 1990, American
Chemical Society. Washington, DC).

of products such as capsidio!. TItis enzyme consisted of two
proteins with molecular weights of 61,500 and 63,500, re-
spectively (Cane, 1990).
A cyclase from Pogostemon cablin (syn. P. patchouli
and P. heyneanus) leaves is capahle of converting farnesyl
pyrophosphate to (- )-patchoulol (14, Fig. 21.7). Cell-free
exlracts catalyze the conversion of farnesyl pyrophosphate
(3) to patchoulol (14) along with a mixtore of cyclic olefins
such as a-, (3-, and 'Y-patchoulene (15, 16, 17) as well as a-
hulnesene (18) and a-guaiene (19). However, sesquiterpene
olefins do not participate as free intermediates in the trans-
formation of farnesyl pyrophosphate to patchoulol (Cane,

Fig. 21.7. Biosynthesis of patchoulol (Cane, 1990; modified and used with pennission of the copyright owner, Copyright 1990. American Chemical
Society, Washington, DC).
374 Sesquiterpenes
1990; Croteau et al., 1987). Furthermore, studies with
[12,13- 14C;6-3Hlfarnesyl pyrophosphate as a precursor iodi-
cate that deprotonation-protonation steps to form bound ole-
finic iotermediates io the biosynthesis of patchoulol do not
occur, providiog support for a hydride shift mechanism (Cro-
teau et al., 1987). Patchoulol synIhase had a molecular
weight of 80,000 and consisted of two identical subunits of
40,000.
In this iostance, the sesquiterpene olefin cyclase activity
could not be separated from the patchoulol synthase activity
and showed similar pH and metal ion requirements, suggest-
ing that the olefinic products are derived by diversion of the
various carbocation iotermediates (Cane, 1990).
Tbe Origin of lIIigor Groups of Cyclic
Sesquiterpenes
Germacranes often are portrayed as beiog derived from a
2-E-6-E-iotermediate. These sesquiterpenes possess a 4,10-
dimethyl-7 -isopropyl cyclodecane system and often have
double bonds io positions 1 (io germacrane A epoxide, 20)
~ CHOH
':'OHIII
NIIH
HOI
h -
carotol sirenin (30)
(a)
Fig. 21.8 (a & b). Sesquiterpenes derived from a 2-E-6-E-famesyl pyrophosphate precursor.
and 4 (Fig. 21.8). The reactive cyclodecadiene system
has been hypothesized to be transferred readily ioto other
mono-, bi-, and tricyclic sesquiterpenes and, thus, the germa-
cranes often are suggested as key iotermediates in the synthe-
sis of other sesquiterpenes. However, io many iostances, it is
probable that no olefinic iotermediates occur, and the actual
iotermediates may be only transient cations. Other major
types of sesqniterpenes are the selioanes (eudesmanes), guai-
anes, pseudoguaianes, elemanes, and eremophilanes (Fig.
21.8) (Riicker, 1973). Guaianes, eremophilanes, and pseu-
doguaines are especially common io the Asteraceae, the last
type occurring only as lactones and in that family (Herz,
1977).
The biosynthesis of many relatively complex sesquiter-
penes, many of them fungal metabolites, has been reviewed
(Cane, 1981). Much biosynthetic study has been carried out
with fungi because of the greater ease of labeliog and culture
of the organism.
In the past, it has been considered Ihat a 2-Z-6-E-precur-
sor gives rise to monocyclic sesquiterpenes with one 6-
a-humulene
~~
0 H
I 0
2 tricbothecin OCOCH=cHCH3
 Sesquiterpenes 375

4)~7 5)A~ ~i- YQy""'i

I Yr,C(HOiH I'
!
~ opp \o..0Pp!
~ a maaliane
•
an aristolane

P~~->B-
~ ~.~
\,;{/)f?y~
I·~ i

rH~
I
• +
a se:inane or eudesmane 0 al
a pseudogu ane

~H
~!
0yPy~~
~O 0
, H , ! 9' ! a germacranolide

ro =
-::- + - peremophilane
?an ~COCH3

rth.
1i H

(b)
~~-~
(+).loDgifolene (22) a germacrane

Fig. 21.8. (continued)

anelemane
CHO

membered ring (bisabolenes) and systems with ai,7-di-
methyl4-isopropyl skeleton (Fig. 21.8). Among these ses-
quiterpenes are the cadinenes, cubebanes, copabomanes, and
ylangenes (Rucker, 1973). However, most (if not all) sesqui-
terpenes are now thought to arise via the intennediacy of 2-
E-6-E-farnesyl pyrophosphate (Cane, 1990). The cyclase for
bisabolene derivatives of Andrographis paniculata has been
examined (Cane, 1990). Although the origin of the cadinenes
[e.g., 'Y-cadinene (21») usually has been explained by a 2-
Z-6-E-precursor, there is considerable evidence for a biogen-
esis involving the all E-precursor (Fig. 21.9) (Arigoni, 1975;
Loontis and Croteau, 1980).
The sesquiterpene alkaloid dendrobine (87, Fig. 21.20)
also appears fonnally to be derived from a 2-Z-6-E-precur-
sor, but is labeled by the E,E-isomer and not by the 2-Z-6-
E-compound (Loontis and Croteau, 1980) (see sesquiterpene
alkaloids Chapter 36).
The monocycIic humulanes (11 -membered ring) and
bicyclic caryophylIanes (cyclobutane-cyclononane) may
arise from a common precursor. In Salvia officinalis,
humulene (10) and j3-caryophylIene (11) appear to have
a common intennediate (a humulyl cation), although
they may be synthesized by separate enzymes, humu-
lene cyclase and caryophyllene cyclase (Croteau and
Gundy, 1984; Dehal and Croteau, 1988). Both enzymes
have a molecular weight of 57,000, and prefer Mg2+
as the divalent cation. Both humulene and caryophylIene
are widely distributed in nature (Riicker, 1973). The
same precursor that leads to caryophylIene also leads to
longifolene (22), longibomeol, and 10ngicycIene, all of
which are found in pine resins (Riicker, 1973). 'Y-Bisabo-
lene (23) occurs commonly in plants, usually accompanied
by compounds of similar structure and apparent biosyn-
thetic origin.
376 Sesquiterpenes
--,Y~l{.
GJ -1'1(
r;I
--
Fig. 21.9. Proposed mechanism for the conversion of E,E-famesyl pyrophosphate to 'Y-cadinene.
BIOLOGICAL ACTIVITY
A number of sesquiterpenes have pronounced biological ac-
tivity both in the plants themselves and toward other organ-
isms. Illudane sesquiterpenes such as ptaquiloside (24) from
bracken and several other ferns are responsible for the car-
cinogenic activity of these plants, including some used as
food products (Fig. 21.10) (Saito et al., 1990).
Allelopatby
Several sesquiterpenes [as well as sesquiterpene lactones
(see the subsection later in chapter)] inhibit the growth of
plants and the germination of seeds (Fischer, 1991a; Fischer
et al., 1989a). The sesquiterpene aldehydes (+ )-vitrenal
(25), ( - )-Iepidozenal (26), and isobicyclogermacrenal from
the liverwort Lepidozia vitrea and plagiochilin (27) from
Plagiochila ovalifolia inhibit growth of other plants. Plagio-
chilin inhibits the growth of rice seedlings at 50 ppm (Fi-
scher, 1991a). A mixtore of ~-bisabolene (23), a-guaiene
(19), a-bulnesene (18), ~-patchoulin (16), and bergamotene
(28) from Ambrosia artemisifolia strongly inhibited germi-
nation of onion, oat, rye grass, and Amaranthus palmeri
seeds (Fig. 21.10) (Fischer, 1991a).
Medicinal Properties
Gossypol (29, Fig. 21.14) has been evaluated as a male
contraceptive. This compound also has direct effects on
sperm and may have potential as a vaginal spermicide. Gos-
sypol is active orally, but sometinles has serious side effects.
In vivo tests reveal that only ( - )-gossypol is active (Anon.,
1984; Bingel and Fong, 1988).
Fungal Pberomones or Cbemotactic Agents
Sirenin (30, Fig. 21.8) is a sexual pheromone from AlIo-
myces macrogynus (Jaenicke, 1991). In this phycomycete
H
r-cadinene (21)
genus (a coenocytic, filamentous aquatic fungus) which re-
produces both sexually and asexually, the gamete-bearing
generation produces small, orange male gametangia and
larger, colorless female gametangia (gametes are haploid sex
cells that unite to produce a zygote). The gametes released
are motile, uniflagellate cells that lack cell walls and are
surrounded by a double membrane. Male gametes are highly
motile and are strongly attracted to the female gametes.
Under the microscope, the male gametes can be observed
to cluster in the vicinity of unopened female gametangia
(the stroctures that bear the gametes). Male gametes also
approach and cluster against a dialyzing membrane that sep-
arates them from a supernatant in which female gametangia
have discharged female gametes. The active compound was
christened sirenin (Mascarenhas, 1978; O'Day and Horgen,
1981). Parisin, a compound of similar but undefined stroc-
tore, which serves as an attractant for the female gametangia,
is produced by the sperm cells (pommerville et al., 1990).
In order to obtain large quantities of material for study,
hybrids of A. arbuscula and A. javanicus that produce about
95% either male or female gametangia were produced. Hy-
brids that gave rise to mostly female gametangia produced
sirenin. Of several analogs tested, I-sirenin (30) (the natu-
rally occurring form) was the most active.
PLAl"IT-ftJNGAL Il'I'fERACDOl'IS
Many sesquiterpenes are produced and accumulated by both
plants and fungi. A variety of different types of biological
activity is expressed. In plant pathogen-plant interactions,
sesquiterpenes play both defensive and offensive roles.
Pbytoalexins
Several sesquiterpenes are phytoalexins (Brooks and
Watson, 1985; Gross, 1977; Kuc, 1992). These compounds
 Sesqu;terpenes 377

HO~
Xb
OH 0

HO OH

ptaquiloside (24) (+)-vitrenal (25) (-)-Iepidozenal (26)

~
:
,
CH,COO H0

I OCOCH,
~",,/
I
CH,COO

plaglocbllin (27) a-goalene (19) «-bulnesene (18)

B-PBkboulin (16) bergamotene (28) longicyclene

longlborneol

Fig. 21.10. Biologically active sesquiterpenes.

are especially common in plants of the Solanaceae and Con-
volvulaceae.
Capsidiol (31), an eudesmane sesquiterpenoid, is fonned
from E,E-famesyl pyrophosphate by the pepper Capsicum
annuum when inoculated with the spores of Moniliafruticola
(Threlfall and Whitehead, 1991). The mode of incorporation
of acetate suggests a biosynthetic scheme in which the angu-
lar group has undergone a 1,2 shift, rather than involving
spiran intennediates, as are involved in the biosynthesis of
other solanaceous phytotoxins (Brooks and Watson, 1985;
Harbome, 1982; Stoessl, 1982).
A number of sesquiterpene phytoalexins accumulate in
potato (Solanum tuberosum) in response to attack by Monol-
iniafruticola, Phytophtlwra infestans, and Alternaria solani.
Among these are rishitin (32), lubimin (33), phytotuberin
(34), and several other sesquiterpenes (Brooks and Watson,
1985; Kuc, 1992). Cell walls of P. ilifestans contain an elici-
tor of phytoalexin accumulation in potato (Kuc, 1982). Simi-
lar phytoalexins are synthesized by a number of other solana-
ceous plants (Harbome, 1986a; Kuc, 1992; Nahrstedt, 1979).
The biosynthetic pathway leading to rishitin involves a vet-
ispirane intennediate, although other similar compounds
such as aubergenol (35) and aubergenone (36) are nonnal
eudesmanes (Beale and MacMillan, 1988).
A sesquiterpene from Nicotiana debneyi, debnyol (37),
is highly fungitoxic to spores of the fungal pathogen Peron-
ospora tabacina (Kuc, 1992).
Ipomeamarone (38) is a fungicide or phytoalexin pro-
duced by the sweet potato (Ipomoea botatas, Convolvula-
ceae) in response to the black-rot fungus, Ceratoeystis fim-
briatum (Fig. 21.11) (Kuc, 1992). Some of the enzymes
involved in the fonnation of this compound have been iso-
lated and studied (Threlfall and Whitehead, 1991). Ipo-
meamarone is not produced by healthy sweet potatoes
(Brooks and Watson, 1985; Coxon, 1982; Threlfall and
Whitehead, 1991), but is thought to be elicited by weevil-
derived polygalacturonase activity (Croteau and Johnson,
1985). Although sweet potatoes are an importaut food for
378 Sesquiterpenes
pbytotuberin (34) rishitin (32)
lubintin (33) solavetivone
01 .~ .. ?Y, . ~" ~
~~~C~H
debneyol (37) capsidiol (31)
Fig. 21.11. Sesquiterpenoid phytoalexins.
humans and livestock, approximately 35% of the annual crop
is lost by spoilage. Phytoalexins, such as ipomeamarone,
often are produced; these compounds are hepatotoxic. Re-
lated compounds produce lung edema. The actual levels of
toxins are not predictable by visual examination, and normal
cooking does not reduce the levels of bioactive compounds
(Beier and Nigg, 1992).
A number of sesquiterpenoid phytoalexins related to gos-
sypol (29, Fig. 21.14) have been isolated from members of
the genus Gossypium (Malvaceae) (Coxon, 1982; Gershen-
zon and Croteau, 1991). These compounds inhibit germina-
tion of conidia of the fungus responsible for verticillium wilt
in cotton at levels well below that of fungicidal activity
(Mace et al., 1985). The principal phytoalexin produced is
hemigossypol (39) (Brooks and Watson, 1985).
Pbytotoxins
Prehelminthosporal (40), a phytotoxin produced by the
fungus Helminthosporium sativum, causes necrosis in cereal
grains (Fig. 21.12) (Ballio, 1981; Stoessl, 1981). Another
compound, helminthosporal (41), probably an artifact, lacks
significant biological activity. The related compound, hel-
minthosporol, has gibberellin-like properties. The phytotox-
ins of Helminthosporium sacchari are three isomeric sesqui-
terpene glycosides (42-44) (Harborne, 1986b; Macko et a!.,
1983). The phytotoxins of several Phoma species also are
sesquiterpenes (Harborne, 1986b).
phytotuberol bentigossypol (39)
anhydro-jl-rotunol aubergenone (36)
o.
ipomeamarone (38) .ubergenol (35)
Other phytotoxins contain the 12,13-epoxytrichothecene
nucleus (such as 45). Most compounds of this group are
potent skin irritunts and are acutely toxic to mammals at low
concentrations. Trichothecenes are powerful mycotoxins
and often have been implicated in fatal human and animal
diseases (Fenwick and Morgan, 1991; Stoessl, 1981). Ali-
mentary toxic aleukia, caused by trichothecenes in cereal
grains, killed tens of thousands of people in the former Soviet
Union, especially in the aftermath of World War II (Fenwick
and Morgan, 1991). T-2 toxin (46) from moldy brewers'
grain has produced death of livestock as well as humans
when consumed. At least 40 beer drinkers in Quebec, the
United States, and Belgium were killed when moldy grain
was used to prepare beer (Beier and Nigg, 1992). Other trich-
othecenes have been reported to possess antitumor activity
(Cordell, 1978). Similar compounds have been isolated from
Fusarium, Myrithecium, and Trichothecium species (Ballio,
1981;· Herout, 1973).
The cyclases from trichodiene systems have been exam-
ined (Cane, 1990).
Trichothecenes and related sesquiterpenes have been iso-
lated from the Brazilian plants Baccharis megapotamica and
Baccharis cordifolia (Asteraceae) (Fig. 21.12). The com-
pounds are chemically identical to fungal metabolites pro-
duced by the soil fungi (Jarvis et al., 1981, 1985, 1988,
1991). Although it had been suggested that these sesquiter-
penes are taken up by the plant and chemically modified,
more recent evidence indicates that they are synthesized by
 Sesquiterpenes 379

the plant (Jarvis et al., 1988). Removal of the seed coats of
these species precluded germination of the seeds; the addi-
tion of trichothecene roridins or baccharinoids (10- 6 fJ.g/ml)
resulted in germination (Kuti et al., 1990). these com-
pounds had pronounced anticancer activity. Only two
species of Baccharis (out of 100 tested) contained these com-
pounds.
Trichothecenes are potent mycotoxins. In the period fol-
lowing the Vietnam War, one such compound achieved no-
toriety as a chemical warfare agent called "yellow rain"
(Jarvis et al., 1981, 1985). However, traces oftrichothecenes
are common in natnre, making identification of the source
difficult.
Mass spectrometry has been useful for the characteriza-
tion of compounds of this group (Plattner et al., 1989).
A number of other sesquiterpenoid phytotoxins and my-
cotoxins have been reviewed (Herout, 1970, 1973; Stoessl,
1981).
PLAl'IT-Al'IIl'IAL INTERACTIONS
Plant aIlomones
Many plants produce sesquiterpenes that are inhibitory
to growth or repellent to at least some groups of insects (Fig.
21.13) (Hedin et al., 1974; Kelsey et al., 1984; Mabry and
Gill, 1979). Several examples from the literatnre are dis-
cussed below.
Several sesquiterpene antifeedants, such as the drimane
dialdehydes, warburganal (47) and polygodial (48), have
been isolated from the East African trees Warburgia stuhl-
mann;; and W. ugandensis (Canellaceae) (Gershenzon and
Croteau, 1991). Polygodial (48) also appears to be wide-
spread in the genus Polygonum (Polygonaceae). Warburga-
nal is a less general antifeedant than azadirachtin (see Chap-
ter 25) and is active against the army worm (Spodoptera
littoralis), but it does not deter locust feeding. Warburganal

HO
~. . ~H'&
0
CHO
~HO
R
helminthosporal (41)
prehe1minthosporal (40) an artifact of workup

rl~o/OH
OH

-::?"Y--f
o
(CH'hCHCH,lLo:u

CH,COO OCOCH,
a trichothecene (45) T-2 toxin (46)

H H

~0"
o OH

) 0

O~
Ol'
,. 011' 10'

OH
3'
S'
4'
H
8'
17,
.'
o
H
baceharinoid 3 roridin E roridinA

RO (y~ RO'M RO M

YJnOR ~OR ~OR

(42) (43) (44)

Helminthosporium sacehari pbytotoxins

R = gal(f) (1 ---->5) gal (f)
Fig. 21.12. Some sesquiterpenoid phytotoxins.
380 Sesquiterpenes
~'
OCOCH3
shiromodial diacetate (SO)
warburgaoal (47)
Fig. 21.13. Sesquiterpene antifeedants.
is highly cytotoxic (0.01 fLglml against a KB cell culture
line) and antifeedant (0.1 ppm/cm2 against the African anny
worm). Warburgana1 (47) and muzigadial (49) are toxic to
snails that are vectors for schistosomiasis at 5-10 ppm (2
h) (Famsworth et aI., 1987; Fraga, 1991; Henderson et aI.,
1987). These compounds have a hot taste to humans and
the plants are used as a spice (Harbome, 1982; Kubo and
Nakanishi, 1977; Mabry and Gill, 1979). A sesquiterpene
dialdehyde blocks the sugar receptor of S. exempta for 10-20
min after two contacts of 2 min (Stadler, 1984).
Polygodial (48) also occurs in the mantle of a dorid nudi-
branch Dendrodoris limbata and has antifeedant properties
against a number of marine and freshwater fish. This sesqui-
terpene defensive compound is synthesized by the nudi-
branch, in contrast to the protective compounds of most nu-
dibranchs that are taken from the sponges on which they
feed (Harbome, 1986b).
Other antifeedants such as shiromodiol diacetate (50)
have been isolated from Parabenzoin trilobum (syn. Lind-
era, Lauraceae). These compounds are active against feeding
by polyphagous and oligophagous insects at the 0.05-0.1 %
level in artificial diets (Mabry and Gill, 1979; Munakata,
1977).
Leaf cutter ants, abundant from Texas to Argentina, are
polyphagous herbivores, but will not attack several plants.
The ant, Alta cephalotes, for example, does not feed on Lasi-
anthaea fruticosa (Asteraceae). The active repellent sub-
stance is lasidiol angelate (51) (Wiemer and Ales, 1981).
Three of four other inhibitory compounds to ant feeding,
nerolidol (7), caryophyllene epoxide (52), kolavenol (a diter-
pene), and caryophyllene (not active), either produced dra-
matic effects on the ants or the fungus cultivated by the ants
(Howard et aI., 1988).
Cotton plants bear glands that contain gossypol (29), a
dimeric cadinene-type sesquiterpene. This compound is as-
sociated with resistance to bollworm larvae, rabbits, rodents,
lasadiol angelale (51) caryophyllene oxide (52)
polygodlal (48) muzigadial (49)
and other herbivores and is responsible for several toxicity
effects when cottonseed meal and other cotton products are
utilized by humans and livestock (Gershenzon and Croteau,
1991). Gossypol is a major component of the resistance fac-
tors of cotton; low gossypol lines are more susceptible to
insect attack. An array of CIS' C2S , and C30 compounds are
found; all are structuraJly related to gossypol. The Cos com-
pounds are toxic to Helicoverpa species. These C2S com-
pounds appear to arise by the addition of ClO units to gossy-
pol or related compounds (Fig. 21.14) (Mabry and Gill,
1979). Caryophyllene oxide (52), another sesquiterpene
present in the pigment glands, also is toxic to the tobacco
budworm. However, this compound synergizes the effects
of gossypol against this species. The boll weevil, a specialist
on cotton, is insensitive to gossypol at the concentrations
in any common cotton cultivars (Gershenzon and Croteau,
1991).
Myoporum deserti (Myoporaceae), a widespread Austra-
lian shrub, has been responsible for serious livestock losses
in that region. These plants cause liver and kidney lesions.
Mydesmone (53) is one of the active compounds (Fig. 21.15)
(Mabry and Gill, 1979).
Famesol (5) has been demonstrated to be a feeding deter-
rent for gypsy moth larvae (Lymantria dispar ) (Doskotch et
aI., 1980; Seigler, 1983).
A number of sesquiterpenes (as well as a variety of other
terpenes) have been isolated from marine algae. These differ
in large part from those of terrestrial plants (De Rosa, 1991;
Hay and Fenical, 1988). A number of sesquiterpenes from
the green alga Cau/erpa ashmeadii appear to strongly inhibit
herbivory by grazing fish and some invertebrates in tropical
waters (Fig. 21.16) (De Rosa, 1991; Paul and Fenical, 1987;
Paul et aI., 1987). Both sesquiterpenes such as flexilin (54)
and diterpenes such as trifarin occur in Caulerpa species.
These two metabolites contain the 1,4-diacetoxy-1,3-diene
(his-enol acetate) moiety, which is now known to be wide-
 Sesquiterpenes 381

spread among compounds derived from green algae (Paul
and Fenical, 1987). Algae of the family Udoteaceae have
been shown to contain similar sesquiterpenoid compounds
such as rhipocephaiin (55) and rhipocephanal (56) (Paul and
Fenical, 1987). Several of the sesquiterpenes and diterpenes
of these algae contain acetylenic linkages. Many of these
terpenoid compounds are active in a variety of bioassays
and are quite likely responsible for the antiherbivore proper-
ties of many green algae toward fish and sea urchins (Paul
and Fenical, 1987). Terpenoid compounds appear to limit
herbivory by large mobile herbivores, but not against the
small and generally sedentary polychaetes and amphipods
that may indirectly be protected by the compounds (Hay et
aI., 1988).
A number of halogenated sesquiterpenes [e.g., dehy-
drochloroprepacifenol (57)] and related compounds (usually
with chamigrane skeletons) have been isolated from red
algae of the genus Laurencia (De Rosa, 1991).
Kairomones
Many sesquiterpenoid plant-derived kairomones have
been reported (Hedin et al., 1974; Kelsey et al., 1984). In
addition to monoterpenes, many sesquiterpenes that are not
highly oxygenated also are found in essential oils. Several
are known to possess kairomonal activity. (+ )-a-Copaene
(58), from orange froits, is an attractant for the Mediterra-
nean froit fly, Ceratitis capitata (Teranishi et al., 1987). a-
Farnesene (59), from the skin of several varieties of apple
and pear froits, attracts newly hatched larvae of the codling
moth, Laspeyresia pomonella, a serious pest of pome froits
(Jacobson, 1982; Sutherland et al., 1977).
( + )-(E)-a-Santalen-12-oic acid (60) and ( + )-(E)-endo-
~-bergamoten-12-oic acid (61), from leaf exudates of Lyco-
persicon hirsutum are the principal oviposition stimulants
for Helicoverpa zea in the leaves of this wild tomato species
(Coates et al., 1988; Douglass et al., 1993).
Synomones
Many essential oils contain sesquiterpenes that are in-
volved in pollination and seed and froit dissemination. One
interesting example is the pollination of the orchid genus
Ophrys by wild solitary bees of the genus Andrena. The
shape and color of the orchid flower closely resemble that of
the female bee. The male descends on the plant performing
"pseudocopulation" and pollinating the flower in the pro-
cess. It is thought that the visual lure of the orchid flower
shape is closely associated with an olfactory attraction and
that the orchid scent mimics the sexual odors of the female
bee, ensuring pollination by the male (Borg-Karlson, 1990).
(E,E)-Farnesol (5) and several monoterpenes are major at-
tractants, especially in one group of Ophrys species (section
Fusci-Iuteae) and to certain bees of the genus Andraena.
The major component of the flower extracts of O. insectifera
was cyclosativene (62). "y-Cadinene (21) is the major odorif-
erous compound of orchids of Ophrys section Fusci-Iuteae).
T -Muurolol (63) and cubenol (64) were present in section
Fusci-Iuteae, as well as in O. tenthredinifera and O. bombyli-
flora. (E,E)-Farnesol (5) and the related esters farnesyl ace-
tate and farnesyl octanoate were found ouly in O. lutea, O.
sph. litigiosa, and, in traces, in O. insectivera (Borg-Karlson,
1990). Borg-Karlson (1990) has suggested division of the
genus into six groups based on the composition of floral
volatiles.
Several pollinator species do show a typical sexual behav-

CHO OH HO CHO
HO OH

HO

r
gossypol (29)

HO~CHOOH
CHO 0
HO~CHOOH
9"
~ I I
"'" HO~I
l Hi 9" I I
HO HO ""
HO ""
o o
o
I
hellocideHl beliocideH4
heliocideHl

Fig. 21.14. Gossypol and related terpenoids from cotton.

382 Sesquiterpenes

mydesmone (53) farnesol (5)

~I::'" CH,O-hexanoyl
~ (a monoterpene)

farnesyl hexanoate geranyl hexanoate

female Arulrena scents

~~~'¥8
(E,E)-a-farnesene (59)

r(--
(+)-(E)-a-santalen-12-oie add (60) (+)-(E)-endo-8-bergamoten-12-oie add (61)

H OH OH!

~~. ~ ~
cyclosativene (62) T·muurolol (63) cubenol (64)

Fig. 21.15. Sesquiterpene allomones, kairomones. and synomones.

ior when exposed to the odors of flowers or female insects
(Borg-Karlson, 1990). Compounds such as (E,E)-famesol
(5) and primary aliphatic alcohols have been demonstrated
to be the most important compounds in the pollinating sys-
tems of Ophrys sections Fusci-luteae and Araneiferae.
Ophrys flowers do not appear to compete with virgin females
or males. Rather, they produce a set of "second class attracti-
vity compounds" that successfully attract only a fraction of
the male population. Many of the behavior-releasing com-
pounds also are present in other flowers and insects. The
possibility of chemical mimesis has been suggested (Har-
borne, 1982; Kullenberg and Bergstrom, 1975, 1976).
Il'ISECT SEl'UOCHEl'UCALS
A1lomones or Defensive Compounds
in Insects
Dendrolasin (65), an acyclic sesquiterpene, is known as
a defensive compounds from ants of the genus Dendrosius.
This compound is also known from the tree Torreya nuci-
lera, a gymnosperm.
Blister beetles (family Meloidae) contain considerable
amounts of cantharidin (66) (sometimes known as Spanish
fly), a powerful irritant once thought to possess aphrodisiac
activity. This compound is synthesized by male beetles and,
during'mating, is transferred to the female. Mating stimnlates
de novo synthesis of the compound by the male beetle. The
lethal dose in man is about 0.5 mg/kg of body weight and
cantharidin has been responsible for human fatalities (Cutler,
1992). The beetle releases the compound by reflex bending
from the knee joints and cantharidin appears to act as a feed-
ing deterrent to predators of the insect. The insects contain
0.2-2.3% of the compound. Famesol serves as a precursor
for cantharidin, whereas geraniol does not (Fig. 21.17)
(Beale and MacMillan, 1988; Cane, 1981; McCormick and
Carrel, 1987; Peter et al., 1977a,b. Meloid beetles contain
sufficient cantharidin to be toxic to livestock (Capinera et
al.,1985).

Insect Pheromones
Most sexual pheromones of insects appear to be derived
from either fatty acid or mevalonic acid metabolism. In a
number of instances, modified monoterpenes or sesquiter-
penes play roles as aggregation pheromones (Prestwich and
Blomquist, 1987).
Germacrene D (67) provides an active mimic of the
American cockroach pheromone, periplanone B (68) (Bow-
ers, 1985).
The hair pencil (an extrusable brush-like structure that
serves for pheromone dissemination during courtship) secre-
tion (69) of the Monarch butterfly (Danaus plexippus) con-
sists of sesquiterpenes (Herout, 1970) (Fig. 21.17). The sex-
ual pheromones (69 and 70) of this insect also appear to be
terpenoid in origin.
The alarm pheromones of aphids often are sesquiterpenes
such as (E)-J3-famesene (71) and germacrene A (72) (Bow-
ers, 1985). Upon release of these compounds, aphids drop
from the plant on which they have been feeding. The com-
pounds are very labile and break down in only a few minutes.
This is important to prevent the aphids from being in a con-
stant state of alarm (Bowers, 1985). Although this sesquiter-
pene elicits response in many species of aphids, the turnip
aphid Lipaphis (Hyadaphis) erysimi responds only weakly.
Addition of plant-derived isothiocyanates to J3-famesene has
a synergistic effect and greatly enhances the effect of 13-
famesene (71) (Dawson et ai., 1987; Harborne, 1989).
c;c:y
The wild potato species, Solanum berthaultii, possesses
OAC
~ OA~ I
Ac
CY "'.~ ~rno
~ ~~ I\.~
~~
CHO
~
CI
'" '" I
tlexilin (54) OAc
rhipocephalin (55)
Fig. 21.16.
Sesquiterpenes 383
trichomes that liberate (E)-J3-famesene (in addition to a
sticky exudate produced by other types oftrichomes). How-
ever, it is not known whether this substance is produced by
the plant as a defense against aphids (Harborne, 1986b).
(Z,E)- and (E,E)-a-famesene (59) and related homoses-
quiterpenes have been reported to serve as trail pheromones
for the imported fire ant of the southern United States
(Vander Meer, 1983).
Insect Juvenile Hormones and Plant
Juvenile Hormone Jllimics
The juveuile hormones of many insects are sesquiter-
penes (Bowers, 1991, 1992; Fraga, 1991; Law, 1983; Menn
and Beroza, 1972).
The first knowledge that plants produce mimics of insect
juvenile hormones was acquired largely by accident. When
the Czechoslovak entomologist, Karel Shima, came to Har-
vard University, he tried to cultivate his research organism,
the European bug, Pyrrhocoris apteris. Strangely, the insect
refused to grow normally and obstinately remained in the
fifth larval stage. After some time, it was discovered that
the filter paper on which the bugs were grown had been
replaced with paper towels (made in the United States).
When the towels were again replaced with filter paper, the
insects began to grow normally. Further study revealed that
U.S. newspapers, but not Japanese or European ones, inhib-
ited growth of the insect. American paper is largely made
from Abies balsamea, the balsam fir, and a compound, ju-
~~CHO
OAc I ~
OAc
OAc
caulerpenyne
CHO
OAc onchidal
OAc dehydrochloroprepaclfenol (57)
Sesquiterpenes from marine plants.
384 Sesquiterpenes
HO~C02H
E,E·I0·hydroxy·3,7~dimethyl~2,6·decadienoic
HOC~C02H
2
(69)
monarch butterny pheromones
E·p·farnesene (71)
germacrene D (67)
~o
~opp_~:_
portions of the farnesyl opp
molecule that are incorporated
into cantharidin
Fig. 21.17.
vabione (75), was isolated from the paper. This compound
appears to be active only against one family of insects. the
Pyrrhocoridae (Slama and Williams, 1965).
Another example of a sesquiterpene-derived insect juve-
nile hormone is that of the giant silkworm moth, Hyalophora
cecropia (Fig. 21.18). Several juvenile hormone mimics
have been found in plants (Bowers, 1985, 1991, 1992; Fraga,
1991; Menn and Beroza, 1972).
When juvenile hormone is present in excess, no metamor-
phosis occurs and adult insects are not formed. Under natural
conditions, synthesis of the hormone ceases at the end of the
juvenile stages of development and metamorphosis occurs.
Although feeding studies indicate that (73) incorporates
three molecules of MVA, (74) incorporates only two and
probably (77) only one. Compound (74) incorporates 1 mole
of propionate and 8 moles of acetate. These cumpounds are
synthesized by the insect. The hormone is synthesized in
the corpora allata glands, which regulate its release into the
blood.
Other types of compounds with juvenile hormone activity
acid
H02C~CH20H
(70)
germacrene A (72)
periplanone B (68)
dendrolasin (65)
crt)o
o
- 0
o
cantharidin (66)
Insect pheromones and allomones.
have been isolated from plants. Juvenile hormone III (76),
a juvenile honnone found in insects, also occurs in leaves
of the sedge Cyperus iria accompanied by methyl (2E, 6E)-
famesoate. Nymphs of the grasshopper, Melanoplus sangui-
nipes, that fed on Cyperus iria grew at a similar rate to
controls, but showed pronounced morphogenetic effects
when they molted to adults (Harborne, 1989).
Compounds with anti-juvenile-hormone activity have
been found in Ageratum houstonianum, Asteraceae (see
Chapter 18). In this case, the insects molt precociously and
produce adults one or two stages too early. The females
produced usually are sterile.
ESSBNTIAL OIL COMPOl'lBl'ITS
Among the most prized of essential oils are those of sandal-
wood, which contains the santalenes (78 and 79), and pa-
tchouli, which contains patchouli alcohol (80) (Fig. 21.19).
Other components such as j3-ionone (81) (actually a tetrater-
pene or carotenoid degradation product) and ct-( - )-bisabo-
 E"
Sesquiterpenes 385

•~ Opp

o O~ ---..

homomevalonate

(77) mevalonate

~C02C"~C02C",
(73) (74)

~C02C"3

farnesol (5) juvabione (75)

~C02C",

juvenile hormone I juveniJe hormone II

juvenile hormone III (76)

Fig. 21.18. Insect juvenile honnones and juvenile honnone mimics (modified from Jennings et al., 1975; modified and used with pennission of the
copyright owner, the Royal Society of Chemistry, Cambridge),

101 (82) are encountered in flower odors and are important
in pollination as well as for their commercial importance as
perfumery ingredients.
SWEETEl'IEKS
The sesquiterpene hernandulcin (83) from Lippia dulcis
(Verbenaceae), a plant used as a sweetener by the Aztecs,
is more than 1000 times sweeter than sucrose (Compadre et
ai., 1985, 1987).
PICKOTOXINS
A complex type of sesquiterpenes known as picrotoxins are
highly toxic and contain a lactone ring. Pictrotoxins, such
as picrotoxinin (84), are found in the Menispermaceae (Men-
ispermum, Cocculus, and Anamirta), Coriariaceae, Euphor-
biaceae (Hyenanche), and Orchidaceae (Dendrobium)
(Cane, 1981; Coscia, 1969). One of these compounds, melli-
toxin (85), is a contaminant of honey in New Zealand, where
the source plant Coriaria arbarea is common. The plant
contains the sesquiterpene tutin (86). A leaf hopper (Scaly-
papa australis) that feeds on the plant is believed to hydrox-
ylate tutin and excrete the metabolite in its honeydew. Bees
collect this material and use it for making honey. Mellitoxin
also is known to occur in the euphorbiaceous plant Hyen-
anche glabasa (Coscia, 1969).
A series of alkaloids belonging to this group of sesquiter-
penoid compounds occurs in the genus Denbrabium of the
Orchidaceae (Cane, 1981; Coscia, 1969). Denbrobine (87)
is one of the most common of these alkaloids.
This series of compounds is derived from copaborneol
(88) (Newman, 1972). Copaborneol may arise via the bioge-
netic scheme proposed by Coates (1976) (Fig. 21.20).
386 Sesqu;terpenes
(78)
a·H·bisabolol (82) p~ionone
Fig. 21.19. Sesquiterpenes and other essential oil components.
SESQUITERPEl'IE LACTOl'IES
Most of the approximately 3500 known sesquiterpene lac·
tones occur in members of the Asteraceae. This family, in
tum, may be the largest of all plant families, with at least
1443 genera and 32,160 species (Hendrych, 1985). These
compounds occur only infrequently in lower plants and in
a few other higher plant families (Fischer, 1989a, 1989b,
1990, 1991a, 1991b; Gershenzon and Croteau, 1991; Pic,
man, 1986a; Seaman, 1982; Yoshioka et al., 1973). Sesqui·
terpenes may constitute up to 5% of the dry weight of the
plant. Because of their taste properties, sesquiterpene lac·
tones are sometimes referred to as bitter principles (as are
many other types of bitter·tasting compounds). Sesquiter·
pene lactones may occur throughout a plant, but they are
most commonly associated with leaves and flower parts and
glandular trichomes (Gershenzon and Croteau, 1991; Mabry
fu'
and Gill, 1979; Picman, 1986a; Yoshioka et al., 1973). Ger·
+ •
. fi
'R
A
copaborneol (88) picrotoxinin (84)
Fig. 21.20. Biogenesis of picrotoxins (modified from Coates. 1976; used with pennission of the copyright owner, Springer-Verlag, Vienna).
(79) (80)
(81) hernandulcin (83)
macranolide lactones are, by far, the most common type
(Fischer, 1990, 1991b). The majority of sesquiterpene lac·
tones from higher plants contain a·methylene''Y·lactone
groups in which H·7 is, without exception, a·oriented. How·
ever, several sesquiterpene lactones from liverworts possess
enantiomeric compounds (Fischer, 1990).
The methods for isolation, purification, and characteriza·
tion of sesquiterpene lactones have been reviewed (Fischer,
1991b; Yoshioka et al., 1973).
BIOOEl'IESlS
Biogenetic schemes for most of the major groups of sesqui·
terpene lactones have been outlined (Fischer, 1990; Seaman
1982). Based on stmctural information, many biomodifica·
tions in the advanced biosynthetic stages of sesquiterpene
lactones involve oxidative reactions. The isolation of a large
tutin (86) mellitoxin (85) dendrobine (87)

ct\- ct\-
cbr-c6y- ~.·. " .". .
rYL:;~oo~
~~~~
py~ 17
H ---+.......
(89)
germacrene A (13)
Fig. 21.21. Proposed biogenesis of lactone ring of sesquitezpene lactones (modified from Geissman and Crout, 1969).
number of sesquiterpene lactones containing epoxide groups
and the natural occurrence of hydroperoxide-bearing sesqui-
terpenes suggests the involvement of epoxides in sesquiter-
pene cyclizations and singlet oxygen-type reactions in allylic
oxidations (Fischer, 1990). Initial cyclization of E,E-farnesyl
pyrophosphate to germacrene A (13) yields a compound in
which all nonolefinic protons (except. at C-8) are activated
for allylic oxidations. Conversion of the isopropenyl double
bond to an epoxide, followed by opening of the epoxide and
oxidation to an acid group (or by an alternative oxidative
pathway) would give an acid (89) that, after introduction of
oxygen into the 6- or 8-position, can serve as a precursor for
germacranolides (Fig. 21.21). Many biosynthetic questions,
especially those related to the sequence of events, remain
open (Fischer, 1990).
Although many details of the biosynthesis of sesquiter-
pene lactones are not established, guaianolides, eudesmanol-
ides, and pseudoguaianolides in the Asteraceae appear to
be derived from germacranolide precursors (Fischer, 1978,
1990; Fischer et al., 1979). Biomimetic reactions leading to
the formation of these and other types of sesquiterpene lac-
tones have been proposed (Fischer, 1990).
CtreIIIOSYSTEJllATIC STUDIES INVOLVIl'IO
SESQUflERPEl'IE LACTOl'IES
Sesquiterpene lactones are known to occur in the following
families of angiosperms: Acanthaceae, Amaranthaceae, Api-
aceae (12 species), Aristolochiaceae, Asteraceae (about 450
Sesqu;telpenes 387
ct:)f-
CHO
6oxygeuatioJl
~ CO,H
17
H
Co,H
+
germacranolides 0 0
species), Bombacaceae, Burseraceae, Canellaceae, lllicia-
ceae, Lamiaceae, Lauraceae, Maguoliaceae (5 species),
Menispermaceae, Polygonaceae, and Winteraceae (Fischer,
1991b; Herz, 1977; Picman, 1986a). Some reports for ses-
quiterpene lactones in the Scrophulariaceae are based on
misinterpretation of Veronica (Scrophulariaceae) for Ver-
nonia (Asteraceae). A number of other families contain lac-
tones described previously under picrotoxins.
The distribution of sesquiterpene lactones often is re-
ferred to as an indication of affmity between the Asteraceae
and the Apiaceae (Hegnauer, 1977). These two families
share polyacetylenes, coumarins, and flavonoids, as well as
other types of compounds. The stereochemical features of
the sesquiterpene lactones found in these families provide
additional support for the relationship (Holub et al., 1987).
The occurrence of sesquiterpene lactones in the tribes of
the Asteraceae is of taxonomic interest. These compounds
are common and complex in the Heliantheae (including
some Helenieae); of intermediate frequency in the Anthemi-
deae, Cichorieae, Cynareae, Senecioneae, Inuleae, and Ver-
nonieae; infrequent and biogenetically less advanced in the
Eupatorieae; and not known in the Mutisieae, Astereae, Ta-
geteae, and Arctoteae-Calenduleae (Dahlgren et al., 1981;
Waterman and Gray, 1987).
Structural studies of sesquiterpene lactones have proven
useful for understanding systematics and evolution in the
genus Ambrosia (Asteraceae). Populations of Ambrosia psi-
lostachya from the coastal islands off Texas produce only
the dilactone compounds psilostachyin (90), psilostachyin B
388 Sesquiterpenes

o~o~o~
p.nostacltyin (90) p.Uostachyin B (91) 0 psUostachyin C (92)

HO~ ~'H ~~H

HO 0 0
o 0 0
0 0 0
ambroslol (%) coronopilin (93) parthenin (94)

~~ ~oo nG-.
~ o
~O~~O 0
confertiftorin (95) desacetylconfertiflorin (99) tomentosin (133)

Fig. 21.22. Sesquiterpene lactones of systematic significance.

(91) and psilostachyin C (92). Collections of the same spe-
cies from the adjacent mainland contained only monolac-
tones, primarily ambrosiol (96), coronopilin (93), and par-
thenin (94) (Fig. 21.22). ht one area of south Texas with
ecology quite similar to the islands, dilactone populations
also were encountered. It has also been observed that a re-
lated species, Ambrosia cumanensis, from Mexico contains
the same three dilactones. There appears to be a close rela-
tionship between the coastal populations of A. psilostachya
and A. cumanensis of Mexico. It is quite probable that the
Mexican plants served as ancestors for the island races which
were established 3000-5000 years ago (Mabry, 1970). Stud-
ies of the volatile essential oils confirmed this relationship.
Populations of Ambrosia confertiflora, a ragweed distrib-
uted widely through Texas and Mexico, reveal complex ses-
quiterpene lactone chemistry. Most populations from south-
central Texas are characterized by a chromosome number n
= 66 and the pseudoguaianolides confertiflorin (95) and
desacetylconfertiflorin (99), whereas plants from northeast-
ern Mexico yield germacranolides and a few eudesmanol-
ides. All of those studied have chromosome number n =
54. A dilactone race (with both n = 54 and n = 66) occurs
further west in Texas and in Mexico along the western slopes
of the Sierra Madre into the area where Ambrosia cuma-
nensis occurs. A fourth race characterized by the presence
of gennacranolides occurs in northwestern Mexico (Mabry,
1972).
Ambrosia chamissonis is similar to most other species of
ragweeds in that it synthesizes a number of sesquiterpene
lactones-in this case, a series of structurally related genna-
cranolides. This species also is extremely variable in tenns
of morphology as well. Ambrosia chamissonis occurs on the
Pacific coast of both North America and South America
(Chile) where it was apparently introduced about 100 years
ago. Five morphological groups have been recognized.
North of San Francisco, there is little correlation of chemis-
try and morphology, whereas south of that point, there is a
greater relationship. It has been suggested that the southern
populations have been more recently introduced from the
north and a founder effect still exists. Furthennore the chem-
istry of the populations from Chile is consistent in sesquiter-
pene lactone chemistry and leaf morphology. This illustrates
how a weedy species can rapidly colouize a new region; all
of the Chilean plants may have come from a single introduc-
tion from California. Both the chemistry and morphology
are quite sintilar to those populations near San Francisco,
suggesting that the source of the genetic line introduced into
Chile may have come from that area (Mabry, 1973).
BIOLOGICAL AC11VITY
A number of sesquiterpene lactones are known to have var-
ious types of biological activity (Bohlmann, 1986; Fischer,
1991 b; Mabry and Gill, 1979; Picman, 1986a; Rodriguez et
 Sesquiterpenes 389

al., 1976; Stevens, 1984). Part of the cytotoxic, allergenic,
and antibiotic properties of this group of compounds are
attributable to the fact that they can form Michael addition
products by the addition to active-site sulfhydryl groups in
key enzymes, as well as desoxyribonuclease and ribo-
nuclease (Hall et al., 1977). This property is dependent on
the presence of the a,l3-unsaturated "V-lactone moiety. Be-
cause of their taste properties, sesquiterpene lactones are
sometimes referred to as bitter principles. Cnicin (97) from
Cnicus benedictus and absinthin (98) from Artemisia ab-
sinthe are the most important bitter principles of the bitter
liqueurs made from these plants. Lactucin (100) is the bitter
principle of the dried juice of wild lettuce or Lactucarium
(Fischer, 199Ib). A number of Asteraceae and some liver-
worts of the genus Frullania are known to produce allergic
contact dermatitis in humans (Fig. 21.23) (Evans and
Schmidt, 1980; Picman, 1986a).
Plant Growth Regulator Activity
Xanthinin (101), a sesquiterpene lactone from many Xan-
thium (cocklebur, Asteraceae) species, is known to be an
antagonist for auxin. Heliangin (102) from Helianthus tub-
erosus also is known to be an antagonist in the Avena coleop-
tile test. Vemolepin (103) from Vernonia hymenolepis has
been reported to be the strongest inbibitor of auxin. It has
been suggested that vemolepin affects an essential step in
cell wall synthesis or extensibility and is not merely a toxic
principle (picman, 1986a).
Allelopatbic Effects
Many plants with sesquiterpene lactones have been sus-
pected to possess allelopathic properties. An American plant,
Parthenium hysterophorus, was introduced into Australia
and India and has subsequently been reported to affect nu-
merous crop plants (Picman, 1986a). The compounds par-
thenin (94) and coronopolin (93) probably are responsible
for this activity. Interestingly, the pollen of this plant, which
also contains these compounds, appears to be responsible
for the inbibition of pollen germination and pollen tube
growth on stigmas of other species (Picman, 1986a).
The compound arbusculin-A (104), from Artemisia spe-

~ ~
AC

d>-~
O_dgIYI 0

HO.&I 0

/fJ~o o
o
o
hecagenin xanlbinln (101) beJcnaJin (Il2)

~
'!
o
~I!!
00 o
i

HO
-...'0

0
0
HO
~
0
H'
0

tenoon (Ill) ambrosin arbusculin-A (104)

#' ,
01'11 0H H0tf>-~ ~
lrn1-{ -Yul~o
~ o
vernolepin (103) bymenovin (Il3) parthenin (94)

0-S-
~
o ~
o ~
o OAc
o
gJaucolide-A (Il4) ainntoJactone (lOS)
(al
Fig. 21.23 (8 & b). Some sesquiterpene lactones with biological activity.
390 Sesquiterpenes
~~
o 0
eremanthine (U8) costunolide (119)
~~
~ :0-~o
~~ o
:~:<~( pM
santamarin (123) reynosin (124)
e1epbantin (132)
(b)
Fig. 21.23.
cies, is responsible for some of the allelopathic effects of
that plant (Fig. 2 I .22) (Mabry and Gill, 1979). Alantolactone
(105), found in many members of the Asteraceae, inbibits
seed germination and growth of the common weedy species
Amarathus retroflexus (Amaranthaceae) and Chenopodium
strictum var. glaucophyllum (Chenopodiaceae) (picman,
1986b). Other examples of allelopathic effects have been
summarized by Picman (1986a).
The sesquiterpene lactones burrodin (106), confertiflorin
(95), desacetylconfertiflorin (99), dihydroparthenolide
(107), parthenin (94), and 7oc-hydroxy-3-desoxyzaluzanin C
(108) inbibited or promoted the germination of seeds of 16
dicot and 9 monocot species, depending on concentration
and species at concentrations as low as 1 r.W1 (Fischer et
aI., 1989a). A sesquiterpene lactone (109) from Iva axil/aris
seeds inbibited germination of Abutilon theophrasti seeds at
10- 3 M. Although axivalin (110) did not inhibit seed germi-
nation, this compound profoundly affected growth of seed-
ling radicles (Spencer et aI., 1984).
Plant Allomones
Many sesquiterpene lactones have antifeedant properties
against animals. Numerous compounds have been evaluated
against insects, especially economically important pests.
These reports have been summarized and many of the spe-
cific effects reviewed (Fischer, 1991b; Picman, 1986a).
~
O!,
- .
00
HO ~
- , go~ze"oHde (120)
plenolin (131)
vernolide (127) yingzbaos. A (129)
(continued)
Sesquiterpene lactones from Parthenium species were
strongly inhibitory to growth of larvae of Helicoverpa zea
and Spodoptera exigua (Isman and Rodriguez, 1983). Tenu-
lin (111), the major sesquiterpene lactone of Helenium
amarum, imparts a bitter taste to milk and is toxic to live-
stock. Helenalin (112) from Helenium microcephalum is
toxic to several mammalian species in oral doses as low as 85
jJ.glkg. Hymenoxys odorata, from which a toxin, hymenovin
(113), is isolated, is economically siguificant, as it is very
toxic to sheep and goats. A similar type of poisoning has
been observed with South African species of Geigera.
Three species of Vernonia that grow in the southeastern
United States differ in their sesquiterpene lactone content.
Vernonia gigantea and V. glauca contain glaucolide-A
(114), whereas the third, Vernonia flaccidifolia, produces
almost none of these compounds. The insect-feeding-deter-
rent properties of these compounds were studied with six
insects, all of which occurred in the same area as the plants.
Three of these insects, the yellow-striped armyworm
(Spodoptera ornithogalli), cabbage looper (Tricoplusius nil,
and the yellow wooly bear (Diacrisia virginica), feed in
nature on Vernonia species that contain glaucolide-A. A
fourth species, the saddle-back caterpillar (Sibine stimulea),
feeds on V. flaccidifolia. The polyphagous southern army
worm (Spodoptera eridania) and fall armyworm (S. [rugi-
perda) occur in the same area, but normally are not seen on
Vernonia species. In feeding tests, the fall, southern, and
 Sesquiterpenes 391

yellow-striped annywonns and the saddle-back caterpillar
all avoided Vernonia species with glaucolide-A. The wooly
bear and cabbage looper seemed to prefer the plants that
contain glaucolide-A (114). ht feeding trials with young in-
sect larvae, those insects that occur on Vernonia species in
the field tended to be the least affected in trials (Mabry and
Gill, 1979). ht feeding trials, rabbits (Sylvifagusfloridana)
preferred V. flaccidifolia over species that had glaucolide-
A. Similar results were obtained with whitetail deer (Odo-
coileus virginianus).
Despite the usual antifeedant or toxic effects observed
with other insects, larvae of the sunflower moth Homoesoma
eleclel/um, Lepidoptera: Pyralidae), a specialist on species
of sunflower (Helianthus), are able to feed on flower parts
that contain appreciable amounts of sesquiterpene lactones
(Gershenzon and Croteau, 1991).
Many sesquiterpene lac tones are toxic to fish (picman,
1986a). Buddlejin A, B, and C (115, 116, and 117) possess a
caryophyllane skeleton and are piscicidal (Fig. 21.24). These
compounds are found in Buddleja davidii (Buddlejaceae)
(Yoshida et aI., 1976). The molluscicidal activity of sesqui-
terpene lactones has been investigated (Marchant et aI.,
1984).
Several members of the Asteraceae such as Vanillos-
mopsis, Eremanlhus, and Moquinea are widely used in Bra-
zil for fencing. The wood is highly resistant to insects and
fungi. The active compounds [eremanthine (118), costunol-
ide (119), and goyazensolide (120)] are sesquiterpenes (Gil-
bert, 1977).
Chemotactic Agents from Parasitic Plants
Several parasitic weeds of the genera Slriga (Scrophulari-
aceae) and Orobanche (Orobanchaceae) attack grasses,leg-
urnes, and other plants (see Chapter 2). Seeds that are in the
soil remain viable for long periods of time, and they only
germinate when a stimulant from the host plant is present.
A sesquiterpene, strigol (121), recently has been isolated
from the roots of colton plants that effects gennination of
Striga seeds in concentrations down to the 10 - 13 M level.
A structurally similar compound from synthetic sources

0% % ~o
buddlejlo A (115) buddl_Jio B (116) buddl_jlo C (117)

o ii i
0
0
0
sanloolo (130) alnnlolo<loo_ (105)

Q=5{0 CQ=: 0~o r~

HO H
-y-o
'f0\.
yo
.
.trigol (121) (122) isoalantolactone (126)

~
o

m~
![J~o
,
h
•. ""O~
0

HO 0 0

(aJ
o
Fig. 21.14 (a & b). Additional biologically active sesquiterpene lactones.
 %.~"'O
392 Sesquiterpenes
,;Y
OH II ./
Yl
0 OH
~ HO
HO 0 0
enieln (97)
~ ~
o
abslntbin (98) artemisinin (quinghaosu) (128)
(b) 7a-bydroxy-3-desoxyzaluzanin C (108)
Fig. 21.24. (continued)
(122) is almost as active (10-9 M). This compound also
promoted gennination of Alectra (Scrophulariaceae), a para-
site of cowpeas, and several Orobanche (Orobanchaceae)
species. These compounds now are being tried to control
parasitic plants in cultivated crops (Johnson, 1978; Pep-
perman and Blanchard, 1985)_
Sesquiterpene lactones such as the eudesmanolides san-
tamarin (123) and reynosin (124) strongly enbance germ-
ination of the seeds of Striga asiatica. Confertiflorin (95),
desacetylconfertiflorin (99), parthenin (94), and dihydropar-
thenolide (107) from Ambrosia species also have high activ-
ity. Sesquiterpene lactones may serve as alternatives to stri-
gol; these compounds are nontoxic to sorghum at the
concentrations employed (10- 9 M) (Fischer et a1., 1989b;
Fischer, 199Ia).
Medicinal Uses
A number of sesquiterpene lactones show antibacterial,
antifungal, and antiprotozoan activity (Fischer, 1991b; Pic-
man, I 986a). Alantolactone (105) and isoalantolactone (126)
have been used as urinary antiseptics. Several compounds
of this group have activity against Entamoeba histolytica
and related organisms. Parthenin (94) from Parthenium hyst-
eropherus and vernolide (127) from Vernonia colorata in-
hibit Entamoeba histolytica at concentrations comparable to
~:7
~ ~ OH
./'
0 O~
0
laetucin (100) dihydropartbenollde (107)
"!l ' O-tlgloyl
:0-0
, H """-\
o o
o o
heliangin (102)
burrodln (106) axivalin (110)
metronidazole, an antiamoebic drug (Borris and Schaeffer,
1992).
Helenalin and a series of related compounds are responsi-
ble for the cardiotonic properties of Arnica flowers. This
drug has long been known for its heart stimulant and analep-
tic qualities (Wagner, 1988). Helenalin (112), tenulin (111),
and eupahyssopin had antiarthritic activity (50-70% inhibi-
tion of edema) at concentrations of 2.5 mglkg (Wagner and
Proksch, 1985). The crude drug Atractylodis rhizoma, from
Atractylodis macrocephala (Asteraceae), and several other
related medicinal plants is used clinically as a diuretic and
for analgesic purposes. The plant also has anti-inflammatory
properties. Active compounds include (+ )-eudesma-4(14)-
7(1l)-dien-8-one and atractylenolide I (Hikino, 1985).
An effective antimalarial constituent, artemesinin (128),
was isolated from a Chinese medicinal herb, Artemisia
annua (Asteraceae). A promising antimalarial, but only
weakly toxic sesqniterpene lactone, was isolated from this
plant (Fischer, 1991b; Klayman, 1985, 1989; Lewis, 1992;
Picman, 1986a). A similar compound, yingzhaosu A (129),
from Artabotrys uncinatus (Annonaceae) also has efficacy
as an antimalarial agent (Borris and Schaeffer, 1992).
Santonin (130), a sesqniterpene lactone from Artemisia
maritima (Asteraceae) has been used as an ascaricide, and
is especially active against roundworms (Ascaris spp.).
A number of sesquiterpene lactones have been demon-

strated to possess activity against the trematode Schistosoma.
Infection by the cerceriae of this organism are responsible
for a disease called schistosomiasis. Certain snails serve as
an intermediate host for the trematode. Several of the active
sesquiterpene lactones kill the vector snails and their eggs
but are not toxic to fish (picman, 1986a).
Many sesquiterpenes have pronounced antitumor proper-
ties (Bohlmann, 1986; Cordell, 1978; Picman, 1986a;
Rodriguez et aI., 1976). In general, the conjugated exocycJic
double bond in the lactone group is necessary for activity,
although at least one antitumor compound lacks this feature.
The ability to inhibit DNA synthesis directly appears to be
a common feature among sesquiterpene lactones with cyto-
toxic and antitumor activity. Most of these compounds are
from plants of the Asteraceae. Some examples are a -santo-
nin (130), vemolepin (103), pJenolin (131), and elephantin
(132) (Mann, 1987). A summary of active sesquiterpene 1ac-
tones and references is given by Bohlmann (1986) and Pic-
man (1986a).
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22
Diterpenes and Sesterterpenes

Introduction INI'KODVcnON
Biosynthesis
Diterpenes Derived from Monocyclic Precursors At least 2500 diterpenes are found in a large number of plant
Cembrene families (Banthorpe and Charlwood, 1980; Croteau and
Taxanes Johnson, 1981; Devon and Scott, 1972; Gershenzon and Cro-
teau, 1991; Hanson, 1991). Most of these compounds fit into
Cocarcinogenic Diterpenes from the Euphorbiaceae and
about 20 major groups (Fig. 22.1). Because diterpenes are
Thymelaeaceae
chemically complex and difficult to isolate, purify, and char-
Bicyclic Diterpenes
acterize, they probably have not been studied as thoroughly
Manool Derivatives
as monoterpenes and sesquiterpenes. Gibberellins and phy-
Labdane Derivatives
tol, the acyclic side chain of chlorophyll, occur in all plants.
Clerodane Derivatives
Diterpenes usually are components of plant resins and
Tricyclic Diterpenes
sometitnes are encountered as by-products from the isolation
Diterpenes related to ent-kaurene (5p,10a-configuration).
of essential oils (e.g., rosin or naval stores from turpentine
Other Structural Types Derived from the ent-Kaurane production). The most commonly encountered diterpenes are
Skeleton nonvolatile acids from conifers and legumes (Croteau and
Gibberellins Johnson, 1985; Langenheim, 1990).
Grayanotoxins Oleoresins characteristically contain 60% or more diter-
Diterpenes with a 5a, lOp-Configuration penes by weight. Because of the resinous nature of this mate-
Resins in Plants rial and its tendency to polymerize in the presence of oxygen,
Diterpenes in Chemosystematic Studies diterpenes are major components of physical barriers to in-
Biological Activity fection at wound sites (Croteau and Johnson, 1985).
Phytoalexins Methods for the isolation, purification, and characteriza-
Phytotoxins tion of diterpenes have been reviewed (Hanson, 1991). Most
Antifeedant Compounds diterpenes are isolated by extraction and purified by chroma-
Insecticidal and Nematicidal Activity tography. Thin-layer chromatography (TLC) and high-per-
Diterpenes with Juvenile Hormone Activity formance liquid chromatography (HPLC) have proven espe-
Diterpenes That Prevent Reproduction in Insects cially useful. The chromatography of diterpenes has been
Trail-Marking Pheromones reviewed (Coscia, 1984).
Diterpenes from Marine Plants A number of alkaloids based on diterpenoid structures
Sweeteners are discussed under Diterpene Alkaloids in Chapter 36.
Medicinal Properties
Antitumor Compounds BIOSYNTHESIS
Sesterterpenes
Biosynthesis The progenitor of C20 isoprenoids is geranylgeranyl pyro-
Biological Activity phosphate (GOPP) (1) (Fig. 22.2). The mechanism of con-
References densation probably is the same as that for sesquiterpenes

398
 Diterpenes and Sesterterpenes 399

levopimaric acid palustricacid abietic aeid (52)

sugiol

neoabietic acid pimaric acid (31) isopimaric acid (69) sandaracoplmaric acid (32)

<a) manool (30) torulosic acid larixol strobicacld

nagilactone G clerodadienoic acid trachylobanic acid incensole

o o
oyO';;{j,
HO~
~ ~o
otJ o 0

ginkgolide B (55) baccatinm

OH
phorbol (14) ryanodol R1=H, R1=OH
cinnzeylanol R,=OH, R,=H (82)
(b)

Fig. 22.1 (a & b). Some representative diterpenes (Croteau and lohnson. 1985; modified and used with permission of the copyright owner, Academic
Press. Orlando. FL).

(see Chapter 21). Geranyllinalyl pyrophosphate (2) also has
been suggested as a intermediate in the fonnation of some
diterpenes.
Acyclic diterpenes are not common. Most known acyclic
diterpenes are derived from hydrolysis of GGPP and rela-
tively simple modifications (Figs. 22.3 and 22.4). The fra-
grant compound geranylgeraniol (3) is accumulated in the
wood of Cedrela toona (Meliaceae) (Croteau and Johnson,
1985). The monounsaturated diterpene, phytol (4), is a com-
ponent of the chlorophyll molecule and is found in all photo-
synthetic organisms. Phytol apparently is derived directly
from GGPP after reaction with chlorophyllide a (West,
1981).
Geranylgeranyl pyrophosphate synthetase activity has
been found in carrot, pumpkin, and castor bean endospenn.
In preparations from pumpkin and castor bean endospenn,
it was possible to separate famesyl pyrophosphate synthetase
and geranylgeranyl pyrophosphate synthetase activity.
400 Diterpenes and Sesterterpenes

geranyIgeranyl pyrophosphate
farnesyl pyrophosphate
FPP GGPP(I)

OPP

~(( ~ct
lyU 6H ~u
geranylgeraniol (3) geranyJlinalyl pyrophosphate (GLPP) (2)

Fig. 22.2. Biogenesis of geranylgeranyl pyrophosphate (GGPP).

geranylgeraniol (3)
Cedrela toona wood, linseed oil
OR Phytophthora cactorum, bumblebees

geranyllinalool

jasmine oil, Norwegian spruce

isophytol
OH
# jasmine oil

9·hydroxygeranylgeraniol
(crinitol)
"" OH Cystoseira ennita, a brown alga

geranylcitronellol (89)
OH bumble bees

E-phylol (4)

Fig. 22.3.
"" OH all plants

Naturally occurring acyclic diterpenes (modified from West, 1981; used with permission of the copyright owner, Wiley, New York).

acyclicditerpenes ~
1 ~~
#i
/
geranylgeraoyl OPP (1)
Sa,IOp·blcyclic dilerpenes
,.....
. . . .:
~ H
H
enantto-series
Sp,lOa-bicyclic diterpenes
macrocyclic diterpenes
Fig. 22.4. Geranylgeranyl pyrophosphate as a branch metabolite.
Geranylgeranyl pyrophosphate synthase (detected in pro-
plastids of infected cells of Ricinus communis) had a molecu-
lar weight of 72,000 and required Mgz+ (Beale and MacMil-
lan, 1988). The enzymes with geranylgeranyl pyrophosphate
synthetase activity also would accept pyrophosphates
smaller than famesyl pyrophosphate, indicating that famesyl
pyrophosphate probably does not lie at the branch between
sterol and carotene metabolism in these organisms (Porter
and Spurgeon, 1981); that is, famesyl pyrophosphate is syn-
thesized by enzymes leading to the two series of compounds
independently.
As is the case in monoterpene and sesquiterpene biosyn-
thesis, overall incorporation of mevalonic acid (MYA) and
other terpenoid precursors is low (about 1%) (Loomis and
Croteau, 1980).
Many different mono-, bi-, trio, and tetracyclic diterpenes
are found and their formation may be rationalized by acid-
catalyzed, stereospecific cyclizations of geranylgeraniol and
analogs to yield a variety of diterpene skeleta. Similar pro-
cesses are assumed to occur in vivo.
Although most bacteria do not make large quantities of
terpenes, the Archaebacteria produce lipids that are Czo iso-
prenyl ethers of glycerol and its derivatives (in addition to
some C zo , C25 , and C30 acyclic compounds). These bacteria
do not synthesize fatty acids; the lipids in their membranes
are exclusively polyisoprenoid (Porter and Spurgeon, 1981).
Diterpenes and Sesterterpenes 401
opp
_ _ Sa,IOp·polycyclic diterpenes
I labdanes
c1erodanes
=:::nes
and romedanes
rosanes
OPP 000=:"
-----+- Sp,10a-polycyclic diterpenes
abletanes
cocarclnogenic diterpenes
----+ casbene
taxanes
cembrenes
DITERPEl'IES DERIVED FROM MOI'lOCYCLIC
PREClJRSORS
Several monocyclic diterpenes occur in nature. Cembrene
(5), found in the resinous material from several gymno-
sperms, is derived from the same intermediate leading to
taxanes (such as 6 and 7) that are only found in the gymno-
spermous family, Taxaceae (Sukh Dev and Misra, 1985)
(Fig. 22.5).
Other series of monocyclic diterpenes occur in angio-
sperms (Fig. 22.6). Most important among these are duva-
trienediol (8) (from tobacco), casbene (9) (from Ricinus
communis, Euphorbiaceae), and complex derivatives of cas-
bene (e.g., 10-13) (pig. 22.6) from the Euphorbiaceae and
Thymelaeaceae. Casbene is formed by the action of casbene
synthetase on geranylgeranyl pyrophosphate, an enzyme
with a molecular weight of 53,000 which requires Mg++ for
catalysis. The enzyme occurs in proplastids of seedlings.
Casbene synthesis peaks about 12 hours after fungal attack
(West et al., 1990). The biosynthesis oftltis diterpene phyto-
alexin appears to involve transcriptional contol (West et al.,
1990). Although conversion of mevalonate into isopentenyl
pyrophosphate was not altered by fungal infection (Rhizopus
stolonifer), the activity of famesyl pyrosphate and geranyl-
geranyl pyrophosphate synthase and casbene synthase were
increased in infected plants (Beale and MacMillan, 1988).
402 Diterpenes and Sesterterpenes
---+
/
GGPP
HO
0 0
OH
(7)
Fig. 22.5. Biogenesis of cembrene and taxinine-K.
Pectic substances derived from the cell wall by the action
of fungal endopolygalacturonase have been identified as el-
icitors (Croteau and Johnson, 1985).
Cembrene
The monocyclic diterpene, cembrene (5), has been sug-
gested to be formed from GGPP with a Z-olefin linkage
(Newman, 1972) (Fig. 22.5). In view of other information,
this compound is probably derived from a normal geranylg-
eranyl-OPP precursor.
Taxanes
Taxanes are found only in the gymnospermous family,
the Taxaceae. Taxane alkaloids (derived from these ter-
penes) are responsible for the extremely poisonous proper-
ties of the genus Taxus (Fig. 22.5).
Cocarcinogenic Diterpenes from tbe
Eupborbiaceae and TbymeJaeaeae
Many plants of the Euphorbiaceae and Thymelaeaceae
have long been known to be intensely irritating to the skin.
Some produce severe skin lesions in humans and in livestock
(Evans and Schmidt, 1980). Members of the genus Euphor-
bia are especially well known for their irritant and poisonous
properties. Polyfimctional diterpene esters of the tigliane,
ingenane, and daphnene types are responsible for the acrid
--
cembrene (5)
OCOCH,
properties. The latex of Euphorbia tirucalli contains a series
of highly unsaturated esters of phorbol (14) and 4-
deoxyphorbol along with some 3-0-acylingenol derivatives
esterified with the same unsaturated fatty acids (Fig. 22.7).
In South Africa, honey from several cactiform species of
Euphorbia called "nors doring" produces a strong burning
sensation in the mouth or throat that persists for several hours
(Sosath et al., 1988). Tung oil and meal from the fruits of
Aleurites is toxic to mammals. The meal can cause irritation
to the skin and internal organs. The oil of Croton tiglium is
an extremely potent cathartic. A number of diterpenes, which
may comprise as much as 5% of the seeds have been isolated
from this oil. One of these diterpenes (15) was toxic to the
larvae of Culex pipiens at 0.6 ppm (Harborne, 1986). The
seeds of Jatropha curcas, J. gossypifolia, and related species
also contain bioactive diterpenes (Hirota et al.; 1988). A
number of the diterpenes from these plants are tumor pro-
moting or cocarcinogenic; that is, they do not induce tumors
themselves, but enhance the activity of carcinogens. When
cocarcinogenic diterpenes were applied after exposure to
subcarcinogenic doses of a carcinogenic compound, tumors
were produced (Hecker, 1971, 1987a, 1987b). The calcium-
and phospholipid-dependent protein, kinase C, is the recep-
tive site of phorbol esters; the specific mechanisms for tumor
promotion are unknown, but they are related to protein ki-
nase C activation (Alcaraz and Rios, 1991).lronically, many
of these same compounds have proven antitumor effects.
Some diterpene esters are inflammatory agents but not pro-
 Y<'
tfjpp~, ~I
- -+
~ ~
geranylgeranyl opp (1)
~~~ ingenane type
-dst~~
daphnane type (12)
2,7,1l-duvatriene-4,6-diol (8)
Fig. 22.6. Diterpenes derived from a monocyclic precursor (modified from Adolf and Hecker, 1977; used with pemrission of the copyright owner,
Laser Pages Publishing, Ltd., Israel).
moters (Alcaraz and Rios, 1991). The toxic effects and distri-
bution of!bese compounds have been reviewed (Alcaraz and
Rios, 1991; Evans and Kinghorn, 1977; Evans and Soper,
1978; Hecker, 1971, 1977, 1987a, 1987b; Kinghorn, 1979).
Many of !bese diterpenes occur as monoesters or diesters.
The most abundant croton oil diester, 12-0-tetradecanoylph-
orbol-13-acetate, is now widely used as a standard tumor-
promoting agent (Marshall and Kinghorn, 1984).
The major structural types known are !be phorbol esters
[e.g., a tigliane from Sapiumjaponicum (17)] (Croton, Sap-
ium, Aleurites, Mancinella, Baliospermum, and Euphorbia),
ingenol esters [e.g., ingenane (18)] (Euphorbia), and daph-
nanes [e.g., daphnetoxin (19)] (Euphorbia, Hum, Hip-
pornane, Excoecaria, Baliospermum, Thyrnelaeaceae) (Fig.
22.7); most of !be plants !bat contain !bese diterpenes are
in subfamilies Crotonoideae and Euphorbioideae (Kinghorn,
1979; Webster, 1975).
Similar mixtures of compounds are found in many species
of !be genus Euphorbia as well as in o!ber species of !be
Euphorbiaceae. 12-Deoxyphorbol (20) is one of !be most
common toxic diterpenoids in latex. This compound nor-
Diterpenes and Sesterterpenes 403
+-+
~
~ ~ cemhrane type
jatropbane type casbene (9)
t1gllane type (11) lathyrane type (10)
20
19
17
jatrophone (13)
mally occurs as a monoester or diester of aliphatic acids or
occasionally as !be ester of an aromatic acid.
Ingenol derivatives are restricted to several species of !be
genus Euphorbia. These compounds exhibit toxicological
and cocarcinogenic properties similar to !bose of !be phorbol
compounds.
A number of plants from !be Thymelaeaceae are known
to be responsible for livestock poisoning. The active princi-
ples of many of !bese plants are cocarcinogenic diterpenes
(Adolf et al., 1988). Among !be poisonous plants of !bis
family are Pimelia prostrata and Daphne mezereum. Intra-
peritoneal injections of !be toxin of Pimelia (from New
Zealand) of 3 fLglg of body weight were toxic to mice in 2
h. The fruit and bark of Daphne species contain daphnetoxin
(19). The seeds contain mezerein (21). Bo!b of !bese com-
pounds can produce irritant dermatitis in humans, and mezer-
ein (21) possesses cocarcinogenic activity as well (Alcaraz
and Rios, 1991). Odoracin (22), a structurally similar diter-
pene from Daphne, possesses nematicidal activity in tests
against the nematode, Aphelenchoides beseyi. At 5 ppm, !bis
diterpene is 100% nematicidal (Mabry and Gill, 1979). The
404 Diterpenes and Sesterterpenes

fl.
:dd
HO HOH CHOH
H
CH.OH
phorbol ester from phorbol ester from
ingenoJ (18) • Croton ligNum Saplumjaponicum (17)

CH.OH OH CH.OH
huratoxin from S-deoxyingenol from daphnetoxin (19)
Hum crepitalls and Euphorbia bigia1U/ulosa
Hippomane 1IUl1lcinella
OCO(CHv 12CH, C.ns OCOCH=CHCH-u=CH(CHV'~3 OCOCH,

~ 0 HO
~ H

HO ,9
o CH.OH
CH.OH

12·deoxyphorhnJ (20) mezereln (21)

goidiglaucin (27) R, = ·(CHv,CH" R. = ·O.CPh, R, = ·O.C(CHV14CH,
(a) gnidilatidin (lS) R, = ·(CH=CH),(CHv,CH" R. = ·O.CPh, R, = ·O.(CHV14CH,

Fig. 22.7 (a & b). CQcarcinogenic diterpenes from the Euphorbiaceae and Thymelaeaceae.

diterpenes ofyuan-hua, Daphne genkwa, have been reported
to be abortifacient (Bingel and Fong, 1988). Four active
compounds have been isolated: yuanhuacine (23), yuanhua-
dine (24), yuanhuaf'me (25), and yuanhuatine (26). Yuanhua·
dine is administered intra-amnionically and yuanhuacine
either intra- or extra-amniotically to induce second-trimester
abortion (Bingel and Fong, 1988).
Several compounds of this series also have antitumor ac-
tivity. Among these are gnidilatidin (27) and gnidiglaucin
(28) from Gnidia lati/olia, Gnidia glaucus, and Diarthron
vesiculosurn (Thymelaeaceae) (Evans and Soper, 1978;
Powell and Smith, 1980; Powell et al., 1985).
The complexity of these structures and their limited dis-
tribution suggest a close relationship between the Eu-
phorbiaceae and Thymelaeaceae (Waterman and Gray,
1987).
BICYCLIC DITERPEl'IES
GGPP is cyclized via two paths to produce the phosphate
esters of the antipodal bicyclic labdadienols, thought to serve
as precursors of the large majority of known bicyclic diter-
penes (Hanson, 1971, 1973) (Fig. 22.8). Little direct mecha-
nistic evidence concerning these cyclizations is available
(West, 1981). The initial cyclization steps yield labdane de-
rivatives with either a 5a,10[3-confignration or a 5[3,lOa-
configuration (Hanson, 1991).

CHpH
odoracin (22)
:~
CH,OH
yuanbuacine (23)
(b) yua.hUaRD. (25)
Fig. 22.7. (continued)
Although these modes of condensation have been consid-
ered to be of systematic and phylogenetic significance,
plants sometimes contain diterpenes with both configura-
tions (e.g., Agathis australis, Araucariaceae). In other in-
stances, different species of the same genus possess diter-
penes with opposite configurations [e.g., Podocarpus
macrophyllus and P. !errugineus, Podocarpaceae
(Oehlschlaeger and Ourisson, 1967)]. Of these two types of
diterpenes, the 5J3,IOo<-configuration is almost certainly the
most widespread. 5o<,I0J3-Enantiomers are commonly re-
ported in the literature, partly because several plants rich in
these compounds are of economic importance. Coniferous
trees, in which this type of diterpene is particularly common,
cover about 8% of the land surface of the Earth (San Feli-
ciano and LOpez, 1991). Diterpenes with the 5o<,IOJ3-con-
fignration are common in gymnosperms, but are also known
from the Asteraceae, Fabaceae, Lamiaceae, Rubiaceae, and
Verbenaceae (de Mayo, 1959; MacMillan, 1971; San Feli-
Dilerpenes and Sesterterpenes 405
°
~
°
CH,OH
yuanbuadine (24)
CH,OH
yuanhuatine (26)
ciano and LOpez, 1991). Most other diterpenes are thought
to be derived from one of the hypothetical cationic species
leading to compounds with these two configurations.
lIIanoolDerlvatives
Sclareol (29) and manool (30) may be derived from a
geranyllinalyl pyrophosphate precursor (Fig. 22.9).
Labdane Derivatives
The bicyclic labdanoid diterpenes are characteristic of the
bark and needle resins of the Pinaceae, whereas tricyclic
types (especially the abietanes and pimaranes) dominate in
the wood resin (Croteau and Johnson, 1985) (Fig. 22.10).
Highly oxygenated derivatives of the labdane series are
widespread in the Asteraceae, Lamiaceae, Verbenaceae, and
in the genus Croton of the Euphorbiaceae.
406 Diterpenes and Sesterterpenes

H'

5a,100...series

labda--8(17),13-dien-15-yl pyrophosphate

--+ OPP
Opp

W
~H;H'" OPP SO,IOu-,eries

Fig. 22.8. Cyclization of GGPP to Iabda-8(17),13-dien-15-yl pyrophosphate (modified from West, 1981; used with permission of the copyright owner,
Wiley, New York).

Clerodane Derivatives phylogeny of the Asteraceae, Lamiaceae, Verbenaceae, and

Diterpenes of this series are fonned by rearrangement of
the labdane skeleton during cyclization (Hanson, 1991;
West, 1981) (Fig. 22.11). Many highly oxygenated diter-
penes of this series are found in the Lamiaceae and Verbena-
ceae. There are over 400 known clerodanes; many of these
are from Teucrium species (Lamiaceae) (Hanson, 1991).
Furan fonnation between C-15 and C-16 is a common
feature" in several groups of plants, notably the Asteraceae,
Euphorbiaceae, Lamiaceae, and Verbenaceae.
As the structures of these compounds are quite complex
possibly Euphorbiaceae (Seigler, 1981).
TRICYCLIC DITERPEl'IES
Tricyclic diterpenes fall into four main classes: those with
the pimarane, abietane, rosane, or cassaine skeleta. Epimers
at C-l3 exist among many groups of tricyclic diterpenes
[e.g., pirnaric acid (31) and sandaracopimaric acid (32) (Fig.
22.1)].

#.-.~# #
and they have restricted distributions, it is probable that their Subsequent modification of the precursor to both 5",,1013-
study will provide useful characters for understanding the and 5J3,10",-diterpenes may lead to diterpenes that differ in

OH

OH OH H

sclareol (29) manool (30) epl,dareol (33)

Fig. 22.9. Sclareol, 13-epi-scIareol, manooi.

 Diterpenes and Sesterterpenes 407

~
"'" opp

H' (I ~ ~H -

geranylgeranyl OPP (1) copalyl OPP (35) labdane

~b ~

cif
~-~
! beyerane

~~~
#v9#$abietane strobane kaurane atisirane
Fig. 21.10. Fonnation of labdane and tricyclic diterpenes (Croteau and Jolmson, 1985; modified and used with pennission of the copyright owner,
Academic Press, Orlando, FL).

configuration at position 13 [e.g., sclareol (29) and 13-epis-
clareol (33) from Salvia sclarea (Fig. 22.9)].
The cyclization of a labdadienyl pyrophosphate to the
tricyclic diterpene, pimara-8(9),15-diene (34) appears to be
straightforward (West, 1981) (Fig. 22.12). The precursor
role of labdadienyl pyrophosphates for tricyclic diterpenes
has been confirmed by the conversion of labda-8(l7),13-
dien-15-yl pyrophosphate (35) to ent-sandaracopirnara-
8(l4),15-diene (36) in cell-free extracts from castor bean
seedlings.
DITERPEl'IES RELATED TO ent-KAVRENE
CSp.IO..·COl'lFlGVRADOI'l)
The most widespread diterpenes are not the hydrocarbons
that generally are found in small quantities, but oxygenated
polycyclic derivatives. Most of these compounds seem to be
based on a relatively small number of hydrocarbon precur-
sors. Probably best known are those envolving ent-kaurene
as the parent (West, 1981).
Most tetracyclic diterpenes possess the 5p,lOa-conftgu-
ration, such as occurs in ent-kaurene (37) (Fig. 22.13), and
intermediate in the biosynthesis of gibberellins. These com-
pounds appear to be widely distributed, but are common in
the Euphorbiaceae (especially in Beyeria), the Asteraceae
(e.g., Stevia) and gymnosperms.
Incorporation of S_[1_2H] geranylgeranyl pyrophosphate
(1) into sandaracopimaradiene proceeds with overall anti-
stereochemistry (Drengler and Coates, 1980). GGPP is ftrst
converted to labda-8(l7),13-dien-15-yl (copalyl) pyrophos-
phate (35) and this intermediate compound is cyclized to a
tricyclic pimarenyl cation in the same manner shown above
(Fig. 22.12). However, instead of generating a tricyclic pi-
maradiene by loss of a proton, cation 38 may further cyclize
to produce the tetracyclic cation. This cation has two fates.
Elimination produces ent-beyerene (39). Cation 38 also can
form a carbonium ion that can react in three different ways.
Cyclization of the C and D ring of diterpenes may also be
viewed as taking place via nonclassical carbonium ion inter-
mediates (Geissman and Crout, 1969).
In a cell-free system from Ricinus communis, GGPP is
408 Diterpenes and Sesterterpenes
lTanS-clerodanes
(this one from Solidago arguta (Asteraceae»
clerodanes
<a>
Fig. 22.11 (8 & b). Proposed pathway from GGPP to the clerodane skeleton of kolavenyl pyrophosphate and some typical clerodanes.
converted into four major products: d-sandaracopimara-
8(l4)-diene (36), ent-beyerene (d-beyerene) (39), ent-tra-
chylobane (I-trachylobane) (40), and ent-kaurene (1-
kaurene) (37). The co-occurring phytoalexin casbene (9) is
derived directly from GGPP (Fig. 22.13). Each of these com-
pounds is synthesized through the intermediacy of ent-l-
labda-8(l7),13-dien-15-yl pyrophosphate (copalyl pyro-
phosphate) (35) that is generated from GGPP by the enzyme
copalyl pyrophosphate synthetase. ent-Beyerene, ent-trachy-
lobane, and ent-kaurene are closely related and it is assumed
that they are produced by closely related cyclases (Croteau
and Johnson, 1985). d-Sandaracopimara-8(14), 16-diene (36)
has the opposite configuration at C-13 and would be ex-
pected to arise by another enzyme. Enzymes converting co-
palyl pyrophosphate to d-sandaracopimara-8(14),16-diene
and to ent-kaurene (I-kaurene) have been isolated (Croteau
and Johnson, 1985).
OTIIER STRUCTURAL TYPES DERIVED FROM
TIlE ent-KAURAl'IE SKELETON
The ent-kaurene skeleton is rearranged and subsequently
modified to produce a nnmber of important types of diter-
penes (Fig. 22.14). The gibberellins (41) (ubiquitous in
kolavenyl OPP
~ R1 Rz
cis·clerodanes
R1=CH3, Rz=H
R1=CHzOAc, Rz=H
R1=CHzOH, Rz=H
R1=CHzOH, Rz=OH
R1=CH zOAc, Rz=OH
plants) (MacMillan, 1971), grayanotoxins (42) (Ericaceae),
and enmeins (43) [lsodon (syn. Rabdosia), Lamiaceae] arise
by migration of bonds in ent-kaurene precursors (Newman,
1972). Feeding of suspected intermediates has demonstrated
that the enmeins, steviol (44) (see the subsection sweete-
ners), and other diterpenes are indeed derived from kaurene
(Fig. 22.14) (Croteau and Johnson, 1985).
A modified type of ent-kaurene system is found in the
diteepene alkaloids of the Garryaceae and the Ranunculaceae
(see Diteepene Alkaloids in Chapter 36).
GibbereJIins
The gibberellins (41) are a large family of tetracyclic
diteepenes apparently found in all plants (Beale and Willis,
1991). These diterpenoid acids were first isolated from the
fungus Gibberella fujikuroi, a pathogen that causes over-
growth of rice seedlings. The fungi may use these com-
pounds to soften cell walls and promote fungal invasion.
The gibberellins were shown to produce this effect and later
were isolated from healthy plants as well.
These diteepenes now are known to have a number of
hormonal effects in plants. Gibberellic acid activity has been
found in all parts of higher plants. In general, the reproduc-
 Diterpenes and Sesterterpenes 409

o
J o
OH
H
1 H
0
o

columbin tloribundie acid tloridiolic acid

g§
a bitter principle from EuodiaJloribunda (Rutaceae)

~O
"...

~
o o
0

......6 0
~O
H
H -ko

o > OH Hoi OH
o o 0
teucrin B

Kg,
teucrin E teucrin F

CO
W
~O

O~OH
! 0

'"
o 0 CH30,C

teucrin G methyl barbascoate

(b) from Teucrium chamaedrys (Lamlaceae)

Fig. 22.11. (continued)

-=

labda-8(17),13-dien.15-yl pyrophosphate
copalyl OPP (35) pimara·8(9),lS·diene (34)

Fig. 22.12. Cyclization of labda-8(l4),13-dien-15-yl pyrophosphate to produce pimara-8(9),15-diene and related diterpenes (West, 1981; modified and
used with permission of the copyright owner, Wiley, New York).
410 Diterpenes and Sesterterpenes

~/
-'~~I (~~~~~ 8(14),16·dlene(36) /

1\1~7~' ~
~
i~-~=xb \ (l)·ent·t.achylobane(40)

+ ~
~g9r~$ ent-atisirene
ent~kaurene «l)~kaurene) (37)

Fig. 22.13. Proposed mechanism for the cyclization of GOPP to polycyclic diteIpenes of 5~,lOCl-configuration (modified from Robinson and West,
1970 and Schechter and West, 1969; used with pennission of the copyright owners, American Chemical Society and American Society for
Biochemistry & Molecular Biology).

.'
~ .
~.
12

OH
H __ H

Cg,H Cg,H
18 19

1 H f ~o OH
HO --- 0 HO OCOCH
HOi H J
gTayanotoxin I (42)

gibberellic acid AJ (41) kaurMI6·ene-15~one HO H 0

OH
enmein (43)

Fig. 22.14. Conversion of kaurene to several other skeletal types of diterpenes.

 Diterpenes and Sesterterpenes 411

tive parts contain more of these compounds than vegetative
parts. Most gibberellins occur in plants as glycosides. Imma-
ture seeds are a particularly good source of these compounds
(Goodwin and Mercer, 1983). Giberellic acid (GA) synthesis
occurs mainly in plastids of shoot and root tips, young
leaves, flower parts, immature seeds, and germinating em-
bryos.
Giberellins stimulate stem elongation in rosettes and cer-
tain mutant plants. GA-stimulated cell elongation is due to
cell elongation, not cell division. These diterpene acids also
stimulate bolting and flowering in many plants. Exogenously
applied GA supplants the need for vernalization of many
plants and stratification in many seeds. Numerous other ef-
fects have been observed (Goodwin and Mercer, 1983).
Methods for the isolation, purification and characteriza-
tion of gibberellins have been reviewed (Beale and Willis,
1991).
The biosynthesis of gibberellins has been studied exten-
sively. These compounds are derived from ent-kaurene (37),
with 5j3,lOa-stereochemislry (Fig. 22.15) (Phinney and
Spray, 1990; Spray and Phinney, 1987; West, 1973). The
pathway to ent-kaurene (37) has been examined in cell-free
cultures from Marah macrocarpus (Cucurbitaceae) and a
number of other plants. The biosynthetic system in fungi
and plants is identical (Loomis and Croteau, 1980).
Grayanotoxins
A number of plants in the Ericaceae contain andromedane
diterpenes that cause poisoning in mammals (Fig. 22.16).
For example, Rhododendron japonicum produces a series of
four closely related toxic diterpenoids in its flowers (45-48).
The leaves of another ericaceous shrub, Leucathoe grayana,
contain several andromedane diterpenes called grayanotox-
ins (42). The toxic principle of Pieris japonica also has been
found to be of this type of diterpenes. The leaves of Agauria
salicifolia and other East African ericaceous plants are toxic
to sheep and goats (Mabry and Gill, 1979). Several species
of Kalmia in North America are highly toxic (Kingsbury,
1964). Ten grayanoid diterpenes from Kalmia latifolia were
found to be antifeedant for the gypsy moth, Lymantria dispar
(EI-Naggar et aI., 1980) and are probably responsible for the
toxicity of this species.

~
.
~I
'" I • OPP-
W·I~OPP
. H
H • ---

. g9.I: .
GGPP(l) labda·8,13·dlen·15·yl

gEl
pyrophosphate

. l·U . v. H.) _ _ ~
. I !
H~....... H-..
• H •
H H
• (. ).kaurene (37) • CO,H

12° OR

17

gibberellic acId A3 (41)

Fig. 22.15. Proposed biogenesis of gibberellins (modified from Beale and MacMillan. 1988 and Birch et aI., 1959; used with permission of the
copyright owners. the Royal Society of Chemistry, Cambridge, and Elsevier Science Ltd., The Boulevard. Langford Lane, Kidlington, OX5 1GB, UK)
412 Dilerpenes and Seslerlerpimes

~ ~
HOH o
H H
HO HO '7
¥O OH ~O oil
HO OCOCH, HO OCOCHzCH,
OCOCH,
grayanotoxin I (42) rhodojaponin I
asebotoxin I
Leucothoe Pieris RhotWdendro.

~ HO~
~O.O

O~ HO
.~
,tto \
~
OH
OCOCH,OH
OCOCHzCH, HO OCOCHzCH,
HO OH OH
(45) (46) (47)

~
HOH
o H
HO

HO OH
HO OH

(48) rhodojaponin In (49)

Fig. 12.16. Grayanotoxins.

Three grayanoid diterpenes are the most active constitu-
ents from dried flowers of the Chinese insecticidal plant,
Rhododendron molle. Rhodojaponin III (49), the major com-
pound, has antifeedant, growth inhibitory, and insecticidal
activity against the larvae of Leptinotarsa decemlineata and
Spodoptera Jrugiperda (Klocke et al., 1991).
DITEKPEl'IES WITH A 5a.IOp·COl'lFlOURATlOI'l
A large series of diterpenes possess a 50l, 1O~-configuration.
These are commonly accumulated in gymnosperms and in
members of the Fabaceae subfamily Caesalpinioideae. These
diterpenes have been isolated as by-products of turpentine
manufacture and by collection of the resin from plants of
this group. Crude mixtures of many of these compounds
have been called "naval stores."
ScJareol (29) and manool (30) (Fig. 22.9) are possibly
derived via the intermediacy of a geranyllinalyl pyrophos-
phate (2) precursor. Formation of the allylic ion (SO) permits
further cyclization to rimuene (51) and abietic acid (52). The
former cation (SO) can again cycJize to compounds such as
phyllocladene (53) and isophyllocladene (Fig. 22.17)
(Oehlschlager and Ourisson, 1967).
Many pimarane and abietane derivatives [mostly with
5a,IO~-configuration, e.g., abietic acid (52)] are found in
gymnosperms, but also are known from the Asteraceae, Eu-
phorbiaceae, Lamiaceae, and the liverwort genus Junger-
mannia (Hepaticae). These compounds occur in the leaf-
surface resins of members of the tribe Ricinocarpoideae of
the Euphorbiaceae (Croteau and Johuson, 1985). Com-
pounds of the rosane type occur in the wood of Erythroxylum
species (Erythroxylaceae) (Fig. 22.18) and those of the cas-
saine type in the Fabaceae (subfamily Caesalpinioideae).
Erythrophleum alkaloids possess the last type of skeleton
(Nakanishi et al., 1974).
A complex series of (probably concerted?) migrations
must be invoked in order to explain the origin of some types
of diterpenes such as rosenonolactone (54).
RESIl'IS Il'I FLAl'ITS
Resins are mixtures of diterpenes (along with monoterpenes
and sesquiterpenes in many instances) that are found in
plants of many different groups (Langenheim, 1990; Thomas
1970). Plants from about 10% of plant families produce res-
ins. Most of the plants that produce large amounts of resins
are tropical; all gymnosperms produce resins, but most only
in small amounts (Langenheim, 1990). Resins also are com-
monly found in the Anacardiaceae, Burseraceae, Clusiaceae
(syo. Gutriferae or Hypericaceae), Dipterocarpaceae, Eu-
phorbiaceae, Fabaceae, Rubiaceae, and Styraceae. In these
families, compounds of both 50l,1O~- and 5~,IOIX-configura­
tions are encountered (Langenheim, 1973, 1981, 1990). Res-
ins from gymnosperms, mostly from the Araucariaceae and
 Dite/penes and Sestertelpenes 413

#-#' +

¢f'w gf/;
(50)
geranylgeranyl pyrophosphate (1) /

~~ CO,H
pbyUocladene (53)
abietic acid (52) rimuene (51)

Fig. 22.17. Biogenesis of phyllocladene and isophyllocladene (modified from Oehlschlager and Ourisson, 1967).

Pinaceae, usually are diterpenes with a 5a,IO[3-configura-
tion. Many plants serve as commerical sources of resins; the
genera Hymenaea and Copaifera (Fabaceae) and Pinus and
Agatha (gymnosperms) are probably the best known produc-
ers. Resins are used as feedstocks for products such as insec-
ticides, incense, varnishes, rosin, and adhesives, and as com-
ponents of drugs and polishes. Fossilized deposits of
diterpenes are known as amber (Langenbeim, 1990).
DITERPENES Il'I CHEMOSYSTEJllATIC STUDIES
Diterpenes appear to be useful for phylogenetic studies of
several groups of plants. Among these are cocarcinogenic
diterpenes of the Euphorbiaceae and Thymelaeaceae, graya-
notoxins of the Ericaceae, cembrene and its relatives in gym-
nosperms, and taxanes of the Taxaceae.
The bicyciic diterpenes of the Asteraceae, Euphorbiaceae,
Lamiaceae, and Verbenaceae appear to have exceptional
promise at the familial and generic level, but more study is
needed (Seigler, 1981).
A series of seco-diterpenes, the ginkgolides (55), are only
known to occur in the leaves and root bark of Ginkgo biloba
(Fig. 22.19) (Nakanishi et aI., 1974).
Many diterpenes isolated from the genus Salvia (about
900 species) (Lamiaceae or Labiatae) possess quinonoid
structures (Luis, 1991). Callus cultures of Salvia miltiorrhiza
established from sterile seedlings produced diterpenes, and
one line accumulated both cryptotanshinone (56) and ferrug-
inol (57) (0.8% and 1.3%, respectively, on a dry weight
basis). The red pigment, cryptotanshinone, is a potent inhibi-

r; ~ g5t~
__ b H
__

b •
H

~~
~: o
rosenonolactone (54) abietic acid (52)

Fig. 22.18. Biosynthesis of rosenonoIactone (modified from Torssell. 1983; used with pennission of the copyright owner, John Wiley & Sons, Ltd,
Chichester),
 90
414 Diterpenes and Sesterterpenes
~H
0H
1 1 °
'"
1.& ° '"
\ Ii
cryptotanshinone (56) rerruginol (57)
(58) a-4,8,13-duvatrien-l,3-diol (59)
Fig. 22.19. Biologically active diterpenes.
tor of platelet aggregation (Charlwood and Charlwood,
1991).
BIOLOGICAL ACTIVITY
Diterpenes are known to play diverse roles in plants. The
ubiquitous acyclic compound, phytol (4), is a part of the
chlorophyll molecule and is essential to photosynthesis. The
biological activity of gibberellins (such as 41) as plant hor-
monal substance is discussed above.
A series of diterpenes with antheridium-deve10ping prop-
erties (antheridiogens) in several ferns is derived from path-
ways related to those that produce gibberellins. Compounds
with this activity have been isolated from Pteridium aquili-
num, bracken fern, and well as several other species. Because
most ferns produce only nanogram quantities of these highly
active substances, the discovery that ferns of the family
Schizaeaceae contained larger amounts has been of value
for continued work with these developmentally important
compounds. A new antheridiogen, ent-1a,10(3-dihydroxy-
9a, 15a-cycI0-20-norgibberell-16-ene-7,9-dioic acid 10,19-
lactone (58), has been isolated from the fern Anemia mexi-
cana (Furber and Mandel, 1988; Furber et a1., 1989).
Duvatriendiols, primarily a- and (3-4,8,13-duvatrien-1,3-
diols (59 and 60), are synthesized in glandular trichomes of
the leaves of tobacco. These preformed compounds have
antifungal properties. Duvatriendiols inhibit spore germina-
tion of Peronaspora tabacino with an ECso of 20 ",giml
(Kuc, 1992).
FhytoaIexins
The famesyl transferase of germinating castor bean (Ri-
cinus communis, Euphorbiaceae) seeds occurs in small quan-
°
::7
ginkgolide (55)
8-4,8,13-duvatrien-l,3-dioI (60)
tities in dark-grown seedlings maintained under sterile con-
ditions. When infected with potentially pathogenic fungi,
this enzyme and a synthetase that converts GGPP to casbene
(9, Fig. 22.6), a mactocyclic diterpene, are greatly increased
(West, 1981). It has been suggested that casbene is a phyto-
alexin as it appears to increase in amount in the presence of
fungi such as Rhizopus stolonifer, Aspergillus niger, and
Fusarium moniliforme.
Oryzalexins A (61), B (62), and C (63) are phytoalexins
isolated from rice infected with Pyricularia oryzae (Fig.
22.20) (Akatsnka et a1., 1985; Brooks and Watson, 1985;
Kono et a1., 1985). These compounds appear to be deriva-
tives of sandaracopimaradiene.
Another series of closely related phytoalexins have also
been reported from rice (Threlfall and Whitehead, 1991).
These compounds, the momilactones (64 and 65), were re-
ported to arise in response to the same organism as oryzalex-
ins above or in response to ultraviolet light (Cartwright et
a1., 1980, 1981; ThrelfaII and Whitehead, 1991).
Momilactones arise from GGPP via 9,(3H-labdadienyl
pyrophosphate (66) and 9-(3H-pimara-7,15-diene (67),
whereas oryzalexins arise via copalyl pyrophosphate (35)
and sandaracopimaridiene (36). Both groups of diterpenes
appear to be synthesized in the cytosol. Only kaurene is
found in tissue not attacked by fungi. Chitin proved to be
the best elicitor of momilactones in cell culture (West et aI.,
1990). Chitinase probably breaks down the chitin to active
fragments (West et a1., 1990). Both types of phytoalexins
from rice are probably important in disease resistance, but
the relative importance of each has not been assessed (West
et a1., 1990).
An epimeric mixture of sclareol (29) and 13-epi-sclareol
(33) has been shown to inhibit germination of spores of sev-
eral rust diseases on tobacco, broad bean, dwarf bean, and
wheat plants at 100 ppm (Wain, 1977).
 Dite/penes and Sestenerpenes 415

Phytotoxins Although fusicoccin is a C-25 compound, GGPP (1) is

Several well-known phytotoxins are diterpenes. Among
these are the colletotrichins, fusicoccin, and the cotylenins.
The colletotrochins are produced by members of the fungal
genus Colletotrichum. These fungi are pathogens on many
plants including sugar cane, peppers, tobacco and maize
(Ballio, 1981; Stoessl, 1981). The fungal antibiotic, fusicoc-
cin (68), also is derived from diterpene metabolism (Fig.
22.21). This compound occurs in the fungus Fusarium amyg-
dati. In addition to the phytotoxic activity (wilting in the
hosts peaches and almonds), it was later discovered that this
group of compounds has plant growth-promoting activity.
Fusicoccin itself is the most active member of the group.
This compound readily induces wilt in tomato seedlings.
Fusicoccins and the cotylenins affect a number of physiolog-
ical processes in plants. Among these are induction of water
uptake, proton extrusion, promotion of growth, stimulation
of seed gennination, opening of stomata, and abscission of
leaves (Ballio, 1981; Ballio etal., 1991; Stoessl, 1981). Fusi-
coccin (68) binds specifically and with high affinity to plas-
malemma-enriched membrane preparations from maize
(Ballio, 1981).
first converted to a cyclic diterpene and then modified to
produce fusicoccin (West, 1981). This compound is similar
in some regards to the ophiobolanes (see the section Sester-
terpenes, below) (Stoessl, 1981).
The cotylenins are leaf growth-promoting substances iso-
lated from a Cladosporium species (Fig. 22.22) (Stoessl,
1981).
Antifeedant Compounds
A number of diterpenes are known to have pronounced
antifeedant activity against herbivores (Mabry and Gill,
1979; Munakata, 1977). Abietic (52), dehydroabietic, 12-
methoxyabietic, sandaracopimaric (32), and isopimaric (69)
acid serve as feeding deterrents for the larch sawfly, Pristi-
phora erichsonii in single needles from new shoots of tama-
rack (Larix laricina) (Ohigashi et al, 1981). The larvae of
this insect do eat tofted needles on short shoots of the same
trees.
Varieties of sunflower (Hetianthus annuus, Asteraceae)
that are resistant to attack by larvae of the sunflower moth

GGPP
.......

#~
W
98H·labdadienyl pyrophospbate (66) copalyl pyropbosphate (35)

i .....

HI

str 1
H

~
;:98;_Pimara·W7'15.diene(67) (+).,and CO Pimaradi:ne(36)

o ~ HO~ H I 0 HH ~ HO~ i H ""0

OH 0 H
o 0
momilactone A (64) momiladone B (65) oryzalexin A (61)

oryzalexin B (62) oryzalexin C (63)

Fig. 22.20. Oryzalexins and momilactones (Threlfall and Whitehead, 1991; modified and used with pennission of the copyright owner, Oxford
University Press. Oxford).
416 Dile/penes and Sesterterpenes
CHO
Fig. 22.21.Biogenesis of fusicoccin and colletotrichins (modified from Stoessl, 1981 and West, 1981; used with permission of the copyright owners,
Academic Press, Orlando, FL, and Wiley, New York).
(Homeosoma eleetellum) contain high concentrations of tra-
chyloban-19-oic acid (70) and (- )-16-kauren-19-oic acid
(71) in their florets. As sunflower florets that contain only
small amounts of these compounds are a major portion of
the diet of first ins tar larvae of this insect, it is likely that
these acids serve as feeding inhibitors. At the 1% level, both
kaurenoic and trachylobanoic acids decreased the growth
of sunflower moth larvae and tobacco budworm (Heliothis
vireseens) by about 50%. At the 0.5% level, both reduced
larval growth of the cotton bollworm and the pink bollworm
to less than 5% (Fig. 22.23) (Mabry and Gill, 1979). The Z-
and E-isomers of ( - )-ozic acid (72) have been isolated from
Helianthus oeeidentalis and may be associated with resis-
tance to insect attack (Stipanovic et aI., 1979).
Several series of complex oxygenated diterpenes are
known to have antifeedant properties. Many of these occur
OH
a colletotrichin
in the Lamiaceae (Labiatae) and Verbenaceae but are found
in other families as well (such as the Asteraceae).
Species from the Lamiaceae contain a large variety of
terpenes. Among these are a number of physiologically ac-
tive diterpenes (Fig. 22.24). One example is the type of com-
pound found in the genus Isodon (syn. Rabdosia). These
ent-kaurenoid diterpenes possess feeding-deterrent activity.
Inflexin (73), isodomedin (74), and kamebanin (from I. in-
flexus, I. shikokianus, var. intermedius and I. kameba) all
exhibit specific toxicity toward lepidopteran larvae, includ-
ing the African armyworm, Spodoptera exempta. These dit-
erpenes also are cytotoxic and have LDso values in the range
of 4-5 J.'g/ml. All three have an exocyclic Ci,f3-unsaturated
carbonyl group and can undergo Michael additions in a simi-
lar manner to sesquiterpene lactones (see Chapter 21) (Kubo
and Nakanishi, 1977).
 Ditelpenes and Sesterterpenes 417

P P
HO CH,OCH3
OH
HO CH,OCH3

Ho,r0':('o
{)l0)"CH,OCH3

°
HO

HO'A--0H HO,A--0H
{)l0)"CH,OCH3 {)l0)"CH,OCH3
Fig. 22.22. Cotylenins (Sroessi, 1981; modified and used with pennission of the copyright owner, Academic Press. Orlando, F1..).

Clerodendrin A (75) and B, from verbenaceous plants,
possess potent antifeeding activity against some insects (e.g.,
Spodoptera litura), but less against others (e.g., Calospilos
miranda). Several genera of plants from this family contain
similar compounds (Clerodendron, Caryopteris, and Calli-
earpa). ent-Clerodane is the same compound as neo-clero-
dane. Clerodendrin A (75) and B, from Clerodendron trieho-
tomum, gave 100% feeding inhibition against Spodoptera
litura at about 250 ppm, whereas clerodin (76) from Clero-
dendron infortunatum was considerably more active. Many
of these compounds have a bitter taste but no direct correla-
tion between bitterness to humans, and feeding-deterrent ac-
tivity of insects could be established. Both clerodendrin A
and B were active against the oriental tussock moth (Eu-
proetis subf/ava) at 1000 ppm and the European com borer
(Ostrinia nubialis) at 5000 ppm (Mabry and Gill, 1979; Mu-
nakata, 1977).
Although clerodanes are feeding deterrents to many in-

~
~ (-)-ozic acid (72)
trachyloban-19-oic acid (70)

{-}-16-kauren-19-oic acid (71) levopimaric acid

Fig. 22.23. Diterpenes from Helianthus.

418 Diterpenes and Sesterterpenes

~
H ..•,,"
.../ 0 0

I
OH .
CH,COO ·····OH O 0;::: bCOCH,
OCOCH,

inflexin (73) ajugarin I (80)

16

OCOCH,
OCOCH, cinnzeylanol (82), R=H

"~_""'£oc.'
H

~"""'OH
CO,H
HO ......
CH, 0 15o:-hydroxy-(-)-kaur-16-en-19-oic acid (79)

s-r-~
C,H' 0 ..,

~
0"
OCOCH,
IbCOCHW'
OCOCH, ; .., /

cJerodendrin A (75)

CO,H

kaur-16-en-19-oic acid (77) (·)·kauran·16«·ol (78)

(a)

Fig. 22.24 (a & b). Diterpenes with biological activity.

sects. they are feeding stimulants for the turnip sawfly, Ath·
alia rosae. The larvae of this insect feed on members of the
Brassicaceae; however, adults feed on Clerodendron tricho·
tomum (Verbenaceae) and sequester derodanes in their bod·
ies (Gershenzon and Croteau, 1991).
Many genera of the Asteraceae contain highly oxygen-
ated compounds similar to those of the Lamiaceae and Ver-
benaceae discussed above. A series of these substances was
found in the widespread, weedy genus Solidago (Asteraceae)
(Cooper-Driver and Le Quesne, 1987). These indude four
ent-kauranes: kaur-16-en-19-oic acid (77), ( - )-kauran-16o:-
01 (78), ISo:-hydroxy-( - )-kaur-16-en-19-oic acid (71), and
17-hydroxy-( - )-kaur-1S-en-19-oic acid (79). These ent-
kauranes had antifeedant activity against Trirhabda cana-
densis (Cooper-Driver and Le Quesne, 1987).
Feeding-deterrent compounds in Ajuga remota, La-
miaceae, the ajugarins (such as 80) (a type related to the
ent-derodanes), exhibited antifeedant activity against
Spodoptera exempta at 100 ppm and S. littoralis at 300 ppm.
Insecticidal and Nematicidal Activity
Many of the antifeedant compounds discussed above
have insecticidal activity as welL Moreover, other diterpenes
are toxic to insects and nematodes when consumed. Ryanod-
ine (81), from Ryania speciosa (Flacourtiaceae) and several
related species, is unique in that its insecticidal activity was
discovered as a part of a search for new insecticides (Crosby,
1971). The toxic principle, ryanodine, is a diterpene esteri-
fied to a pyrrole-2-carboxylic acid (Crosby, 1971). Ryanod-
ine inhibits cardiomuscular calcium transport (Croteau and
Johnson, 1985).
Two diterpenes, cinnzeylanine (82) and cinnzeylanol

0 O·glyc:osyl·glyeosyl
~ ~
CO,CH3
(85)
4W
o ;
J. i!
• 0
HO H
Isodonal (86) enmein(43)
o
(Y-o
NH
(b) ryanodlne (81)
(83), from Cinnamomum zeylanicum (Lauraceae), have been
demonstrated to possess insecticidal activity. At 2-4 ppm,
these compounds inhibited larval ecdysis in Bombyx mori
(Isogai et al., 1977; Seigler, 1983).
Diterpenes from the roots of Daphne odora (Thyme-
laeaceae) are nematicidal against Aphelenchoides besseyi.
Odoracin (22) caused 100% mortality at 5 J.Ioglml, whereas
the related compound odoratrin (84) possessed greater activ-
ity (Fig. 22.7) (Chitwood, 1992).
Diterpenes with Juvenile Hormone Activity
A diterpene (85), from Persea (Lauraceae, avocado)
leaves, has been reported to possess juvenile hormone activ-
ity (Mann, 1987).
Dlterpenes That Prevent Reproduction
in Insects
The diterpenes from Rabdosia (syn./sodon) species (La-
miaceae) exhibit an inhibitory effect on the mitochondrial
oxidative phosphorylation of the ovary of a termite queen
of Macrotermes subhyalinus. Among the compounds tested
were isodonal (86), enmein (43), oridonin (87), and nodosin
(88) (Kubo et al., 1981).
Trail.Marking Pheromones
Several acyclic diterpenes such as geranylgeranial and
geranylcitronellol (89), Fig. 22.3} have been isolated from
Diterpenes and Sesterterpenes 419
~
OH HO
I I
CO,·glyeosyl
~ HO
stevloside (94) (102)
!
H
OH
oridonin (87) nodosin(88)
zoopolanol (99)
Fig. 22.24. (conlinued)
ants (Lasius carniolicus) and bumblebees (Bombus ter-
restris and at least eight other species). These compounds
are used by male bumblebees to mark their flight routes.
The markings are species specific. The secretions of the ants
setve as recognition marks in an alarm·defense system (Ahl-
quist et al., 1978; Bergstrom et al., 1970; Svensson and Berg-
strom, 1977). It is not known if these compounds are synthe-
sized by the insects or if they are taken from plants.
Cembrene derivatives also are found in some termites of
the genus Nasutitermes, where they may playa role as trail-
marking pheromones (Nahrstedt, 1982).
Diterpenes from Marine Plants
A number of diterpenes (as well as a variety of other
terpenes) have been isolated from marine algae. These differ
in large part from those of terrestrial plants (De Rosa, 1991;
Hay and Fenical, 1988). The diterpene trialdehyde, halirned-
atrial (90) produced by many species of Halimeda (a calcar-
eous green alga of the Chlorophyta) is one of the most active
compounds from this group of plants. Halirneditrial (90) has
structural similarities to warburganal and inhibits feeding by
reef fishes (Hay and Fenical, 1988). Both sesquiterpenes,
such as flexilin, and diterpenes, such as trifarin (91), occur
in Caulerpa species. These two metabolites contain the 1,4-
diacetoxy-1,3-diene (bis-enol acetate) moiety, which is now
known to be widespread among compounds derived from
green algae (De Rosa, 1991; Paul and Fenical, 1987). Algae
420 Diterpenes and Sesterlerpenes
of the family Udoteaceae have been shown to contain similar
sesquiterpenoid compounds such as rhipocephalin and rhi-
pocephanal (Paul and Fenical, 1987). Several of the sesqui-
terpenes and diterpenes of these algae contain acetylenic
linkages. Many of these terpenoid compounds are active in
a variety of bioassays and are quite likely responsible for
the antiherbivore properties of many green algae toward fish
and sea urchins (Paul and Fenical, 1987).
Brown algae from the order Dictyotales produce diter-
penes such as pachydictyol A (92). This compound deters
feeding by tropical parrotfishes, the tropical sea urchin Dia-
dema antillarum, and the temperate omnivorous fishes La-
godon rhomboides and Diplodus holbrooki, but not by the
temperate sea urchin Arbacia punctulata, or the temperate
amphipod, Ampithoe longimana, or the cosmopolitan poly-
chaete Piatyneris dumerilii. A related compound, dictyol-E
(93), deters feeding by the temperate fishes Logodon and
Diplodus and by the temperate sea urchin Arbacia; however,
it is not effective against the temperate amphipod Ampithoe
longimana or the polychaete Platyneris. These data suggest
that diterpenes of this type limit herbivory by large mobile
herbivores, but not against the small and generally sedentary
polychaetes and amphipods which may be protected indi-
rectly by the compounds (De Rosa, 1991; Hay et al., 1988).
Sweeteners
Stevioside (94, Fig. 22.25), a diterpene from Stevia re-
baudiana (Asteraceae), a plant from Paraguay, is intensely
sweet. Steviol, the parent diterpene, is an oxygenated ent-
kaurene derivative and the biosynthesis involves ent-kaur-
16-en-19-oic acid (West, 1981). Stevioside is about 300
times as sweet as sucrose on a molar basis (Harborne, 1982;
Hodge and Inglett, 1974; Pezzuto et al., 1985; Soejarto et
al., 1982). Steviol and related glycosides occur in amounts as
high as 8% by weight of the plant leaves (Kinghorn, 1992).
A sweet labdane diterpene arabinoside, gaudichaudioside
A (95), has been isolated from aerial parts of Baccharis
gaudichaudiana (Fullas et al., 1991).
JIIedicinai Properties
The 7-hydroxymethyl derivative of 6-Z-geranylgeraniol
from Croton (Euphorbiaceae) stems appears to serve as a
prostaglandin analog. This compound protects the digestive
tract from the effects of ulceration and in promoting wound
healing (Croteau and Johnson, 1985).
An unusual glycoside, wedeloside (96), from Wedelia
asperrima (Asteraceae), inhibits mitochondrial ADP/ATP
carrier protein and has the ability to protect animals against
the toxic effects of aflatoxin B, (Croteau and Johnson, 1985;
Node et aI., 1982). The diterpene forskolin (97), from Coleus
barbatus and C. forskohlii (Lamiaceae), is an activator of
adenylate cyclase, and is an active inhibitor of the action of
brefeldin A (a fungal metabolite with pronounced effects
on protein trafficking in cells) (De Sousa and Shah, 1988;
Schreiber, 1992; Valdes et al., 1987; Wagner, 1988). This
compound also is of interest as an antihypertensive agent
(Alcaraz and Rios, 1991; Hanson, 1991).
The fruit oil of the leguminous tree Pterodon pubescens
contains geranylgeraniol (3) and its terminal epoxide (98).
This terminal epoxide is highly lethal to the cercariae of
Schistosoma mansoni, the causative agent of schistosomiasis
(Gilbert, 1977). Other unsaturated diterpenes such as dehy-
droabietic acid, agathic acid, and copalic acid prevent cercar-
ial penetration.
A series of diterpenes from Sideritis (Lamiaceae) species
have anti-inflammatory activity. These plants also contain
anti-inflammatory flavonoids (Alcaraz and Rios, 1991).
Gingkolides from Ginkgo bi/oba have anti-inflammatory ac-
tivity and antagonize platelet aggregation factor (Walton,
1992).
Diterpene acids from Ponderosa pine needles when in-
gested by cattle lead to reproductive failure. This is thought
to occur by interference with normal steroid metabolism
(Croteau and Johnson, 1985).
Diterpenes from zoapatle (Montanoa tomentosa, As-
teraceae) are the active components of an aqueous extract
of the plant used for inducing labor, for increasing the tone
and frequency of uterine contractions during labor, for de-
creasing postpartum bleeding, and potentially as a fertility-
regulating agent (Bingel and Fong, 1988). Zoapatanol (99)
is one of the abortifacient diterpenes from this plant (Hanson,
1991).
Antitumor Compounds
A number of antitumor norditerpenes, such as nagilactone
C (100) and nagilactone F (101) from the gymnospermous
genus Podocarpus (Podocarpaceae), have activity against
human non-small-celliung tumor and colon tumor cells in
culture (Alcaraz and Rios, 1991; Cassady et al., 1990). An-
other interesting tumor-inhibiting diterpene is compound
(102) isolated from Taxodium distichum (Newman, 1972).
A casbane-type diterpene from Agrostistachys hookeri
(Euphorbiaceae) is active in the P-388lytuphocytic leukemic
cell culture system (Choi et aI., 1988).
Triptolide (103) and tripdiolide (104) from the celastra-
ceous plant, Tripterygium wilfordii, exhibit antiturltor activ-
ity in the L-121O (lytuphoid leukemia), P-388, and KB test
systems (Cordell, 1978).
A series of cytotoxic kaurene and B-secokaurene diter-
penoids from Rhabdosia species (Lamiaceae) have potential
antitumor activity. Oridonin (87), lasiokaurin, emnein (43),
and nodosin (88) are some of the early bio.ctive compounds
isolated from members of this genus (Alcaraz and Rios,
1991).
Certain cocarcinogenic diterpenes also possess antitumor
activity (see above).
SESTERTEKPEl'IES
Sesterterpenes, C25 terpenoids, are relatively uncommon,
primarily fungal metabolites, although some compounds of
this series are known from higher plants and others from
insect protective waxes (Cordell, 1974; Crews and Naylor,
1985; Hanson, 1972). The principal type of sesterterpenes
includes the fungal metabolites known as ophiobolanes. Two
 Dite!penes and Sesterterpenes 421

OH

& 1

\
HO

OH
,
......' ' ' -
0

OCOCH3
OH

1
" OH

wedeloside (96) forskolin (97) HO

OH

HO~
~
CHO
OH
~ ~ .._"CHO
gaudichaudioside A (95)
H""
# CHO

halimedatrial (90)

pachydictyol A (92)

dictyol-E (93)

~ OH geranylgeraniol (3)

~
CH3COO

'" I ~
I I~ I~ I~ I
~OH (98)
OCOCH3
(a) trifarin (91)

OH

o o

triptolide (103) tripdiolide (104)

HO

(b) nagilactone F (101) nagilactone C (100)

Fig. 22.25 (a & b). Medically interesting ditetpenes.

422 Dilerpenes and Seslerterpenes

ophioboli. A (105) ophiobolin B (106)

cbeilanthatriol (107) gascardic acid (110) C01H

~~ r!fO~'"CO'H
notholaenic acid (109)

Fig. 22.26. Some representative sesterterpenes.

of the best known compounds of this series are ophiobolin BIOSYI'ITHESIS

A (105) and B (106) (Fig. 22.26).
A second type of sesterterpenes including cheilanthatrlol
(107) has been isolated from the fern Cheilanthes farinosa.
This compound appears similar in certain structural aspects
to some trlterpenes (Khan et aI., 1971).
A third type, including gascardic acid (110), appears to
only be known from the insect Gascardia madagascariensis
(Hanson, 1972).
Sesterterpenes are derived from geranyJfarnesyl pyrophos·
phate (108) (Fig. 22.27) (Hanson, 1972). In the synthesis of
ophiobolins and gascardic acid, the pyrophosphate leaving
group acts as the leaving·group initiating cyclization to an
intermediate containing an II·membered ring. A I: 5 hy·
dride shift leads to the unusual 8-membered ring system of
the ophiobolins (Hanson, 1972).

! !

HO
opbiobolins
gascardic acid

Fig. 22.27. Proposed biosynthesis of opbiobolins and gascardic acid (Hanson, 1972; modified and used with pennission of the copyright owner,
Academic Press, London).

BIOLOGICAL ACTIVITY
A number of sesterterpenes from the genera Helminthospor-
ium and Cochliobolus are phytoxins for their plant hosts.
Ophiobolin A (105) is found in many species of these two
genera. Ophiobolins induce chlorosis and necrosis of rice
shoots and induce leakage of betacyanins from beet roots
(Ballio, 1981).
Notholaenic acid (109) from Notholaena standleyi af-
forded anti-HSV-I activity at a relatively high concentration
(25 f.Lgldisk) (Rinehart et aI., 1990).
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23
Triterpenes and Steroids

Introduction
Squalene biosynthesis
Compounds Derived by Direct Cyclization of Squalene
Squalene 2,3-Epoxide
Triterpenes Derived via a Chair-Boat-Chair-Boat
Transition State.
Fonnation of Cycloartenol
Phytosterols
Fonnation of Cholesterol
Fonnation of Other Plant Sterols
Biological Activity of Plants Sterols
Progestans in Plants and from Animals
Progestagens from Insects
Ecdysteroids
Phytoecdysteroids
Chemotaxis in Fungi
Cucurbitacins
Triterpenes Derived via a Chair-Chair-Chair-Boat
Transition State
Biological Activity of Triterpenes
Iridals and Irones from the Iridaceae
References
INTRODUCTION
Triterpenes constitute a significant portion of the lipid sub-
stances of all plants; more than 4000 triterpenoids have been
isolated. These compounds are precursors to steroids in both
plants and animals. Steroids are components of membranes
in plants. Both triterpenes and steroids occur free, as glyco-
sides (Boar and Allen, 1973), or in other combined fonns.
Correct structures for many were not forthcoming until about
1940 (Connolly and Overton, 1972). The structures of
triterpenes and steroids may be subdivided into about 40
major types (Fig. 23.1) (Connolly and Hill, 1991; Devon
and Scott, 1972).
In contrast to the previously discussed mono-, sesqui-,
and diterpenes that are biosynthesized by linear condensa-
tion of five carbon units, triterpenes arise via dimerization of
two farnesyl pyrophosphate units to produce an intennediate
compound, squalene (1) (Fig. 23.2). Squalene (usually as
the 2,3-epoxide) may then be cyclized by several mecha-
nisms from different confonnations on an enzyme surface
to produce the parent skeletal types of many different kinds
of triterpenes that undergo subsequent modification (Banth-
orpe and Charlwood, 1980; Harrison, 1985). The structures
of many triterpenes and steroids may be explained by the
"biogenetic isoprene rule" (see Chapter 18) (Connolly and
Hill, 1991).
When squalene 2,3-epoxide (2) is cyclized via a
chair-boat-chair-boat sequence, the fIrst isolable cyclic in-
tennediate (in plants) is cycloartenol (3) (Fig. 23.6). Cycloar-
tenol proves to be a key intennediate in the synthesis of
certain other triterpenes and plant sterols. Many steroids are
common [if not ubiquitous, e.g., fl-sitosterol (4), stigmas-
terol (5), and campesterol (6) (Fig. 23.6)] and it is probable
that these pathways exist in all plants (Goad and Goodwin,
1973; Grunwald, 1975; 1980). Cholesterol (7) occurs in
small quantities, but appears to be a universal constituent of
plants. This sterol serves as a key intennediate in the synthe-
sis of a number of other steroidal compounds. A new system
of numbering sterols was recommended in 1989 (Goad,
1991a).
The analytical procedures and methodology for isolation,
purification, and characterization of plant sterols (Connolly
and Hill, 1991; Goad, 1991a; Patterson, 1984), as well as
general chromatographic techniques for triterpenes (Con-
nolly and Hill, 1991; Coscia, 1984), the application of C-13
nuclear magnetic resonance (NMR) spectroscopy to charac-
terization oftriterpenoids and steroids (Goad, 1991a; Knight,
1974; Wehrli and Nishida, 1979), and the application of mass

427
428 Triterpenes and Steroids
HO
6-sitosterol (4)
HO
cholesterol (7)
HO
parkeol (53)
Fig. 23.1.
spectrometry to structure elucidation of triterpenes (Goad,
1991a; Ogunkoya, 1981) have been reviewed.
A number of alkaloids containing steroid and triterpene
skeleta are discussed under Triterpenoid and Steroid Alka-
loids in Chapter 36.
SQUALEI'IB BIOSYNTHESIS
Squalene is derived from two farnesyl pyrophosphate (8)
units joined in a head-to-head (1'-1) condensation (Fig.
23.2). The stereochemistry of this process is known from
tracer studies and the pathway includes presqualene pyro-
phosphate (9) as an intermediate. Mechanisms have been
proposed that explain most stereochemical features (Poulter,
1990); other evidence supports an ion-pair mechanism for
the rearrangement (Fig. 23.2) (Croteau and Johnson, 1985;
Poulter, 1990).
The condensation of farnesyl pyrophosphate (FPP) units
stigmasterol (5) campesteroI (6)
22 24 26
21 20
1623~":"
,"
I '
HO 0
lanosterol (15) estrone (21)
OH
o
malabaricol
squalene (1)
Some representative triterpenes and steroids.
to yield presqualene pyrophosphate (9) is effected by the
enzyme squalene synthase (EC 2.5.1.21). This synthetase is
a microsomal enzyme in every source that has been exam-
ined and requires a divalent cation such as Mg2+ or Mn 2+
(Goodwin, 1985). Squalene synthetase can be solubilized
from yeast microsomal membranes with detergents such as
deoxycholate and has been purified to homogeneity. The
enzyme is a single polypeptide with a molecular weight of
47,000. This enzyme catalyzes both portions of the biosyn-
thesis of squalene (1) from farnesyl pyrophosphate (9)
(Agnew and Popja!<, 1978; Sasiak and Rilling, 1988; Zhang
et aI., 1993). The first step, a 1'-2,3 prenyltransfer, yields the
intermediate presqualene pyrophosphate (9). The reaction
producing presqualene pyrophosphate (9) is substantially
more rapid than the overall synthesis of squalene (1) (Poulter
and Rilling, 1981). In in vitro studies, this intermediate
seems free to leave the enzyme, whereas, in contrast, under
in vivo conditions, presqualene pyrophosphate is accumu-
lated only in small amounts (Sasink and Rilling, 1988).
 Triterpenes and Steroids 429

5 H4 2 H 2 acceptor
PPOCH~"~ 1~3
3 CH3 I I PPOCH,.....- \.~
'-7 CM3 I I rotation
- - ~PPO.
{ppo, CH) -
P ~ SHR
.--:; h 0
CH3
H
around bond
•... ~... .,,; ,9
5' H 4' 3' 2' S .' H 2' 3' 44 donor

famesyl pyrophosphate (8) (numbers correspond to those of farnesyl pyrophosphate)

(numbers correspond to those of mevalonic acid)

PPOCH2 1 2
H

4'

(R)·presqualene pyrophosphate (9)

(a) (numbers correspond to those offarnesyl pyrophosphate)

PPO'

presqualene pyrophosphate (9) /

~~
'H'~~
H
~,~
OPP'
")'. +... /
',

'H'

NADPH'\

~~
HR~
t Q ,9

4(2)

squalene (1)
HS HR
(b) (numbel'S in parentheses are those of mevalonic acid) (other numbers are those for farnesyl pyrophosphate)

Fig. 23.2 (a & b). Squalene biosynthesis.

430 Triterpenes and Steroids
One protein is required for squalene synthesis, but two
catalytic sites may be involved: one for the synthesis of pre-
squalene pyrophosphate and one for the reduction of this
compound to squalene (Sasiak and Rilling, 1988). Although
the enzyme is membrane bound by the carboxyl terminal
domain, the catalytic domain apparently is free in the cytosol
(Zhang et al., 1993). Squalene synthase isolated by detergent
treatment from daffodil microsomal membranes was acti-
vated after the fIrst step of purifIcation by liposomes of phos-
phatidylcholine (Beriingheri et al., 1991).
Nerolidyl pyrophosphate does not serve as a precursor
for squalene (poulter and Rilling, 1981). The condensation
requires NADPH in yeasts and, if this reductant is not pres-
ent, famesyl pyrophosphate (8) accumulates. During the
course of the reaction, two pyrophosphate groups are re-
leased, one hydrogen lost and one hydrogen replaced by a
hydrogen from NADPH. One (lS)-hydrogen atom is re-
moved from famesyl pyrophosphate.
The fIrst reaction involves a prenyl transfer step in which
C(l') of one of the allyJic substrates (the donor) is bonded
to the C(2)-C(3) double bonds of the other (the receptor)
to produce a cyc1opropylcarbinyl diphosphate with a CI'-2-
3 structore (Poulter, 1990). In this manner, famesyl pyro-
phosphate (8) yields presqualene pyrophosphate (9). Only
(R)-presqualene pyrophosphate has been found in nature.
In studies of the biosynthesis of presqualene alcohol with
[l-0 181famesyl pyrophosphate, exchange of oxygen did not
occur. These observations indicate that the pyrophosphate
group of one famesyl pyrophosphate molecule occurs in the
product without change of confIguration in presqualene py-
rophosphate (Popjak et al., 1975).
In the second reaction, the latter compound rearranges to
ai'-I structore with a saturated linkage between the two
original famesyl residues in a series of steps that involve
loss of inorganic pyrophosphate and incorporation of hy-
dride from NADPH to yield squalene (4) (poulter, 1990).
Presqualene pyrophosphate (9) is formed from famesyl
pyrophosphate (8) with inversion at C-I' and concomitant
H02~
H~
chrysanthemic acid (11)
o OH
HO~OH 2
mevalonic add (10)
Fig. 23.3. Presqualene pyrophosphate and chrysanthemic acid and inhibitors for squalene biosynthesis.
loss of the pro-S hydrogen at that center. The pro-R-hydro-
gen atom at C-I' of the second famesyl pyrophosphate mole-
cule appears at C-I' of the cyclopropane ring (based on fam-
esyl pyrophosphate numbering) anti to the vinyJic
substituent (Popjak et al., 1975). The prenylation offamesyl
pyrophosphate (8) occurs at the (2-si-3-re) face of the double
bond of the prenyl acceptor, and C-I' of the donor is inverted
during the process (Poulter and Rilling, 1981). In experi-
ments with [5- 2H2 1mevalonate (10), the squalene produced
had three deuterium atoms and one hydrogen atom on the
two central carbons. The proton furnished by NADPH dur-
ing the fmal conversion of presqualene pyrophosphate to
squalene (4) occupied the pro-S-position. C-I of the acceptor
famesyl pyrophosphate (8) is undistorbed during the initial
condensation, but suffers inversion in later steps of the bio-
synthesis. In the subsequent rearrangement to squalene, both
C(l) and C(l') are inverted (poulter, 1990). The apparent
net retention of the center that accepts the proton from
NADPH (C-I' in Fig. 23.2) may be explained by two inver-
sion steps.
The mechanisms of the various steps of the biosynthesis
of squalene have been reviewed (Coates, 1976; Poulter,
1990; Poulter and Rilling, 1981).
The structore of presqualene resembles that of chrysan-
thentic acid (11), a monoterpene acid found in pyrethrins
(Fig. 23.3) that may be biosynthesized from two moieties
of dimethylallyl pyrophosphate (DMAPP) in a fashion anal-
ogous to the formation of presqualene pyrophosphate
(Poulter, 1990; Poulter and Rilling 1981).
The steric and electronic factors regulating the complex
series of steps have been explored using substrate analogs.
2-Methyl FPP (12) and 3-demethyl FPP (13) (Fig. 23.3) act
as efficient substrates for the second site on the enzyme
(i.e., the analogs serve as an acceptor) but do not undergo
pyrophosphate expulsion or proton loss at the fIrst site (they
cannot serve as donors). Ouly products of condensation with
endogenous FPP (as the donor) are observed (Poulter and
Rilling, 1981).
presqualene pyrophosphate (9)
Opp
OPP
(13)

The mechanism probably resembles that for prenylation
of dimethylallyl pyrophosphate, geranyl pyrophosphate, and
farnesyl pyrophosphate to yield mono-, sesqui-, and diter-
penes, respectively (Hanison, 1985). Mechanisms in which
an "X-group" is involved, followed by a trans elimination
and similar reactions, appear to be ruled out (Hanison, 1985;
Poulter, 1990; Poulter et al., 1979).
The biosynthesis of squalene is similar to that of phytoene
in tetraterpene biosynthesis, except that in the fmal step, a
double bond is formed by elimination in tetraterpenes,
whereas a hydride from NADPH is added in triterpene bio-
synthesis (Poulter, 1990).
COMPOUi'lDS DERIVED BY DIRECT
CYCLIZATlOI'l OF SQVALEl'IE
A few simple eukaryotic organisms can cyclize squalene but
do not produce sterols. For example, Tetrahymena pyri-
formis (a protozoan) produces tetrahymanol (14), a pen-
tacyclic analog of lanosterol (15) (Fig. 23.1), from squalene.
The mechanism of condensation of squalene (1) to tetrahy-
manol in Tetrahymena pyriformis does not involve squalene
2,3-oxide (2) and includes a protonation step, cyclization,
and, finally, addition of hydroxyl group from the medium.
The stereochemistry of the proton predicted to be incorpo-
rated at the 2113-position of the compound has been estab-
femane(l6)
CHzOCzHs
24-ethoxyhopane (17)
Fig. 23.4. Triterpenes derived by direct cyclization of squalene.
Triterpenes and Steroids 431
lished by deuterium labeling experiments and NMR spec-
troscopy.
Several pentacyclic triterpenes found in ferns also appear
to be formed from squalene (I), but not via the intermediacy
of the 2,3-epoxide (2) (Fig. 23.4). Compounds, such as fer- .
nane (16), are found in several ferns (Goodwin, 1973). 24-
Bthoxyhopane (17) has been reported from the fern Onoclea
neriifolia. Although these triterpenes apparently are distrib-
uted widely in ferns, triterpenes derived from condensation
of squalene 2,3-oxide frequently co-occur with them.
SQVALEl'IE 2.3-EPOXIDE
Squalene (1) is converted to (3S)-squalene 2,3-epoxide (2)
by the action of microsomal squalene epoxidase in the pres-
ence of O2 and NADPH (BC 1.14.99.7) (Goad, 1991b;
Goodwin, 1985). Bpoxidation can occur at either end of the
squalene molecule, suggesting that an intermediate form is
released from the synthetase enzyme complex prior to epoxi-
dation and cyclization. Squalene epoxidase (squalene mo-
nooxygenase; BC 1.14.99.7) is a two-component system.
The natore of the terminal oxidase has not been examined
in detail. The second component, a flavoprotein, has now
been fully characterized as an NADPH-cytochrome c re-
ductase. The monooxygenase from rat liver has a molecular
weight of - 47,000, and the protein requires NADPH, cyto-
fllicane
diplotene
432 Triterpenes and Steroids
chrome P-450 reductase, FAD, and a detergent Triton X-
100 for reconstitution of monooxygenase activity. The mo-
nooxygenase from Candida albicans was destroyed when
mixed with Triton X-IOO (Harrison, 1985, 1988).
The degree to which cyclization of (3S)-squalene 2,3-
epoxide (16) to the tetracyclic state is a concerted process
has been the subject of much speculation. Because squalene
2,3-epoxide cyclizes chemically more rapidly than similar
epoxides, it has been suggested that epoxide opening in this
precursor receives anchimeric assistance from the adjacent
double bonds (VIIJ;! Tamelen et al., 1966, 1968).
TRITERFEl'IES DERIVED VIA A
C~OAT-CH~BOATTKANSn10N
STATE
A large number of triterpenes and all steroids in plants are
derived by cyclization of squalene (as the 2,3-epoxide) via
a chair-boat-chair-boat transition state (Fig. 23.5). The
cyclic structures formed can all be rationalized in terms of
the ways that the squalene 2,3-epoxide (2) may be folded
(pseudo-chair-and-boat conformations) on the enzyme sur-
face, with due consideration given to the stereoelectronic
requirements for cyclization. Cyclization usually is initiated
by acid-catalyzed opening of the ring of (3S)-2,3-squalene
gammacerane
#
H H
euphane
Fig. 23.S. Major structural types of triterpenes that arise from cyclization of squalene (as the 2.3-epoxide) via a chair-boat-chair-boat confonnation.
epoxide and may be a completely concerted process or, in
other cases, may be interrupted at an intermediate stage to
allow rearrangement to occur. Evidence from a wide variety
of biosynthetic systems indicates that only the (3S)-stereo-
isomer is utilized. The initially formed cationic species are
purely hypothetical, but if these exist, they could presumably
be stabilized by enzymic interaction (Fig. 23.6).
Formation of Cycloartenol
Cycloartenol (3) is the major product of condensation of
squalene 2,3-epoxide (2) by a chair-boat-chair-boat transi-
tion state in plants. This condensation is effected by squa-
lene-2,3-oxide-cycloartenol cyclase (Fig. 23.6). Micro-
somes from Rabdosia japonica (Acanthaceae) showed
activity for cyclizing·squalene 2,3-epoxide into cycloartenol,
~-amyrin, and a-amyrin. Purified cycloartenol cyclase had
a molecular weight of 54,000 (Abe et al., 1989a, 1989b).
The enzyme squalene-2,3,-oxide-cycloartenol cyclase is
inhibited by a series of compounds designed to mimic the
carbocationic intermediates that are postulated to participate
in the reaction process (Goad, 199Ib).
Squalene 2,3-epoxide (2) was converted into cycloartenol
(3) in 22% yield by a microsomal fraction from Ochromonas
malhamensis (an alga). Retention of configuration at C-19
(the cyclopropyl carbon) is observed.
cycloartane wcurbitane
lanostane dammarane

H+
H !
~j0
H0V1--Y ~"''''.''''~
H I
H H t
HO
HO
Fig. 23.6. Cyclization of squalene 2,3-epoxide via a chair-boat-chair-boat confonnation (modified from Luckner, 1972; used with the pennission of
the copyright owner, Academic Press, Orlando, Fl.).
FHYTOSTBKOLS
Many steroids (compounds with a tetracyclic cyclopentanop-
erhydrophenanthrene ring system that have suffered the bio-
synthetic loss of methyl groups) are found in plants. Sterols
playa major structural role in membranes of plant cells; the
greatest sterol content is in the plasma membrane (Goad,
1977, 1991a; Goodwin 1980, 1981; Heftrnan, 1973). All eu-
caryotic organisms synthesize sterols or have an absolute
requirement for them in the diet.
In plants, sterols arise through the intermediacy of
cycloartenol (3) and 2,3-oxidosqualene:cycloartenol cyclase
(EC 5.4.99.8), whereas, in animals, sterols arise from lanost-
erol (IS) and 2,3-oxidosqualene:lanosterol cyclase (EC
5.4.99.7) (Figs. 23.7 and 23.8). Despite several reports (all
Triterpenes and Steroids 433
H
12
23 cycloarteool (3)
of which are now considered erroneous), lanosterol has not
been found in plants. When labeled lanosterol is fed to
plants, no label ends up in cycloartenol, but labeled cycloar-
tenol is incorporated readily into other phytosterols. Some
fungi and certain other organisms appear to utilize either
or both pathways. 2,3-0xidosqualene:lanosterol cyclase (BC
5.4.99.7) has been isolated from several plants (Goodwin,
1985).
Formation of Cholesterol
Cholesterol (7), the major sterol in most animals, also is
found in small amounts in many plants, where it serves as
a precursor for other steroid derivatives, such as the proges-
tagens and cardiac glycosides (Heftman, 1984). In plants,
algae, and fungi, a variety of other phytosterols may serve
434 Triterpenes and Steroids

squalene (1)

(cbair·boat·cbair·boat)

HO

norlanosterol obtusifoliol (18)

HO
progestagens

t
dehydrolophenol desmosterol cholesterol (7) cardiac glyoosides

Fig. 23.7. Cholesterol biogenesis in plants (modified from Grunwald, 1980; modified and used with pennission of the copyright owner, Sprioger-
Verlag, Berlin),

in
animals
squalene (1) --+- --+-

HO
HO

lanosterol (15) cholesterol (7)

Fig. 23.8. Cholesterol biosynthesis in animals and some fungi.


80
cycloeucalenol (19)
Fig. 23.9. Cycloeucalenol and obtusifoliol.
as substrates for further metabolism, whereas in animals,
cholesterol is the source of all steroid metabolites (Grun-
wald, 1980; Harrison, 1988).
Experiments in which com, Zea mays, seeds produce ob-
tusifoliol (18) from cycIoeucalenol (19) upon gennination
in 2H20, the IH_NMR spectra indicate significant incorpora-
tion of deuterium into the C-19 methyl group (Fig. 23.9).
Experiments of this type provide some direct evidence for
the intennediacy of these compounds in the biosynthesis of
cholesterol in plants.
The three methyl groups that are lost in the fonnation of
cholesterol (one at C-14 and two at C-4) probably are re-
moved via the oxidative sequence -Me to -CH2-OH, to
-CHO, to -C02H and decarboxylation, as indicated for the
24,15-dihydrolanosterol
80
o
Fig. 23.10. Demethylation to produce cholesterol (Harrison, 1985; modified and used with penmssion of the copyright owner, The Royal Society of
Chemistry, London).
Triterpenes and Steroids 435
80
obtuslfoliol (18)
methyl group at C-14 (Fig. 23.10). The order of removal of
methyl groups appears to vary from system to system.
Formation of Other Plant sterols
In most plants, (3-sitosterol (4), campesterol (6), and stig-
masterol (5) are the most abundant phytosterols. These com-
pounds arise from cycIoartenol (3) by a series of reactions
including modification of the side chain (Fig. 23.11) (Goad,
1991 b; Grunwald, 1980; Heftman, 1973). A series of olefinic
intennediates has been postulated and several metabolites
of this type have been isolated. Several basic skeletons of
phytosterols are encountered; these, together with some of
the biogenetic pathways by which they might arise, are given
80
cholesterol (7)
436 Triterpenes and Steroids

cycloartenol (3) 24·methylenecycloartenol cycloeucalenol (19)

obtusifoliol (18) 4a·methylergosta· 4a-methylergosta-

8,14,24(28).trien·3B·ol (20) 8,24(28)·dien·3B·ol

HO ~~~
•
H
I

24·methylenelophenol
--.
H0 1H
.
I

24-ethylidenelophenol
--
HO
H
I

stigmasta-7,24(28)·dien-30-ol
--+

eampesterol (6) stigmasterol (5)

Fig. 23.11. Proposed biosynthetic origin of plant sterols (modified from Grunwald. 1980; used with permission of the copyright owner, Springer-
Verlag, Berlin).

below (Fig. 23.11); again, a series of different pathways may
be involved (Mann, 1987).
Microsomal extracts from maize seedlings are capable of
catalyzing the alkylation of cycloartenol (3) by S-adenosyl-
methionine to produce 24-methylenecycloartenol (Fig.
23.11) (Harrison, 1988). The enzymes involved in transfor-
mations of cycloeucalenol (19) to obtusifoliol (18) (cycloeu-
calenol : obtusifoliol isomerase), obtusifoliol to 4a-methyl-
ergosta-8,14,24(28)-trien-3(3-01 (20) (14a-methylsterol
14a-demethylase), 4a-methylergosta-8,14,24(28)·trien-3(3-
01 to 4a-methylergosta·8,24(28)-dien-3(3-01 (L~14-sterol re-
ductase), 4a·methylergosta-8,24(28)-dien-3(3-01 to 24-
methylenelophenol (1:>.8 .... 1:>.7-sterol isomerase), and sitos-
terol to stigmasterol (sterol-I:>.22-desaturase) have been stud-
ied (Fig. 23.11) (Goad, 1991b; Goodwin, 1985).
Alkylation of the side chain may occur at C-24 with suc-
cessive methyl groups derived from S-adenosyl methionine.
The first addition is catalyzed by a sterol-S-adenosylmethio-
nine methyl transferase (Goad, 1991b; Goodwin, 1985). The
side chain of (3-sitosterol (4) may be derived as in Fig. 23.12.
Biological Activity of Plant Sterols
A number of plant sterols have been reported to possess
growth-regulating activity and developmental modification
properties in plants (Heftman, 1975a, 1975b, Mandava,
1979). For example, (3-sitosterol (4) initiates flower buds
in Chrysanthemum species; exogenously applied lanosterol
(15) (not a plant product) also stimulates flowering in these
plants. Estrone (oestrone) (21) and related compounds are

reported to increase the number of flowers in Ecballium ela-
terium and to influence sex expression. None of these pro-
ceSses are well understood (Mandava, 1979). Despite the
reports of in vitro growth-regulating activity of progestagens
in plants, there is no evidence for in vivo activity.
Probably the most effective compound of this type for
the modification of plant growth discovered to date is brass-
inolide (22), 2u,3u,22u,23u-tetrahydroxy-24u-methyl-f3-
homo-7-oxa-5u-cholestan-6-one, a steroidal lactone first
isolated from the pollen of rape, Brassica napus (Brassica-
ceae) (Fig. 23.13) (Grove et aI., 1979; Mandava, 1988). Al-
though the mechanism(s) by which this compound functions
are not known, the effects are rapid (Meudt, 1987). Brassino-
lide affects specific target tissues that are sensitive to the
plant hormone indole-3-acetic acid and tissues that are gravi-
perceptive. Picomole quantities of brassinolide applied to
young bean seedlings cause cell elongation, cell division,
and splitting of the treated internode. The symptoms are
confined to the treated area, suggesting that brassinolide is
not translocated. A series of related compounds have now
been isolated from several different plants (Meudt, 1987).
Phytosterols are of particular importance to insects, nem-
atodes, and certain crustaceans, because they cannot synthe-
size cholesterol de novo. These organisms degrade dietary
C 28 and C29 -phytosterols to C27 -sterols (usually cholesterol)
or obtain C2?,sterols directly from other organisms (Ikek-
awa, 1983). These steroidal products are then used in the
synthesis of biologically active sterols that the organisms
require. There is evidence that dealkylation of phytosterols
proceeds as indicated in (Fig. 23.14) (Harrison, 1985; Ikek-
awa, 1983).
Many animals convert steroidal precursors to vitamin D
(23) and related compounds (DeLuca and Schooes, 1983)
(Fig. 23.13). Vitamin D is involved in the assimilation of
Fig. 23.12. Proposed biogenesis of ~-sitosterol (Knights, 1973; modified and used with pennission of the copyright owner, The Royal Society of
Chemistry. London).
Trite'penes and Steroids 437
calcium ions from the diet, stimulates transport of calcium
ions in vivo, and, in conjunction with parathyroid honnones,
mobilizes calcium ions from bone (Williams et aI., 1989).
A South American plant, Solanum malacoxylon, produces
a lu,25-dihydroxy-vitamin D3 (24) glycoside with similar
biological activity. Cattle that consume leaves of this plant
exhibit all the symptoms of hypervitaminosis D (Williams
et aI., 1989).
The polyphagous insect Helicoverpa zea exhibited re-
duced growth on plants of Petunia hybrida. Steroidal com-
pounds, such as petuniasterone A (25), proved responsible
for this activity (Fig. 23.13) (Elliger and Waiss, 1989; Elliger
et aI., 1988).
A mixture of free sterols, steryl ferulates, and diglycerides
from rice grain were found to induce oviposition of the rice
grain weevil, Sitophilus zeamais. When the individual com-
ponents of the mixture were tested separately, however, they
repelled the female from egg laying (Harborne, 1987).
5f3-Cholestan-3,24-dione (26) serves as a trail-marking
pheromone for the gregarious caterpillars of Malacosoma
neustria andM. americanum (Lepidoptera: Lasiocampidae).
Larvae in the vanguard offoraging columns establish chemi-
cal trails as they explore new territory. These exploratory
trails are overmarked by fed larvae returning to the tent (Pe-
terson, 1988). Successful foragers recruit colony mates to
feeding sites (Peterson, 1988). The caterpillars have a thresh-
old sensitivity of 10- 11 g/mm of trail (Harborne, 1989).
PROGESTAGENS
Progestanes in Plants and from Animals
Progestagens are steroids with 21 carbon atoms. Many
of these compounds have been isolated from animals (Fig.
438 Triterpenes and Steroids

HO

la,lS·dihydrocholeealclferol (24)

o
petuniasterone A (25) brasslnolide (22) 58·cholestan·3,24-dione (26)

Fig. 23.13. Biologically active sterols (modified in part from DeLuca and Schnoes, 1983).

Fig. 23.14. Dealkylation of phytosterols (modified from Hanison, 1985; used with pennission of the copyright owner, The Royal Society of Chemistry,
London).

HO
cholesterol (7)
'
~
.
* cytochrome P-4S0, 02,
OH
HO~
~Irr
o
estradiol (31) cortisone (synthetic)
androst-S-en-3p-ol-17-one
Fig. 23.15. Progestagens from animals.
23.15), but a number of these steroids have been isolated
from various plants as well (Farnsworthet al., 1975a, 1975b;
Heftman, 1975a, 1975b). Among the plant-derived progesta-
gens are pregnenolone (27) and progesterone (28) (which
also occur as animal hormones). These compounds are pre-
cursors of other plant progestagens (Fig. 23.15) (Grunwald,
1980). A number of these compounds are identical to those
in animals and other plant progestagens closely resemble
them (Geuns, 1978).
In animals, the corticosteroids are syuthesized from pro-
gesterone in the cortex of the adrenal gland. These very
important 21-carbon steroids also may occur in plants.
The C2rsteroids are derived from sterols by oxidative
cleavage of the C-17 side chain. Cholesterol (7) is converted
to pregnenolone (27) (by C-17 side-chain cleavage) in a
number of plants, although C2.-sterols [e.g.,Il-sitosterol (4)]
also may be converted (Grunwald, 1980). The conversion
of cholesterol to pregnenolone has been demonstrated in a
number of plants (Fig. 23.16). Intermediates in the process
are 221l-hydroxycholesterol (29) and 20,22-dihydroxycho-
lesterol (30). The conversion of pregnenolone (27) to proges-
terone (28) requires rearrangement of a double bond [A5(6)
- A4 (5)]. The reverse reaction also has been observed in
plants (Grunwald, 1980).
Compounds with estrogenic activity occur in plants and
Triterpenes and Steroids 439
~usP
HO::""
pregnenolone (27)
!
H-
0 b
-
H
progesterone (28)
!
r(i
OH
--"00
Oay.-
.
testosterone (34)
aldosterone estrone (21)
have been shown to have pronounced effects on plant growth
and development (Geuns, 1978). Several cause increases in
growth of various plant parts [e.g., estrone (21) increases
growth of root tips]. This compound also increases growth of
the pollen tube of Rumex tenuifolius. Application of estradiol
(31) to plants of Callistephus chinensis (Asteraceae) and
Lemna minor (Lemnaceae) induces flowering. Application
of 171l-estradiol can replace the inductive cold period neces-
sary for flowering in Cichorium intybus. Further effects on
sex determination on plants and flowers have been observed
(Geuns, 1978). In the past, many of these treatments have
been difficult to repeat. The poor solubility of many of these
compounds and the necessity for an appropriate cosolvent
may be a major reason for these difficulties (Geuns, 1978).
As previously mentioned (see Chapter 11), a number of
isoflavones and their derivatives also possess estrogenic ac-
tivity, possibly because the overall shape of the molecules is
similar to that of steroids (Farnsworth et al., 1975a, 1975b).
Progestagens from Insects
Several arthropods are rich sources of steroidal defensive
compounds. These progestagens are particularly common in
water beetles of the subfamilies Colymbetinae and Dytisci-
nae. Beetles of these families accumulate steroidal toxins as
440 Triterpenes and Steroids
cholesterol (7) 22~-hydroxycholesterol
• cytochrome P-4S0, 02
pregnenolone (27) progesterone (28)
12-hydroxy-4,6-pregnadien-3,20-dione (32)
Fig. 23.16. Proposed progestagen biogenesis in plants (modified from Grunwald, 1980; used with pennission of the copyright owner, Springer-Verlag.
Berlin) and progestagens from insects.
a poisonous milky liquid in the prothoracic glands. The ac-
tivity of the toxin is not detected by the predator, until it bas
actually swallowed a beetle. Within a few minutes, it sickens
and disgorges its prey. Predatory fish, feeding on the same
beetles, fall into a narcotic state and, subsequently, do not eat
the beetles. Most of these water beetle toxins are pregnane
derivatives; at least 15 structures have been identified from
a similar number of beetles. An individual Mexican water
beetle, Cybister tripunctatus, contains as much as 1 mg of
12-hydroxy-4,6-pregnadien-3,20-dione (32). Each C.limba-
Ius beetle contains the same amount of cortexone (33) (Fig.
23.16). In addition to the pregnance derivatives, one beetle,
llybius, contains testosterone (34), dehydrotestosterone, es-
tradiol (31), and estrune (21) (Harbome, 1982; Herout, 1970;
Schildknecht, 1970, 1971).
ECDYSTEROmS
Some of the most interesting insect phytosterol derivatives
are the so-called moulting hormones or ecdysteroids (Fig.
23.17) (Hirino and Hirino, 1970). The first ecdysteroid (25
(29) 20,22-dlhydroxycholesterol (30)
11 ~deoxycorticosteroDe
cortexone (33)
mg), now named ecdysone, was isolated in 1954 from 500
kg (one-half ton) of silkworm pupae after about 10 years of
work (Butenandt and Karlson, 1954; Karlson, 1956a,
1956b)_ These hormones, produced by the insect larva, act
upon the epidermal cells and cause initiation of molting. The
overall balance of juvenile hormone and the ecdysteroids
controls the process of larval development and metamorpho-
sis (Bowers, 1991; Camps, 1991; Rees, 1983). It is generally
agreed that 20-hydroxyecdysone «(3-ecdysone) (35) is the
active hormone that contruls different events during molting
(Camps, 1991). Crustaceans also have an ecdysteroid re-
qnirement. For example, callinecdysone-B (36) is found in
the soft-shell crab and 20-hydroxyecdysone «(3-ecdysone)
(35) in crayfish.
Although phytosterols are converted into other sterols
(such as cholesterol) that serve as components of membranes
and in other functions, one of the principal reasons that in-
sects require phytosterols is for conversion to ecdysteroids.
Insects differ in their ability to utilize different phytosterols
(Svoboda and Thompson, 1987). Although cholesterol (7)
will satisfy this demand in most insects, most plants contain
only traces of this sterol (Svoboda and Thompson, 1987).

In some instances, the symbionts of insects may synthesize
or modify steroids used by the host insect (Herout, 1970).
An interesting example of insect-host plant specificity
that involves phytosterols and ecdysterones is found in the
Sonoran Desert area of North America. Four Drosophila
species that are not especially closely related exhibit remark-
able specificity in choosing to feed variously on rotting limbs
of four cactus species from the Sonoran Desert (Frank and
Fogleman, 1992). Each species feeds on a specific cactus
with very few exceptions.
Drosophila pachea is limited to the senita cactus (Lopho-
cereus schottii) by a biochemical dependency on sterols
found in that cactus. Unlike most insects that can utilize such
compounds as l3-sitosterol (4) to synthesize ecdysones, flies
of this Drosophila species must have the compound schot-
tenol (37) in which a particular double-bond position is
found (Fig. 23.18) (Harborne, 1982; Herout, 1970; Kircher,
1982). This cactus contains 3-lS% dry weight of complex
isoquinoline alkaloids that are toxic to both adults and larvae
of Drosophila nigrospiracula, D. mojavensis, and D. mela-
nogaster.
Individuals of Drosophila nigrospiracu/a use saguaro
(Carnegiea gigantea) on the mainland and cardon (Pachy-
cereus pringlei) in Baja California. The two cacti are mor-
phologically and chemically similar (Frank and Fogleman,
1992). Both have low concentrations of isoquinoline alka-
loids.
The host plants for Drosophila mojavensis are agria
(Sfenocereus gummosus) and organ pipe cactus (Stenocer-
eus thurberi). The insect uses agria on the peninsula and
organ pipe cactus on the mainland. These cacti do not contain
alkaloids, but instead possess medium-chain fatty acids
(C.-C l2 ) and triterpene glycosides (Frank and Fogleman,
1992).
Females of Drosophila mettleri oviposit in soil soaked
HO
ergosterol (39)
OH
HO
HO
0 0
p-ecdysone (35)
Fig. 23.17.
Triterpenes and Steroids 441
with material from necrotic tissues of saguaro and cardon.
This species can tolerate concentrations of secondary com-
pounds greater than the other fly species (Frank and
Fogleman, 1992).
Cytochrome P-4S0 oxidases are involved in host-plant
utilization by these Sonoran Desert Drosophila species
(Frank and Fogleman, 1992).
Phytosterols in the various cactus species exist as glyco-
sides or saponins. Yeasts found in the rotting cactus plants
hydrolyze these saponins and make the phytosterol agly-
cones available to the insects (Spencer, 1987). Both 24R-
and 24S-methyl groups occur in phytosterols. Individuals of
Drosophila me/anogaster utilize both 24R- and 24S-meth-
ylcholest-S,7-dien-313-01 (37), whereas those of D. pachea
prefer the 24S-isomers and those of D. mojavensis prefer the
24R-isomers (Rees, 1983).
The co-occurring yeasts are an additional part of the co-
adapted system, as they are capable of hydrolyzing steroid
glycosides, and produce volatile compounds attractive to the
flies. Steroidal aglycones selectively inhibit Drosophila mo-
javensis at levels that occur naturally in the plants (Fogleman
and Armstrong, 1989). The array of cactus alkaloids present
was not poisonous to this species of fly. Nonadapted and
nonspecialized insects do not exhibit selective tolerance to-
ward any given compound arrays and are susceptible to tox-
icity by either steroidal aglycones or alkaloids or both. The
aglycones may be relatively specific toxins for species of
Drosophila. Thus, the alkaloids appear to be a general deter-
rent to herbivory, and the triterpenoid glycosides, and associ-
ated hydrolytic glycosidases provide a specific toxification
against Drosophila species (Spencer, 1987).
The complement of both alkaloids and phytosteroids now
is known to be more complex than previously thought, and
a complex relationship of saponins, aglycones, alkaloids, and
yeasts determine on which of the cacti a particular Droso-
OH
OH
HO
HO
o
OH
HO
HO
callinecdysone B (36)
Ecdysteroids.
442 Triterpenes and Steroids
2. dealkylation
atC-24
HO
3. oxidation
P-sitosterol (7)
oo?
H 2. oxidation
HO
24-R-methylcholest-5,7-dien-3B-ol (38)
Fig. 23.18. Proposed path of synthesis of molting hormone from f3-sitosterol or schottenol (modified from Harhorne, 1982).
phila species will be successful (Frank and Fogleman, 1992;
Spencer, 1987).
In another example, metamorphosis of the beetle Xyleb-
orus ferrugineus will occur only if the larva receives the
metabolic assistance of the fungus Fusarium solani. The
latter organism has the ability to introduce a b. 7 double bond
into the nucleus of dietary sterols; such functionality is an
essential feature of all ecdysteroids. Larvae without the sym-
biotic fungus will metamorphose only if provided with er-
gosterol (39) (Fig. 23.17), a sterol that has this double bond
(Kircher, 1982).
An important group of plant and animal pathogens, the
nematodes, also possess a requirement for dietary sterols
(Chitwood et aI., 1987).
PHYTOECDYSTEROlDS
A number of plants synthesize ecdysteroids and sequester
them in much greater concentrations than do insects (Fig.
23.19). It is probable that these compounds serve as defen-
sive systems in the plant much in the same way as juvenile
hormone mimics. For activity, a cis-A,B-ring fusion, a 6-
keto-7-ene group, a full sterol side chain with a 22R-oxygen
function, an oxygen function at C-3, and oxygen groups at
C-14 and 2f3 are necessary. However, not all insects may
respond in an identical manner (Camps, 1991).
Because plants can synthesize ecdysteroids from meva-
lonic acid (10) and acetate, it is clear that they (in contrast
to insects) possess the entire pathway leading to these impor-
tant compounds.
The pathway leading to ecdysteroids in plants is not en-
tirely understood, but probably proceeds via intermediate
OH
OH
HO
HO
o
a-ecdysone (34)
tI 1. dealkylation at C-24
schottenol (37)
(40). Cholesterol (7) has been shown to be a precursor of 20-
hydroxyecdysone (35) in Podoearpus elata and Polypodium
vulgare (Goodwin et aI., 1970; Heftman et al., 1968). It is
not clear, however, that cholesterol is an obligatory precur-
sor. When [4<x-3Hl, [4f3- 3Hl and [3a- 3Hlcholesterol were
administered to Polypodium vulgare,label from the 3a-posi-
tion was found to have migrated to C-4, that from 4f3 to C-
5, and that from 4a remained at C-4 (Davies et al., 1980).
This leads to the proposal of the following mechanism in-
cluding cholest-7-en-3f3-01-5,6-epoxide as an intermediate
(Fig. 23.20). Hydroxylation of the side chain occurs late in
the biosynthetic sequence and introduction of a hydroxyl
function at C-20 seems to be the last step in the synthesis.
Although complex in appearance, the pathways that lead to
this group of compounds are widely distributed, presumably
arose early in evolution, and have been maintained in many
extant groups of plants.
Approximately 100 phytoecdysteroids have been re-
ported to occur in plants of about 80 plant families. Results
of a sensitive bioassay capable of detecting 5 X 10-9 g of
20-hydroxyecdysone (35) suggest that phytoecdysteroids are
found in 111 families (Camps, 1991). These compounds are
most common in the ferns, Podocarpaceae (Gymno-
spermae), and the Amaranthaceae. Among the angiosperms
in which phytoecdysteroids are known to occur are Ajuga
(Lamiaceae), Aehryanthes, Spinaeea, and Chenopodium
(Amaranthaceae), Vitex (Verbenaceae), Stachyurus (Stachy-
uraceae), and Diploelisia and Abuta (Menispermaceae)
(Harbome, 1986; Hikino and Takemoto, 1974; Miller et aI.,
1985). Phytoecdysteroids are not found in most fern allies
(Camps, 1991). A series of ecdysones were discovered even
in the marine red alga Laurencia pinnata (Harbome, 1989).
The bracken fern, Pteridium aquilinum, has been shown
 Triterpenes and Steroids 443

OH

HO

HO

q5P
ponasterone A (42) inokosterone ponasterone B

Vo
(callinecdysone A)

OH
"",,,OHr

HO HO i
I (lH
HO HO H
o
pterosterone ponasterone C cyasterone

Fig. 23.19. Some representative phytoecdysteroids.

22 21 24
27
25

HO
cholesterol (7) 7-deoxycholesterol (40)
OH

OH

HO

o
o
Fig. 23.20. Proposed pathway leading to the fonnation of 20-hydroxyedcysone from cholesterol (modified from Davies et aI., 1980; used with
pennission of the copyright owner, the Biochemical Society. London).
444 Triterpenes and Steroids
to contain ecdysone (a-ecdysone) (41) and 20-hydroxyecdy-
sone (35), as well as compounds that appear to be juvenile
honnone mimics (Kaplanis et al., 1967). Although the com-
pounds had activity (including death without molting) when
injected into the nymphs of Sehistoeerca gregaria (the desert
locust), they were inactive when fed to the insects. However,
to the larvae of the cecropia silkwonn, Hyalophora cecropia,
ponasterone A (42) was highly active when incorporated
into artificial diets. Toxicity (interfering with development
and reproduction) has been shown in other insects as well
(Camps, 1991; Robbins et al., 1970).
Although there is evidence that phytoecdysteroids do af-
fect insect growth and development upon ingestion, this role
should be evaluated in the context of multifaceted chemi-
cally based resistance in plants (Camps, 1991).
Brassinolates (see above) are similar to phytoecdysteroids
in structure (Camps, 1991).
CHEMMAXIS Il'I fUNGI
In the phycomycete genus AchJya (a coenocytic water mold),
sexual reproduction is controlled by a set of two steroidal
derivatives: antheridiol and oogoniol. None of the strains
of Aehlya ambisexualis and A. heterosexualis fonn sexual
organs when grown alone, but when cultures of anyone type
are grown with an opposite type, sexual organs fonn and
gametes are produced and fertilized. A complex series of
events is involved in this process. Antheridiol (43) is re-
leased by female cells and induces the development of the
male sex organs (the antheridia) as well as the synthesis of
oogoniols (44 and 45) from fucosterol (46) (Jaenicke, 1991).
A specific set of proteins is induced when the antheridia are
exposed to antheridiol. The antheridia are attracted to the
oogonia (an antheridium is a structure responsible for pro-
ducing male gametes and an oogonium is a structure respon-
sible for producing female gametes). Fertilization tubes orig-
inating in the antheridia penetrate the oogonia and reach the
eggs. The nuclei from the male gametes migrate through the
tubes and to the eggs.
The presence of these honnones was demonstrated when
male and female fungi were separated by membranes. An-
theridiol (43) was first extracted from female hyphae and
later synthesized. When this compound was put on small
polystyrene beads, antheridial hyphae were attracted to the
beads. Antheridiol (a C 29 steroid) initiates antheridial
branches at 5-10 pg/ml. The structural requirements are
highly specific (Fig. 23.21).
A second honnone, produced by the male hyphae, has
been shown to be a mixture of oogoniols 1 and 2 (44 and
45). These steroidal compounds are active at 620 and 460
ng/ml, respectively. Cultures of Achlya ambisexualis pro-
duced oogoniols only afrer treatment with antheridiol. An-
theridiol appears to induce the fonnation of an enzyme nec-
essary for the production of oogoniols (Mascarenbas, 1978;
O'Day and Horgen, 1981).
Labeling studies with [3- 3Hl-fucosterol (46) (the major
sterol of Aehlya) indicate that antheridiol and oogoniols 1
and 2 are derived from this compound.
CVCURBITACIl'IS
The most bitter and distasteful triterpenoids in plants proba-
bly are the cucurbitacins, a series of about 20 tetracyclic
triterpenes occurring in a number of plants of the Cucurbita-
ceae (Fig. 23.22) (Ferguson and Metcalf, 1985; Gershenzon
and Croteau, 1991; Lavie and Glotter, 1971; Mabry and Gill,
1979). Cucurbitacin B (47) and E (48) are the most common
of these compounds. Plant materials containing cucurbitac-
ins are toxic to mammals, have strung purgative action, and
play a role in the defense against mammalian herbivores.
Many have LCso values in the range 1-7 mg/kg (interperito-
neally) and 5-40 mglkg orally in mice. Humans can detect
the bitter taste of certain cucurbitacins as low as 1 ppb (Met-
calf, 1986), although not all cucurbitacins are bitter. For
example, the rhizomes of I(emsleya earnosijlora (Cucurbita-
ceae) contain six cucurbitacins: one is tasteless, two are
sweet, and three are bitter (Harborne, 1989). Cucurbitacin
B (47) (from Jpomopsis aggregata, Polemoniaceae) is cyto-
toxic and has a EDso of 0.032 I1g/ml. Cucurbitacin F (49)
(from Elaeoearpus doliehostylus, EJaeocarpaceae) 0.52
I1g/ml in the KB cell cultures system and lI-deoxocucurbi-
tacin (50) had an EDso of 0.002 I1g/ml in the P-388 cell
culture system (Arisawa et al., 1984; Fang et al., 1984;
Reddy et al., 1988).
These highly oxygenated triterpenes have been recently
shown to be interrelated chemically to the lanostane series.
They also are products of a chair-boat-chair-boat squalene
condensation. A biogenetic sequence for cucurbitacins based
on Coates (1976) is proposed (Fig. 23.23).
Seedlings of cucumber, Cueumis sativus, converted the
triterpene (51) into cucurbitacin C (52); microsomal frac-
tions from seedlings of Cueurbita maxima converted squa-
lene 2,3-epoxide into lOa-cucurbita-5,24-dien-3j3-01. Nei-
ther parkeol (53) (Fig. 23.1), cycloartenol (3), 11-
ketocycloartenol, or 24,25-dihydro-9a,lIa-epoxyparkeol
were incorporated significantly, and no products with a cu-
curbitane skeleton were isolated (Balliano et aI., 1983; Harri-
son, 1985).
Cucurbitacins originally were isolated from the Cucurbi-
taceae (they are found in most members of this family that
have been examined), but are now known to occur in other
families. Among these are the Begoniaceae (Begonia),
Brassicaceae (Jberis), Datiscaceae, Desfontainiaceae (Des-
Jontainia), Elaeocarpaceae (Elaeocarpus), Euphorbiaceae,
Liliaceae (Phormium), Polemoniaceae (/pomopsis), Primu-
laceae (Anagallis), Rosaceae (Purshia), Rubiaceae (Hin-
tonia), Scrophulariaceae (Gratiola, Picrorhiza), Sterculia-
ceae (Helieteres), and Thymelaeaceae (Gyrinops) (Arisawa
et aI., 1984; Blasko and Cordell, 1988; Dreyer and Trousdale
1978; Fang et aI., 1984; Hegnauer, 1989; Kupchan et aI.,

antheridlol (43)
(CH,),CHCOO
<JOgoDiol-! (44)
HO
ruCOlilerol (46)
Fig. 23.21. Structure of antheridiol and oogoniois.
1978; Mata et at, 1990; Paris and Tessier, 1972; Reddy et
at, 1988; Reguero et al., 1987; Stuppner et al., 1991). In
cucurbits, cucurbitacins are known from all plant parts (Met-
calf, 1986).
Cucurbitacins are reported to possess growth-regulating
activity in plants (Mandava, 1979). In animals, they exert
cytotoxic activity and are purgatives. Cucurbitacin E gluco-
side, from Gratiola officinalis (Scrophulariaceae) has
cardiotonic activity (Wagner, 1988). Cucurbitacins from
several plants have cytotoxic activity and antitumor proper-
ties (Blasko and Cordell, 1988). Cucurbitacin F (49) is cyto-
toxic in the KB and P-388 in vitro cell culture lines.
The presence of cucurbitacins is correlated with the inhi-
bition of feeding by the polyphagous mite Tetranychus urti-
cae, which is often damaging to nonbitter cucurbits. These
compounds also inhibit feeding by a number of leaf beetles;
among them are Phyllotreta undulata, P. tetrastigma, and
Phaedon cochleariae. In/beris amara (Brassicaceae), cucur-
bitacins I and E (48) from the seeds and the green parts are
potent inhibitors for the flea beetle Phyllotreta nemorum
(Mabry and Gill, 1979).
Other insects seem to have evolved systems to avoid the
Triterpenes and Steroids 445
OH
oogoniol-2 (45)
allomonal effects of cucurbitacins. The beetle, Epilachna
borealis, has developed a system of "trenching" or cutting
a circular area of tissue off from the rest of the leaf and
apparently preventing movement of cucurbitacins into the
area. The beetle eats this tissue and then relocates. The
amount of cucurbitacins in wounded plant tissue has been
shown to increase, and beetles fed this tissue show a reduc-
tion in fituess (Carrol and Hoffman, 1980; Tallamy, 1985).
Despite the fact that transport of cucurbitacins into the
wounded area is a possible explanation, there is currently
little evidence for the transport of cucurbitacins in plants.
Although cucurbitacins serve as allomones for most other
insects, these compounds are kairomones, or attractants, for
many insects associated with the Cucurbitaceae (Metcalf,
1985). For example, when cucumber beetles are offered a
choice of nonbitter and bitter (cucurbitacin containing)
fruits, they feed almost exclusively on the bitter fruits (11
: 1). When given the same choice, the honeybee, Apis mellif-
era, will select food materials lacking the cucurbitacins (Har-
borne, 1982).
A scenario for the evolutionary and behavioral interac-
tions between plants of the Cucurbitaceae and their herbi-
446 Triterpenes and Steroids

HO 0

OAc OAc

HO

o HO'"''

OH HO 0

OH OH

HO

o 0

OH

OH
OAc
HO

OH

ll·deoxocucurbitacin (50)
22.deoxocucurbitacin D

Fig. 23.22. Representative cucurbitacins.

lanosterol (in animals)

HO

parkeol
squalene 2,3-epoxide
H

OAc
3'oxidation
ll-oxidation
• side chain
oxidation HO
acetylation

Fig. 23.23. Biogenetic pathway for cucurbitacins (Hanison et aI., 1985; modified and used with pennission of the copyright owner, The Royal Society
of Chemistry, London).

vores has been proposed (Andersen and Metcalf. 1987; Met-
calf. 1986; Metcalf and Lampman. 1989). Plants that possess
the ability to produce these compounds do not suffer attacks
by generalist herbivores. When changes io ability of co-
adapted herbivores to handle the cucurbitacins present occur.
some of the iosects develop detoxification and excretion
pathways to neutralize the harmful effects of cucurbitacios.
As these herbivores expand ioto a new ecological niche. a
concommitant change io the ability to detect these com-
pounds is favored. and. ultimately. the herbivore develops
high blood and tissue levels of conjugates of cucurbitacios as
defensive substances (Andersen and Metcalf. 1987; Metcalf.
1986).
There seems to have been an ancestral association of leaf
beetles of the tribe Luperioi (Coleoptera: Chrysomelidae:
Galerucioae) and plants of the family Cucurbitaceae. The
scope of this association presently is worldwide. In the New
World. the subtribe Diabroticioa contaios some of the most
important insects of the world. io an economic sense. Among
these are cucumber beetles and com root worms. These io-
sects are capable of recogniziog cucurbitacios. which serve
as kairomones for most (if not all) members of this group of
beetles. at extremely low levels. A number of these diabrotid
beetles appear to accumulate cucurbitacios as allomones for
protection against predators (Ferguson and Metcalf. 1985).
Although primarily adults feed on plants with these com-
pounds. both the eggs and larvae also contain cucurbitacios.
which may play a role io discouragiog egg predators such
as ants (Ferguson and Metcalf. 1985; Metcalf. 1986).
TRITEKPBI'IES DERIVED VIA A
CIIA1K-CHAIR-CHAIK-BOAT TRAl'ISITION
STATE
Cyclization of squalene 2.3-epoxide (2) via a
chair-chair-chair-boat transition state gives rise to many of
the most common plant triterpenes. Pentacyclic triterpenoid
compounds such as a- and l3-amyrin (54 and 55). oleaoolic
acid (56). taraxerol (57). taraxasterol (58). lupeol (59). be-
tulin (60). euphol (61). friedelio (62). and ursolic acid (63)
may constitute several percent of the dry weight of many
plants (Fig. 23.24). The bark of trees such as the cork oak.
Quercus suber. and the white birch. Betula alba. contaio
large amounts oftriterpenes. Friedelio (62) and cerio (71) are
the maio compounds io cork (Croteau and Johnson. 1985).
Biogenetic schemes for the formation of most of these
groups of triterpenes have been proposed (Figs. 23.25 and
23.26) (Coates. 1976). Most of these iovolve shifts of methyl
and hydride groups along with skeletal rearrangements to
achieve the final structures. In practice. most of these ioter-
mediates have not been substantiated.
The cyclization of 2.3-epoxysqualene to l3-amyrin (55)
by microsomal fractions from pea cotyledons. which io-
volves the enzyme 2.3-oxidosqualene: l3-amyrin cyclase
(EC 5.4.99). has been demonstrated (Abe et al.. 1989a.
Triterpenes and Steroids 447
1989b; Croteau and Johnson. 1985; Goodwin. 1985). 13-
Amyrin cyclase from Rabdosia japonica had a molecular
weight of 28.000. whereas that from peas had a molecular
weight of 35.000 (Abe et al .• 1989a. I 989b).
In the oleanane-ursane group of triterpenes. postulated
hydride shifts [as proposed by Eschenmoser and co-workers
(1955)1 have now been demonstrated. Incorporation of [4-
13C]MVA into oleaoolic acid (56). ursolic acid (63). and
several other metabolites was accomplished with tissue cul-
tures of Isodon japonicus (Lamiaceae). Followiog introduc-
tion of [4- 13C]mevalonate and [1.2- 13C2 1acetate. the pen-
tacyclic triterpene compounds were examined by 13C_NMR
spectroscopy. Rings 0 and E were formed by the routes
predicted by Eschenmoser et al. (1955). The labeling pattern
at carbons 4. 23. and 24 of 3-epi-maslioic acid (64) indicates
that this series is formed from (3S)-squalene epoxide. rather
than from the (3R)-epimer.
The 13C_NMR spectrum showed enrichment of carbons
13. 18. and 19 io oleanolic acid (56) and confirmed the se-
quence 65-68 in the formation of oleananes (Fig. 23.26)
(Harrison. 1988).
Incorporation of [3.5- 13C21mevalonate into ursolic acid
by cell cultures of Perillafrutescens var. acuta (Lamiaceae)
has been examioed. In another series of experiments with
[2- 13C,4,4-2H2 1mevalonate. the postulated 1.2 migration of
the hydride ion from C-19 to C-20 (ursane numbering) was
confirmed (Harrison. 1988).
Thus. the origioal proposals of Eschenmoser and co-
workers (1955) have proven largely accurate in predicting
the routes of biosynthesis of many pentacyclic triterpenes.
Compounds such as (69) (from gum mastic. Pistacia len-
liseus. Anacardiaceae) and (70) (Fig. 23.24) may be regarded
as products of trapping of a cationic intermediate of the cycli-
zation of squalene 2.3-epoxide (2) to tetracyclic and pen-
tacyclic triterpenes (Harrison. 1988).
BIOLOGICAL ACTIVITY OF TRlTEKPBI'IES
Although triterpenes have been considered to be relatively
ionocuous plant constituents. several have been established
recently to have pronounced physiological activity. Many
triterpenes have antiherbivore activity. Although phytoster-
ols are required for iosect and fungal growth. triterpenoid
compounds may interfere with this process and exhibit anti-
herbivore or antifungal effects (Croteau and Johnson. 1985).
In general. those that are highly oxygenated seem to be more
active io this regard (Seigler. 1983). Triterpenes and steroids
with sugar moieties attached have soap-like properties.
These compounds. called saponios. are discussed io Chapter
24. Another group of triterpenes with highly modified struc-
tures. restricted to a group of closely related plant families.
are discussed io chapter 25.
Toxic triterpenoids are major constitueuts of plants from
popUlations of Lantana camara (Verbenaceae) that produce
poisoning of livestock. The active compounds often are 1an-
448 Triterpenes and Steroids

o no

friedelin (62) p·arnyrin (55) oleanolic acid (56)

no no
a·amyrin (54) ursolic acid (63) taraxerol (57)
(.)

no
no
# #

"'~
""
!H~~,
euphol (61)
no
Ii

lupeol (59)
dammaradienol

no no
no
betulic acid germanicol
(b) betulin (60)

fi fi ~

no
0
(70)
(69)
no
(0)

Fig. 23.24 (a-c). Representative pentacyclic triterpenes.

 Triterpenes and Steroids 449

-
[1.2- 13 Cl-acetate

HO HO
lupeol other pentacyclic triterpenes a-amyrin (54)
(a)

#
""

HO
HO
I
'II
'.
II

(66)
i
-- HO

,. /
21
/
HO
HO

ursolic acid (63) (68) oleanolic acid (56)

(b)

Fig. 23.25. Biogenesis of pentacyclic triterpenes from chair-chair-chair-boat confonnation of squalene (modified from Harrison, 1985 and Herbert,
1981; used with permission of the copyright owners, the Royal Society of Chemistry, London and Chapman & HalJ, London), respectively.
450 Triterpenes and Steroids

HO

ursolic acid (63)

3-epi-maslinic acid (64)

Fig. 23_26. Incorporation of labeled mevalonic acid into oleanolic acid (Harrison, 1988; modified and used with pennission of the copyright owner,
The Royal Society of Chemistry, London).

jacquinonic acid (75) Iantadene A (72) n·hydroxytingenone (76) OH

o 0
HO
HO~O
soyasapogenol B (74) tingenone (maitenine) (77) papyriferic acid (73)

Fig. 23.27. Biologically active triterpenes.

 Triterpenes and Steroids 451

tadenes A (72) and B (Fig. 23.27). These triterpenes are
toxic intraruminally to sheep at doses of 80 and 200 mg/kg
of body weight, respectively. A related compound, the C4 -
hydroxy derivative of lantadene A, has been isolated from
a species Lippia rehmanni and found to be toxic to rabbits
(Mabry and Gill, 1979).
Detailed investigations of the browsing behavior of the
snowshoe hare (Lepus americanus) on the Alaska paper
birch (Betula resinifera) and the green alder (Alnus crispa),
particularly during winter months, suggest that certain deter-
rent chemicals provide protection to particular stages in the
life cycle, at certain seasons, or in some tissues, and not
others (Harborne, 1986). Juvenile growth-phase internodes
are made unpalatable to the hare by extremely high concen-
trations of the triterpene papyriferic acid (73) (up to 30%
dry weight). This is more than 25 times the level in mature
internodes. Furthermore, the acid is deterrent to hares at the
2% level in oatmeal (Harborne, 1986).
Ursolic acid (63) plays a role in the a1lelopathic effects
of several other types of secondary metabolites in sandhill
vegetation. Dihydrocinnamic acid (derived from ceratiolin)
from Ceratiola ericoides (Empetraceae), a series ofmonoter-
penes including camphor, myrtenal, borneol, and carvone
from Conradina canescens (Lamiaceae), and the monoter-
penes menthofuran, epievodone, and calarninthone from
Calamintha ashei (Lamiaceae) all displayed biological ac-
tivity. However, when these compounds were dissolved in
a saturated aqueous solution of ursolic acid, allelopathic ac-
tivity was greatly increased. Later work suggests that monot-
erpenes may be sufficiently soluble in water to produce toxic

~R:".
'" I -.
~R:::,., ~R!\
1'....H~
....
O H c ' F RH
"'"
He-;
h
'" '"

-
h h h
HOH,C
HOH,C

OH
/
HOH,C
OHC~ OH H
H

~
/HCh

HOH,C H
OHCH OH 0

(+)-22-me~I-Y'CYclOiridal '-....... Q~+ ~

......... .........

iridal
-
three isomers of irone from natural Iris oil

Fig. 23.28. Iridals (modified from Jaenicke and Marner. 1986; used with pennission of the copyright owner, Springer-Verlag, Vienna),
452 Triterpenes and Steroids
effects in any case (Fischer et al., 1994; Weidenheimer et al.,
1993). Ursolic acid (63) appears to act as anatoral surfactant
(Fischer et al., 1988).
As the roots of parasitic plants attach to those of the host
plant, a special structore, the haustorium, is formed. The
formation of haustoria in induced by exudates from the host
plant. When the roots of the hemiparasite Agalinis purpurea
(Scrophulariaceae) approach those of the host, Lespedeza
sericea, soyasapogenol B (74) induces haustorial formation
(Fig. 23.27) (Lynn, 1985).
Jacquinonic acid (75) from Jacquinia pungens
(Theopbrastaceae) inhibits feeding by the leafcutter ant Alta
cephalotes. As this compound is nonvolatile, tactile contact
by the ant is probably necessary for sensing the presence
of this triterpene. A mixture of triterpenoids from Cordia
alliodora (Boraginaceae) similarly prevents feeding by this
ant (Harborne, 1987).
Several pentacyclic nortriterpene quinonemethides occur
in plants of the Celastraceae (Catha, Euonymus, Glyptopeta-
lum, May tenus, Peritassa, Plenckia, and Salacia) (Bavovada
et al., 1990). These compounds are cytutoxic in several sys-
tems. 22-Hydroxytingenone (76) had an EDso of 0.073
""g/ml in P-388 and 0.62 ""giml in a KB cell cultore system
(Bavovada et al., 1990). Maitenine (or tingenone) (77) ex-
hibits in vivo antitumor activity, cytotoxicity, and a pro-
nounced inhibitoty effect on protein and RNA synthesis
(Cordell, 1978). Tinger,Jne completely inhibits Trypano-
soma cruzi in vitro at 30 ""giml (Borris and Schaeffer, 1992).
IRIDALS AI'ID IRONES FROM THE IRIDACEAE
Extracts of iris (Iris, lridaceae) rhizomes have a pungent and
bitter taste. Tissue of the yellow flag iris, Iris pseudacorus,
of Europe, is poisonous to man and animals, either fresh
or dried, and produces unpleasant irritations of the mucous
membranes, vomiting, and bloody diarrhea. Rhizoma iris
was formerly a constituent of folk medicine and was consid-
ered a potent purgative. An essential oil is prepared from
the roots of Iris pa/lida and I. germanica. Mter harvesting
and sun-drying, the roots assume a pleasant violet-like scent
which increases with time. The oil obtained by steam distilla-
tion is . 'essence d'iris" or . 'orris root oiL" The odoriferous
principle is called "irone." Three isomers are the major
component of this essential oil (Fig. 23.28). In contrast to
the ionones that are widespread in nature, irones are found
primarily in orris root oil. Freshly harvested rhizomes do
not contain irones; the scent develops gradually over 3-4
years of storage of the root stocks. It seems unlikely that
irones arise by enzymatic processes; oxidizing agents accel-
erate formation of these compounds. The precursor of these
compounds is iridal (Jaenicke and Marner, 1986), which is
derived from squalene. A biogenetic pathway has been pro-
posed which rationalizes the formation of iridal and related
compounds (Jaenicke and Marner, 1986). Methylation at C-
22 appears to be involved in formation of irones possibly
via 22-methyl-'Y-cycloiridal.
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24
Saponins and Cardenolides
Introduction
Steroidal saponins
Triterpenoid Saponins
Biological Activity of Saponins
Saponins in Food and Forage Plants
Saponins and Insects
Medicinal Uses of Saponins
Alteration of Taste Properties
Sweeteners
Cardenolides
Biosynthesis
Distribution of Cardiac Glycosides
Biological Activity of Cardiac Glycosides
Interactions with Insects and Other Animals
Medicinal Properties
Arrow Poisons
References
Il'ITKODVCTIOI'l
Saponins are compounds that possess a polycyclic aglycone
moiety with either a steroid (typically C27 ) or triterpenoid
(C30 ) structure attached to a carbohydrate unit (a monosac-
charide or oligosaccharide chain) (Fig. 24.1). These sugar
units are composed variously of pentoses, hexoses, or uronic
acids. The existence of uridine-5'-diphosphate-glucose
(UDPG):sterol transglucosylase actiVity in particulate prepa-
rations from higher plants is well established (Goodwin,
1985).
Saponins are classified into two major groups based on
the structore of the aglycones that are known collectively as
sapogenins. Steroidal sapogenins usually contain 27 carbon
atoms; those of triterpenoid sapogenins contain 30. Approxi-
mately 360 sapogenins and 750 triterpene glycoside struc-
tures are known, but it is only recently that full structore
456
elucidation of many saponins has been possible (Hostett-
mann et al., 1991).
The most common sugars of triterpenoid saponins are
hexoses (mainly o-glucose and o-galactose), pentoses
(mainly 0- and L-arabinose and o-xylose), methyl pentoses
(L-rhamnose and quinovose), and uronic acids (o-glucuronic
acid and n-galacturonic acid). Different sugars, mainly glu-
cose, galactose, rhamnose, xylose, and arabinose have been
identified as components of the carbohydrate moiety of ste-
roid saponins (see Chapter 15).
The complexity of saponins resnlts from the variety of
combinations of the different sapogenins and numerous sug-
ars. For example, the saponins of alfalfa, Medicago sativa,
(Fabaceae) vary in composition as well as in absolute
amount. Some alfalfa varieties contain as many as 30 differ-
ent saponins (Applebaum and Birk, 1979).
Many of the biological properties for which saponins are
known are due to this hydrophobic/hydrophilic asymmetry
and consequent ability to lower surface tension (Gershenzon
and Croteau, 1991; Hostettmann et al., 1991). In general,
both the sugar and the aglycone are necessary for actiVity.
Saponins have soap-like properties in aqueous solutions.
This is a major reason for acute toxicity when they are in-
jected intravenously. These compounds have been used to
captore fish (as piscicides) since ancient times (Howes,
1930). Saponins in the diet are more toxic to cold-blooded
than to warm-blooded animals. Most saponins hemolyze red
blood cells (Marston and Hostettmann, 1991).
When macerated plant material or plant extracts contain-
ing saponins is shaken with water, a thick stable foam usually
results (Hostettmann et aI., 1991). This is the basis of a
simple, reasonably specific test for the general presence of
these compounds. Saponins also are detected by the Lieber-
mann-Burchard test, which is useful for distinguishing be-
tween triterpenoid and steroidal saponins (Chandel and Ras-
togi, 1980).
Saponins are widespread among plants, having been re-

P-D-glucosyl H~~~O
OH 0 0
o HO
a_L-rhamnosy~o#.o-.,....<.OH
HO~HO
~O.
OH
sarsaporilloside
Co,?~O
~OH
OH OH W OH
Co,?~~l
~H~ OH OH
HO
HO
FIg. 24.1. Typical sapunins.
ported from more than 500 plants from at least 90 different
families (Bondi et aI., 1973), these substances have heen
isolated from all parts of plants: leaves, stems, roots bulbs,
flowers, and froits, although they tend to be concentrated in
the roots of many species. There is considerable seasonal
variation in the amounts of saponins present, and often sub-
stantial variation within plant populations in the amount of
compound is present. Low saponin lines of many crop plants,
for example, alfalfa, have been selected. However, as much
as 30% by weight of some plants is saponins (Hostettrnann
et aI., 1991).
Several plants produce saponins in plant tissue culture.
Among these are Dioscorea species, Trigonella foenum-
graecum, Agave wightii, and Tribulus terre.tris (EIlis,
1988). Because of its economic importance, much research
has been directed toward producing diosgenin in culture. The
highest level of diosgenin-like saponins has been obtained in
suspension cultures of Dio.corea deltoidea, where 7-8% of
the dry weight was obtained (Ellis, 1988).
Only in the last few years has isolation of single compo-
nents from mixtures of saponins been feasible. In many pre-
vious studies, the sugar portion was removed by hydrolysis
and the mixture of sapogenins fractionated. Many of the
techniques needed for isolation of the intact saponins have
Saponins and Cardenolides 457
OH
oH~OH
OH
H
;0 P-D-glucosyl
H
0
OH
disoc:ln
0
asparanin B (9)
OH
been reviewed (Hostettrnan, 1985, 1986; Hostettrnan et aI.,
1991; Mahato et aI., 1982; Marston and Hostettrnan, 1991).
Among the most useful techniques are high-performance liq-
nid chromatography (HPLC), centrifugal thin-layer chroma-
tography (CTLC), column chtomatography, and Qroplet
countercurrent chromatography (DCCC) (Hostettrnan, 1986;
Hostettrnan et aI., 1991; Marston and Hosteltmann, 1991).
Mass-spectrometry techniques such as field ionization de-
sorption (FlO), chemical ionization (CI), and fast atom bom-
bardment (FAB) have proven useful for determination of
structures of intact saponins (Hostettrnann et aI., 1991; Mar-
ston and Hostettrnan, 1991).
A number of saponic alkaloids are discussed in Chapter
36.
Steroidal SaponiDs
Steroidal saponins (those based on C27-steroidal sapoge-
nins) are found in a large number of plant families, but are
particularly common in the monocotyledonous families
Agavaceae, AmaryIlidaceae, Dioscoreaceae, and Liliaceae
(Dahlgren et aI., 1981). The vast majority of steroidal sapo-
nins are based on furostan- or spirostan-type precursors
(Hostettrnan et aI., 1991). A series of steroidal saponins from
458 Saponins and Cardenolides
Lilium pardarinum has been isolated and characterized by
a variety of high-field nuclear magnetic resonance (NMR)
techniques (Shimomuraet aI., 1989). In many of these com-
pounds, there is an AlB cis relationship (i.e., rings A and
B are joined in a cis manner). These compounds also are
commonly encountered in the dicotyledonous families Scro-
phulariaceae and Solanaceae. Other types of steroidal sapo-
nins have been reported from the Arecaceae, Fabaceae, Fou-
quieriaceae, and Zygophyllaceae.
In most plants in which these steroidal saponins occur,
the sapogenins are combined with a number of sugars to
form saponins. Generally, as many as five sugar units may
form a chain that comprises the glycoside linkage. The link-
age to the sapogenin is always f3 and always in the C-3
position (Grunwald, 1980; Takeda, 1972).
As is true for most phytosterols, cholesterol is the usual
precursor (see Chapter 23), but in some instances f3-sitos-
terol, demosterol, or other phytosterols can serve in this role.
Several steroidal saponin sulfates have been reported
from starfish (Hostettmann, 1985). Sea cucumbers secrete
water-soluble glycosides, holothurins, that possess greater
hemolytic ability than saponlns of plant origin. These com-
pounds are mixtures of glycoside snlfates (Agarwal and Ras-
togi, 1974).
Alkaloids such as solanidine and tomatidine are related
to diosgenin in terms of structure. These cholesterol-derived
metabolites usually occur as the 3-0-glycosides (e.g., sola-
nine and tomatine) (Mann, 1987) (see Chapter 36).
Trlterpenoid Saponins
Triterpenoid saponins also are widespread in nature,
being known from at least 90 families of plants (Agarwal
HO
soyasapogenol A soyasapogenol B
HO
~ HH
CHzOH
•
soyasapogenol D
0
HO
HO
medicagenic acid (3)
Fig. 24.2. Several triterpenoid sapogenins from the Fabaceae (modified from Applebaum and Birk, 1979; used with permission of the copyright owner,
Academic Press, New York),
and Rastogi, 1974; Chandel and Rastogi, 1980; de Mayo,
1959). These glycosides may possess from I to 10 sugar
units (Agarwal and Rastogi, 1974). Triterpene glycosides
are especially common in the Aceraceae, Amaranthaceae,
Asteraceae, Campanulaceae, Caryophyllaceae, Chenopodia-
ceae, Hippocastanceae, Lamiaceae, Oleaceae, Papaveraceae,
Phytolaccaceae, Polygalaceae, Rubiaceae, Rutaceae, Sapin-
daceae, Sapotaceae, Verbenaceae, and Zygophyllaceae. Sa-
ponins involving f3-amyrin, or other biosynthetically related
triterpene moieties, are widespread among plants (Boar and
Allen, 1973). Some representative triterpenoid sapogenins
from the Fabaceae are illustrated (Fig. 24.2) (Applebaum
and Birk, 1979).
BIOLOGICAL ACTIVITY OF SAPOl'llNS
Many saponins have generalized antibiotic properties, such
as antifungal and antimicrobial effects. Phytopathogenic
fungi often are sensitive to the presence of saponins. The
effects of steroidal and triterpenoid saponins are sometimes
quite different (Agarwal and Rastogi, 1974).
Water-soluble bidesmosidic saponlns (those with sugars
atrached to two different parts of the aglycone) lack the typi-
cal properties of saponlns and, generally, are inactive as anti-
biotics. It has been proposed that these bidesmosidic com-
pounds are transport forms from leaves to other parts of
the plant (Hostettmann et al., 1991). Once the tissues are
damaged, enzymes convert bidesmosidic saponins into mo-
nodesmosidic derivatives that have defensive functions. The
conversion of ot-hederin (1) from hederasaponln C (2) in
soyasapogenol C
hederagenin (4)

g1c
I
ara-O
I
glc
(5)
CHO
o-(l/
glc
I I
ara-Q
I I
glc
(7)
Fig. 24.3. Saponic phytotoxins from oats.
H edera helix (Araliaceae) is thought to represent such an
example (Fig. 24.4) (Hostettmann et aI., 1991).
Because saponins are surface-active agents and act as
detergents, they can inactivate a number of enzymes. Many
saponins also cause disintegration of membranes and, in the
case of erythrocytes, they cause hemolysis. This action is
related to the presence of cholesterol, as addition of choles-
terol counters some of the deleterious effects of saponins
(Agarwal and Rastogi, 1974). Addition of cholesterol also
causes precipitation of certain saponins from aqueous solu-
tions (Bondi et aI., 1973).
Saponins can cause changes in the microstrucmre of cell
membranes. An attempt has been made to relate the hemo-
lytic activity to the struclnre and composition of the saponin
molecule. Saponins that contain medicagenic acid (3) and
hederagenin (4) (Fig. 24.2), as their aglycones can be precip-
itated by cholesterol and have strong hemolytic activity.
Blocking of the carboxylic acid groups in medicagenic acid
results in complete loss of hemolytic activity. The sapogenin
to sugar ratio is also important in this activity.
Alfalfa saponins are known to inhibit the germination of
letmce seeds, as are those of certain other species. They also
inhibit growth of the soil fungus Trichoderma viride.
The resistance of oats (Avena sativa, Poaceae) to the take-
all fungus Ophiobolus graminis is due to a fluorescent "wot
tip glycoside." This resistance factor, "avenacin," has
proven to be a mixmre of four pentacyclic triterpene glyco-
sides (5-8). Compounds (5 and 7), which possess anthranilic
acid residues as a part of the molecule, have the greatest
fungicidal properties (Fig. 24.3) (Harborne, 1986).
Saponins and Cardenolides 459
n
(6)
o NHCH,
glc
ara-O
g1c (8)
Larvae of the leek-moth, Acrolepiopsis assectella, feed
on the leaves of various Allium species, but usually avoid
the flowers. The saponin aginoside was isolated from these
flowers and shown to be toxic to the larvae. The level of
toxicity was reduced by addition of cholesterol or sitosterol
to the diet of the larvae (Harmatha et aI., 1987).
Saponins, such as asparanin B (9) (Fig. 24.1) from the
seed of Asparagus adescendens (Liliaceae), are active
against the nematode Meloidogyne incognita at concentra-
tions as low as 200 IlgiL (Chitwood, 1992).
Many active molluscicides are saponins (Farnsworth et
aI., 1987; Henderson et aI., 1987; Marston and Hostettrnann,
1991). These compounds are important because of the poten-
tial for controlling the snail vectors for schistosomiasis (bil-
harzia), which affects about 300 million people worldwide.
Four triterpenoid saponins with strung molluscicidal activity
are found in the fruits of ivy (Hedera helix Araliacene), and
others in the fruits of Lonicera japonica (Caprlfoliaceae)
(Hostettmann, 1986).
The saponins from Phytolacca dodecandra (Phytolacca-
ceae) contain a mixture of triterpene glycosides (mainly
based on oleanolic acid) that are highly active against several
of the intermediate snail hosts of schistosomiasis. This was
fIrst discovered by the observation of dead snails along
streams in Ethiopia where the fruits of Phytolacca are used
for laundry purposes (Hostettmann, 1985; Hostettmann et
aI., 1991). To date, one of the.most effective sources of
molluscicidal saponins is the fruit of Phytolacca dodecandra
(Phytolaccaceae), These fruits contain up to 25% glycosides,
460 Saponins and Cardenolides
primarily those of oleanolic acid. The most active compound
in the mixture of saponins from these fruits is lemmatoxin,
[4'-O-(j3-o-glucopyranosyl-3'-O-(j3-o-galactopyranosyl)-j3-
o-glucopyranosyllolean-12-ene- 28-oic acid (10) (Fig. 24.4)
(Henderson et ai., 1987). Lemmatoxin is toxic in the range
1.5-3.0 mg/L (Marston and Hostettmann, 1991).
An emulsion from Balanites aegyptiea (Zygophyllacene)
containing three molluscicidal saponins killed not only the
snail vectors but also the free-living stages of the schisto-
some (Henderson et al., 1987). This emulsion is also lethal to
fish and tadpoles (Marston and Hostettmann, 1991). Extracts
from Solanum nodiflorum and from S. mammosum contain
effective molluscicides (LD.5 25 ppm, 24 h). The active
components are steroidal saponic alkaloids (Henderson et
al., 1987). One of the most promising molluscicidal plants
to date is Swartzia madagaseariensis (Fabaceae). The fruits
of this plant, common in many regions of Africa, are effec-
tive against both common species of schistosomiasis-trans-
mitting snails, and are a fish poison (Marston and Hostett-
mann, 1991).
saponins in Food and Forage Plants
Saponins generally are not absorbed readily in the intes-
tinal tract. Often these compounds must be accompanied by
an irritant in the intestines to have much activity. Despite
the fact that they are not absorbed, saponins do produce
severe gastroenteritis in the intestines.
Saponins are present in many pastore plants (Bondi et
al., 1973). Appreciable quantities accumulate in some, espe-
cially in certain forage legumes. These compounds are prob-
ably involved in the condition known as ruminant bloat. By
altering the surface tension of the ruminal contents, saponins
cause gas formed in the rumen by anaerobic bacterial fer-
mentation to be entrapped as a froth. When fed to cattle,
saponins elicit characteristic symptoms of bloat. In mono-
gastric animals, saponins are responsible for reduced growth
rate and decrease in food consumption. Poultry are particu-
larly sensitive to alfalfa that contains saponins. Swine are
less sensitive (Applebaum and Birk, 1979).
Soybeans and sugar beets also contain saponins that have
been shown to be deleterious under some circumstances (Ap-
plebaum and Birk, 1979; Bondi et al., 1973).
A pseudocereal of the Andes of South America, Cheno-
podium quinoa, owes its bitter taste to the presence of tri-
terpenoid saponins. These must be removed before the seeds
are eaten. A number of the most important saponins have
been characterized (Bumouf-Radosevich et al., 1985).
saponins and Insects
Soybean saponins have been shown to be detrimental to
the larvae of Callosobruehus chinensis, an oligophagous in-
sect that lives on several legumes but that cannot live on
soy beans, peanuts, and certain other legumes.
In studies with the rust-red flour beetle Tribolium casta-
neum, alfalfa saponins inhibited growth, but this effect was
reduced by addition of cholesterol to the diet.
Forage legumes are unsuitable for the development of
several locust species. A diet of alfalfa increases mortality
and extends the duration of larval development of Mela-
noplus sanguinipes and M. differentialis. Adults derived
from these larvae have small, and usually short, forewings.
Similar results are obtained with Schistocerca gregaria.
Feeding of Locusta on Trifolium pratense also results in high
mortality. Fecal pellets of saponin-fed locusts are wet, in
contrast to the dry pellets of locusts on a saponin-free diet.
Water resorption is impaired in the hindgut and the hemo-
lymph volume decreases as a consequence. Studies with
other surface active agents indicate, however, that the sapo-
nins have a specific effect in addition to the surface-active
properties. Inclusion of saponins from alfalfa in diets of in-
sects that normally eat this plant had little affect on them.
The presence of saponins in woods of Ternstroemia ja-
ponica (Temstroemiaceae or Theaceae) is reputed to be re-
sponsible for the antitermite effects observed in ancient
woods of temples (Agarwal and Rastogi, 1974).
Medicinal Uses of saponins
Certain saponins have antitumor, piscicidal, mollusci-
cidal, spermicidal, sedative, expectorant, and analgesic prop-
erties (Hostettman et al., 1991). Preparations such as glycyrr-
hizae radix (from Glycyrrhiza glabra, Fabaceae), are useful
as expectorants and antitussive agents. The major saponic
compound, glycyrrhizin (glycyrrhizic acid) (11) (Fig. 24.6)
is responsible for the sweetuess (50 times sweeter than su-
crose), antiulcer, and glucocorticoid-like properties of the
drug (Hikino, 1985). Glycyrrhizin preparations are used in
Japan to treat chronic hepatitis and cirrhosis (Hikino and
Kiso, 1988). The saponins of Zizyphus jujuba (Rhamnaceae)
exert sedative activity in mice (Hikino, 1985).
Some saponins have anti-inflammatory properties. The
mixtore of saponins from Bupleurum falcatum (Apiaceae)
(a crude drug used in oriental medicine) is effective (400
mg/kg) for the treatment of edema in rats and possesses anti-
inflammatory activity (Hikino and Kiso, 1988). The sapo-
nins saikosaponin a and d appear to be responsible for most
of the activity.
The crude saponins of Thea sinensis (Theaceae) also have
pronounced antiexudative and anti-inflammatory properties.
Phytolaeea americana roots are reputed to possess anti-
inflammatory properties in Korean medicine (Chandel and
Rastogi, 1980; Hostettmann et al., 1991). Similar properties
have been demonstrated for a number of other saponins
(Agarwal and Rastogi, 1974).
Ginseng, Panax ginseng and P. quinquefolium (Aralia-
ceae), contains a series of triterpenoid saponins. Over
350,000 pounds of ginseng, worth more than $25,000,000,
were shipped from the United States in 1978 (Shibata et al.,
1985; Tyler et al., 1981). Ginseng is a favorite remedy in
Chinese and Korean medicine and is used primarily as a
means of maintaining balanced homoestasis or tu restore
Yang (Shibata et al., 1985). A number of physiological ef-
fects have been observed (Chandel and Rastogi, 1980);
 Saponins and Cardenolides 461

non·molluscicidal
OR saponin from PhYto Iocca dodecandra
o

RO"'-~ _0 RO
R'O~O
RO RO~ _'''0, ,
RO~O
OR

OR
RO"'-~ _0 RO
R~~O
RO RO~ _"'0, ,
RO~O
OR CR,OR

moJiuscicidal saponin from Phytolacca dodecandra

OR
RO~ ~O
RO~~ .~ ____ 0,
RO
,

RO~
lR(:: ;t~0 lemma!oxi" (10)

(a) OR

l
! ~~~OR
O~.~ORO~OR
HO~OR 0

~
OR
OR
RO~O, '
RO~O OR OR
CR,OR hederasaponin C (2)

RO --r---...oJ
~ RO
OR

RO~O, '
RO~O

RO ---r----..oJ
(b)
~ RO

Fig. 24.4. Molluscicidal saponins.

462 Saponins and Cardenolides
RO
diosgenin (12)
progesterone (14)
Fig. 24.5. Diosgenin. progesterone, and an intennediate in the biosynthesis of diosgenin.
whether any of these are sufficient to explain the purported
medicinal value of ginseng is open to question. Both the
Oriental and American species contain a similar complement
of saponins; the chemistry and techniques for analysis of
these compounds has been reviewed (Shibata et a1.. 1985).
The same array of ginseng saponins are produced in root
cultures as in the intact plants; furthermore. the saponin con-
tent of the cultures exceeded that of the plants (CharI wood
and Charlwood, 1991; Ellis, 1988; Shibata et aI., 1985).
A related plant, Eleutherococcus senticosus or Siberian
ginseng, has been used for medicinal purposes as well (Farn-
sworth et al., 1985).
The sapogenin, diosgenin (12), which occurs as the 3-0-
glycoside in several species of Dioscorea (Dioscoreaceae),
is important as a precursor for the chemical synthesis of
cortisone (13) and a number of contraceptive drugs, such as
progesterone (14). The sapogenin is found in the roots of
these plants in quantities as large as 5-6% of the dry root
weight. Diosgenin is biosynthesized from cholesterol via in-
termediate (15), but the complete pathway has not been elu-
cidated (Fig. 24.5).
Several saponins have been found to have cardiotonic
activity, but usually less than that observed for the cardenol-
ides (see the following section) (Mahato et aI., 1982).
Glycyrrhizin (11) appears to inhibit HIV-l cell binding
(Kinghorn, 1992).
Alteration of Taste Properties
A class of triterpenoid saponins called gymnemic acids
[based on gymnemagenin (16) (Fig. 24.6)] has been identi-
OR
(15)
cortisone (13)
fied in the leaves of an asclepiadaceous vine Gymnema sylv-
estre. These saponins have been called taste-distortion
agents because of their ability to suppress the perceived
sweetness of sugars and, to a lesser extent, the taste of amino
acids. Chewing the root of this plant blocks perception of
the sweet taste of sugars, saccharin, and cyclamates for hours
(Hodge and Inglett, 1974). These compounds may protect
plants against mammalian and insect herbivores by dimin-
ishing the animals ability to sense the presence of sugars
(Harborne, 1982).
Sweeteners
Several saponins are known to taste sweet to humans.
Glycyrrhizin or glycyrrhizic acid (11), a triterpenoid glucu-
ronide from Glycyrrhiza glabra (licorice, Fabaceae), is about
50 times as sweet as sucrose (Fig. 24.5). Licorice is added
to chewing gum, chocolate candy, cigarettes, smoking mix-
tures, chewing tobaccos, and snuff. Pharmaceutically, lico-
rice is used to mask the flavor of many distasteful drugs.
Licorice root extract also is used to treat peptic ulcers. Large
amounts of glycyrrhizic acid can modify heart action (Hodge
and Inglett, 1974; Tyler et aI., 1981).
Another sweet-tasting saponin, osladin (17), occurs at
rather low concentrations (about 0.03%) in the roots of the
fern Polypodium vulgare (Hodge and Inglett, 1974). Similar
steroidal glycosides have been isolated from the rhizomes
of Polypodium glycyrrhiza (Kim et aI., 1988; Kim and Kin-
ghorn, 1989). The major intensely sweet compound of that
plant is polypodoside A, a 26-0-a-L-rhamnopyranosyl-pol-

ypodogenin-3-0- a-L-rhamnopyranosyl-(I - 2)-/3-o-gluco-
pyranoside (18). Podogenin, (22S,25R,26R)-3/3,26-dihy-
droxy-22,26-e poxy-6-oxo-5a-cholest-7-ene, serves as the
aglycone (Kim and Kinghorn, 1989). The glycoside is ap-
proximately 600 times sweeter than a 6% solution of sucrose.
Polypodogenin is the A7 •8 -isomer of osladin (Kim et aI.,
1988). A flavonoid glycoside, (+ )-afzelechin-7-0-/3-o-api-
oside, from the same plant, has a pronounced bitter taste
(Kim and Kinghorn, 1989).
The sweet-tasting compounds from Abrus fruticulosus
andA. precatorius (Fabaceae) also are a mixture of triterpene
glycosides related to cycloartenol (Choi et aI., 1989; Fullas
et aI., 1990). Abrusosides A-D (19-22) are 30-100 times
sweeter than a 2% solution of sucrose.
The triterpene glycoside, mogroside V (23), from the
dried fruits of Thladiantha grosvenorii (Cucurbitaceae) is
approximately 250 times sweeter than sucrose (Hussain et
aI., 1990; Matsumoto et aI., 1990).
HO~O, !>
HO~
~O osladin (17)
OH
HO
(a) gymnemagenln (16)
Fig. 24.6 (a-c). Saponins with sweet or taste~modifying properties.
Saponins and Cardenolides 463
CARDEI'IOLIDES
Cardiac glycosides or cardenolides (mostly CZ3 compounds)
are an important group of secondary metabolites that are
used medicinally and, under other circumstances, for arrow
poisons and for ordeal ceremonies (Connolly and Hill,
1991). All cardenolides have a 3/3-oxygen function, a 14/3-
hydroxyl group, and an a,/3-unsaturated-"y-lactone attached
at the 17/3 position (Connolly and Hill, 1991). These bioac-
tive glycosides are especially well known in plant-insect
interactions. Several examples of cardiac-active compounds
are known, but most plant-derived cardenolides are sapo-
nins. The sapogenin usually is derived from CZ1 progesta-
gens and modified by an additional acetate (from malonate)
unit to form a 5- or 6-membered lactone ring (Miller, 1973).
Large numbers of individual glycosides are found in various
plant tissues. For example, at least 24 cardiac glycosides
are found in the leaves of Strophanthus boivinii. In general,
O'HO~
'V--'v --;t(
glycyrrhetic acid
464 Saponins and Cardenolides

·....'0 ...·''''0

~
polypodoside A (18)
OH

HO OH OH
HO~ _0 . o
HO~O
o
HO ---r--.. o )
~ HO

HO (19)

HO~ _0 0
HO~
OH

HO
HOH~O (20)
HO~ __ O, ,0
O
HHO~
OCH)

HO
HO~ __ O, ,0
HO HO~
HO~ ~O. ? (21)
HO~
(b) OH

HO
OHO~ ..--0. ,0
HO HO~
HO~ -~ :0
Iio~
OH OH

HO
HO~P ~..--O. ~
HO~-----O~
OH t?o.~.--"~~,/
OH
(0)

Fig. 24.6. (continued)


cardenolides are accumulated in epidermal cells, laticifers,
and phloem elements of both external and internal phloem
of leaves and stems. In tissue culture of Digitalis, cardenol-
ides are accumulated in the vacuoles (Malcolm, 1991).
Many of the sugars found in cardenolides are restricted
in distribution (see Chapter 15). These include D-glucose,
D-fucose, D-digitoxose, D-digitalose, D-diginose, D-sarmen-
tose, D-cymarose, D-thevetose, and L-thevetose (Connolly
and Hill, 1991).
The procedures for isolation, purification, and characteri-
zation of cardiac glycosides have been reviewed (Connolly
and Hill, 1991; Malcolm, 1991). Several effective methods
for the isolation and purification of cardenolides by HPLC
(Groeneveld et al., 1990, 1991) and TLC (Malcolm et al.,
1989; Martin and Lynch, 1988) have been reported.
The 13C_NMR spectra of several cardenolides are of value
for characterization of this group of compounds (Tori et al.,
1973).
HO
cholesterol
RO~O~
(24)
HO,!
~CO>H_
HO •
scillaren A
glucosyl-O-rhamnosyl- 0
Fig. 24.7. Some intennediates in the biogenesis of cardenolides.
Saponins and Cardenolides 46S
BIOSYNTHESIS
Cardenolides typically have 23 carbon atoms, possess a 14-
l3-hydroxyl group, an a,l3-unsaturated "V-lactone ring, and
various sugars attached at the 313-position (Harbone, 1991).
Biosynthesis of cardenolides in Digitalis involves three dis-
tinct phases: the formation of a mevalonate-derived steroid
nucleus, the formation of a butenolide ring by addition of
an additional unit of acetate (malonate), and glycosidation
with up to four sugars (Groeneveld et al., 1991). Cardenol-
ides in most plants are formed by condensation of a C21 -
pregnane derivative [pregnenolone (3-I3-hydroxypregn-5-
en-20-one) or progesterone] with acetate (malonate) (Fig.
24.7). Labeling work with Strophanthus kombe demon-
strated that [4- 14C]3-I3-hydroxy-5a-pregnane-20-one (24)
and progesterone (14) are incorporated into cardiac glyco-
sides. Incorporation experiments with stem disks and slices
demonstrated an acetate-derived butenolide ring in calo-
,tropbanthldln
o 0
466 Saponins and Cardenolides
tropin (25) and uscharidin (26) (Fig. 24.8) in Asclepias cura-
ssavica (Lee and Seiber, 1983); however, feeding of [1-
l3C]acetate at lower levels to Asclepias curassavica stem
disks produced uscharidin in which there was no significant
introduction of l3C into the portion of the butenolide ring
containing C-22 and C-23 (Groeneveld et aI., 1990, 1991).
More than 20 sugars, most of these uncommon from other
sources, have been identified from cardiac glycosides (see
Chapter 15) (Miller, 1973; Seiber et aI., 1984). The sugar
moieties of cardenolides are normal sugars or unbranched
aldohexoses, mostly of the 6-deoxy or 2-deoxy type.
The cardenolides of the Asclepiadaceae differ from those
of the Apocynaceae and the Scrophulariaceae, in that the
former have a Sa(trans AlB) and the latter a S(3(cis AlB)
ring junction. The latter type is useful clinically in humans,
whereas the former normally is not (Seiber et al., 1984).
At least 30% of the cardiac glycosides of young plants of
Asclepias curassavica occurs in the latex (Groeneveld et al.,
1991).
DISTRIBUTION OF CARDIAC GLYCOSIDES
More than 400 cardiac glycosides are known. Most occur
in the Apocynaceae, Asclepiadaceae, Celastraceae, Brassi-
caceae, Fabaceae, Euphorbiaceae, Moraceae, Ranuncula-
ceae, Scrophulariaceae, Tiliaceae, Sterculiaceae, and Lilia-
ceae. Related compounds with 6-membered lactone rings
(bufadienolides) occur in the Liliaceae and Ranunculaceae
(Malcolm, 1991).
A number of frogs and toads and some plants make car-
diac-active compounds that have steroidal structures but are
not glycosides (Miller, 1973).
BIOLOWCAL ACTIVITY OF CARDIAC
GLYCOSIDES
Despite the fact that cardenolides usually are described as
bitter tasting, milkweed poisoning in livestock is a persistent
problem. Normally, animals will not eat the apparently dis-
tasteful plants, but in time of scarcity, many animals (espe-
cially sheep) succumb to this type of poisoning (Malcolm,
1991; Seiberet al., 1984). As little as 0.8 oz. of dry Asclepias
labriformis leaf is fatal to a 100-lb sheep (Harbome, 1991).
Although it is well known that cardiac glycosides are
sequestered by insects, it is less well known that parasitic
plants of the family Loranthaceae also sequester these com-
pounds when they grow on hosts containing cardenolides
(Boonsong and Wright, 1961; Rothschild, 1973).
Interactions with Insects and Other
Animals
Most members of the milkweed family (Asclepiadaceae)
and many members of the related family Apocynaceae syn-
thesize cardiac glycosides. These substances are both bitter
tasting and poisonous to higher animals (Fig. 24.8) (Har-
borne, 1991; Seiber et al., 1984). Nonetheless, insects from
about eight orders feed on these plants. Most are coadapted
species capable of consuming plants that contain cardiac
glycosides. Many of the compounds are metabolized by the
insects, but others are taken up and sequestered unchanged
(Harbome, 1989, 1991). Many ofthese insects are aposemat-
ically labeled (Rothschild, 1973).
Among these are the monarch butterflies, Danaus plexip-
pus. When the larvae of these butterflies feed on Asclepias
species such as Asclepias curassavica, they store the toxic
compounds cal actin (27) and calotropin (25) within their
bodies. As few other insects can eat these milkweeds, the
insect has little competition for its food source. The larvae
pass the compounds on to the adult stage of the insect which
is brightly colored and distasteful and/or toxic to many pred-
ators. This warning coloration is called aposematic marking
or labeling. The larvae of monarch butterflies have potent
emetic properties when fed to blue jays (not a normal preda-
tor of the monarch butterfly). Birds that consume the larvae
quickly learn not to repeat the mistake. In central Mexico,
where the insects winter, other birds eat the adult butterflies
with no apparent ill effects (Brower, 1984; Harbome, 1982;
Herout, 1970; Malcolm, 1991). These birds remove the outer
portions of the insect that contain the emetic compounds,
and ouly eat the inner parts that lack the compound.
Because the butterfly carries warning coloration
(aposematic labeling) that the bird learns to recognize
quickly, only a fraction, about 50% of the insects, need to
have the toxic compounds within their bodies for all of the
insects to be protected (Brower, 1969). Both the plants and
the insects differ in cardenolide content. Monarch butterflies
do not accumulate each of the compounds in the plant
equally well. Some cardenolides are absorbed intact, others
are biochemically modified, and yet others are excreted.
Over its natural range in North America, the female mon-
arch butterfly may lay her eggs on several Asclepias species
that differ in the complement and amount of cardenolides
present. By TLC analysis of adult butterflies, it is possible
to determine the species upon which the larva feed. Depend-
ing on the complement and quantity of cardenolides present
in the host plant, the larvae are able to adjust their diet to
modify the amount of cardenolide sequestered (Harborne,
1991).
The cardenolides within the monarch butterfly's tissues
are tightly bound to the cuticle in the various organs. Presum-
ably, this is a mechanism to avoid self-poisoning and to keep
these cellular toxins away from neuronal tissues (Harbome,
1991).
Certain other butterflies mimic the color pattern of the
Monarch butterflies and also are protected from the predators
even though they do not have the cardiac glycosides in their
bodies.
Other aspects of the chemical ecology of Danaus species
involve pyrrolizidine alkaloids and their metabolites (see
Chapter 30).
 Saponins and Cardenolides 467

HO

HO
HO

ouabagenin scillarenin A
(a)

o o

~
OCH3

HO 0 OH

!HO~,o
o

••,,,....
d
4'
5'
0
2'
1'.,
H "''>'0
oleandrin (28)

o calotropin (25)

o
~
OCH3" 19
HO" 3' 0 OH,1

6' 5' l' 3, 7 OH

OH

o neriifnlin(3!) ~O ••",

,,,,,,,lo1"""'o
° 0
calactin (27)

)rO""
,lAA,,·,o
uscharidin (26)

""" 0 H
(b)

Fig, 24,8 (a-c), Represen t ative cardiac glycosides,

468 Saponins and Cardenolides
erysimoside (29)
uo~ ...--0. ~~o\
UOiio~O ~O
ou OU
erycbroside (30)
(0)
Ul'~
o
OU
0
~ OU
Fig. 24.8.
Insects such as Iygaeid bugs fed on Nerium oleander also
accumulate cardiac glycosides, as does a bright yellow
aphid, Aphis nerii (Rothschild, 1973). The sugar~rich secre~
tion of these aphids, called honeydew, contains cardenolides
found in the host plant (Molyneux et aI., 1990). The ability
of this aphid to acquire these compounds suggests that they
are found in the phloem of Nerium oleander plants (Moly-
neux et aI., 1990).
The larvae of the bug, Caenocoris nerii, feed on ripening
seed pods of Nerium oleander plants and also accumulate
cardenolides such as oleandrin (28). At night, when
aposematic colors are less useful, these insects abandon the
conspicuous pods and shelter in twos or threes on the under-
side of leaves of the plant (Rothschild, 1973).
After attacking and consuming milkweed bugs (Oncopel-
tus fasciatus) raised on seeds of milkweed (Asclepias syr-
iaca), the mantid Tenodera ardifolia sinensis regurgitates
and shows signs of poisoning by cardenolides (Berenbaum
and Miliczky, 1984).
The North African aposematic grasshopper, Poekilocerus
bufonius, like the monarch butterfly, also feeds on milk-
weeds and accumulates the cardenolides. Unlike the mon-
arch, the grasshopper ejects the cardenolide materials as a
noxious foam from specially located poison glands (Seiber
et aI., 1984).
Gravid females of Pieris rapae oviposit on several mem-
bers of the Brassicaceae and other families that possess glu-
cosinolates; however, they avoid plants of the genera Erysi-
mum and Cheiranthus (see Chapter 17) (Rothschild et aI.,
1988; Sachdev-Gupta et aI., 1991). Fractionation of the de-
OU
0
OU
(continued)
terrent fractions of Erysimum cheiranthoides and characteri-
zation of the active compounds revealed that cardenolides
are responsible for this avoidance. In particular, the strop-
hanthidin glycosides, erysimoside (29) and erychroside (30),
were strongly deterrent to the females of Pieris rapae (Fig.
24.7) (Dimock et aI., 1991; Renwick et aI., 1990, 1991; Sach-
dev-Gupta et aI., 1991). A strophanthidin glycoside was iso-
lated from leaves of Cheiranthus X allionii which had simi-
lar activity (Rothschild et aI., 1988). This cardenolide had
no effect on another crucifer pest, the diamondback moth,
Plutella xylostelta (Renwick et aI., 1990).
When neriifolin (31) is applied to the roots of canteloupe
plants, more than 70% mortality of neonate larvae of the
codling moth (Laspeyresia pomonelta) occurred (Reed et
ai, 1982). The toxin appears to have a systemic effect. The
development and molting of larvae of Acrolepiopsis assec-
tella are inhibited when the larvae are fed digitonin. This
insect normally feeds on species of Allium (Liliaceae) that
do not have cardenolides. The addition of cholesterol to the
diet prevents these deliterious changes (Arnault and Mau-
champ, 1985).
An African mammal, the hyrax, eats oleander with im-
punity and seems to excrete the cardiac glycosides in its
urine, which is used by Cape Bushmen for tipping poison
arrows (Rothschild, 1973).
The larvae of a number of chrysomelid beetles synthesize
and accumulate cardiac glycosides (pasteels et aI., 1988,
1989). In this instance, the beetles do not take the compounds
from the host plants (many of which lack cardenolides) but
biosynthesize them from cholesterol.

l'Iedicinai Properties
Cardiac glycosides or cardenolides have a highly specific
and powerful effect on the cardiac muscle in mammals. Ou-
bain (32) and other cardiac glycosides inhibit vertebrate so-
dium pumps [(Na+ + K+)-ATPasel that play an essential role
in maintaining transmembrane ionic gradients (Malcolm,
1991). There are two principal types: the cardenolides and
the bufadienolides (Tyler et a!., 1981). Cardenolides have a
5-membered and bufadienolides have a 6-membered unsatu-
rated lactone ring. In some instances, these saponic com-
pounds are emetic and they are frequently toxic. The
(Na++ K+)-ATPase in cardiac muscle has been proposed as
the pharmacological receptor for cardiac glycosides (Seiber
et a!., 1984). The therapeutic level is often about 50% of
the toxic dose (Tyler et a!., 1981). Cardiac glycosides are
saponins and have most of the properties ascribed to these
compounds as well.
Many plants containing cardiac glycosides have been
used for medicinal purposes (Kinghorn, 1992). Digitalis
(Scrophulariaceae) is particularly important, but ouabain
(from the seeds of Strophanthus spp. or wood of Acokanth-
era schimperi, both Apocynaceae) also is widely used. Di-
goxin (34) from Digitalis lanata is the most widely used
""~", o~~~/~"
~ 08
08
80
80
bryophyUin B (35)
Fig. 24.9.
Saponins and Cardenolides 469
cardiovascular drug (Lewis, 1992). Digitoxin (33) is the
main saponic glycoside from digitalis (Tyler et a!., 1981).
This glycoside is absorbed readily from the intestinal tract;
intravenous and oral toxic doses are almost equal. In con-
trast, ouabain (32) is much more toxic when given intra-
venously (Malcolm, 1991). The toxicities of some common
cardenolides have been summarized (Malcolm, 1991).
Several cardiac glycosides have been reported to have
antiviral properties (Vanden Berghe et aI., 1985). Others
have been reported to have antitumor or cytotoxic properties.
Among these are calotropin (25) from Asclepias curassavica
(Kupchan et a!., 1964) and neriifolin (31) and 2'-acetylnerii-
folin from Thevetia thevetioides (Apocynaceae) seeds
(McLaughlin et aI., 1980).
The cardioactive compounds from Bryophyl/um species
are bufadienolides with potent cytotoxic activity (Yamagishi
et aI., 1989). Bryophyllin B (35) (Fig. 24.9) from Bryophyl-
fum pinnatum possesses an unusual orthoacetate-containing
structure; this compound has an EDso of less than 80 ng/ml
in the KB cell culture system (Yamagishi et a!., 1989).
Arrow Poisons
A number of plants containing cardiac glycosides [e.g.,
seed extracts of Strophanthus gratis and S. kombe (Apocyna-
o
~o, 0
08
~
08
ouabain (32)
Medically important cardiac glycosides.
470 Saponins and Cardenolides
allosyl-O-deoxyallosyl-O
OH
allosyl-O-deoxyallosyl-O
OH
Fig. 24.10. Cardenolides from Lophopetalum toxicum.
ceae) species1 have been used as arrow poisons (Lewis,
1992). In some cases, the active compounds have been iso-
lated and confinned to be cardenolides. The active principles
of the arrow poison from Lophopetalum toxicum (Celastra-
ceae) consists of four cardiac glycosides (Fig. 24.10).
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TYLER, V. E., L. R. BRADY, and 1. E. ROBBERS, Pharmacognosy,
8th ed., Lea and Febiger, Philadelphia, 1981.
VANDBN BBRGHE, D. A., A. J. VLlBTINCK, and L. VAN HOOF, Present
status and prospects of plant products as antiviral agents, in
Advances in Medicinal Plant Research (A. J. Vlietinck and R. A.
Domisse, ods.), 47-99, Wissenschaftliche Verlagsges. Stuttgart,
1985.
YAMAGlSm, T., M. HARUNA, X. YAN, J. CHANG, and K. LEB, Antitu-
mor Agents, 110. Bryophyllin B, a novel potent cytotoxic bufa-
dienolide frum Bryophyllum pinna/urn, J. Nat. Prod., 52,
1071-1079 (1989).
25
Limonoids, Quassinoids, and Related
Compounds
Introduction
Biosynthesis
Limonoids (Tetranortriterpenoids)
Quassinoids (Decanortriterpenoids)
Pentanortriterpenoids
Chemosystematic Studies
Biological Activity
Antifeedant Activity
Medicinal and Antitumor Properties
Limonin in Orange Juice
References
INTROovcnOI'l
Two major groups of metabolically altered triterpenes, the
limonoids (tetranortriterpenoids) and the quassinoids (dec-
anortriterpenoids) are derived from euphol (1) (Fig. 25.1)
or tirucallol (2) (Fig. 25.2). To date, these compounds are
restricted in distribution to the Rutaceae, Meliaceae, Cneora-
ceae, Simaroubaceae, and, perhaps, the Burseraceae (Con-
nolly and Hill, 1991), and occur variously in seeds, fruits,
and wood of plants of these families. In general, the limonoid
and quassinoid content of leaves has not been examined
(Taylor, 1983).
Small amounts (0.33%) of quassins are produced by cal-
lus and suspension cultures of Picrasma quassinoides
(Charlwood and Charlwood, 1991).
BIOSYl"fl1lESIS
Both limonoids and quassinoids are derived from a cation
such as (3) (Fig. 25.2), produced by condensation of a
chair-chair-chair-boat configured squalene 2,3-epoxide
(4) precursor. By subsequent rearrangement, many other
types of triterpenes are fonned. There is little direct evidence
for many of the intennediates and enzymes involved in the
synthesis of limonoids, quassinoids, and other compounds
of this general derivation. Proposed biogenetic schemes are
based largely on the occurrence of probable intennediate
compounds. Euphol (1) and tirucallol (2), which differ in
configuration at C-20, are both fonned from this pathway.
Although most quassinoids and C30 triterpenes of the Rutales
have the C-20 (R) configuration, suggesting tirucallol as
the precursor, C-20 (S)-euphol also was converted to the
limonoid nimbolide (6) (Fig. 25.1) more efficiently than tiru-
callol inAzadirachta indica leaves (Champagne et aI., 1992).
The identity of the actual precursor of limonoids and quassi-
noids is not known with certainty. A7 -Euphol (8) and/or A 7 _
tirucallol (butyrospennol) (7) appear to be later intennedi-
ates in the biosynthetic sequence. The apo-rearrangement
occurs with introduction of a 14-unsaturation, migration of
the C-14 methyl group to C-8, and introduction of oxygen at
C-7 (Connolly, 1983), and may involve opening of a 70<,80<-
epoxide (9 and/or 10).
Relatively simple C30 compounds, sometimes called pro-
tolimonoids, that appear to be derived from apo-euphol (11)
and/or apo-tirucallol (12), have features suggesting their role
as precursors and lack ring opening, are found in the Melia-
ceae and Rutaceae (Connolly, 1983; Dreyer, 1983). It is not
certain whether oxygenation precedes or follows the apo-
rearrangement, as both melianone (13) (in which the C-14
methyl group has not migrated) and grandifoliolenone (14)
(in which migration has taken place) have been isolated (Fig.
25.3).
A similar compound, turreanthin (5), from Turreanthus
africanus (Meliaceae), has a side-chain oxidation pattern that
suggests a potential furan ring (Connolly, 1983).
Limonoids (Tetranortriterpenoids)
The limonoids (more than 300 described compounds) are
a stereochemically homogeneous group of tetranortriter-
473
474 Limonoids. Quassinoids. and Related Compounds

P
~~ ySP';
H H~~
H6~ I _0

CH'C~O
O
HO" HO" CH,Co-O.yJOH

Co
eupbol (1) tUndlssol grandifollone

rc~
if o
0

'0
limonin (19)

®
kbivorin (23) mexicanolide (25)

CH~O'C
, OCH,

o I o "
CH,-O I

CH'C~ ~C:;H' o
! 0 0

nimbin (26) nimbolide (6) quassio (31)

Fig. 25.1. Some representative metabolically altered triterpenes.

~oo~- squalene 2,3-epoxlde (4) + (3) \

~ ;~--~~~
HO

! ':
,~ (A'-UrucaJlol)
butyro.permol(7)
HO

tirucallol (2) H
HOr·
eupbol (I) \
R
H

HO #
l""
~~:~#~
\ ,,_.
o

~
HO
0
(9)
--

~
HO
I

oo~~ ~
Amencan SocIety of Pbannacognosy, Downers Grove, Dlinois).
••
Fig. ~.2. Bi,osynthesis of apo-eupbol and apo-tirucallol (modified from . . . .
SiddiqUI et aI., 1988; used with pennission of the copyright owner, the
 Limonoids. Quassinoids. and Related Compounds 475

0
OH

!{r4!~ 00

~~o#o¥ o~
turreanthin (5) me1ianone (13) grandlfoliolenone (14)

(Y0H (Yo
,
o
°
(15) (16)

Fig. 25.3. Protolimonoids.

penes only found in the Meliaceae, Rutaceae, Cneoraceae,
and Harrisonia (Simaroubaceae) (Champagne et al., 1992;
Harborne, 1991). A report from Balsamodendron pubeseens
(Bursemceae) warrants reconfirmation (Taylor, 1983). Li-
monoids have a furan ring attached as a side chain at C-
17 to a cyclopentenophenanthrene nucleus which may have
undergone oxidative opening of one or more rings (Taylor,
1983).
Oxidative modification eventually results in the removal
of the four terminal side-chain carbons and formation of a
l3-substituted furan ring. A hemiacetal (15) and a lactone
(16) from Chisoeheton panieulatus (Meliaceae) represent
stages between the intact side chain and the furan ring.
Cedrelone (17) and a series of other compounds have
suffered cleavage of the side chain but retain the apo-euphol
tabolites in various plants that synthesize and accumulate
limonin supports this pathway. As members of the genus
Citrus (Rutaceae) synthesize only nomilin (20) in the leaves
and stems (the principal site of biosynthesis), this compound
appears to be moved to other sites (e.g., the fruits) and subse-
quently modified (Hasegawa et aI., 1984).
Other compounds undergo A-ring cleavage as well; for
example, tricoccin S22 (21), from the Cneoraceae (Connolly,
1983).
Cleavage of ring B of intermediate compounds similar to
khivorin (23) (Fig. 25.1) may give rise to compounds such
as andirobin (22) and methyl angolensate (24) (a B,D-seeo-
limonoid) (Fig. 25.6). This cleavage also may be concealed

c>
skeleton intact (Fig. 25.4) (Connolly and Overton, 1972).
Other classes of limonoids may have the A, B, C, or D
ring (or a combination of rings) cleaved. For example, gedu-
~O
I

o~
nin (18) has a cleaved D ring (D-seeo-lirnonoids) (Fig. 25.4),
whereas limonin (19) has both a cleaved A ring and D ring
(A,D-seeo-limonoids) (Fig. 25.5). The initial products of the
oxidation process are concealed by secondary cyclization. °
Both the epoxide and II-lactone systems are characteristic of
limonoids. OH
°
A plausible pathway for the formation of 1imonin from
cedrelone (17) gedUDin (18)
d '-tirucallol (7) has been proposed (Fig. 25.5) (Arigoni et
al., 1960; Dreyer, 1984). The presence of related minor me- Fig. 25.4. Limonoids with an intact apo-eupbol skeleton.
476 Limonoids, Quassinoids, and Related Compounds

HO

Ll7 -tirucallol (7)

k)
1'0 Q5P''0H~
~O ,~O

""~- O~OO
0- OH

0
HO - 0 0
o
deacetylnomilinate deacetylnomilin

nomilin (20) obucanone (47) obacunoate

o ~O C)
.nomilin ~-
~'Oo_O~lloo
acetyl-lyase 0 0 0 ~
** obacunone
A-ring lactone
hydrolase isoobacunoate Jimonin (19)

Fig. 25.5. Proposed biosynthetie pathway to limonin (modified from Dreyer, 1984; used with pennission of the copyright owner, Marcel Dekker, Inc.,
New York).

by other reactions (Connolly and Overton, 1972) such as
those seen in the fDlmation of mexicanolide (25) which has
a bicyclo[3.3.IJnonane system (Connolly, 1983). Cleavage
of ring C yields compounds such as nimbin (26) (a C-seco-
limonoid) (Fig. 25.6) (Connolly, 1983). Most compounds
of this group occur in the genera Melia and Azadirachta
(Connolly, 1983).
As previously mentioned, gedunin (18) (Fig. 25.4) has
undergone cleavage of the Dring. D-Ring cleavage is often
associated with other modifications of the molecule as well
(Connolly, 1983).
Quassinoids (Decanortriterpenoids)
Quassinoids are decanortriterpenes known to occur only
in the family Simaroubaceae (Polonsky, 1983, 1986). More
than 120 compounds and 5 major structural types have been
described (Polonsky, 1986).
The biosynthetic precursors of quassinoids are similar
to those of limonoids. Li?-Euphol (8) and/or Li? -tirucallol
(butyrospermol) (7) (Fig. 25.7) appear to be early intermedi-
ates in the biosynthetic sequence. The apo-rearrangement
occurs with the introduction of a 14-unsaturation, migration
of the C-14 methyl group to C-8 and the introduction of
oxygen at C-7 (Connolly, 1983) and may involve opening
of a 7a,8a-epoxide. As is true for many limonoids, the D
ring of an intermediate compound is expanded by the biolog-
ical equivalent of a Baeyer-Villiger reaction to produce a
S-lactone (Polonsky, 1983). Opening of that lactone, fol-
lowed by recyclization to the 7-hydroxyl group (and produc-
tion of another 8-lactone) (27) yields a possible intermediate
for the different routes required for subsequent transforma-
tions (Polonsky, 1983). Several C25 -quassinoids could logi-
cally be derived from this intermediate (Fig. 25.7). Among
these are simarolide (28), picrasin A (29), and soulameolide
(30). All possess a C-l7 and none possess a C-12 oxygen
function (Polonsky, 1983). Introduction of an oxygen at C-
12 could lead to cleavage of the C J3 -C l7 bond and formation

nimbin(26)
andirobin (22) mexlcanolide (25)
c>
«ft
fo ~i ::;;-
0 0 0
o 0 ~ bution of limonoids and quassinoids, it seems probable that
COZCHJ
methyl angoJensate (24) tricoccln Su (21)
Fig. 25.6. Limonoids that exhibit B-ring or C-ring cleavage.
of C20 quassinoids (Fig. 25.8). All members of this last group
contain C-12 oxygen functions (Polonsky, 1983).
Quassin (31), the parent compound of this group, shares
certain structural similarities with merogedunin (32) that can
he produced by treatment of gedunin (18) (Fig. 25.4) with
alkali. Gedunin suffers a fragmentation to a a-lactone and
furan-3-aldehyde. The reaction is typical of limonoids hav-
ing the O-ring structure of gedunin and is called the "meroli-
monol rearrangement" (Connolly and Overton, 1972; Geiss-
man and Crout, 1969). Although it has heen suggested that
quassinoids could arise in this manner, such a synthesis re-
quires nonphysiological conditions.
inadequate data exist to define clearly the pathway of
biosynthesis.
Pentanortrlterpenoids
A series of pentanortrlterpenoids has been isolated and
studied from the family Cneoraceae (Fig. 25.9). This family
has been placed in the Rutaceae by some (Thome, 1976)
but differs (among other features) in the presence of this
group of compounds. Although limonoids are found in the
family, those closely related to limonin itself are lacking. A
number of isomers of the cneorin-tricoccin series are
known; these compounds are representative of the Cneora-
Limonoids. Quassinoids. and Related Compounds 477
ceae (Dreyer, 1984; Mondon and Epe, 1983). Many tetranor-
triterpenoids (such as 21, Fig. 25.6) also have been isolated
from eneorum tricoccum (Epe and Mondon, 1979; Mondon
and Epe, 1983).
CHEl'IOSYSTEJllATIC STUOmS
This series of compounds and pathways provides one of
the best examples of the application of terpene chemistry to
phylogeny. Limonoids characterize the family Meliaceae,
where they are diverse and abundant; a more limited range
of structures is found in the Rutaceae and Cneoraceae
(Champagne et aI., 1992). Rearrangement of the A ring leads
to formation of the typical rutaceous limonoids (also found
in Harrisonia), whereas rearrangement of both the A and B
rings results in the highly derived limonoids characteristic
of the Cneoraceae. In the subfamily Sweetenoideae of the
Meliaceae, D-seco-limonoids are further oxidized to B,D-
C>
seco structures, which may then be extensively rearranged
tu yield more complex structures. in contrast, members of
the subfamily Melioideae produce limonoids through a vari-
...·OH
ety of pathways leading tu B-, A-, AB-, and C-seco com-
pounds (Champagne et aI., 1992). Quassinoids are found
only in members of the Simaroubaceae. Based on the distri-
the Meliaceae and Simaroubaceae arose independently from
Rutaceae-like ancestors. The Simaroubaceae has the most
highly modified triterpenoid chemistry of the three families
(Simao et aI., 1991; Waterman, 1983). Within the Rutaceae,
other chemical changes have occurred that presumably arose
after the separation of the Meliaceae and Simaroubaceae
from Rutaceous stock (da Silva et aI., 1984; Gershenzon and
Mabry, 1983; Hegnauer, 1983; Seigler, 1981).
Data from triterpenes and chromosomes shed light on the
placement of several enigmatic groups. Nymania capensis,
a small South African tree that previously has been placed
in a number of families, contains limonoids that strongly
suggest affiliations with the Meliaceae. The compounds
present are similar to those of the genera Guarea, Trichilia,
and Aphanamixis species and support placement of the genus
in the subfamily Melioideae (MacLachlan and Taylor, 1982;
Taylor, 1983). Another such problem involves the genus
Ptaeroxylon (Ptaeroxylaceae), which produces chromo-
somes similar to the genera Spathelia and Harrisonia but
lacks limonoids. The presence of limonoids in the genus
Harrisonia suggests that genus may be misplaced within the
Simaroubaceae. Other studies suggests that Harrisonia is
related to the genus Spathelia (Taylor, 1983; Waterman,
1983). Indeed, placement of the entire trihe Spathelioideae
is somewhat questionable and, in many regards, is intermedi-
ate to the Rutaceae, Cneoraceae, and Ptaeroxylaceae (Water-
man, 1983). The separation of these taxa from proto-simar-
oubaceous ancestors must have come before the evolution
of the quassinoid pathway. All (except Spathelia) have lost
the ability to synthesize alkaloids, Harrisonia and Spathelia
478 Limonoids, Quassinoids, and Related Compounds

HO
¥~y5P~¢0I~
A7••• phol (20~) (8)
I ---+-
HO
::0 ---..
HO

HO
....----+-
OH
21

20
23
COzH
.1.7·tirucallol (20a.) (7)
17

o
o

soulameolide (30) picrasin A (29) simarolide (28)

Fig.· 25.7. Possible scheme for the formation of quassinoids (modified from Polonsky, 1983; Academic Press, London).

have lost the ability to synthesize coumarins, and the Ptero·
xylaceae have lost the ability to synthesize limonoids (Wa·
tennan, 1983).
BIOLOGICAL ACTIVITY
Many metabolically altered triterpenes contain epoxides,
lactones, furans, and cyclopentanoid systems, functional
groups of plant metabolites. Some compounds of this group
taste bitter to humans and, presumably, to other mammals
(Champagne et aI., 1992). Both vegetative parts and the
wood of many plants of the Rutaceae, Meliaceae, and Sima·
roubaceae are resistant to insect attack. In accord with these
observations, many limonoids, quassinoids, and their rela-
tives possess a variety of biological activities.

rttfu
units that are associated with biological activity in other Antifeedant Properties
A number of limonoids and quassinoids from the Ruta·
° CH3
ceae, Meliaceae, and Simaroubaceae are insect antifeedants.
o '" These compounds have been extensively investigated, as
CHJO they may provide relatively specific, biodegradable insecti·
--. I H cides and antifeedants.
I "0 0 Although extracts of seeds of many meliaceous plants
have many interesting bioactivities, the best known example
(27) quassin (31) is extracts of the neem tree (Anon., 1992; Klocke et aI.,
1989; Kraus et aI., 1987; Saxena, 1989; Smutterer et aI.,

~ ~
H 1980). The neem tree, Azadirachta indica (MeJiaceae), is
I OH I OH native to India, but grows commonly in the Near East and

o 17 0 0 HO~' 0 0
in certain regions of Africa. Extracts of the seed oil have
both insecticidal and antifeedant properties (Harbome, 1989;
Kraus et aI., 1987; Stone 1992); at least 200 species of insects
and mites are affected (Champagne et aI., 1992). In Israel,
merogedunin (32) merokhivorin
it has been noted that the tree is never eaten by the desert
Fig. 25.8. Czo and C Z5 quassinoids. locust, Schistocerca gregaria, a generalist insect known to

cneorin C cneorinK
o
tricoccin C14
Fig. 25.9. Pentanortriterpenes and tetranortriterpenes from the Cneoraceae.
eat virtually all vegetation. Extracts of neem tree seeds are
repellent at low concentrations. The probable active com-
pound is the tetranortriterpene azadirachtin (33) (Fig. 25.10)
(Broughton et al., 1985; Kraus et al., 1985, 1987; Ley et aI.,
1987, 1992; Schroeder and Nakanishi, 1987). Azadirachtin
gives 100% feeding inhibition at 40 JLglL against Schistoc-
erca gregaria (desert locust) (Kubo and Nakanishi, 1977)
and against the fall armyworm (pC9S = 0.1 JLgldisk) (Kubo
and Klocke, 1981). Azadirachtin has an ECso of 0.36 ppm
against larvae of Peridroma saucia, the variegated cutwonn
(Champagne et al., 1989). In contrast, azadirachtin has no
antifeedant activity against nymphs of the migratory grass-
hopper, Melanoplus sanguinipes, although the topical EDso
is 4.5 JLglg insect (Champagne et al., 1989). Feeding deterre-
ncy involves interaction with one set of sensory receptors,
whereas the toxic effects probably involve different systems
in the insect.
The mode of toxicity of azadirachtin when consumed by
insects appears to involve the neuroendocrine regulation of
juvenile and molting honnone titers (Rembold, 1989). Azad-
irachtin produces no observable effects on larvae between
molts. Only after the initiation of the insect molting cycle
(occurring simultaneously with the fonnation of new cuticle)
does the toxicity become evident. The larvae usualIy die as
a result of being encased in the unshed exuviae that prevents
feeding, excretory, and locomotory functions (Kubo and
Klocke, 1981). Cedrelone (17) (Fig. 25.4) is the only other
compound of this series known to inhibit ecdysis (Klocke,
1987). This compound inhibited molting of the milkweed
Limonoids, Quassinoids, and Related Compounds 479
-t--t--f-O
o
bug, Oncopeltus fasciatus (Champagne et al., 1989), but
other studies failed to reproduce this activity (Champagne
et aI., 1992). Insect ecdysis inhibitors from plants have been
reviewed (Kubo and Klocke, 1986).
Extracts and exudates of neem trees, Azadirachta indica
(MeIiaceae), have biological activity against a variety of dif-
ferent nematodes. For example, a neem seed extract applied
to tomato plants as a root drench at 125 JLg/ml inhibited
reproduction of the root-rot nematode Meloidogyne javanica
(Chitwood, 1992). Azadirachtin (33), at 10 JLg/ml, inhibits
microfIlarial release in the animal-parasitic nematode,
Brugia pahangi. A similar mode of action may be involved
in phytoparasitic nematodes (Chitwood, 1992).
Curiously, when azadirachtin (33) is fed as a part of a
blood meal to Rhodnius prolixus, a vector of Chagas disease,
subsequent parasitic infestation of the arthropod by the try-
panosome Trypanosoma cruzi is prevented, but azadirachtin
is not directly toxic to the trypanosome (Borris and Schaef-
fer, 1992).
Other compounds from Azadirachta indica, including Ii-
monin (19), nomilin (20), nimbin (24), nimbalide, azidirone,
and salannin also are feeding deterrents. Nimbolide (6) has
cytotoxic activity (LDso of 0.25 JLg/ml against KB and 0.065
JLglml against P-388 celI culture systems (Kigodi et aI.,
1989).
Another widely grown meliaceous tree, the chinaberry or
Persian lilac (Melia azadirachta), also contains a variety of
toxic limonoids. This tree is known for its cathartic, emetic,
and anthelminthic properties (Kraus et al., 1987). Although
480 Umonoids, Quassinoids, and Related Compounds
azadirachtin (33)
CH3COO""...
CH 3COO"·..··
CH,CH,CH(CH,)CO- 0
(CH3lzCHCO-O
meliatoxin 8 1 (35)
Fig. 25.10.
azadirachtin has been reported from this plant and might be
expected to occur there, the presence of this compound from
Melia azadirachta requires confirmation (Kubo and Klocke,
1981). Furthermore, chemical variation in this widely dis-
seminated species exists, complicating interpretation of phy-
tochemical reports.
Meliatoxins Al (34), BI (35), Az (36), and B2 (37) are
the compounds responsible for most of the fruit toxicity of
some variants of this plant (Oelrichs et a1., 1983), but other
insect antifeedants also are present. These fruits are espe-
cially toxic to swine (Oelrichs et a1., 1983). Other com-
pounds isolated from Melia azedarach include ohchinolid
A and B, nimbolidin A and B, and nimbolinin B (Kraus et
aI., 1982).
Melianone (13) (Fig. 25.3) from the leaves of Melia azad-
irachta has antifeedant activity. Meliantriol (38) (Fig.
25.11), from the fruit, inhibits feeding of the desert locust
Schistocerca gregaria (Lavie et aI., 1967).
Toosendanin (39) from the Chinese species Melia toosen-
danan displays activity as strong as azadirachtin against lar-
vae of Spodoptera litura and has better activity than azadi-
rachtin against the yellow stemborer, Scirpophaga
incertulas, and the Asiatic comborer, Ostrinia furnacalis
(Fig. 25.11) (Towers et aI., 1989).
Despite the fact that the neem tree is widely known, limo-
noids from other sources also have pronounced effects on
insect feeding and growth; many of these have been tabu-
lated (Champagne et aI., 1992). Apart from the C-seco limo-
"Co
23
2O~
12
~ 21
",'
CH3CO-O
CH3CH,CH(CH3)CO· 0
meliatoxin At (34)
meliatoxin B2 (37) (CH3hCHCO· 0 meliatoxin A2 (36)
Some antifeedant limonoids.
noids [such as azadirachtin (33)], the most active compounds
appear to be intact apo-euphollimonoids with a 14,15-epox-
ide and either a 19/28 lactol bridge or a cyclohexenone A
ring (Champagne et aI., 1992). Examples of the latter type
include anthothecol, cedrelone (17), sendanin (40), trichiro-
kanin (41), toosendanin (39), and meliacin Az (36).
Certain other meliaceous seed extracts were equally ac-
tive to azadirachtin in bioassays (Mikolajczak and Reed,
1987). Those of Aglaia cordata were more potent than ex-
tracts of neem toward larvae of Spodoptera jrugiperda (Mi-
kolajczak et aI., 1989). A Iimonoid compound from Carapa
procera had antifeedant activity comparable to that of azadi-
rachtin, but much weaker insecticidal properties. This com-
pound, methyl 313-isobutyryloxy-l-oxomeliac-8(30)-enate
(42), also was found in Khaya senegalensis and K. nyasica
(Mikolajczak et aI., 1988).
Toonacilin (43) and 6-acetoxytoonacilin (44) from the
bark of Toona ciliata (Meliaceae) (B-seco-limonoids) ex-
hibit powerful antifeedant activity against the Mexican bean
beetle (Kraus et aI., 1978).
Four additional bioactive compounds with intact apo-eu-
phol skeletons were isolated from the meliaceous tree Trichi-
lia emetica (syn. T. roka) of East Africa (Nakatani et aI.,
1981). The Iimonoids of this tree had antifeedant properties,
but none were as potent as azadirachtin (Kubo and Klocke,
1981). Trichilin A (45) differs from meliatoxin Al (35) only
in the presence of a hydroxyl substituent at C-12 (Oehlrichs
et aI., 1983).
 Limonoids. Quassinoids. and Related Compounds 481

A series of six quassinoids isolated from Simaba mul-
tiflora and Soulamea soulameoides were shown to be active
as growth inhibitors and as antifeedants against Heliothis
virescens (cotton budworm) andSpodopteraJrugiperda (fall
armyworm) (Klocke et al., 1985).
A nomilin derivative (46) from the seeds of a Xylocarpus
species [erroneously reported as being from Uncaria gambia
(Rubiaceae)] has been studied (Ahmed et al., 1978). The
identify of the Xylocarpus species has been suggested to be
X. mol/uscensis, but possibly should be Xylocarpus gra-
natum.
A species of enigmatic affinities, Harrisonia abyssinica,
usually placed in the Simaroubaceae (but see the discussion
above), contains both the widespread Iimonoid bitter princi-
ple, obacunone (47) and a second Iimonoid, harrisonin (48).
Harrisonin has insect antifeedant activity, is cytotoxic, and
has antibacterial activity. This compound inhibits feeding
activity of Spodoptera exempta at the 20-ppm level in leaf-
disk tests and has antibiotic and cytotoxic activity (2.2
fLg/ml, KB test). Although the East African variety of Harri-
sonia abyssinica contains harrisonin, the West African vari-
ety lacks this compound (personal communication, P. G.
Waterman).
Medicinal and Antitumor Properties
Several Iimonoids have anticancer activity. Bioassay-
guided fractionation led to the isolation of amoorastatin (49),
a cytotoxic limonoid from Aphanamixis grandifolia that has
the same B-, C-, and D-ring substituents and the same rela-
tive stereochemistry as meliatoxin A2 (Fig. 25.11) (Cham-
pagne et al., 1992; Oehlrichs et al., 1983). 14,15-Epoxy-
prieurianin (SO) from Guarea guidona also possessed
antitumor activity. Aphanostatin (51), sendanin (40), and 12-

OH

HO~H OCOCH,CO

~
HO j'

.o~
I
o 0
CH,COO OH
HO H

r:
meliantriaol (38) toosendanin (39) sendanin (40)

OCOCHkO OH. o

~
OO "
CH,COO '
o 0 0
OH CH,CO O· OH
CH,CH,CH(CH,)COO H
OCOCH(CH,)CH,
methyl 38wisobutyryloxy- trichirokanin (41) trichilin A (45)
l-oxomeliac-8(30)-enoate (42)
OH 1: 0

CH'C~OO
CH,CH,CH(CH,)CHOHCo-O
i iii
HO I
..... 0 0
o CH,COO' OH
CH,CH,CH(CH,)COO H
CO,CH,

C>
4fiP
OCOCHJ 15,16-epoxyprieurlauin (SO) apbanostatin (51)

CH,COO 1-'0
~ CHCOO 6)--0 1: 0

~o
HO Ii
1i
o l
'" o 0 0
o CH,CO 0 OH
CO,CH, i OCOCH, HO
OHO OH H
toonacllin (43) 6-acetoxytoonacilin (44) harrisonin (48) amoorstatin (49)

Fig. 25.11. Some biologically active limonoids.

482 Limonoids, Quassinoids, and Related Compounds
hydroxyamoorastatin also had pronounced activity in tests
against a murine P-338 lymphocytic leukemia cell line
(Champagne et a!., 1992), However, most limonoids lack in
vivo activity.
The limonoid nimbolide (6) (Fig, 25, I) from Azadarichta
indica inhibited Plasmodium Jalciparum in vitro (LDso 0.95
fJ-g/ml), but was inactive in vivo in mice.
Several quassinoids are known to have antileukemic ac-
tivity (Blasko and Cordell, 1988; Cordell, 1978; Polonsky,
1983). Only compounds with a Czo skeleton have antileuke-
mic activity. Quassimarin (51) from Quassia amara and
bruceoside A (52) from Brucea javanica and a series of other
quassinoids from Brucea antidysenterica (all Simarou-
baceae) (Fig. 25.12) are active in this regard. Bruceantin
(53) has a high degree of antitumor activity in P-388, LE,
LL and B 16 tissue culture systems (Cordell, 1978). Six quas-
sinoids from Simaba multiflora and Soulamea soulameoides
were shown to be active against several tumor systems
(Klocke et a!., 1985).
Bruceantin binds tightly to ribosomes and this is the major
mechanism by which it inhibits protein synthesis (Blasko
and Cordell, 1988).
Other quassinoids are known to have antiviral activity
(Polonsky, 1983). Among these are isobruceine A (54), si-
malikalactone D (55), chaparrinone (56), glaucarubolone
(57), and castelanone (58).
Certain quassinoids [e.g., simalikalactone D (55)] are ac-
HO ';lH_ OH
O~:~~'o~~~ _<-O~o·,co:ct(
yu. ~J. W'''O~O
quassimarin (51) isobrucein A (54)
OH
chaparrinone (56)
castelanone (58)
simaIikalactone D (55) bruceantin (53)
Fig. 25.12. Medicinally promising quassinoids.
tive against Plasmodium Jalciparum, one of the organisms
responsible for malaria (Polonsky, 1983). Bruceantin (53)
and simalikalactone D (55) had ICso of 0.8 ng/ml and 0.9
ng/ml values, respectively, against PlasmodiumJalciparum.
These compounds were the most potent of a series tested
for antimalarial, antileukemic, and cytotoxic activity (Blasko
and Cordell, 1988; Borris and Schaeffer, 1992). Several
other quassinoids have in vivo antimalarial activity, but tox-
icity precludes use of most of these in man. Simalikalactone
D also has powerful antileishmaniacal activity (Borris and
Schaeffer, 1992).
A mixture of quassinoids from Hannoa undulata (Sima-
roubaceae) prevented penetration of tomato roots by infec-
tive juveniles of the root-rot nematode, Meloidogyne javan-
ica, at 1-5 fJ-g/mI. The major components of the mixture
were chapparrinone (56), klaineanone (59), and glaucaruba-
lone (57) (Chitwood, 1992). The primary effect appeared to
be on the motility of the nematodes.
Limonin in Orange Juice
Fruits of the genus Citrus constitute one of the world's
most important horticultural crops. Production is at least 45
million tons, of which about 45% is converted into a variety
of processed products (Maier, 1983). After expression of
citrus juices, especially orange juice, precursors that occur
in the juice are converted to bitter limonoids, primarily li-
OH
o~,. ~J.OH
bruceoside A (52)
OH OH
glaucarubolone (57)
klaineanone (59)

o
W
o
o
i!
0
Co
OH
CO,H
limonoie acid A-ring lactone (OO)
Fig. 25.13. Limonoic acid A-ring lactone and nonbitter debydro-derivative of limonin.
monin (19) (Fig. 25.5) and, to a lesser extent, nomilin (20).
The bitter taste of limonin can be detected at concentrations
ranging from 0.075 to 5 ppm (Champagne et al., 1992).
Losses to the California citrus industry attributable to unac-
ceptable bitterness in juice products alone are estimated at
$8,000,000 per year.
No evidence of limonoid biosynthesis in fruit or seed
tissues exists, despite the fact that most of the limonins are
found in the seeds of mature fruits. Limonoid synthesis oc-
curs in the leaves and limonoids are transported into the
fruits (Maier, 1983). In citrus tissues, the natorally occurring
precursor of limonin is a salt of limonoic acid A-ring lactone
(60) (Fig. 25.13) in which the A ring is closed and the D
ring is open. This tasteless compound is stable only in the
salt form (Maier, 1983). In the presence of acid or the en-
zyme citrus limonoate D-ring hydrolase, the D-ring lacton-
izes to form limonin (19). The rate oflactonization is acceler-
ated by pasteurization of the juice. In the fruit, the precursor
appears to be located in a compartment of the cell where
the pH is neutral or alkaline, probably the cytoplasm (Maier,
1983).
A number of methods have been developed to prevent
the formation of limonin in orange juice. Application of
auxin (and a number of synthetic compounds with auxin
activity) in a preharvest treattnent prevents the synthesis of
nomilin (20) and hence the formation of limonin (19) (Ha-
segawa et al., 1986). Five species of bacteria have been re-
ported that have the ability to metabolize limonins. The use
of immobilized Arthrobacter globiformis cells at a favorable
pH (where both limonin D-ring lactone hydrolase and limo-
noate dehydrogenase of the bacteria are active) to convert
limonin to the nonbitter dehydro-derivative (61) is effective
in prevention of bitterness in orange jnice (Hasegawa et al,
1982; Maier, 1983).
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26
Tetraterpenes or Carotenoids

Introdnction Carotenoids are C40 polyolefinic metabolites derived

Biosynthesis from mevalonic acid. Almost all members of this group are
Fonnation of Geranylgeranyl Pyrophosphate acyclic or have chains that tenninate with one or two 6-
Fonnation of Prephytoene Pyrophosphate membered rings. All have the potential for a vast number of
Fonnation of Phytoenes geometric isomers, but, in practice, almost all have entirely E
Acyclic Carotenoids (trans) configurations; many carotenoids are coloted be-
Alicyclic Carotenoids cause of the extended conjugated systems they contain. The
Oxygenated Carotenoids stroctures for approximately 500 carotenoids are known, but
Site of Synthesis only about one-fourth of these are from plants (Britton,
Chemosystematic Studies 1983). The leaves of all green plants contain the same major
Carotenoids in Algae carotenoids: (3-carotene (usually 25-30% of the total) (1),
Cartenoids in Fungi lutein (about 45%) [(3R,3'R,6'R)-(3,E-carotene-3,3' -diol] (2),
Biological Activity violaxanthin [(3S,5R,6S,3'S,5'R, 6'S)-5,6,5',6'-diepoxy-
Carotenoids in Photosynthesis 5,6,5',6'-tetrahydro-(3,(3-carotene-3,3'-diol] (3), and neoxan-
Photoresponses in Plants thin [(3S,5R,6R,3'S,5'R, 6'S)-5',6'-epoxy-5,6,5',6'-tetra-
Carotenoids and Vision hydro-(3,(3-carotene-3,5,3'-triol] (4) (Young, 1993a, 1993b).
Development in animals Carotenoids also are found in fruits [e.g., Iycopene (5) (Fig.
Pigmentation in Animals 26.5) in tomatoes and capsanthin (6) in red pepper] and flow-
Pigmentation of Flowers and Fruits ers (often (3-carotene or Iycopene). (3-Carotene is the orange
Uses of Carotenoids pigment of carrots (Mann, 1987). Although usually in
Metabolites of Carotenoids smaller percentages, E-carotene [(6'R)-(3,E-carotene] (7) may
Plant Growth-Regulating Compounds occur in amounts up to 40% of the carotene fraction. The
Carotenoids Metabolites as Fungal Pheromones most widespread carotenoids are a- (7) and (3-carotene (1)
References (Fig. 26.1).
The properties and stroctures of tetraterpenes differ
markedly from those of the lower terpenes (Ramage, 1972).
Im'RODVcnOI'l Carotenoids (the major representatives of this class) are
mostly linear polyene systems. The high degree of unsatu-
Carotenoids, which occur in all plants, bacteria, and fungi, ration renders them both heat and light sensitive. These
are probably the most widely distributed of all natural pig- compounds are an experimentally demanding group of
ments; they are involved in many fundamental processes compounds with which to work (Britton, 1983; Ramage,
such as photosynthesis and mammalian vision. These highly 1972).. Methods for purification of carotenoids are similar
unsaturated lipids also serve as vegetative, floral, and fruit to those for other terpenoids, but, because of the highly
pigments in plants and as pigments in the feathers of birds, unsaturated nature of the compounds, special care must
outer parts of insects, as well as the skins of fish and other be taken (Britton, 1991). Care to avoid oxidation is most
animals (Britton, 1976, 1983; Buchecker, 1982; Kayser, important; extracts that contain chlorophyll must be han-
1982). dled with special care. The presence of chlorophyll often
 Tetraterpenes or Carotenoids 487

a-carotene (7)

J3~carotene (l)

HO
fucoxanthin (17)
~"'"""' OH

~4 o
HO capsanthin (6)

HO
""$0
..
C,.., ",

neoxanthin (4) OH
OH

lutein (2) OH

HO
violaxanthin (3)

Fig. 26.1. Common carotenoids.

leads to photoisomerization of carotenoids (Britton, 1991).
Chromatographic separations should be carried out under
reduced light. Most carotenoids also are sensitive to acid
(Britton and Goodwin, 1982, Britton and Young, 1993),
and most plant tissues are sufficiently acidic to isomerize
labile tetraterpenes. Reversed-phase high-performance liq-
uid chromatography (HPLC) is a useful method that averts
structural modification of most carotenoids. Particularly
common is the production of the furanoid derivatives (5,8-
epoxides) from carotenoids that contain 5,6-epoxide
groups. General chromatographic data for carotenoids have
been reviewed (Britton, 1991; Britton and Goodwin, 1982,
Britton and Young, 1993, Coscia, 1984; Young, 1993a,
1993b). The saponification of total extracts prior to isola-
tion or analysis of carotenoids is a common practice (Brit-
ton and Young, 1993).
Ultraviolet and visible spectroscopy have been important
for characterization of this group of compounds. Circular
dichroism also is of value for establishing the stereochemis-
try of many tetraterpenoids (Noack, 1982). Mass spectrome-
try (Budzikiewicz, 1982) has proven to be a useful technique
for elucidation of structures of carotenoids. However, nu-
clear magnetic resonance (NMR) is undoubtedly the most
powerful technique for the investigation of carotenoid struc-
tures (Britton, 1991; Britton and Young, 1993; Englert,
1982). In a high-field IH_ or I3C-NMR spectrum, signals
due to the olelfinic region of the carotenoid molecule are
resolved well, can be assigned, and their coupling relation-
488 Tetraterpenes or Carotenoids
ships identified, and the geometric configuration of the ca-
rotenoid determined (Britton and Young, 1993).
BIOSY1'lTIlESIS
Tetraterpenes or carotenoids are synthesized from mevalo-
nate precursors. Those involved in photosynthesis are syn-
thesized in the chloroplast, but the enzymes specific for
carotenoid biosynthesis are encoded in the nucleus, synthe-
sized in cytoplasmic ribosomes, and transported into the
chloroplast (Britton, 1993). Chloroplasts at different stages
in development seem to differ in their ability to synthesize
carotenoids autonomously from CO2 or by importation of
isopentenyl pyrophosphate (isopentenyl diphosphate) (Brit-
ton, 1993).
Isopentenyl pyrophosphate isomerase and geranylgeranyl
pyrophosphate synthase are particularly important in the bio-
synthesis of plastid terpenoids (carotenoids, chlorophylls,
plastoquinones, tocopherols, and phylloquinones) (Dogbo
and Camara, 1987). Development of cell-free systems have
been important for the study of biosynthesis of carotenoids
(Bramley, 1985). The general features of carotenoid biosyn-
thesis are similar in higher plants, algae, fungi, and bacteria.
Biosynthesis of the first carotenoid in the pathway, phytoene
(8), may be divided into two basic steps: (I) formation of
geranylgeranyl pyrophosphate (9) and (2) dimerization of
geranylgeranyl pyrophosphate to yield prephytoene pyro-
phosphate (10) followed by concomitant rearrangement to
phytoene (Dogbo and Camara, 1987; Poulter, 1990). Forma-
tion of further carotenoid products involves a series of reduc-
tion, oxygenation, and ring-closure steps.
Formation of Geranylgeranyl
Pyrophosphate
The enzymes of carotenoid biosynthesis have been iso-
lated from chromoplast stroma after osmotic shock of iso-
lated chromoplasts. Several steps of purification are required
to separate the desired activities from nonspecific phospha-
tases and prenyl pyrophosphate hydrolases. The initially iso-
lated enzyme complex has several other types of activity
(GPP synthase, FPP synthase, GGPP synthase, GGPp-gera-
nyl transferase, and phytoene synthase), and additional chro-
matographic steps are needed to resolve IPP isomerase and
GGPP synthase activity. Isopentenyl pyrophosphate iso-
merase (EC 5.3.3.2) from Capsicum chromoplasts is a mono-
meric protein with a molecular weight of 33,500. Geranyl-
geranyl pyrophosphate (GGPP) synthase from the same
source also displays dimethylallyl transferase (2.5 .1.1), gera-
nyl transferase (2.5.1.10), and farnesyl transferase (2.5.1.30)
activity (Britton, 1993; Dogbo and Camara, 1987). This di-
meric enzyme has a molecular weight of 74,000. The close
association of these two enzymes may provide a mechanism
for channeling IPP toward synthesis of GGPP. GGPP syn-
thase from this source is capable of using isopentenyl pyro-
phosphate (IPP), dimethylallyl pyrophosphate (DMAPP),
geranyl pyrophosphate (GPP), or farnesyl pyrophosphate
(FPP). C IO or C l5 prenyl derivatives do not appear to be
products, in agreement with former studies on GGPP syn-
thase from Cucurbita (see Chapter 22). Although GPP and
FPP are involved as intermediates, GGPP probably is the
first product to leave the active site (Dogbo and Camara,
1987) Data from affinity-labeling studies confirm that
DMAPP, GPP, and FPP are all bound at the same site on
the enzyme.
Formation of Frephytoene Pyrophosphate
The first step in the formation of prephytoene pyrophos-
phate (10) and phytoene (8) is the prenyl-transfer step, dur-
ing which C(I ') of one of the allylic substrates is bonded
to the C(2)-C(3) double bond of the other to produce a
cyclopropyIcarbinyl pyrophosphate with a Cl'-2-3 structure
(Fig. 26.2). In this manner, geranylgeranyl pyrophosphate
(9) yieldS prephytoene pyrophosphate (10) (Poulter, 1990).
In some instances, the ability to produce prephytoene py-
rophosphate (10) is closely linked to the production of phy-
toene (8) and appears to involve one enzyme with two activi-
ties (Britton, 1993; Dogbo et al., 1988). With an enzyme
isolated from Capsicum chromoplast preparations, biosyn-
thesis procedes via condensation of two molecules of gera-
nylgeranyl pyrophosphate (9) directly to phytoene (8)
(Dogbo et al., 1988). The enzyme phytoene synthase has
been purified to homogeneity; phytoene synthase from this
source is a monomer with a molecular weight of 47,500
(Dogbo et al., 1988).
Although the enzyme from Capsicum has both types of
activity, prephytoene pyrophosphate is an isolable product in
other situations. The conversion of GGPP (9) to prephytoene
pyrophosphate (10) has been demonstrated with a soluble
tomato plastid enzyme system and chloroplasts isolated from
Phaseolus vulgaris by nonaqueous methods (Spurgeon and
Porter, 1983). The only cofactor that appears to be required
is Mg2+ or Mn2+. There is no requirement for a reduced
pyridine nucleotide as exists for the formation of squalene.
Prephytoene pyrophosphate (10) appears to be the only isola-
ble intermediate involved in the process. This compound has
the same absolute stereochemistry as presqualene pyrophos-
phate.
Formation of Phytoenes
In the second step of phytoene formation, inorganic pyro-
phosphate is expelled and a proton is eliminated. Pyridine
nucleotide cofactors are not involved, as is the case in
triterpene biosynthesis (Fig. 26.3) (Poulter, 1990).
Both 15,15'-Z- (11) and 15,15'-E-phytoene (12) isomers
appear to be formed in vivo, with concomitant loss of one
I-pro-(S)-hydrogen [originally the 5-pro-(S) of MVA] from
each molecnle of GGPP (I5,15'-Z-phytoene) or one I-pro-
(R)-hydrogen (15,15'-E-phytoene) (Fig. 26.4) (Britton,
1993; Harrison, 1988; Poulter, 1990; Spurgeon and Porter,
1983).
 Tetraterpenes or Carotenoids 489

H
geranylgeranyl phyrophosphate (9)

PPOCH
H'"

rotation around bond

prephytoene pyrophosphate (10)

Fig. 26.2. Proposed mechanism for the conversion of GGPP to prephytoene pyrophosphate.

NADPH'~

Iycopersene (13)

E-15,15'-phytoene (12)

Z-15,15'-phytoene (11)

Fig. 26.3. Proposed mechanism for the conversion of prephytoene pyrophosphate to lycopersene, Z~phytoene, and E-phytoene (Poulter, 1990; adapted
and used with permission of the copyright owner, the American Chemical Society, Washington, DC).
490 Tetraterpenes or Carotenoids

HO\/ H,s;H
H01~~ R -----110>
: 3 4 5 OH opp

geranylgeranyl pyrophosphate ~
(SR)·[2-'''c,s.3H,Jm.valonic acid
"':= 14C

.;)!Y .
HO,e ,
o
\
3
3H 3H

'" 4 OK

3H
i H

Z-15,15'·phytoe•• (11)

E-15,15'·phyt.... (11)
t

Iycopene (5)

Fig. 26.4. Labeling patterns of band E-15,15'-phytoene and lycopene (Goodwin, 1973 and Williams et aI., 1967b; modified and used with pennission
of the copyright owner, the Biochemical Society, London).

It does not appear that Iycopersene (13), a tetraterpene
homologous to squalene, is an intennediate in tetraterpene
biosynthesis (Bramley, 1985). This compound does, how-
ever, occur in a number of organisms including carrot roots.
In most plants that have been studied, 15-Z-phytoene
(7,8,1l,12,7',8',1l',12'-octabydro-t!J,t!J-carotene) (11) is the
predominant form, although in some bacteria the 15-E form
(12) is most common (Spurgeon and Porter, 1983).
When (3R,S,5R)-[2- 14C,5- 3Htlmevalonate was incubated
with slices of tomato, the phytoene isolated shOWed a 3HJ 14C
ratio of 8: 8 (Fig. 26.4). These results indicate that there was
no loss of the 5R hydrogen of mevalonate (based on Fig.
26.4, formation of Z-phytoene occurred). However, in exper-
iments with [2_ 14C,5-3H2 ]mevalonate, the ratio was closer
to 14:8, instead of the 16:8 ratio expected, corresponding
to loss of two hydrogens. Thns, in the formation of Z-phy-
toene (11), both of the pro-(R) hydrogens of mevalonate are
retained, whereas the two pro-S hydrogens are lost (Fig. 26.3
and 26.4) (Spurgeon and Porter, 1983).
Acyclic carotenoids
Once formed, 15,15'-Z-phytoene (11) is desaturated to
produce Iycopene (5) via stereospecific removal of pairs of
hydrogens alternatively to the left and right of the central
triene system (Fig. 26.4) (Britton, 1993). The hydrogens re-
moved were originally the 5-pro-(R) and 2-pro-(S) hydro-
gens of MYA (Spurgeon and Porter, 1983). In higher plants,
evidence for the involvement of NADP+ and FAD has been
presented (Britton, 1983).
In tomatoes and other higher plants, formation of Iyco-
pene (5) from Z-phytoene (11) occurs via ,-carotene (16).
Z-phytoene (11) is converted to Z-phytufluene (14), E-
phytofluene (15), ,-carotene (16), neurosporene (17), and,
fmally, Iycopene (5) by extracts of tomatu fruit plastids
(Fig. 26.5) (Porter et al., 1984; Spurgeon and Porter, 1983).
The desaturase (and following cyclase) enzymes are
integral membrane proteins that can be solubilized by the
detergent CHAPS. Enzymatic activity is lost when the
enzymes are solubilized, but it is restored when reconstitu-
ted in proteoliposomes (Britton, 1993). In the first phase
of desaturation, the conversion of (15Z)-phytoene into
(15ZH-carotene occurred in the dark, with oxygen as an
essential requirement. The reaction was independent of
cofacturs such as NADP+ and NADPH. (15ZH-Carotene
could not be desaturated further, but when this compound
was isomerized by light, the isomeric mixture formed
underwent further desaturation to produce Iycopene, not
 Tetraterpenes or Carotenoids 491

as the all E fonn, but as the (7Z,9Z,7'Z,9'Z)-isomer, proly-
copene (14) (Fig. 26.6) (Britton, 1993). Part of the uncer-
tainty of products in many studies may arise from the
inability to distinguish isomers by chromatographic and
absorption spectral techniques.
In certain other plants (including other types of toma-
toes), prolycopene (14) is the main carotenoid produced.
The structures for a number of Z compounds related to
prolycopene have been resolved recently (Porter et aI.,
1984). The importance of these compounds has not been
resolved at present.
Alicyclic Carotenoids
Lycopene (5), a major pigment of tomatoes, is the final
acyclic carotenoid; subsequent cyclization gives Il- and 13-
carotenes (7 and 1). Three types of ring closure are shown
(Fig. 26.7) (Spurgeon and Porter, 1983). However, as many
other types of terpenoid closures now are known to occur
by ionic mechanisms, it is quite possible that a similar mech-
anism may prevail here as well.
In higher plants and algae, these desaturation reactions
and the subsequent cyclization reactions appear to be under
direct nuclear control, although the carotenoids of photo-
synthetic tissues are fonned in the chloroplast (Britton,
1993). In fruits, these changes occur in chromoplasts (Brit-
ton, 1983).
Several types of evidence indicate that the 13 ring (13-
ionone) does not arise by isomerization of the € ring (Il-
ionone) (Britton, 1993). Use of [2- 14C,2- 3H 2 1mevalonate
(Fig. 26.8) as substrate in carrot root slices indicates that
four hydrogens are lost frum carbon atoms that arise from
C-2 of mevalonate in the desaturation of phytoene (8) to
Iycopene (5). As the two types of rings (i.e., 13 and €)
arise independently, in subsequent steps one additional
tritium should be lost in the fonnation of the € ring and

HO,eP --
H H
O H H

OH
Opp

geranylgeranyl OPP (9)

mevalonic add

lopp

~;:H
~
I prephytoene OPP (10) ~

1
lycopersene(13)

15,15I~E·phytoene (12)
H H
IS,IS'-Z-phytoene (11)

(a) 15,lS'·Z-phytofluene (14)

Fig. 26.5. (continued)

492 Tetraterpenes or Carotenoids

IS,IS'-E-phytoOuene (15)

neurosporene (17)

!
'" "" '"
::,... ::,..
"" '" '"
lycopene (5)

j
"" "" '" ::,..
""
::,..

(b)

Fig. 26.5 (8 & b). Biogenesis of acyclic carotenoids (modified from Britton, 1993. used with pennission of the copyright owner. Chapman & Hall,
London).

none in the formation of the J3 ring. J3-Carotene should
have a 3H/'4C ratio of 12:8 compared to a value of 16:8
for phytoene. The expected value for a-carotene would
be 11: 8. In experimental work, these ratios were closely
approximated (Fig. 26.8) (Spurgeon and Porter, 1983).
Proposed pathways for the formation of a number of
alicyclic carotenes are summarized in Fig. 26.9 (Britton,
1993; Spurgeon and Porter, 1983).
The cyclases responsible for formation of cyclic carot-
enoids are integral membrane proteins, as are the desatura-
tion enzymes described above. The desaturation reactions
require oxygen, whereas the cyclase reactions require strictly
anaerobic conditions. All E-lycopene did not serve as a sub-
strate despite the fact that all the products were exclusively
all E-isomers. Cyclization was shown to proceed only with
the (7Z, 9Z, 7'Z, 9'Z)- and (7Z, 7'Z)-isomers. However, in

11 15
:::,.., :::,.., :::,..,
1Z IJ 14 15'

7'

prolycopene (14)
[(7Z,9Z,7'Z,9'Z}-lycopene]

Fig. 26.6. Prolycopene.

 Tetraterpenes or Carotenoids 493

Fig. 26.7. Ring closure of carotenoids and types of 6·membered alicyclic end rings (modified from Herbert, 1981; used with pennission of the
copyright owner, Chapman & Hall, London).

o HsH.
T }
H01~ll4 ~ •
5
OH
HR Hs Hs lHR
T
(4R)~[2~14C,4.lH]~mevalonate

N o HsH
TW.T"",}_T
H
H

}
.
1 •
HOzC 1 3 4 , -+-
I •

TT
• OH
3H 3H H H
H

l2~14C,2-3Hl]-mevalonate
~T
}
_=14c

T T
FIg. 26.8. Labeling patterns for biosynthesis of alicyclic rings (Goodwin and Williams, 1965 and Williams et al., 1967a; modified and used with
permission of the copyright owner, the Biochemical Society, London).
494 Telralerpenes or Carolenoids
15,15 ·Z·phytonuene (14) _ _
;r~~~~~,,~~~~~~~~~~~~~~;r,,~~
Fig. 26.9. Summary of biogenesis or alicyclic carotenes (Britton, 1993; modified and used with pennission of the copyright owner, Chapman & Hall,
London),
the green alga Scenedesmus, cyclization only occurred after
the light-catalyzed isomerization of prolycopene to the all
E-isomer (Britton, 1993).
Oxygenated Carotenoids
Oxygenated derivatives of carotenoids also are common
and widely distributed. These colored substances are known
collectively as xanthophylls. The formation of xanthophylls
involves an aerobic mechanism. (3-Carotene is converted ox-
idatively to lutein (2), zeaxanthin [(3R, 3'R)-(3,(3-carotene-
3,3'-diol] (15), and, finally, to violaxanthin (3) (Fig. 26.10)
(Britton, 1993). Labeling studies have shown that hydroxyla-
tions such as those involved in the conversion of zeaxanthin
and lutein are formed by the direct replacement of the hydro-
gen by OR (Britton, 1993).
Rearrangement of these compounds leads to metabolites
such as capsanthin [(3R, 3'S, 5'R)-3,3'-dihydroxy-(3,k-caro-
ten-6'-one] (6), a red pigment from peppers (Capsicum an·
nuum, Solanaceae). This compound may be derived from
rearrangement of an epoxide intermediate as shown (Fig.
26.10) (Riittimann, 1982). Capsanthin (6), capsorubrin (16),
and cryptocapsin are the major pigments of red peppers (Riit-
timann, 1982).
r p.carotene (1)
Site of Synthesis
Carotenoids are synthesized in the chloroplasts of plants,
but are under direct nuclear control (Britton, 1993; Young,
1993a). These pigments also appear to be synthesized in
tissues such as flower petals, roots, and fruits. Extracts of
tomato plastids have the ability to utilize IPP to produce
phyloene as well as other carotenoids.
CHEIIIOSYSTEl'IATIC STUDIES
Both carotenoids and xanthophylls have been found in all
leaf tissues examined. Cyclic carotenes and xanthophylls
from leaf tissues have both (3- and .-ring types. Only dicyclic
xanthophylls, and particularly those with C-3 or C-3', have
been found in the biosynthetic tissues of higher plants. Acy-
clic carotenoids normally are not present (Young, 1993a).
The same four m~or carotenoids, namely (3-carotene (I),
lutein (2), violaxanthin (3), and neoxanthin (4), have been
found as the major carotenoid constituents of leaf tissues of
all plants examined to date (Young, 1993a). Purple and green
phototrophic bacteria rarely contain any of the monocyclic

and dicyclic carotenoids found in plants, algae, and cyano-
bacteria (Britton, 1993).
Carotenoids in Algae
Although carotenoids have been of limited taxonomic
value in higher plants, data concerning the distribution of
these compounds have proven useful in studies of algal and
bacterial groups (Britton, 1983; Goodwin, 1971, Young,
1993a). Many algae differ from higher plants in the carot-
enoids found in their chloroplasts. Acetyienic carotenoids
are restricted to aquatic, mainly marine, animals and algae.
Fucoxanthin (17) (Fig. 26.1) (from Fucus) is a widespread
pigment in brown algae (Young, 1993a). j3-Carotene and
violaxanthin also are present in high amounts. The chloro-
plast content of green algae (Chlorophyta), however, is quite
similar to that of higher plants, suggesting a closer evolution-
ary link than between angiosperms and other groups of algae
f3-carotene (1)
~ OH
HO
(3R,3'R).zeaxanthin (15)
HO
HO
V. ,
o :::::-...:::-..
(3S,5R,3'S,5'R)·capsorubin (1:
OH
HO
capsanthin (6)
Fig. 26.10. Biogenesis of oxygenated carotenoids or xanthophylls modified from (Milborrow et al., 1982 and data from Camara and Moneger, 1981.
Tetraterpenes or Carotenoids 495
(Britton, 1983; Young, 1993a). Many members of the Chlo-
rophyceae possess the ability to accumulate secondary carot-
enoids in response to stress conditions. The pigment compo-
sition of the Euglenophyceae more closely resembles that
of the chromophyte algae than those of the Chlorophyta
(Young, 1993a). Red algae possess both j3-carotene (1), Ci-
carotene (7), and oxygenated derivates, such as lutein (2)
and zeaxanthin (15) (Young, 1993a).
In some instances, carotenoids are present outside the
chloroplast. The pigment of the light-sensitive "eye-spot"
of Euglena and of reproductive areas in certain algae (such as
Ulva) is comprised partially of carotenoids (Britton, 1983).
Carotenoids in Fungi
Carotenoids are found widely, but not universally, aroong
fungi. However, most fungi synthesize a very limited spec-
trum of these compounds. The yellow pigment of the edible
OH
lutein (2)
OH
violaxanthin (3)
OH
~ ~
OH
-A-
'" 0'
496 Tetraterpenes or Carotenoids
mushroom Cantharellus cibarius is an unusual carotenoid
(Britton, 1983).
BIOLOGICAL ACTIVITY
Most carotenoids are colored and absorb light in the visible
range of the spectrum. The specific wavelength of absorption
is a function of the structure, in particular, the number and
arrangement of double bonds and oxygenated substituents,
but also the solvent and other factors (Britton, 1983). Most
carotenoids are yellow to orange (sometimes red) when iso-
lated.
Carotenoids in Photosynthesis
As mentioned above, the leaves of all green plants contain
the same major carotenoids: J3-carotene (1), lutein (2), viola-
xanthin (3), and neoxanthin (4). Smaller amounts of other
compounds are often present. These compounds are located
in the chloroplast grana as chromoproteins (Britton, 1983;
Britton et al., 1982).
Each photosystem consists of two multiprotein binding
complexes, namely the core complex, or reaction center, and
the antenna pigments organized into light-harvesting com-
plexes. The pigment content and composition of photosys-
tern 11 is not as well documented as that for photosystem I,
largely because there are still difficulties in obtaining clean
and relatively uncontaminated preparations of the individual
complexes. Photosystem I from higher plants contains a core
complex that is enriched in J3-carotene and chlorophyll a.
"'" "'" "'" "'" ""
violaxanlhln (3)
HO
anderaxanthln (18)
"'" "'" "'" "'" "" "'" "'"
(3R,3'R)·......lhin (15)
Fig. 26.11. The "xanthophyll cycle" (modified from Demmig-Adams and Adams, 1993; used with permission of the copyright owner, Chapman &
Hall. London).
The light-harvesting complex of photosystem I has been iso-
lated and shown to contain 80-120 molecules of chlorophyll
(Young, 1993b).
The light-harvesting complexes, particularly those associ-
ated with photosystem 11, are rich in both chlorophylls and
xanthophylls (Young, 1993b). Of the approximately 250
chlorophyll molecules per P-680 in photosystem II, it has
been estimated that about 80% are found in the chlorophyll
alb-xanthophyll complexes of the light-harvesting complex
II (Young, 1993b).
Carotenes are essential accessory pigments in photosyn-
thesis, but their exact role is not known. In in vitro experi-
ments, carotenoids do not fluoresce, but they are able to
sensitize the fluorescence of chlorophyll in green plants
(Britton, 1983).
Carotenoids also protect the cell from damage due to pho-
tooxidation catalyzed by light-absorbing pigments such as
chlorophylls. This effect was noted in comparisons of nor-
mal carotenoid-containing bacteria with mutants in which
the carotenoids are replaced by the more saturated and color-
less carotenoid, phytoene (8) (Ramage, 1972). Many bleach-
ing herbicides inbibit carotenoid biosynthesis; the plants
usually die because of photooxidation (Britton, 1991).
Three carotenoids, violaxanthin (3), antheraxanthin (18),
and zeaxanthin (15), undergo rapid, light-induced changes
in concentration. These interconversions sometimes are
called the "xanthophyll cycle" (Fig. 26.11) (Demmig-
Adams and Adams, 1993). The content of violaxanthin in
leaves can be reversibly altered in plants by exposure to
light. In the presence of light, violaxanthin is deepoxidized
to produce first antheraxanthin and then zeaxanthin. This
Jr
OH
""
Jr

plant <arotenoids t
stored as palmitate and stearate
~~;:,...
U~'''CH'OH b~';:,...
~ ;:,...
I -.
isomerase
r
retinol (vitamin A) (19)
I"'·'·""no' ........""'"
~~~ all.E·retinai (20)
~t
opsin + nerve impulse
Fig. 26.12. Chemistry of visual pigments.
reaction is catalyzed by violaxanthin deepoxidase. In dark-
ness, violaxanthin again accumulates. This reaction is cata-
lyzed by zeaxanthin epoxidase. The enzymes responsible are
found in the thylakoid membranes of the chloroplast. The
degree to which violaxanthin is converted into zeaxanthin
varies with the light level or photon flux density (Demmig-
Adams and Adams, 1993). However, zeaxanthin can ouly
increase in excessive light until the violaxanthin pool is ex-
hausted. The maximal degree of conversion of violaxanthin
to zeaxanthin typically is reached at photon flux densities
exceeding those required for normal growth of the plant. In
full sun at noon, violaxanthin (3) represented ouly about
5-12% of the total xanthophyll cycle pool. Shade leaves
tend to form and accumulate zeaxanthin (15) at photon flux
densities much below those that would lead to formation of
zeaxanthin in a sun leaf. The deepoxidation reaction, in ef-
fect, leads to thermal dissipation of excess solar energy. The
excess is removed in a safe and controllable fashion that
protects the photosynthetic apparatus against the adverse ef-
fects of excessive light (Demmig-Adams and Adams, 1993).
The "xanthophyll cycle" has been found in higher plants,
ferns, mosses, and both green and brown algae.
Photoresponses in Plants
Carotenoids also may be concerned with other functions,
for example, photoresponses such as phototropism in fungi
Tetraterpenes or Carotenoids 497
t
stored as palmitate and stearate
I
17
! l1.z·RII"~
ll-Z-retinol CRlOR
. "......""'..
CHO
.
protem·(CH,).·NH
.#
rhodopsin (21)
and higher plants, or phototaxis in algae (Spurgeon and Por-
ter, 1980).
Carotenoids and Vision
Animals require vitamin A (retinol) (19) or a carotenoid
precursor for normal growth and vision (Liu, 1982). An early
symptom of vitamin deficiency is a decreased ability to see
in dim light. Vitamin A aldehyde, or lI-Z-retinal (20), has
an essential role in vision (Fig. 26.12); this pigment is the
chromophore of the visual pigment rhodopsin (Buck et al.,
1991). lI-Z-Retinal is formed in the intestinal mucosa by
oxidative cleavage of (3-carotene, a process catalyzed by the
enzyme (3-carotene dioxygenase (Britton, 1983). The lI-Z
isomer of retinal combines with a protein, opsin, via a Schiff-
base linkage to form rhodopsin (21). Rhodopsin is located
in the rods and cones of the retina, and when exposed to
light, geometric isomerism occurs, producing all E-retinal
with concomitant release of the protein moiety. This confor-
mational change is somehow translated into a nerve impulse
and transmitted to the brain. lI-Z-Retinal is regenerated in
a further sequence of reactions and the net result is vision
(Britton, 1983; Buck et al., 1991; Liu, 1982).
Development in Animals
Carotenoids appear to playa fundamental role in develop-
ment in animals. For example, all E-retinoic acid (22) ap-
498 Tetraterpenes or Carotenoids
14-hydroxy-4,1l-retro-retinol (24)
retinol (vitamin A) (23)
o
canthaxanthin (25)
Fig. 26.13. Biologically active carotenoids and carotenoid derivatives.
pears to be a natural signaling substance involved in limb
pattern formation in chicks (Thaller and Eichele, 1987)_ Reti-
nol (23) is essential for the growth of a variety of cell types in
culture. A retinol derivative, 14-hydroxy-4,14-retro-retinol
(24), has growth-promoting properties in animal cells (Fig.
26.13) (Buck et aI., 1991).
Pigmentation in Animals
The colors of the yolks of eggs of birds, many bird feath-
ers, the skin of fishes, and the pigments of many animals
other than mammals may be directly attributed to the pres-
ence of carotenoids (Buchecker, 1982; Castillo, 1982;
Kayser, 1982; Yamaguchi, 1982). The pink color offlamin-
gos is produced by ketocarotenoids, mainly canthaxanthin
(25) (Britton, 1983).
Many of the colors used for aposematic labeling by ani-
mals (bright reds, oranges, and yellows) are produced by
carotenoid pigments (Rothschild, 1975, 1978). These com-
pounds ultimately arise from plants (or from symbiotic bac-
teria?), as animals cannot synthesize carotenoids.
Complexes of carotenoids with proteins in animals often
are responsible for pigmentation, especially in instances
where colors other than yellow or orange are involved. This
is especially true of purple, green, blue, and black pigments
(Britton, 1983; Britton et aI., 1982). Although the precise
manner in which these interactions occurs is not understood,
absorption maxima of the complexes are different from those
of the carotenoids themselves. The blue color of lobsters,
for example, is composed of crustacyanin and a protein. Pec-
tonoxanthin (alloxanthin) (26) and a similar protein complex
is responsible for the color of the giant scallop, Pecten max-
E-retinoic acid (22)
o
imus (Fig. 26.14) (Goodwin, 1983). Complexes of this type
also are partly responsible for the colors of bird feathers and
other animal pigments. These complexes are readily dena-
tured by heat. Many of the carotenoids of invertebrates ap-
pear to be rare.
Pigmentation of flowers and Fruits
The background pigmentation of the aboveground parts of
most plants is green. In the course of evolution, selection also
has occurred for colors other than green in more specialized
plant parts, especially those involved in reproduction. At the
same time, selection for animal visual systems capable of vis-
ualizing these flowers, fruits, pollen, and other plant parts
with modified colors has occurred. In general, the vision of
birds and mammals is especially sensitive to reds, yellows,
and blues. The vision of many insects differs and, although
insects often are sensitive to colors visible to other animals,
these organisms are also sensitive to portions of the ultraviolet
spectrum (Britton, 1983). These pigments serve as syno-
mones or kairomones that are involved in attraction of the ani-
mals to plants. These coloration patterns also may serve as
warning signals for would-be hervivores or predators.
The major pigments of plants often consist of anthocya-
nins, other flavonoids (see Chapter 11), chlorophyll, and
a complement of carotenoids. It is not unusual to observe
instances where all three types of pigments are implicated,
even in the same plant or plant structure.
The yellow coloration of flowers may be produced by a
number of substances, but carotenoids frequently are impor-
tant among them (Fig. 26.14). Almost all yellow and lemon-
yellow flowers contain xanthophylls, such as zeaxanthin (15)

and its 5,8-epoxides auroxanthin and f1avoxanthin (27), as
major pigments. Deep-orange flowers may contain large
amounts of J3-carotene (1) or Iycopene (5). The carotenoids
in petals are concentrated in the chromoplasts and may be
present in bound form linked to protein or esterified with fatry
acids (Britton, 1983, 1991; Harborne, 1982). These pigments,
accompanying pigments of other chemical classes (especially
f1avonoids), and the associated morphology of flowers are all
important in the effective reproduction of plants.
The immature fruits of most plants are green. These green
fruits usually contain the same pigments as leaves of the
plant on which they occur. As the fruits mature, the numher
of chloroplasts and the amount of pigmentation increases.
Chloroplasts are converted to chromoplasts and the chloro-
phylls gradually disappear. The major pigments of tomatoes
are lycopene (5) and J3-carotene (1); that of watermelon is
phytoene (8). Carotenoids constitute the most abundant pig-
ments of Pyracantha (Rosaceae), Sambucus, Citrullus vul-
garis, Citrus, Taxus, Rosa, Cotoneaster, Capsicum, and
many other fruits.
USES OF CAKOTEI'IOmS
Carotenoids, especially J3-carotene (I), often have heen used
for coloring food products. This is especially common in
such fatry foods as margarine. Bixa orellana, achiote or an-
croeein (29)
gI.cosyl.O·gI.cosyl·O,C
Iycopen. (5)
HO
pectenoxanthin (26)
(alloxanthin)
HO
Fig. 26.14. Carotenoid pigments.
Tetraterpenes or Carotenoids 499
natto, has been used as a food colorant and flavoring in Latin
America for generations, a practice now common in most
tropical areas of the world. The seeds of this plant contain
bixin (31), the methyl ester of 6,6'·diapocarotenoic acid. In
the Iberian peninsula, the use of Crocus sativus (saffron,
Iridaceae) as a food coloring material is widespread. Some
of the yellow pigments of this plant, such as crocein (29),
also are carotenoids (Rothschild, 1975). Many carotenoids
(e.g., J3-carotene) are antioxidants. This property has led to
the suggestion that they are important in the diet and can
afford protection against some forms of cancer and other
diseases (Britton, 1991).
JllETABOLITES OF CAKOTEI'IOmS
Many compounds with fewer than 40 carbon atoms, but with
carotenoid·like structures, are found in nature. Synthesis of
these compounds, sometimes called apocarotenoids, appears
to occur mainly by catabolism of carotenoids (Parry and
Horgan, 1991). Apocarotenoids in the range of C,-C[3 are
found in plant essential oils, but others, ranging up to C30
compounds, are essentially nonvolatile. However, knowl-
edge of the biochemistry of carotenoid metabolism is limited
(parry and Horgan, 1991). In vitro, photuoxidation of carot-
~·carotene (1)
CO,.gI....yl.()..gl.c..yl
DRvoxanthin (27)
500 Tetraterpenes or Carotenoids

~'"~
trixagol (40) jhanic acid (41)

CPu (42)
o
~~
,
'::;0

(43)
o -- HO
~

OH

3-hydroxy-5,6-epoxy-5,6-dihydro-J}-ionol (30)

3-oxoactinidol (31) p-damascenone (33) 1-(2,3,6-trimethylphenyl)-but-2-ene-l-one (32)

cI
megastigma-5,8(E)-dien-4-one (34) megastigma-5.7(E)-9-trien-4-one (35) (36)

~
"".,..
H
~ '.
o ""'"'
(37) (38) (39)

Fig. 26.15. Metabolites of carotenoids.

enoids produces a range of C9 -C 15 products similar to those
found in plants, but it is not known how the process occurs
in vivo.
Some carotenoid metabolites apparently arise during the
processing of plant material [e.g., (3S, SR, 6S)-3-hydroxy-
S,6-epoxy-S,6-dihydro-j3-ionol (30), 3-oxoactinidiol (31),
and 1-(2,3,6-trimethylphenyl)-but-2-ene-I-one (32)] are
formed during curing of tobacco (Fig. 26.IS). These com-
pounds are related to j3-darnascenone (33) and the aromatic
carotenoids.
Megastigma-S,8(E)-dien-4-one (34) has been obtained
from Virginia tobacco, from passion fruit, and, along with
megastigma-S,7(E),9-trien-4-one (35), from Osmanthus ab-
solute (an oil used in perfumery). The passion fruit, Pas-
siflora edulis, has also afforded two other related compounds
(36) and (37) and two further edulan derivatives (38) and
(39).
The structures of two carotenoid-like diterpenoids, trixa-
gal (40) from Bellardia trixago (Scrophulariaceae) and
jhanic acid (41) from Eupatorium jhanii, have been deter-
mined. The defensive secretions of two species of termites
contain (42) and (43).
PLAl'IT GROWTH RBGULATING COMPOUNDS
(+ )-(S)-Abscisic acid (44) is involved in a number of hor-
monal roles in plants (Fig. 26.16) (Milborrow, 1983). This
plant growth-regulating compound, probably found in all
higher plants, acts as a growth inhibitor and is involved in
bud and seed dormancy. (+ )-(S)-Abscisic acid is a potent
effector of stomatal closure. Abscisic acid also is linked to
water stress resistance in plants. To date, the presence of
abscisic acid has not been confirmed in bryophytes (Milbor-
row and Netting, 1991).
Although abscisic acid is synthesized as a sesquiterpene
 Tetraterpenes or Carotenoids 501

in several fungi (e.g., Cereospora rosicola), this apparent
sesquiterpene is derived by modification of carotenoids in
higher plants (Willows and Milborrow, 1989). The syn-
thetic compound fluridone inhibits carotenoid metabolism
at the stage of phytoene dehydrogenase (Parry and Horgan,
1991); treatment of maize seedlings with this inhibitor
strongly inhibits formation of abscisic acid (Moore and
Smith, 1984). The stereochemistry of abscisic acid pro-
duced by either process is identical (Willows and Milbor-
row, 1989).
The most likely precursors of abscisic acid (44) are 9'-
Z-violaxanthin (45) and 9-Z-neoxanthin (46). E-Violaxan-
thin (3) is converted to 9'-Z-neoxanthin in fluridone-treated
etiolated plants of Lyeopersieon and Phaseolus seedlings
following exposure to light (Parry and Horgan, 1991). Cleav-
age of these xanthophylls across the 11,12- (11',12'-) double
bond may produce xanthoxin, which is readily converted to
abscisic acid by plant tissues. Xanthoxin (47) serves as a
source of abscisic acid in tomato and wheat. The epoxide
oxygen atom becomes the tertiary hydroxyl oxygen atom of
abscisic acid.
Abscisic acid and similar sesquiterpenoid compounds,
such as phaseic acid (48), xanthoxin (47), and E-farnesol,
are capable of initiating stomatal closure in plants, a process
involved in drought resistance (Fig. 26.16) (Harborne, 1982;
Milborrow and Netting, 1991; Varner and Ho, 1976).
carotenoids l'IetaboliUes as Fungal
Pheromones
Compounds such as trisporic acids serve as pheromonal
substances in the reproduction of fungi of the order Mucor-
ales (Zygomycetes) (Fig. 26.17). The principal genera in-
volved are Mucor, Phyeomyees, and Blakeslea (Mascaren-
has, 1978). The same pheromones apparently initiate sexual
development in all mucoraceous fungi; furthermore, this pro-
cess appears to be more complex than originally envisioned
(Jaenicke, 1991; Miller and Sutter, 1984; Sutter and Whi-
taker, 1981).
The mating type of a heterothallic strain of these fungi is
not apparent when the mycelium is growing vegetatively or
during asexual reproduction. However, when adjacent colo-
nies of opposite mating types grow together and nutrient lev-
els are adjusted to modify purely vegetative growth, zygo-

~,
CO,HO

(+)·(S)-absclsie acid (44)

MM o
"'"
OH

phasele acid (48)

~
CO,HHO

xanthonin (47)
0"'" CHO

9'·Z-violaxanthin (46)

OH

~C~
~OH
9'·Z_neoxanthin (45)

/~
HO

X~~CHO ~O'H
OH
"'" ~- "'"
OH ~ -. "'" OH ~
HoU~l 0
Q CHO
0

xanthonin (50) abscisic acid (44)

Fig. 26.16. Probable biosynthesis of abscisic acid (modified from Parry and Horgan. 1991; used with pennission of the copyright owner, Elsevier
Science Ltd.. The Boulevard, Langard Lane. Kidlington OXS 1GB. UK).
502 Tetraterpenes or Carotenoids
phores are produced. These are well developed in Mucor, the
organism usually studied. Zygophores are formed even when
the two mating types are of different species. The zygophores
are recognizable because they show an increased level of ca-
rotenoid pigmentation. After contact occurs, septa form, and
the nuclei from the ( + ) and ( - ) type undergo sexual combi-
nation (Mascarenhas, 1978). In addition to the accumulation
of j3-carotene, mixed cultures also produce trisporic acids
(Fig. 26.18) that mediate sexual reproduction in the Mucor-
ales. The necessary complement of trisporic acids is not pro-
duced by single strains of either mating type or by other heter-
othallic species. Some apparently cooperative mechanism is
involved (Bu'Lock, 1983; Mascarenhas, 1978).
Trisporic acids are formed from j3-carotene (1) via retinal
(20) with further loss of two carbon atoms. As these com-
pounds induce additional carotenoid biosynthesis, biosyn-
thesis of these compounds is self-amplifying. Yields of
trisporic acids in mixed cultures (+ and -) are typically
200-1000 ",g/m!.
(+ )-Cultures of Phycomyces blakesleeanus make a mix-
trisporic acid B (49)
o
trisporol B
trisporol C
o H
OH
methyl trisporate C
Fig. 26.17.
ture of trisporate pheromones: the methyl esters of trisporic
acid B (49), trisporic acid C (50), and trisporic acid E, as
well as the corresponding 4-dihydro-derivatives of these
compounds (such as 51) (Sutter, 1986; Sutter and Whitaker,
1981). These mating-type-specific pheromones induced the
formation of zygophores in (- )-cultures of both Phyco-
myces blakesleeanus and Mucor mucedo. (- )-Cultures of
Phycomyces blakesleeanus are at least 100-fold more effec-
tive than ( + )-cultures in converting the methyl esters into
trisporic acid C (Miller and Sutter, 1984; Sutter, 1986; Sutter
and Whitaker, 1981). However, trisporic acids are inactive in
(- )-cultures. Trisporin (52) [with the pro-(S)-methyl intact]
and trisporol (53) [with the pro-(S)-methyl converted to a
carbinol group] are ( - )-pheromones [i.e., produced by ( - )-
cultures] (Jaenicke, 1991; Sutter and Whitaker, 1981). Both
( + )- and ( - )-cultures oxidize the 4-hydroxy to a carbonyl
group, apparently by the same enzyme. This reaction may
be important in (+ )-cultures to avoid self-stimulation by
compounds capable of inducing formation of zygospores
(Jaenicke, 1991).
~H/ CO,H
.0
:? ......" OH
trisporic acid C (SO)
o
trisporin C
~'
trisporin B
OH
H
OH
methyl4·dihydrotrisporate C (51)
Trisporic acid and related metabolites.
 Tetraterpenes or Carotenoids 503

o
p·carotene (1) --+

4-dihydrotrisporin
~O
OR /

~"
OR
4·dlhydrotrisporol !
(+) OR
trisporol (53)

~" __------------~~~~O
metbyl4-dihydrotrisporate

~Co~O~--------+-----~
I'·'
o

o
trisporic acid
Fig. 26.18. Reactions in the fonnation of trisporic acids (Sutter and Whitaker, 1981; modified and used with pennission of the authors).

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Wn..LOWS, R. D. and B. V. Mn..BORROW, The stereochemistry of
the hydrogen atoms at C-5' of abscisic acid, Phytochemistry.
28, 2641-2642 (1989).
Tetraterpenes or Carotenoids 505
YAMAGUCHI, M., Carotenoids in sponges, in Carotenoid Chemis-
try and Biochemistry (G. Britton and T. W. Goodwin, eds.),
225-235, Pergamon, Oxford, 1982.
YOUNG, A. J. Occurrence and distribution of carotenoids in
photosynthetic systems, in Carotenoids in Photosynthesis (A.
Young and G. Britton, eds.), 16-71. Chapman & Hall, Lon-
don, 1993a.
YOUNG, A. 1. Carotenoids in pigment-protein complexes, in
Carotenoids in Photosynthesis (A. Young and G. Britton,
eds.), 72-95, Chapman & Hall, London, 1993b.
27
Introduction to Alkaloids
Introduction
What Is an Alkaloid?
Isolation of Alkaloids
Biosynthetic Origin of Alkaloids
Some General Reactions Involved in the Formation of
Alkaloids
Distribution of Alkaloids
Biological Activity
Biological Activity of Alkaloids in Plants
Biological Activity of Alkaloids in Animals
Alkaloids as Allomones and Kairomones
Uses of Alkaloids by Man
References
Il'ITKODVCTION
Although plants containing alkaloids have been used by man
for at least 3000 years as medicines, teas, and potions (Cor-
dell, 1978), the compounds responsible for activity were not
isolated and characterized until the 19th century. Many
proved to be challenging chemical problems and the struc-
tures were resolved only in recent years. At present, there
are at least 10,000 characterized alkaloids (Dalton, 1991;
Wink, 1993). The exact number is difficult to estimate, be-
cause many alkaloids listed in compendia are not naturally
occurring. Based on the NAPRALERT Database, almost
16,000 alkaloids have been reported from plant, animal, and
marine sources (Verpoorte et aI., 1991). About 20-30% of
higher plants accumulate alkaloids. Perhaps 60-70% of spe-
cies of the Solanaceae and Apocynaceae contain alkaloids
(Hartmann, 1991; Verpoorte et al., 1991; Wink, 1993).
Because of their importance, many attempts have been
made to produce alkaloids in plant tissue culture. About 30
alkaloids account for most commercial interest, primarily as
medicines, flavorings, or poisons (Verpoorte et al., 1991).
Approximately 300-500 metric tons of quinine and quini-
506
dine and about 3600 kg of ajmalacine are produced annually.
Many of these alkaloids come from trees that require several
years for growth and production of alkaloids; some are ex-
tremely expensive. For example, vincristine from Catharan-
thus roseus has a value of about $22,000 per gram (Ver-
poorte et aI., 1991). To date, however, attempts to produce
alkaloids by biotechnological methods usually have not pro-
vided sufficient quantities of alkaloids to be economically
useful. Berberine is the alkaloid closest to industrial-scale
production, but uses for the pure compound are limited. The
prospects for sanguinarine perhaps are better. Nonetheless,
there is a need for studies leading to insight into the regula-
tion of secondary metabolism in order to produce levels of
alkaloids necessary for industrial processes. On the other
hand, cell cultures provide an excellent system for studying
biosynthesis (Verpoorte et aI., 1991).
The nuclear magnetic resonance (NMR) spectroscopy of
most major groups of alkaloids and the determination of
alkaloid structores by spectral methods such as NMR and
mass spectroscopy (MS) have been reviewed (Crabb, 1982;
Highet and Wheeler, 1985). Many chromatographic tech-
niques for alkaloids have been surveyed (Baerheim Svend-
sen and Verpoorte, 1983; Hashimoto et al., 1988; Verpoorte
and Baerheim Svendsen, 1984).
Wbat Is an Alkaloid?
Probably the ouly single character that distinguishes all
alkaloids is that they have nitrogen. In general, this nitrogen
comes from amino acids, is incorporated into a heterocyclic
ring, and is basic. Pelletier (1983) defined an alkaloid as a
cyclic compound containing nitrogen in a negative oxidation
state, which is of limited distribution among living organ-
isms. Some authors accept a series of more narrowly defined
groups, based on biosynthetic origin (Hegnauer, 1988). Al-
kaloids almost always have physiological activity in animals,
although some have limited effects (e.g., betalain pigments).

Alkaloids are derived from many biosynthetic pathways, in-
cluding those of amino acid, polyketide, shikimic acid, ace-
tate, and terpenoid metabolism. In this book, a broad per-
spective is adopted; simple amines, nitrogenous bases of
terpenoid origin, neutral compounds such as colchicine, and
purines are all considered to be alkaloids. Many alkaloids are
poisonous to mammals and a large number are medicinally
useful.
Many of the topics briefly mentioned in this introductory
chapter will be discussed in more detail in subsequent chap-
ters.
Isolation of Alkaloids
The basic properties of alkaloids simplify isolation of
these compounds as a group, although separation of individ-
ual compounds from mixtures of alkaloids may be difficult
(Hartmann, 1991; Waterman, 1993). Alkaloids generally are
extracted with nonpolar solvents such as chloroform, which
is, in turn, extracted with an acidic solvent. This acidic liquid
is then made basic and reextracted with a nonpolar solvent
to yield a mixture of free alkaloids. However, some alkaloids
occur as nonbasic forms such as quaternary amines or as N-
oxides. N-Oxides must be reduced to the corresponding
bases before they can be extracted in acid. There are many
color and precipitation reactions for the detection of alka-
loids (Waterman, 1993). Most of these are of value for the
detection of alkaloids as a group, but they do not permit
identification of particular compounds. Some of these re-
agents, such as those that form "Reinecke salts," permit the
investigator to isolate the precipitate and regenerate alka-
loids. The preparation of many alkaloid testing reagents and
wet chemical methods is outlined (Cordell, 1978, 1981;
Cromwell, 1955).
Biosyntbetic Orlgln of Alkaloids
Numerous biosynthetic studies of alkaloids have been
published since the seminal article by Robinson (1917) pre-
CH,NH,
I
fH,NH,
fH, fH,
~H, fH,
~HNH, fH,
CO,H
fHNH, nicotinic acid
ornithine
CO,H
lysine
(()X
I I
~
~ NH,
CO'H
anthranilic acid
NH
tryptophan
Fig. 27.1. Amino acids commonly involved in the fonnation of alkaloids (Geissman and Crout, 1969),
Introduction to Alkaloids 507
dicting the general direction for approach to these nitrogen-
ous secondary metabolites.
Most alkaloids are derived biosynthetically from orni-
thine, lysine, nicotinic acid, anthranilic acid, phenylalanine,
tyrosine, and tryptophan (Fig. 27.1) (Leete, 1983). In some
groups, however, the source of the nitrogen is not from an
amino acid.
Feeding studies of labeled precursors for the study of
alkaloids have been summarized and reviewed (Leete,
1983).
Some General Reactions Involved in tbe
Formation of Alkaloids
Certain chemical reactions are common to the formation
of many types of alkaloids (Geissman and Crout, 1969).
Among these are decarboxylation, Schiff-base formation,
Mannich-base condensation, and imino-aldol-type conden-
sations.
Schiff-base formation may occur between any amine and
carbonyl compound to yield an imine system (Fig. 27.2a).
In the Manuich condensation, a C-C-N system is gener-
ated by the addition of a carbanion to the Schiff base formed
by condensation of a ketone or aldehyde with an amine. Both
primary and secondary amines may participate (Fig. 27.2b).
Charged intermediates produced by the involvement of sec-
ondary amines facilitate the reaction by increasing the elec-
tron deficiency at the carbon atom which is subject to attack
by the carbanion species. As Manuich condensations occur
best at about pH 6-7, appreciable amounts of the protonated
Schiff base and the attacking anionic species can exist
(Geissman and Crout, 1969).
Aldol and aldol-like condensations between compounds
containing imino groups also occur frequently. This enamine
variation of the aldol-type reaction may be illustrated by the
formation of tetrahydroanabasine, as in Fig. 27.2c.
In addition to these reactions, several other common or-
ganic chemical conversions occur. Hydrogenation of imino
~CO'H
V NH,
phenylalanine
~CO'H
(X
7'1
CO'H
HO
~ NH,
~ NH,
tyrosine
r=rTCO,H
HN~N NH,
histidine
588 Introduction to Alkaloids

a) :::e=o
" ,
b) -CH +
+ HlN-R

C=O
--
H,O

/' /'

--
with 8 primary amine
/ R-Nlt-C-C
//
R-NH, + O=C"
\\

--
with a secondary amine

R"NH+ ./ OH·
R/ O=C,

H
-';I:(;H-CH,- _ _ -NH-cr-cH, -

o o
-CH"CH=N- -CH-CII=N-

~ cg:.....,B~
c)

N N+

0-0
4,l-piperldeine

G,oH NH
N
tetrahydroanabaslne

0 - -- 0
d)

-2H+
·20 0
N
-2B+
·20
N
-2H+
--+
·20
-2H+
0 N
e) ::::C=N- ~ 'CH-NH- """-
/CH-NH-
~ ./
'C=N-
+20 ./

I) -N=C-CH- -NH-C=C--
I I I I o
OH [0]" [0]
g) :::::~-CH- - /N-CH,- -
" N-C-II amide
./
carbinolamine

Fig. 27.2. Some general reactions involved in the fonnation of alkaloids (Geissman and Crout, 1969).

functions is found commonly (Fig. 27.2d). The reverse of
this reaction (i.e., dehydrogenation of saturated amines) is
also observed (Fig. 27.2d). This process may continue sev-
eral times and, in ring systems, may produce aromatic com-
pounds (Fig. 27.2e).
Isomerization of an imino to an a,f3-unsaturated amino
function also occurs (Fig. 27.2f). This isomerization occurs
in the mechanism postulated for the conversion of ~ '-piper-
ideine into the tetrahydroanabasine above (Fig. 27.2c).
Oxidation may occur at an activated position adjacent to
nitrogen. The products usually are carbinolamines or amides
(Fig. 27.2g).
a-Amino acids are converted to the corresponding a-keto
acids by reaction with one form of vitamin B6 , pyridoxal-
5'-phosphate, a coenzyme that is of fundamental importance
in amino acid metabolism (Fig. 27.3). This compound exists
in two biologically active forms, pyridoxal-5'-phosphate and
pyridoxamine-5-phosphate (Fig. 27.3a). Reactivation of the
coenzyme is effected by a simple reversal of the sequence
called transamination. In other instances, a-keto acids are
converted into a-amino acids (Geissman and Crout, 1969).
The reaction of amino acids to produce keto acids with flavin
adenine dinucleotide (FAD), which occurs in animals and
microorganisms, also may be important in the formation of
alkaloids (Figure 27.3b).
Decarboxylation and transamination proceed via the in-
termediacy of an amino acid-pyridoxal phosphate complex.
Pyridoxal phosphate is related to vitamin B6 and is of pivotal
importance in amino acid metabolism. This cofactor occurs
in two forms: pyridoxal-5'-phosphate (aldehyde form) and
pyridoxamine (amine form), which mediate a reversible in-
terconversion of a-amino acid and a-keto acids via a Schiff-
 Introduction 10 Alkaloids 509

a)

pyridoxal pyridoxamine

RCHC02H '--- RCOCO,H

I
NH,

pyridoxal pyridoxamine
HO,CCH,CH,COCO,H ~_=:::::::..-G== HO CCH CH CHCO H
.. ' "I '
NH,
",·ketoglutaric acid glutamic acid

HO,CCH,CH,COCO,H RCOCO,H + HO,CCH,CH,CHCO,H

I
NH,

b) RCHCO H FAD FADH, RCCO,H

I ''---=_/!:::..:.... II _
H,O
RCOCO,H+ NH,
NH, 0

Fig. 27.3. Transamination by pyridoxal phosphate (Geissman and Crout, 1969).

base intennediate. In cases where symmetrical labeling is
observed, the free base may be fonned, but, in many cases,
the label of symmetrical molecules is incorporated nooran·
domly, suggesting that a cofactor·bound compound is in·
valved.
N·Methyl groups often are present. These usually are de·
rived from S·adenosyl methionine. The point at which the
methyl group is introduced varies from pathway to pathway.
The fonnation of cinnamic acid and p.coumaric acid from
phenylalanine and tyrosine, respectively, is another enzy·
matic process of importance in the fonnation of alkaloids
(Fig. 27.4).
Primary amines often are converted to the corresponding
aldehydes by oxidation (Fig. 27.4). These aldehydes then
may participate in additional reactions such as the fonnation
of Schiff bases. 'The enzymes that catalyze these reactions
are known as monoamine oxidases and diamine oxidases.
Monoamine oxidases act on monoamines, whereas diamine

o
~CO'H
~
CO'H
phenylalanine ammonia lyase
19'1
Nu, (PAL) "'" +NH,

~
COlH

~
"",CO'H
19'1 tyrosine ammonia lyase

HO "'" NH, (TAL)

"",I
HO +NH,

monoamine
oxidase
a) RCHO

b) CH,NH, CHO
diamine
I
(CH,).
oxidase I 0=2, putrescine
(CH,).
I
CH,NH,
I 0=3, cadaverine

CH2NH2

Fig.17.4. Phenylalanine ammonia lyase and tyrosine ammonia lyase; monoamine and diamine oxidases (Geissman and Crout, 1969).
510 Introduction to Alkaloids
oxidase enzymes act on diamines, such as putrescine and
cadaverine.
Examples of each of the above types of reactions will be
given in the chapters that follow.
DlSTRlBUfION OF ALKALOIDS
At least 20% of all plant species contain alkaloids in quan-
tities of about 0.01 % of the dry weight or greater. Alkaloids
may occur in any plant part, but they are usually accumulated
in plant parts involved in biological interactions, for exam-
ple, in the plant epidermis (Hartmann, 1991; Wink, 1993).
Data from the distributional patterns of alkaloids often are
taxonomically useful (Gomes and Gottlieb, Hegnauer, 1988;
Mothes, 1966; Seigler, 1977; Waterman, 1993; Waterman
and Gray, 1987).
The most important alkaloid containing families are the
Amaryllidaceae, Apocynaceae, Asteraceae (Eupatorieae, Se-
necioneae), Boraginaceae, Euphorbiaceae, Fabaceae, Laur-
aceae, Liliaceae, Loganiaceae, Menispennaceae, Papavera-
ceae, Ranunculaceae, Rubiaceae, Rutaceae, and Solanaceae
(Cordell, 1978; Dalton, 1991).
Alkaloids are found most commonly in dicotyledonous
angiosperms and are uncommon in algae, bryophytes, ferns,
and monocotyledonous angiosperms. However, alkaloids are
known from the lower plant Lycopodium, and from the mon-
ocotyledonous families Amaryllidaceae, Dioscoreaceae, Lil-
iaceae, Orchidaceae, and Poaceae. Alkaloids are not com-
mon in gymnosperms, although they are encountered in
several conifers and occasionally in other gymnospermous
groups.
Although alkaloids largely are plant products, a number
of these compounds are found in animals such as insects
and amphibians. Many of the alkaloids found in animals also
occur in plants (Nahrstedt, 1982).
BIOLOGICAL ACTIVITY
Biological Activity of Alkaloids in Plants
Most alkaloids are subject to relatively rapid turnover in
plants; diurnal variations in concentration have been ob-
served in many. The amounts of other alkaloids vary season-
ally. For example, the amount of pedoline in tall fescue is
less than 1000 ",gig dry weight, except in July and August,
when levels exceeding 3000 ",gig dry weight are reached.
The fate of the catabolized alkaloid molecules is not well
understood (Robinson, 1974; Waller and Nowacki, 1978).
Although few alkaloids have been tested for plant growth-
regulatory activity, several are known to inhibit growth of
plants. For example, tomatine, a steroidal alkaloid from to-
matoes, and narciclassine and narciprimine from daffodils
have antimitotic activity in plants. Lycoricidinol and lycori-
cidine from Lycoris radiata showed growth-inhibiting activ-
ity on Avena coleoptile sections (Mandava, 1979).
A number of alkaloids have been demonstrated to act as
phytoalexins (Brooks and Watson, 1985). Among these are
lupanine in Lupinus species and rutacridone epoxide in Ruta
graveolens.
Many alkaloids are large molecules with pathways quite
distinct from those of primary metabolism, and the cost to
the plant may be related to production of the compounds
themselves rather than just allocation of nitrogen (Bernays,
1983).
Biological Activity of Alkaloids in Animals
Although more than 10,000 alkaloids are known, fewer
than 2-5% have been studied for their biochemical proper-
ties (Wink, 1993). The ecological interpretation of patterns
of alkaloid distribution have been summarized (McKey,
1974). Despite the potent physiological effects of many alka-
loids, there are many fewer articles dealing with the chemical
ecology of this group of compounds than might be predicted.
The activity of alkaloids against herbivores, toxicity in verte-
brates, cytotoxic activity, the molecular targets of alkaloids,
mutagenic or carcinogenic activity, antibacterial, antifungal,
antiviral, and allelopathic properties, and their possible roles
as phytoalexins have been tabulated (Wink, 1993). Many
alkaloids are sufficiently toxic to animals to cause death
if eaten. Several (e.g., nicotine and anabasine) are used as
insecticides (Jacobson, 1982).
Many alkaloids act on the nervous system, one of two
important information systems in animals. The nervous sys-
tem transmits perceived environmental changes rapidly to a
specific processing center. The fundamental unit involved
in this change is the neuron, with the information being trans-
ferred across a minute gap (2 x 10-5 mm) called a synapse
(Cordell, 1981). Although the information is passed electri-
cally within the neuron, it is passed chemically between neu-
rons by neurotransmitters. The four most commonly recog-
nized neurotransmitters are acetylcholine, noradrenaline,
dopamine, and serotonin. The reactive site for these chemi-
cals on the adjacent neuron is called a receptor (Cordell,
1981).
There are two main parts to the nervous system: the cen-
tral nervous system (CNS) and the autonomic nervous sys-
tem (ANS). The CNS is the major integrating system of the
body. The ANS connects the spinal cord at each vertebra
and connects the CNS to each muscle and to glands. The
ANS is divided classically into two systems: the sympathetic
and parasympathetic (Cordell, 1981).
Neurons that release acetylcholine, noradrenalin, dopa-
mine, and serotonin are called cholinergic, adrenergic, dopa-
minergic, and serotonergic, respectively (Cordell, 1981).
Cholinergic drugs elicit responses that mimic stimulation
of cholinergic nerves by direct action on effector cells sup-
plied by cholinergic nerves (choline), by indirect action in-
volving the inhibition of cholinesterase (which maintains
high levels of acetylcholine postsynaptically) (e.g., physo-
stigmine), and by direct stimnlation of cholinergic effector

cells (pilocarpine, arecoline, nicotine, and muscarine) (Cor-
dell,1981).
Cholinergic blocking agents do just the opposite. Three
main groups of these drugs are also recognized. Atropine-
like compounds occupy the postsynaptic receptor site and
prevent normal neurotransmitter action. Curare and similar
drugs antagonize the nicotinic action of acetylcholine at the
motor end plates of skeletal muscles. Ganglionic blocking
agents depress autonomic ganglia by depolarizing the end
plate (Cordell, 1981).
Adrenergic drugs are those that elicit responses similar
to the stimulation of adrenergic nerves, that is, release of
noradrenaline. Epinephrine and ephedrine are examples. Ad-
renergic blocking agents prevent stimulation of sympathetic
nerves by antagonizing the effects of drugs such as epineph-
rine. Many of the ergot alkaloids have this type activity (Cor-
dell,1981).
Alkaloids as Al10mones and Kairomones
Many alkaloids play roles as allomones (Hedin et al.,
1974; Levinson, 1976; McKey, 1974). A large number of
these compounds limit hervivory by non-coadapted herbi-
vores.
Alkaloids generally are not present in nonflowering
plants. It has been suggested that the rise and diversification
of this group of compounds is a result of coevolution with
mammals. Alkaloids taste bitter to most mammals; many of
these animals avoid food plants with high alkaloid content
(Swain, 1977). As reptiles cannot detect alkaloids as well
as mammals (they are about 30 times less sensitive), it was
suggested that alkaloids may have had an important role in
the demise of dinosaurs (Swain, 1977). The status of this
idea must be revised, as dinosaurs now are considered more
closely related to birds than reptiles, and the demise of dino-
saurs appears to be linked to the collision of a large meteor
with the earth.
In systems involving coadaption, alkaloids may play roles
as kairomones (Levinson, 1976). In other instances, animals
even use alkaloids as pheromonal substances (Robinson,
1979).
Uses of Alkaloids by Man
Many of the most important therapeutic agents for man
are alkaloids; among these are atropine, berberine, caffeine,
cocaine, codeine, colchicine, emetine, ephedrine, ergota-
mine, hyoscyamine, morphine, physostigmine, pilocarpine,
quinidine, quinine, reserpene, scopolamine, strychnine, the-
ophylline, tubocurarine, and yohimbine.
Alkaloids are among the most important groups of antitu-
mor compounds that have been studied (Cordell, 1978, 1981;
Suffness and Cordell, 1985). Vincristine and vinblastine,
from Catharanthus roseus (periwinkle, Apocynaceae), are
used in the treatment of lenkemia.
Others alkaloids are drugs of abuse. These include areco-
line, cocaine, N ,N-dimethyltryptamine, lysergic acid (as the
Introduction to Alkaloids Sl1
synthetic diethyl amide, LSD), mescaline, morphine (often
as the synthetic diacetyl derivative heroin), and nicotine.
Alkaloids are particularly important in arrow poisons
based on Chondrodendron (Menispermaceae) and Strychnos
(Loganiaceae) species, but they are the active ingredients of
arrow poisons from many other species as well (Cordell,
1978).
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Library., Vol. 23B), 1-435, Elsevier, Amsterdam, 1984.
VERPOORTE, R., R. VAN DER HEIJDEN, W. M. VAN GULIK, and H.
1. G. TEN HOOPEN, Plant Biotechnology for the Production of
Alkaloids: Present Status and Prospects, Vol. 40 of The Alka-
loids (A. Brossi, ed.), 1-187, Academic Press, New York, 1991.
WALLER, G. R. and E. K. NOWACKI, Alkaloid Biology and Metabo-
lism in Plants, Plenum Press, New York, 1978.
WATERMAN, P. G., Alkaloids: General observations, in Alkaloids
and Sulphur Compounds (P. G. Waterman, ed.), Vol. 8ofMeth-
ods in Plant Biochemistry (P. M. Dey and J. B. Harborne, eds.),
1-16, Academic Press, London, 1993.
WATERMAN, P. G. and A I. GRAY, Chemical systematics. Nat.
Prod. Rep., 5, 175-203 (1987).
WINK, M., Allelochemical Properties or the Raison d'Etre of Alka-
loids, Vol. 43 of The Alkaloids (G. A. Cordell, ed.), 1-105,
Ac~demic Press, New York, 1993.
28
Simple Amines, Simple Aromatic
and Pyridine Alkaloids

Introduction a large number of plants that are not necessarily closely

Simple Amines related.
Biogenesis of Simple Amines
Biological Activity of Amines in Plants
Biological Activity of Amines in Animals SIMPLE AJIIINES
Amines from Capsicum Species
Diamines and Polyamines in Plants Several simple aliphatic monoamines, formed by decarbox-
Polyamine Alkaloids ylation of amino acids or by transamination of aldehydes,
Simple Aromatic Alkaloids occur widely in plants (Fig. 28.1) (Geissman and Crout,
Hordenine 1969; Guggisberg and Hesse, 1983; Smith, 1977a,b). Many
Ephedrine involve subsequent N-methylation. These compounds are
Khat called "protoalkaloids" in some references (Hegnauer,
Mescaline and Related Alkaloids 1988); more than 1100 compounds of this type are known
Gramine (Verpoorte et aI., 1991).
Psilocybin The chemical and instrumental techniques for the isola-
Pyridine Alkaloids tion and characterization of amines have been reviewed
Nicotine (Crabb, 1982; Smith, 1993).
Ricinine and Related Alkaloids
Biogenesis of Simple Amines
Areca Alkaloids
Dioscorea and Related Alkaloids The biosynthesis of simple amines appears to involve a
Other Pyridine Alkaloids single enzyme with broad specificity. An enzyme with this
References activity, isolated from red algae (Rhodophyceae), was capa-
ble of decarboxylation of the L-forms of leucine, valine, iso-
leucine, norvaline, 2-aminobutyric acid, phenylalanine, me-
thionine, cysteine, and homocysteine. A number of other
INI'RODVCTlON amino acids were unable to serve as precursors (Smith,
1980).
Many alkaloids are formed by simple, usually short, series Although methylamine is widespread in plants, it is prob-
of reactions that are quite common in plants. For instance, ably produced as an artifact of isolation in many cases. Other
simple amines are derived in a one-step reaction from amino simple amines arise from transamination. An enzyme system
acids by decarboxylation. AIkaIoids of this type subse- from Mercurialis perennis (Euphorbiaceae) was capable of
quently may be modified, and, in some instances, quite com- producing a series of amines from ethylamine to undecylam-
plicated products arise. Among these easily derived com- ine in the presence of the corresponding aldehydes and ala-
pounds are simple amines, diamines, and simple aromatic nine (Fig. 28.2) (Smith, 1980).
and pyridine alkaloids. These short pathways, usually based Isobutylamine occurs as amides of various unsaturated
on common reactions, appear to have arisen many times in aliphatic and aromatic organic acids in the Asteraceae (along
the course of plant evolution. Simple aIkaIoids are found in with acetylenic amides), Piperaceae, and Rutaceae. Several

513
514 Simple Amines, Simple Aromatic and Pyridine Alkaloids

fH,CO,H
NH,
methylamine
glycine
CH,CH,NH, CH'fHCO,H histamine (11) histidine

(lr-r;H,
NH,
ethylamine
alanine tryptamine (1)
~N} ~

o
~CO'H

phenylethylamine (8) phenylalanine

~IH, tryptophan O:)(
: :,. . I I NH,
CO'H

NH

~
CO'H

~I Many N-methyl- and N,N-dimethyl-

derivatives of these amines also
HO :::,... NH, occur in nature.

tyramine (9)
tyrosine

Fig. 28.1. Simple amines.

of these derivatives are insecticidal (Jacobson, 1971; Smith,
1980). Other aliphatic amines are known to occur in plants,
especially in the above families, as well as in the Caryophyl-
laceae, Rosaceae, and Staphyleaceae (Waterman and Gray,
1987) (Fig. 28.3). Thin-layer chromatographic (TLC) and
high-performance liquid chromatographic (HPLC) methods
of analysis for alkamides are available (Bauer and Remiger,
1989).
Aromatic amines also are known to occur in plants. The
aromatic amine tryptamine probably arises from decarboxyl-
ation of tryptophan, but, in addition, may arise from indole.
Tryptamine (1) appears to be a precursor of the plant
growth hormone fAA (indole acetic acid) (2) (Fig. 28.4).
This compound also is produced in the metathoracic glands
of the leafcutter ant, Atta sexdens, and is a factor in the ant's
culture of fungi on fresh leaf material. Gall-forming wasps
and a number of other insects also synthesize fAA (Schild-
knecht, 1976).
Another important compound derived from tryptamine,
5-hydroxytryptamine (3) or serotonin, is derived by hydrox-
ylation and is found in many plants (Fig. 28-5). Serotonin
is widely distributed in nature and is a natural nerve transmit-
ter in the central nervous system, responsible, at least in
part, for sleep patterns. There also is some evidence that
this compound is involved in causation of depression and,
perhaps, of schizophrenia. Ingestion of large quantities of
serotonin in plantains (Musa species) in West Africa may be
responsible for some human health problems (Smith, 1977a;
Smith 1981).
The corresponding N ,N-dimethyltryptamine derivative,
bufotenine (4), is hallucinogenic and is found in Anadenan-
thera (Piptadenia) peregrina (Fabaceae, Mimosoideae)
(Schultes and Hofmann, 1973). Both serotonin and bufotenin
have 5-hydroxy groups (Fig. 28.5).
N,N-dimethyltryptamine (5) occurs in the leaves, stems,
and sap of Banisteriopsis argentea (Malpighiaceae), several
Virola species (Myristicaceae), and a number of mimosoid
legumes (Scbultes and Hofmann, 1973). This compound ap-
pears to serve as a hallucinogen only when used as a snuff
because it is metabolized by a monoamine oxidase when
taken orally (Smith, 1977a). Co-occurring l3-carboline alka-
loids may accentuate the activity, as they are monoamine
oxidase inhibitors.
The grass Phalaris tuberosa accumulates mostly N,N-
dimethyltryptamine (5), 5-methoxy-N,N-dimethyltrypta-
mine, and bufotenin (4), whereas P. arundinacea accumu-
lates mainly gramine (6) and hordenine (7). Although the
level of alkaloids is too low to cause acute poisoning in

CO,H CO,H

CH,CHNH,
I
CH,CH,CHO --+ CH,-c=O
I
alanine propanal pyruvic acid propylamine

Fig. 28.2. Biogenesis of propanal in Mercurialis.

 Simple Amines, Simple Aromatic and Pyridine Alkaloids SIS

methylamine herbivorous animals, there is a sufficient amount to de-

crease dry matter intake. However, sheep consume more
ethylamine Phalaris tuberosa dry matter with about 0.01 % gramine
than dry matter that lacks alkaloids (Waller and Nowacki,
CH3CH,CH,NH, n..propylamine 1978).
CH3CH,CH,CH,NH, n-butylamine Phenylalanine, tyrosine, and 34-dihydroxyphenylalanine
(DOPA) decarboxylases have been found in several plants.
CH3(CH,),CH,NH, n-amylamine Each causes the formation of the corresponding amine. Phen-
CH3(CHzl.CH,NH, n-hexylamine ylethylamine (8) and tyramine (9) are widespread among
plants and may occur at high levels. These amines are com-
CH3(CH')5CH,NH, n-heptylamine mon in the Cactaceae, Fabaceae, Rosaceae, and Rutaceae
(Wagner, 1988).
CH3(CH,),CH,NH, n..octylamine
~H3 Biological Activity of Amines in Plants
CH3CHNH, iso..propylamioe Several simple amines may be involved in protecting
fH 3
plants from various types of pathogens. A number of conju-
gates with cinnamic or fatty acids are known. Some of these
CH3CHCH,NH, iso-butylamine compounds, which appear to be widespread, have antifungal
fH3 activity.
CH3CHCH,CH,NH, iso-amylamine Aliphatic amines are especially common in algae and
CH3 particularly in the red-algae Rhodophyceae. These amines
I may protect the algae from microorganisms; several of
CH3CH,CHCH,NH, 2-methylbutylamine these amines are known to be toxic to a range of other
microbes.
HSCH,CH,NH, 2-thioethylamine
Several monoamines and diarnines are known to serve
CH3-S-CH,CH,CH,NH, 3-methyltbiopropylamioe as pollinating agents in plants. In general, these amines
are involved in the attraction of various types of fly. Plants
3-thiopropylamioe such as Helleborus joetidus, Heracleum sphondylium,
many members of the Asclepiadaceae, and a number of
ethanolamine plants in the Araceae are pollinated in this manner. The
pollination mechanisms used by Arum nigrum and A. mac-
2"propanolamine ulalum have been studied in some detail. The bright purple
spathe opens overnight to reveal the spadix in which
respiration is rapid and temperatures of up to 30°C have
Fig. 28.3. Aliphatic monoamines in plants.
been measured. The heat generated helps to volatilize the
amines that are released. Dung beetles and flies are at-
tracted, fall into the bottom of the flower, and are trapped.
The insects are essentially kept prisoners and, as such,

o:rr:
transfer pollen to the receptive styles (Harbome, 1982;

::::,..
I
NH
I NH
'
CO'H

----+-
CCJ(
I I °
::::,.. NH
COlH

tryptophan indole pyruvic acid

!
~Hl
~N} ~ - ~~
~N)
~CO'H
~N}
tryptamine (1) indole acetaldehyde indolyl 3-acetic acid (2)

Fig. 28.4. Biogenesis of IAA (modified from Smith, 1980; used with pennission of the copyright owner, Springer-Verlag, Berlin).
516 Simple Amines, Simple Aromatic and Pyridine Alkaloids

CtJ):,
I I
CO'H

~H'-
~N} ~
NH -
~ NH '

tryptophan
tryptamine (1)

H0'(t:0
~ I I H°'Cc)J1 --
"NH
NH
' -- ~ I NH
NHCH3

serotonin (3)

H0'Cc)J
~ I I ~(CH'),
NH
N(CH3l, ~N} ~
bufotenin (4) N,N·dimethyltryptamine (5)

~N(CH3l'
~N}
00 JYl
~
1
NH
I

HO
~ I N(CH,h

gramine (6) indole (to) hordenine (7)

Fig. 28.5. Formation of bufotenin in Anadenanthera (Piptadenia) peregrina and other simple amines (modified from Smith. 1980; llsed with
permission of the copyright owner, Springer-Verlag, Berlin).

Smith and Meeuse, 1966; Vogel, 1983), A similar system
is found in Victoria (Nympheaceae) (Vogel, 1983).
As previously mentioned, tryptamine (1) serves as a pre-
cursor for indoleacetic acid, a plant growth hormone.
Indole (10) is a synomone (i.e., the compounds benefits
both the producing and the receiving organism) in the polli-
nation of a number of plants and is a fairly common compo-
nent of flower essential oils. The biosynthesis of indole in
plants is uncertain. Indole apparently occurs as an enzyme-
bound intermediate in the biosynthesis of tryptophan, but

R; (CH,hCHCH;CH(CH,k
(CH,l,CH(CH,l.-
(CH,hCH(CH,ls- '
C H -~O J Y NHCOR I
(CH,hCH(CH,l7-
HO ~
(CH,hCHCH;CH(CH,ls-
(CH,hCHCH,CH;CH(CH,k
CH,CH,(CH,)CH(CH,).-
CH,CH,(CH,)CHCH;CH(CH,l,-
CH,(CH,l.-
CH,(CH,h-
CH,(CH,l.-
CH,(CH,),-
,
C H -~ I
0 X ) " NHCO(CH')4CH;CHCH(CH,h

CH,(CH,l..-
HO ~
CH,CH,(CH,)CH(CH,l4-
capsaicin (12)
CH,(CH,lu-

Fig. 28.6. N-(4-Hydroxy-3-methoxybenzyl) amides or capsaicinoids from Capsicum species (Suzuki and Iwai, 1984: llsed with permission of the
copyright owner, Academic Press, Orlando, FL).

appears to be derived from degradation of tryptophan in
other instances (Cordell, 1981).
Histamine (11) and serotonin (3) are found in the stinging
hairs of several species such as Cnidoscolus texanus (Eu-
phorbiaceae), Mucuna pruriens (Fabaceae), and Urtica di-
oica (Urticaceae), as well as vegetative materials of Cnidos-
colus urens, and fruits of the banana, Musa sapentium
(Lookadoo and Pollard, 1991; Seigler and Bloomfield, un-
published data; Smith, 1980).
The wings of bumet moths (Zygaena Jilipendulae) con-
tain small amounts of histamine (11) and the cyanogenic
glycoside linamarin. Furthermore, the addition of small
amounts of histamine to linamarin-containing solutions re-
sulted in the rejection of solutions normally consumed by
quail (Coturnix coturnix coturnix). It was suggested that
histamine plays a role in defense of the moth from predatory
birds (Muhtasib and Evans, 1987).
Biological Activity of Amines in Animals
Several of these amines are found in animals and some
are involved in nerve transntission (see Chapter 27). When
plant amines are consumed by animals, they can be quite
toxic. For example, phenylethylamine (8) in Acacia berlan-
dieri is poisonous to livestock (Smith, 1977b). The presence
of amines in foods consumed by humans also has been noted.
Catecholamines, indoleamines, and histamine (11) fulfill im-
portant metabolic functions, especially in the nervous system
and in the control of blood pressure. The occasional presence
of greater than usual amounts of tyramine in cheese can
cause severe episodes of hypertension, especially in the pres-
ence of monoamine oxidase inhibitors, which often are used
in the treatment of depression (Sntith, 1981). Amines can
be formed from bacterial activity in foods (Smith, 1981).
Amines from Capsicum Species
The pungent principles of the fruits of pepper (Capsicum
species, Solanaceae) areN-(4-hydroxy-3-methoxybenzyl)al-
kyl amides (Fig. 28.6). This plant should not be confused
with black pepper, Piper nigrum (Piperaceae) (see the dis-
cussion of pungent principles of black pepper in Chapter
29). The major and best known of these compounds is capsa-
icin (12) (Suzuki and Iwai, 1984). Capsaicin and its relatives
comprise about 0.5-1.5% of some hot pepper cuItivars.
Other pepper cultivars have been selected for their very low
content of these compounds. Capsaicin is synthesized in the
fruit of Capsicum species (Suzuki and Iwai, 1984).
Disease resistance in peppers is correlated with the pres-
ence of capsaicin, although other compounds, such as the
sesquiterpene capsidiol, may also be involved. In animals,
these compounds produce strong irritation and inflammation
of the skin, mucous membranes, and eyes, and can even be
fatal if large doses are given at one time. In smaller doses,
capsaicin stimulates the flow of digestive juices and has a
laxative effect on the colon. Consumption of capsaicinoids
causes increases in respiration and vasoconstriction and ele-
Simple Amines. Simple Aromatic and Pyridine Alkaloids 517
vates blood pressure. A drop in body temperature is pro-
duced by intraperitoneal or subcutaneous administration that
may be associated with vasodilation (Suzuki and Iwai,
1984).
Diamines and Polyamines in Plants
A number of diamines occur in plants, animals, and fungi
(Smith, 1977a, 1977b, I 977c; 1984). Several are toxic to
mammals, whereas others have interesting physiological
properties. Putrescine (13) accumulates in plants with potas-
sium deficiency and under osmotic and other stress condi-
tions. This diamine is moderately toxic; it also serves as a
precursor for a number of alkaloid types in plants. Animals,
yeasts, and most filamentous fungi synthesize putrescine by
decarboxylation of ornithine; plants and bacteria are able to
synthesize putrescine from either ornithine decarboxylase
or from arginine through a pathway initiated by arginine
decarboxylase (Fig. 28.7). Both systems can be specifically
inhibited (Slocum and Galston, 1987). Accumulation ofpu-
trescine in barley, oat, wheat, and maize leaves in response
to osmotic shock is linked to a pathway from arginine (Fig.
28.8).
Putrescine is catabolized to "y-aminobutyric acid in both
monocotyledonous and dicotyledonous plants, but by differ-
ent pathways (Flores and Filner, 1985).
Cadaverine (14), a five-carbon diantine, also is known to
occur in plants and may be derived from either homoarginine
or from lysine (Fig. 28.9). This compound serves as a precur-
sor for several types of alkaloids. In the biosynthesis of most
alkaloids, cadaverine is derived from lysine.
Several polyamines are widely distributed in plants. In
plants and in Escherichia coli, spermine (15) and spermidine
(16) are synthesized by aminopropyltransferases that use de-
NH, CO,H
I I
NH,CNH(CH,),CHNH, arginine
f'
NH,CNH(CH,).(CH,).,NH, agmatine
N..ca.rbamylputrescine
putrescine (13)
Fig. 28.7. Synthesis of putrescine from arginine (modified from Smith,
1980; used with pennission of the copyright owner, Springer-Verlag,
Berlin).
518 Simple Amines, Simple Aromatic and Pyridine Alkaloids

HO,CCH,CHCO, H
HO,CCH,CHNHCNH(CH.J,CHCO,H
I I I I aspartate
NH.""';....-_ __
CO,HNH, NH,
arginosllccinate lyase
argininosuccinate OCHONDRIAL MATRIX

H1N»NH(CH.J'iHC01H
fumarate o NH,
o citrulline
CYTOSOL
II ornithine transearbamoylase
H, NCNH, urea ( 00
1111
H1NCNH(CH1)'IHC01~arginase IH1 H,NCOrOH carbamoyl phosphate

arginine Nil H
N H
1
H, N(CH.J,CHCO, H - - . - - - / OH
~ba::: pbosphate

\---
ornithine ~hase

~---
H NCNH(CH ) NH .....!..,. H1NCNH(CH1}4NHZ ~ HIN(CH~4NH2 ~ polyamine
1 II 14 1 II biosynthesis
NH 0 putrescine
agmatine N~carbamoylputresclne

... agmatine iminohydrolase ** N-carbamoylputresclne amJdohydrolase

Fig. 28.8. Biosynthesis of polyamines (Slocum et aI .• 1984; modified and used with pennission of the copyright owner, Academic Press, Orlando, FL).

carboxylated S-adenosylmethionine as the aminopropyl
group donor (Slocum and Galston, 1987). Another system
that catalyzes the formation of a Schiff base from putrescine
and aspartic j3-semialdehyde and subsequent reduction to
spermidine has been isolated from Lathyrus sativa (Leete,
I 983b). Spermine and spermidine are derived in animals
and yeast from putrescine and S-adenosylmethionine (Fig.
28.10).
Amides of polyamines with compounds such as feruIic,
p-coumaric, and caffeic acid are widespread among higher
plants (e.g., caffeoylputrescine, feruloylputrescine, and p-
coumaroyltryptamine) and appear to be the main phenolic
constituents of the reproductive organs of many plants. Ad-
ducts include those of most of the common diamines and
polyamines, tyramine, and tryptamine. Known products en-
compass both basic simple amides and neutral diamides (Ca-
banne et aI., 1981; Martin-Tanguy et aI., 1978).
Putrescine (13), cadaverine (14), spermine (15), and sper-
midine (16) exhibit marked antisenescence activity when
applied to cereal grain leaves and isolated protoplasts (Slo-
cum et aI., 1984) (Fig. 28.9).
At physiological pH in plants, polyamines exist as proton-
ated forms. These protonated forms bind to the negatively
charged phospholipid head groups and other anionic sites in
membranes and alter the stability and permeability character-
istics of such membranes. Polyamines also stabilize chloro-
plast thylakoid membranes and retard chlorophyll loss in
senescing barley leaf tissue. Polyamines also influence mem-
brane fluidity, affect membrane localized proton pumps, and
alter plant hormone responses, perhaps by competing for

Fig. 28.9. Polyamines commonly found in plants.

 Simple Amines, Simple Aromatic and Pyridine Alkaloids 519

NH,

N~IHHNN"11 adenine
a-keto-y-methylthio- 5-methylthioribose- ~_,jLN
butyric acid ~ I-phosphate N
putrescine (13)

/ \ \ N:)NH' NH
H,CSCH,CHCO,H I I /)
kH' methionine
H,C(CHOH),CHCH,SCH,
Lo~ --
....N NCH(CHOH) CHCH SCH
Lo~"

1
S-adenosylmetbionine (SAM)
5'-methylthioribose

:)NH'
5'-methylthioadenosine

NH
NHl S-adenosylmethionine N...... I /) +
NH de<arboxylase...K ~N NCH(CHOH) CHCH SCH (CH,' NH
:) ,
N~ / L 'I ' , ", ,
~I.v ~ 0-' spermidine (16)
N NC0.::JHC, ~H'(C~HNH'CO'H de<arbosylated SAM

X
polyamine
biosynthesis
*ACC,ynthase ~ NH, NH

l-amlnocyclopropane- H,N
I-carboxylic acid (ACC)
CO,H t.~ )N NCH(CHOH),CHCH,SCH,
L-o-.:J H,N(CH'),NH(CH,)~(CH,),NH,
CH,=CH, +CN' + CO, spermine (14)
5'-methylthioadenosine
ethylene

Fig. 28.10. Spennidine and spennine biosynthesis (Slocum et a1., 1984; used with pennission of the copyright owner, Academic Press, Orlando. FL).

H02C(CH2hC0 2H succinate

* y-aminobutryaldehyde !
dehydrogenase HO,C(CH,),CHO
NH diamine oxidase
H,N~ '~
I
succinic semialdehyde

putrescine (13) ~o
'9' NH.
GADA-transaminase

- H,N(CH,),CO,H

'Y-aminobutyric acid
Al.pyrroline
H'N~NH~NH,
spermidine (16)

H,N(CH,),NH, - + - H,N(CH,),CO,H
l,3-diaminopropane p-alanine
/'0.. ./'.. /'-.. ./'.. ,NH /'-.. ,NH,
H,N' "-'" 'Nil "-'" "-'" "-'" "-'"

spermine (15) POLYAMINE

DEGRADATION
1-(3-aminopropyl)-pyrroline

Fig. 28.11. Oxidative degradation of polyamines by amine oxidases (Slocum et al., 1984; modified and used with pennission of the copyright owner,
Academic Press, Orlando, FL).
520 Simple Amines, Simple Aromatic and Pyridine Alkaloids
honnone-binding sites or by counteracting honnone-induced
changes in membrane penneability (Slocum et ai., 1984).
Polyamines also appear to regulate nucleic acid structure at
several levels of organization. Spennine-DNA complexes
have a regular confonnation that stabilizes the nucleic acid
molecule against thennal denaturation in vitro. Polyamines
modify the confonnation and activity of bacterial and yeast
tRNAs. Spennidine is an intrinsic component of the RNA
core of a plant virus. Because the activities of many enzymes
appear to be regulated by reversible phosphorylation, polya-
mine modulation of protein phosphorylation may indirectly
result in the regulation of cellular enzymes. Spennidine or
spennine reversibly prevent the activation of the chloroplast
enzyme, fructose-I,6-bisphosphatase, without affecting the
catalytic activity of already activated enzyme. Polyamines
have long been known to increase protein synthesis when
added to cell-free systems. Onset of DNA and RNA synthe-
sis in plants is preceded by increased rates of polyamine
synthesis (Slocum et ai., 1984). Polyamines and ethylene
appear to have antagonistic functions in plant cells, but the
underlying mechanisms are presently unknown.
12
lunarine (18)
oncinotine (21)
codonocarpine (24)
(a)
Fig. 28.12.
There is an absolute growth requirement for polyamines
in some microorganisms, mammalian cells, and higher
plants. Active growth and cell division are correlated with
increased rates of macromolecular and polyamine synthesis.
Increased polyamine biosynthesis during the G, phase of the
cell cycle, just preceding the onset of DNA synthesis in
dividing cells, appears to be a universal phenomenon in ani-
mals and plants (Slocum et ai., 1984).
Spennine (15) and spennidine (16) stimulate growth of
Helianthus tuberosus in explant cultures, but are effective
spore inhibitors against a number of fungi, including Penicil-
lium digitatum. Spennidine is used for stimulating lactic acid
bacteria in the dairy industry. Polyamines are converted into
a variety of products that are summarized in Fig. 28.11 (Slo-
cum et ai., 1984).
POLYAMIl'IE ALKALOIDS
Spennidine (16) has been reported to occur in a number of
plants in small amounts. Among these are several cereals,
spinach, cabbage, and artichokes. Sym.-homospennidine
palustrine (19) palustridine
inandenine A (22) inandenine B (23)
HN~N~NH&O
N" 0
H~\ ~
~&::~ ""
o "" T'I ?' OH
I I
agrobactine (20)
(continued)
 Simple Amines, Simple Aromatic and Pyridine Alkaloids 521

H 0
H 0

:~J g?
~~:J
HO
Sf
H
H
OH
HO

H
H
o

CSHll CsHlI

cannabisaliven. (28) anhydrocannablsativine (29)

NO
C_ if
H, r
~ h homalin. (27)

OHN~I
HN~Z:
CH,(CH,)~
o
~ IINH
N'~ ~NH

~NH~
0

""" I I ~
pitheroJlobine (26) "'" 0 Q
(main component)
OCH, OH

(b) isococionocarpioe (25)

Fig. 28.12 (a & b). Some representative polyamine aIka1oids.

(17) has been reported from the leaves of Santalum album
(Santalaceae). The biosyntheses of these two componnds
have been studied and they appear to be derived from putres-
cine (13), which is, in turn, derived from arginine or orni-
thine (see the discussion of simple amines above).
Alkaloids based on these structural units are widespread,
but sporadically distributed, in nature; at least 125 alkaloids
of this type are known (Verpoorte et aI., 1991). The first
reported was lnnarine (18), from Lunaria biennis (Brassica-
ceae), which was reported in 1908, although the correct
structure was established only in 1965 (Fig. 28.12). Palus-
trine (19), from Equisetum palustre (Equisetaceae), also was
reported quite early (Badwani et al., 1973).
Simple amine derivatives apparently occur in most, if not
all, plants, and the alkaloids derived from them are wide-
spread.
Several polyamine alkaloids appear to be involved as sid-
erophores (i.e., microbial iron-transport agents, in bacteria).
For example, agrobactine (20) is thought to play this role in
Agrobacterium tumefaciens (Fig. 28.12) (Guggisberg and
Hesse, 1983).
The main alkaloid of Oncinotis nitida (Apocynaceae) is
the spermidine alkaloid oncinotine (21). This group of alka-
loids is based on the biogenic amine spermidine (Guggisberg
and Hesse, 1983). The other part of the molecule is derived
from a C l6 fatty acid. Isomeric componnds also are fonnd
in the same plant. The main alkaloids of Oncinous inan-
densis are the 21 -membered ring lactones, inandenine A and
B (22,23) (Fig. 28.12) (Guggisberg and Hesse, 1983).
Another alkaloid related to lunarine, codonocarpine (24),
has been isolated recently from Codonocarpus australis. Al-
though this plant has been placed in the family Phytolacca-
ceae, its true affinities are not known with certainty (Fig.
28.12) (Guggisberg and Hesse, 1983). Isocodonocarpine
(25) has been isolated from Capparis decidua (Capparida-
ceae) (Ahmad et al., 1989).
Pithecolobine (26) has been isolated from Pithecelobium
saman (syn. Samanea saman, Fabaceae: Mimosoideae). Pi-
thecolobine consists of a substituted fatty acid and spermine.
Recently, the structure has been clarified (Fig. 28.12) (Bad-
wani et al., 1973). Similar alkaloids have been isolated from
the related plantAlbizia amara (pezzuto et al., 1991). Certain
of the isolates from this plant inhibit the catalytic activity
of DNA polymerase, RNA polymerase, and HIV-l reverse
transcriptase (Mar et al., 1991).
Other spermidine alkaloids occur in Homalium pronyense
 ux:
522 Simple Amines. Simple Aromatic and Pyridine Alkaloids
CO'H
__
~I
::::,.. NH,
- HO~ (Y:H,~
(32)
Fig. 28.13. Biogenesis of N~methyltyramine and hordenine (modified from Daly et al., 1972; used with pennission of the copyright owner, Birkhliuser
Verlag, Basel).
(Homaliaceae) (27) (Fig. 28.12). The Homaliaceae may be
confamilial with the Flacourtiaceae. These alkaloids also are
known to occur in Aphelandra squarrosa (Acanthaceae),
Cannabis sativa (Cannabaceae) (28, 29), Pleurostylia afri·
cana (Celastraceae) (30), Chaenorrhinum spp. (Scrophulari·
aceae), and a number of other sources (Cordell, 1981; Gug·
gisberg and Hesse, 1983).
SIMFLE AROJIIATIC ALKALOIDS
Hordenine
In barley (Hordeum vulgare, Poaceae), phenylalanine is
converted to tyrosine and then to tyramine. Tyramine (1) is
subsequently methylated and converted to hordenine (7)
(Fig. 28.13). A related species, Hordeumdistichum, converts
labeled phenylalanine into N·methyltyramine (31), a reac·
tion that is believed to procede via the intermediacy of the
so·called NIH shift (32) (Fig. 28.13). The half·life of
hordenine in barley is about 42 h (Waller and Nowacki,
1978). Hordenine has been suggested to playa role in alle·
lopathy in cultivated barley fields and is a feeding repellent
for grasshoppers (Smith, 1977b).
Ephedrine
Ephedrine (33) occurs in the Chinese drug "rna huang,"
Ephedra sinica (Ephedraceae), a drug used in China for more
than 5000 years (Tyler et al., 1981). The active ingredient
is ephedrine, a well·known adrenergic, bronchodilating
agent that is a common ingredient of both patent and pre·
9' I
~
CO'H
HO """ NH,
--
HO OJ
I::::,..
hordenine (7)
N(CH,>.
N·methyltyramine (31)
88% retention of tritium
scription medicines. This compound stimulates the central
nervous system and elevates blood pressure. The effects are
similar to epinepbrine. Most ephedrine·like compounds used
today are prepared synthetically. The compound amphet·
amine (34) is related structurally to ephedrine, but is not
naturally occurring.
The biosynthetic pathway to ephedrine appears to be as
presented in (Fig. 28.14) (Cordell, 1981; Yamasaki et aI.,
1973).
Incorporation of ephedrine at 0.1 % into artificial diets
is totally lethal to the larvae of Callosobruchus maculatus
(Janzen et al., 1977).
Kbat
The use of khat (Catha edulis, Celastraceae) is common
in several areas of northeastern Africa and in Yemen. AI·
though the leaves and young stems are usually used as a
masticatory, a tea is sometimes prepared (Brenneisen and
ElSohly, 1992). The active compounds of khat are two
closely related compounds: d·pseudonorephedrine (35) and
( - )·{X·arninopropiophenone or cathinone (36) (Crombie et
al., 1990; Szendrei, 1980) (see also Chapter 36). These com·
pounds have central nervous stimulant activity (Tyler et al.,
1981). (S)·Cathinone is thought to be responsible for the
cardiac stimulating activity of khat (Wagner, 1988).
Mescaline and Related Alkaloids
A series of simple alkaloids are found in a variety of
members of the cactus family, the Cactaceae. One of these
compounds, mescaline (37), disturbs normal mental function
 Simple Amines, Simple Aromatic and Pyridine Alkaloids 523

o
o
~CO'H

~
CH'OH
Nu,-- ~I
"" NH,

-- d'LH' ~NH' ~NH'

OH

() ,"".H () , .••• H

ephedrine (33) ampbetamine (34) cathinone (36)

(+)-norpseudoephedrine (35)
• The two carbon unit may come from serine, glycln~ alanine, propionic
acid, aspartic acid, glucose or formate (Cordell, 1981),
Fig. 28.14. Biogenesis of ephedrine and related alkaloids (Cordell, 1981; modified and used with permission of the copyright owner Dr. Geoffrey
Cordell).

and causes hallucinations and euphoria. Unusual and bizarre
color perception occurs (Schultes and Hofmann, 1973; Tyler
et aI., 1981). Although most commonly isolated from the
peyote cactus, Laphaphara williamsii, mescaline occurs in
related species as well. Mescaline is hallucinogenic and is
used as an integral part of religious activities by many Amer-
ican Indians. Mescaline is nonaddictive.
Tyrosine and tyramine (9) are established firmly as the
precursors of this group of aJkaloids. Dopamine (3,4-dihy-
droxyphenethylamine) (38) is incorporated in peyote and 5-
hYdroxy-3,4-dimethoxyphenylethylamine has been detected
in peyote (Fig. 28.14). The presence of 3-methoxy4-hy-
droxy- and 4-hydroxy-3,5-dimethoxyphenylethylamine (39)
in Trichacereus pachanai, another mescaline-producing spe-
cies, reveals another possible alternative pathway (Fig.
28.15).
Mescaline has an LDso p.o. (per as, or oral) of 100 mg/kg
in Agelaius (red-winged blackbirds) (Wink, 1993).
A number of other alkaloids which involve more complex
reactions but which also occur in the Cactaceae will be dis-
cussed in Chapter 33).
Gramme
Gramine (6) is found in several Acer species (Aceraceae,
maples), barley (Hardeum vulgare), and a number of other
plants. The mechanism of the side-chain modification which
produces gramine from tryptophan is not well understood.
Tracer studies indicate that the indole unit is incorporated
intact, but the origin of the second nitrogen atom is in doubt.
The methylene carbon of gramine is the same as the methyl-
ene in the same position in tryptophan (Fig. 28.16).
It is thought that hordenine (7) and gramine (6) are allelo-
pathic agents, as fields of barley are usually weed-free.
Gramine inhibits radicle growth of several plants (Wink,
1993). At 0.1 % in artificial diets, both gramine and nicotine
were totally lethal to the bruchid beetle Callasabruchus mac-
ulatus (Janzen et aI., 1977). Gramine is a feeding deterrent

~
-
CO'H
HO~ _ _ CH"O~

HO
~ I
........
NH--+
, HO~ NH, HO~ NH,

dopamine (38)

CH'-OYJ CH"O~ CH'O~

HO:::'" I -
NH, HO:::'" , NH, -- CH,O :::".
, NH
,
OH OCH, OCH,
(39) mescaline (37)

Fig. 28.15. Proposed route of mescaline biogenesis (modified from Smith, 1980; modified and used with pennission of the copyright owner, Springer~
Verlag, Berlin),
524 Simple Amines, Simple Aromatic and Pyridine Alkaloids

~co,~
~NJ
+ CHO
Nu,
O:t:YtCO,H

"" NH
POCH
{1 - t. 0'

POCH~O' ~
f
1
u...~.( pyridoxal phosphate CH3
~+ CH3 H
H

~NH'
~N} -- -- ~N(CH3l'
~N}
gramlne(6)
0r
~NH~
isogramine (40)
N(CH3l,

Fig. 28.16. Biogenesis of gramme (modified from Cordell, 1981; modified and used with permission of the author).

Ct:J):
""'I
""
1
NH
NH
'
CO'H

-- ~
~N} N(CH3), -
OH HO, pH
l' . . o
~(CH3l'-
psilocin (41)
°
Ct:n(
psilocybin (42)
CH3l'

H0'(Jc:(J
"" 1 NH
1 NH,

serotonin (3) bufotenin (4)

,. (Y0H
(t:jN~
catJeoylputrescine p-coumaroyltryptamine

Fig. 28.17. Psilocybin and related compounds (modified from Geissman and Crout, 1969).
 Simple Amines, Simple Aromatic and Pyridine Alkaloids 525

and insecticide for certain aphids, has antibacterial and anti-
fungal properties, and uncouples photophosphorylation
(Wink, 1993).
Central Asian camels refuse to eat a certain type of
"reed" due to the presence of gramine (6). When Erdtrnan
and co-workers synthesized this a1kaloid and the isomeric
compound, isogramine (40), Erdtrnan tasted a small sample
of isogramine. To his surprise, it tasted bitter sweet and
numbed his tongue. Gramine, however, did not have local
anesthetic properties (Sneader, 1985).
PsDocybln
Species of the mushroom genus Psilocybe (as well as
those of several other genera) produce metabolites such as
psilocin (41) and psilocybin (42) that have 4-hydroxyl
groups (Fig. 28.17) (Antkowiak and Antkowiak, 1990).
These compounds have hallucinogenic properties similar to
those of LSD; psilocybin interacts with the serotonin recep-
tor (Wink, 1993). The properties of these mushrooms have
been recognized in Central and South America for at least
3000 years (Mann, 1987; Schultes and Hofmann, 1973;
Tyler et al., 1981).
Tryptophan and tryptamine are incorporated into psilocy-
bin. Psilocin is an apparent intennediate for the biosynthesis
of psilocybin (Antkowiak and Antkowiak, 1990).
Psilocybin has an LD5• i. v. of 285 mg/kg in mice (Wink,
1993).
PYRIDINE ALKALOIDS
Alkaloids that possess an aromatic pyridine ring often are
called pyridine alkaloids (Leete, 1980; Pinder, 1993; Strunz
and Findlay, 1985); approximately 250 alkaloids of this type
are known (Verpoorte et al., 1991). Although many are de-
rived from nicotinic acid (Fig. 28.18), others arise from aro-
matization of piperidine alkaloids and other pathways (Wal-
ler and Nowacki, 1978). This chapter includes several of
the most important compounds of this type, although others
(such as a number of monoterpene-derived a1kaloids, Nu-
poor alkaloids, and sesquiterpene alkaloids of the Celastra-
ceae) are discussed in Chapter 36.
Nicotine
The most important a1kaloid of this group, nicotine (43),
is common and found in many plant families (see Leete,
1979, 1980; 1983a, 1983b). (S)-Nicotine is best known from
Nicotiana species (tobacco, Solanaceae). Nicotinic acid (44)
and ornithine serve as efficient precursors for nicotine. Orni-

CHO /CO,H
1 CH,
bH------
CHOH
I ?, +
CH0r>' /\

r
H,N
CO,H
OH
glyceraldehyde aspartic acid quinolinic acid
-3-phosphate

aN
pbosphoribosyl pyrophosphate nicotinic acid
adenine

a - a
dinucleotide
CO,H NH,

L:X~
wO -P-O
CO,H a C O ' H / '" +1 ~~ CO,H

"N+
CHJ
I --
"'N
I
nicotinic acid H
0 N° o-p-o-p-°lcd
U . .
()H
"IOOHNN
+
0- OH HH
HHH
t
a
OHOH
nicotinic acid mononucleotide OR OH I HO OH

"'N+ 1
CONH, aCONH,

-- '" 1 _____ a 1
CONH
'
t NH,

N:XN~
ll}

1
. N '" 0 0 HN N

~CONH:iCOaCN ~CN JQr0-~_-o-t~o1QL NAD

O~NjJ ----... 0 ~ Il .,.lo

N nicotine, anabasine OH OR HO OR
eH] CH 3 eH 3 and ='fJ:idlne
N-methyl-S-carbamoyl nudiftorine ricinine
2-pyridone

Fig. 28.18. Biosynthesis of pyridine alkaloids (Waller 1966; used with pennission of the copyright owner, the American Society for Biochemistry and
Molecular Biology).
526 Simple Amines, Simple Aromatic and Pyridine Alkaloids

Cu'
:.:p/CO,H
In plants: H~~'CH CO,H aCO,H
I I
°
(
:9'} (
I,tH
--+

aH
HPOH --+ - - "N "-N
II CH CO,H
-O-P-o/ ~ CO,H
b-~ quinolinic acid nicotinic acid (44)
glyceraldehyde
-3-phosphate aspartic acid co~
H"'~' #
'\~
a
N+ N-methylpyrrolidine
I
H N b CH,

~.~Q.. )
H".J.() .. ~ NH H D 0;:D °

!
~ ~
~
N

0?IH
~N)
NH H''''? Q
!) N ! H

0 0
CH,

A 0- 0
(S)-(-)-anabasine(4S)

U
~
N
H
1
NHHH

"'"
N
IHHN "",IH~
N C~
anatabine (46) nornicotine (47) nicotine (43)

Fig. 28.19. Biogenesis of nicotinic acid and nicotine (modified from Leete, 1977; modified and used with pennission of the copyright owner,
Academic Press, London).

thine is incotporated via putrescine, a symmetrical interme-
diate. Nicotinic acid is not incorporated via a symmetrical
intermediate (Fig. 28.19). Furthermore, nicotinic acid in
plants is not synthesized by the same biosynthetic pathway
as in animals. Many of the feeding studies involving Nicoti-
ana species have been summarized (Leete, 1983b).
An average 60-day-old tobacco plant contains about 250
mg of nicotine. Based on the net carbon dioxide fixation and
the rate of turnover of nicotine in the plant, maintenance of
this amount of nicotine may represent as much as 10% of
the plant's total metabolism (Robinson, 1974). The half-life
of nicotine in tobacco plants is about 22 b (Waller and No-
wacki, 1978). The alkaloid content of plants of Nicotiana
sylvestris undergoes a fourfold increase following damage
to the leaves (Hartmann, 1991). The production of nicotine
and related pyridine alkaloids such as anabasine (45), anatab-
ine (46), and nomicotine (47) in plant tissue, cell, and hairy
root cultures has been reviewed (Vetpoorte et al., 1991).
Nicotine (43) inhibits radicle growth in Lepidium and is
toxic to Lemna (Wink, 1993). It is a useful insecticide and
probably serves as a defensive compound in the plant (Wink,
1993). Some coadapted insects, such as the tobacco hom-
worm, Manduca sexta, are highly resistant to the effects of
nicotine. Tobacco homworm larvae, and those of many other
insects that feed on tobacco, excrete nicotine rapidly. Several
other mechanisms that degrade residual amounts of nicotine
also exist (Brattsen, 1986). PA50 enzymes that convert nico-
tine to the much less toxic compound cotinine are important.
Nonetheless, plants of Nicotiana section Repandae are
highly toxic to this insect. Topical application of I mg of
the crude exudate of leaves of N. repanda to larvae caused
100% mortality in 24 h. Plants of this species were shown
to contain N-acyl derivatives of nicotine such as (48) (Har-
borne, 1989).
Approximately 40-60 mg of nicotine (43) is a lethal dose
for an adult human; the LD,o i.v. in mouse is 0.3 mg/kg
(Wink, 1993). This base is the main pharmacologically ac-
tive component of tobacco smoke and probably is responsi-
ble for the addictive nature of cigarettes. The pharmacology
of nicotine and other Nicotiana alkaloids has been reviewed
(Fodor and Colasanti, 1985). Nicotine mimics acetylcholine
and activates acetylcholine receptors (Wink, 1993).
Plants of Nicotiana tabacum release nicotine through
their roots. Nicotine is stored in the roots and transported to
the upper parts of the plant. These alkaloids are accumulated
in all leaf parenchyma cells and in the vacuoles, extraplasmic
 Simple Amines. Simple Aromatic and Pyridine Alkaloids 527

CO'H
CONH
cr :::,. I __ c
:::,. r
I __' :::,. r
: :,.N+ r
1CN- c 1-CN

N c
N N I
CH,
nicotinic acid (SO)

a -t.)" --
I NON
CH3
CN ~CN
OH

CH3
0
~C~
N
OCH,

l~.A
I
0
CH,
~
~CN
t.AHN 0
+
I
.. senescent yellow leaves CH3
ricinine (49) •• fresh green leaves

o
D ~I
~
CN

0
bO~OH
OCH,

NH
CN
OH

OH
aCO'H uCO'CH'

N+
I
N
I
CH, CH, CH,
nudiftorine (50) acalyphin (51) trigonelline (54) arecoline (52)

~~ OH (48)

lNJ O~(CH~~
Fig. 28.20. Ricinine biogenesis and other pyridine alkaloids (modified from Waller et aI., 1966 and Skurskyet aI., 1969; used with pennission of the
copyright owner, the American Society of Biochemistry and Molecular Biology).

Q-- -
" ·6
CO,H

~
N

1# I ('~ {~
--~
NI

CO,H
o O-H H+
00.';
(53)
nicotinic acid

------.. ~CO'H
~7Y~ HN

~ ~ HO I
OHHO,C HO,C

dioscorlne

Fig. 28.21. Biogenesis of dioscorine (modified from Leete. 1980; modified and used with pennission of the copyright owner, Springer-Verlag, Berlin).

528 Simple Amines, Simple Aromatic and Pyridine Alkaloids
space between the membranes of the plastid envelope, plas-
tid vacuoles, and in the endoplasmic reticulum (Neumann,
1975).
Nicotine (43) and anabasine (45) are produced by hairy
root cultures of Nicotiana rustica (Fiores et aI., 1987). Dif-
ferentiated cultures of Duboisia species produce nicotine
(0.2-0.9%) as well as tropane alkaloids (Ellis, 1988).
Nomicotine (47) (in which the N-methyl group is absent)
is the major pyridine alkaloid in many other Nicotiana spe-
cies. This alkaloid has an LDso i.p. 23.5 mg/kg in rat (Wink,
1993). Nornicotine is a feeding deterrent to Melanoplus. An-
abasine (45) (with two 6-membered rings) is the principal
alkaloid of Nicotiana glauca (Strunz and Findlay, 1985).
Ricinine and Related AIkaloids
A series of compounds that appear to be derived from
nicotinic acid is found in a number of euphorbiaceous plants.
Ricinine (49), an alkaloid from Ricinus communis, is derived
from nicotinic acid via nicotinamide (50). This alkaloid may
occur in quantities as great as 1% of the plant dry weight.
A crude enzyme preparation has been isolated that will con-
vert a series of pyridinium salts into ricinine and related
compounds (Fig. 28.20) (Fodor and Colasanti, 1985). This
alkaloid disappears completely from senescent leaves. Ri-
cinine (49) has an LDso p.o. of 42 mglkg in Agelaius (Wink,
1993).
A number of related alkaloids, such as nudiflorine (50),
are found in related plants such as those of the genus Trewia.
Introduction of labeled nicotinic acid resulted in the intro-
duction of label into several of these (Strunz and Findlay,
1985).
A cyanogenic compound, acalyphin (51), that appears to
have a similar biosynthetic origin has been isolated from
Acalypha indica (Nahrstedt et al., 1982).
Areca Alkaloids
Areca catechu (Arecaceae, betel nut) is the world's most
commonly used masticatory. This palm seed is used in con-
junction with Piper betle leaves, Acacia catechu bark, lime,
and other accompaniments (Gowda, 1951) by perhaps 1 bil-
lion of the world's inhabitants daily. Arecoline (52) is the
most commonly studied alkaloid of Areca catechu seeds.
This alkaloid has muscarinic action (mimics acetylcholine
and binds to acetylcholine receptors) (Wink, 1993). Low
doses produce vasodilation and a fall in both systolic and
diastolic blood pressure. Arecoline exerts stimulatory effects
on the gastrointestinal tract and enhances diaphoresis. Arec-
oline has an LDso s.c. of 100 mglkg in mouse. This alkaloid
is a feeding deterrent to certain insects (Wink, 1993).
Dioscorine and Related Alkaloids
A series of alkaloids have been isolated from members
of the genus Dioscorea (Dioscoreaceae). These compounds
are derived from nicotinic acid and compound 53 appears
cP:
OAc
H
OAc '
~ 0 0
'"N I anibtne (55)
~
~NJHO~OCH'
duckein(Slt)
Fig. 28.22. Additional pyridine alkaloid>.
to be a likely intermediate (Fig. 28.21) (Strunz and Findlay,
1985; Specialist Periodic Reports 1978, 1979).
other Pyridine AIkaloids
Trigonelline (54), first isolated from fenugreek seed (Tri-
gonella foenum-graecum, Fabaceae), is now known to be
widespread in plants (Fodor and Colasanti, 1985). Trigonel-
line promotes cell arrest in G 2 of the cell cycle in plants
(Wink, 1993).
The Chinese plant Tripterygium wilfordii (Celastraceae)
contains compounds with insecticidal properties. On alkaline
hydrolysis, these compounds give rise to wilfordic acid (57)
and hydroxywilfordic acid (Strunz and Findlay, 1985).
Anibine (55) and duckein (56), from Aniba duckei (Laur-
aceae), are components of commercial rosewood oil (Fig.
28.22). These compounds appear to be derived by extension
of a nicotinoyl precursor by two or three acetate units, re-
spectively (Strunz and Findlay, 1985).
Several pyridine alkaloids are known to occur in both
plants and insects (Nahrstedt, 1982).
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29
Pyrrolidine, Tropane, Piperidine,
and Polyketide Alkaloids

Introduction PYRROLIDIl'IE ALKALOIDS

Pyrrolidine Alkaloids
Biogenesis of Pyrrolidine Alkaloids
Distribution of Pyrrolidine Alkaloids
Biological Activity of Pyrrolidine Alkaloids
Alkaloids of the Stemonaceae
Tropane alkaloids
Biogenesis of Tropane Alkaloids
Cocaine
Biological Activity of Tropane Alkaloids
Distribution of Tropane Alkaloids
Piperidine Alkaloids
Alkaloids from Piper Species
Piperine Alkaloids Involving Condensation with
Acetate/Malonate
Sedum Alkaloids
Lobelia Alkaloids
Lycopodium Alkaloids
Piperidine Alkaloids in Insects
Polyketide-Derived Alkaloids
Coniine
Polyketide Alkaloid Phytotoxins
Polyhydroxy Piperidine Alkaloids
References
INTRODVcnOI'l
A number of alkaloids are derived from ornithine and lysine
by decarboxylation, conversion by amine oxidases to the cor-
responding aldehyde, and cyclization to a 5-membered ring
system (pyrrolidine alkaloids) and a 6-membered ring system
(piperidine alkaloids). Several other alkaloids that coinciden-
tally have similar structures have been discussed under the
groups of alkaloids to which they are most closely related. .
Both lH_ and 13C_NMR spectra of the alkaloid types
above and the nuclear magnetic resonance (NMR) and mass
spectroscopy (MS) analysis of tropane alkaloids have been
reviewed (Crabb, 1982; Lounasmaa, 1988).
The approximately 80 known pyrrolidine alkaloids possess a
5-membered nitrogen-containing ring (Massiot and Delaude,
1986; Pinder, 1993). Several subgroups of pyrrolidine alka-
loids arise by condensation of these units with other mole-
cules. Pyrrolidine bases usually are modified by additional
Schiff-base formation, Mannich condensation, and aldol-
type processes to yield other alkaloids of this general class.
For example, condensation of pyrrolidine derivatives with
nicotinic acid is involved in the formation of pyridine alka-
loids such as nicotine (see Chapter 28). Pyrrolidine units
react with acetyl- or malonyl-CoA and condense via a Man-
nich condensation to form compounds such as hygrine and
cuscohygrine and tropane alkaloids (see below).
Biogenesis of Pyrrolidine Alkaloids
Pyrrolidine alkaloids are derived via the intermediacy of
putrescine (1). Putrescine is derived by decarboxylation of ar-
ginine or ornithine; the enzyme ornithine decarboxylase (E.C.
4.11.1.17) has been detected in tobacco roots (Leete, 1980)
(also see Chapter 30). Arginine decarboxylase (E.C. 4.1.1.19)
first converts arginine to agmatine, and subsequently to car-
bamoylputrescine, and then to putrescine (see Fig. 28.7 of
Chapter 28). In several studies, arginine, rather than ornithine,
appears to be the major precursor (Leete, 1990).
In tobacco, label is introduced into both the 2' and 5'
carbons of nicotine (2), indicating that the free diarnine is
involved; that is putrescine occurs as a symmetrical interme-
diate at some stage of the biosynthetic process. Further, hy-
grine and cuscohygrine formed from [5- 14C]ornithine are
labeled equally at the C-2 and C-5 positions (Leete, 1990).
In instances in which an asymmetric intermediate is in-
volved, methylated and enzyme-bound forms of putrescine
have been suggested. The N-methyl groups of N-methylpyr-
rolidine are derived from S-adenosyl-L-methionine (Fig.
29.1) (Geissman and Crout, 1969) and their formation in-
volves putrescine-N-methyltransferase (Leete, 1980, 1990).

531
532 Pyrrolidine, Tropane, Piperidine, and Polyketide Alkaloids

,H,NH, ,H,NH, CH,NHCH, CH,NHCH, ~

I I
iH, iH, iH, iH,
CHz ---+- CHz CH, __ N OH
~ CHz ---+-
I
CHNH,
I I I I
CH,NH, CH,NH, CHO CH,
I
o
L
CO,H putrescine N.methylputrescine
(may be bound to H·OH

Q c;j (J"
ornithine
enzyme)

o
(or arginine)

N N+
N I I I
CH, CH, CH,
Al.pyrrolideine N·methylpyrrolldine N.methyl.Al.pyrroUnium cation (3)

Fig. 29.1. Biogenesis of N·methylpyrrolidine and modification of the N·methylpyrrolidine structure (modified from Leete, 1990; used with pennission
of the copyright owner, Georg Thieme Verlag, Stuttgart).

An enzyme that catalyzes the fonnation of 4-N-methyl-
aminobutanal from N-methylputrescine has been isolated
from several sources. The enzyme that fonns the N-methyl.
b.1-pyrrolinium salt (3), N-methylputrescine oxidase, has
been isolated from tobacco roots (Leete, 1980, 1990).
Ornithine is incolporated into pyrrolidine rings unsym-
metrically in several Datura species, but a symmetrical inter-
mediate is involved in Nicotiana species, Erythroxylum
coca, Duboisia leichardtii, Hyoscyamus albus, and Nicandra
physaloides (Leete, 1990).
The first product of the cyclization, N-methyl-b. l_pyrrol_
ideine (or the N-methyl-b. l-pyrrolinium cation) (3), has been
proposed to condense with acetoacetate (in torn, derived
from the condensation of two units of acetyl-CoA) (Herbert,
1986) to produce the pyrrolidine alkaloid (R)-hygrine (4)
that is known from several plant families. Acetic acid is
incolporated into this part of hygrine and tropane alkaloids,
but despite several efforts, an enzyme capable of catalyzing
this condensation has not been identified. The product is
fonned, in some instances, after denaturation of proteins.
Labeling stodies for tropane alkaloids (see below) suggest,
however, that acetate or malonate may be added in steps
(Fig. 29.2) (Leete, 1990).
Subsequent reaction of hygrine with another unit of N-

Q
o

!::NH, )-OH ~_~

n r:::. CH n
J
bH, COS·CoA
I -- N+# \- N S.CoA N
CHNH, I COSCoA I I
bo H CH, CH, -CH -CO,H CH,

[2.":1.
ornithine
(3) ~\OSCOA / (19)1
COS·CoA

l.,/ (fl ~
OJJ:) N N
~I+/
~
JH,
hygrine (4)

I I
CH, CH,
cuscobygrine (5)

Fig. 29.2. Biogenesis of hygrine and cuscohygrine (modified from Leete. 1990; modified and used with pennission of the copyright owner, Georg
Thieme Verlag. Stuttgart).

CH'.O~
I HO
CH.O~HO
~ ,
CH,·O
o NH'
ruspolinone (6)
HO
OH 0
ftcin.(8)
CH,O
o
phyUospadin. (11) Isoneln. (9)
Fig. 19.3.
methyl-a l-pyrrolideine (3) yields cuscohygrine (5) (known
only from the Convolvulaceae, Erythroxylaceae, and Sola-
naceae) (Massiot and Delaude, 1986). Cuscohygrine fre-
quently is a by-product of the production of tropane alkaloids
in tissue and cell cultures (Verpoorte et a1., 1991).
Deprotonation of the I-methyl-a l_pyrrolinium salt (3)
yields 1-methyl-a2-pyrroline, which is in equilibrium with
the salt (Leete, 1990).
Distribution of PyrroUdine Alkaloids
As these alkaloids are derived by a short biosynthetic
sequence involving reactions that appear to be widespread
in plants, it is not surprising that pyrrolidine alkaloids are
commonly encountered. Many of the families in which pyr-
rolidine alkaloids are found are not particularly closely re-
lated. Monocotyledenous and dicotyledenous angiosperms
and ferns are represented (Massiot and Delaude, 1986). In
most cases, these alkaloids are found only sporadically
among the various members of these families.
Pyrrolidine alkaloids such as ruspolinone (6) and norrus-
polinone (7) have been found in RuspoJia hypercrateriformis
(Acanthaceae) (Fig. 29.3) (Roessler et a1., 1978). These com-
pounds are similar to the proposed precursors of the alkaloids
of Tylophora species (see Chapter 30).
An unusual type of pyrrolidine alkaloids involving flavo-
noid structures (8-11) has been reported from the Combreta-
ceae, Moraceae, Vochysiaceae, and Zosteraceae (Fig. 29.3)
(Houghton, 1987; Leete, 1982; Massiot and Delaude, 1986).
Similar alkaloids are found in the Rubiaceae and Meliaceae
(Houghton, 1987); none of these families are particularly
related. The NMR spectra of these compounds have been
reviewed (Houghton, 1987).
Pyrrolidine, Tropane, Piperidine, and Polyketide Alkaloids 533
HO~
7 P,
~ h
0 NH NH
norruspolinone (7) norruspolin
OH
CH,O
vocbysine (10)
~ .0
~v HN
~oH
H·odorlnol (11)
Selected pyrrolidine alkaloids.
In addition to a number of piperidine alkaloids, at least
19 pyrrolidine alkaloids have been reported from secretions
of thief ants and ftre ants of the genera Solenopsis and Mono-
morium. In general, these compounds occur in minute
amounts (50 fLglant) (Jones and Blum, 1983; Massiot and
Delaude, 1986; Numata and Ibuka, 1987).
BiolOgical Activity of PyrroUdine Alkaloids
These alkaloids are minor products in many important
drug plants, especially those of the genus Erythroxylum
(Erythroxylaceae) and of the Solanaceae. In general, the ac-
tivity of pyrrolidine alkaloids is overshadowed by the more
active tropane alkaloids with which they co-occur (Massiot
and Delaude, 1986).
(- )-Odorinol (12) (Fig. 29.3) from Aglaia odorata (Mel-
iaceae), a cinnamic acid and isovaleric acid diamide, has
antileukemic properties (Nahrstedt, 1985).
Alkaloids of the Stemonaceae
Alkaloids of the roots of plants of the Stemonaceae have
insecticidal activity. Several alkaloids have been isolated
from the root extracts that have been used to eradicate zoo-
parasites from man and agricultural animals. Among these
are stemospironine (13), stemofoline (14), and stemonine
(15) (Fig. 29.4) (Sakata et a1., 1978).
TROPANE ALKALOIDS
Alkaloids formed by "bridging" the 5-membered ring
with a three-carbon portion derived from acetate/malonate
are commonly known as "tropane" alkaloids (Fig. 29.5).
534 Pyrrolidine, Tropane, Piperidine, and Polyketide Alkaloids

...CH! /CH J

N'\r--(CO,CH, • :~' Ho?Q

~OCOC.,H,
H
7 4
3
H
• OCOCH(CH,OH)C.,H,
cocaine (16) hyoscyamine (18) (-)-tropic acid (22)

,CHJ ,CHJ

'~~oa;'~:J--
convoJamine
00 OCHJ tropine senecioic ester
0

valeroidine scopolamine (17) tropinone (20)

Fig. 29.5. Some representative tropane alkaloids.

About 300 compounds with the characteristic 8-azabi-
cycIo[3.2.11octane system are known (Leete, 1990; Ver-
poorte et al., 1991; Wooley, 1993). The methods forisolation
and purification of tropane alkaloids have been reviewed
(Wooley, 1993).
Tropane alkaloids are produced in the roots of plants and
transported to the aereal portions. In grafting experiments,
when aereal portions of Datura ferox, D. stramonium, D.
innoxia, and Atropa belladonna were grafted onto roots of
Cyphomandra betacea (normally not alkaloid containing),
the aereal portions lacked alkaloids. In the reverse situation,
aereal portions of C. betacea plants grafted onto roots of
the other species contained tropane alkaloids (Waller and
Nowacki, 1978).
Although the production of tropane alkaloids in tissue
culture of solanaceous plants usually is low, hairy root cul-
tures of Duboisia leichhardtii produced 1.1 % (dry weight)
of scopolamine (Ellis, 1988). Cultures of this genus have
been studied widely because they synthesize both nicotine-
and tropane-type alkaloids. The" production of tropane alka-
loids in plant tissue, cell, and hairy root cultures has been
reviewed (Verpoorte et al., 1991).
Biogenesis of Tropane Alkaloids
Tropane alkaloids result from addition of
acetate/malonate to a precursor such as the 1-methyl-~ ,_
pyrrolinium cation (3), followed by intramolecular cycIiza-
tion (Leete, 1990) (Figs. 29.2 and 29.6). (R)-Hygrine (4) in
several plants, primarily those of the Solanaceae and Eryth-
roxylaceae, may react intramolecularly to form tropane alka-
loids (Fig. 29.6). Pyrrolidine alkaloids, such as (R)-hygrine
(4) and cuscohygrine (5), frequently co-occur with tropane
alkaloids.
Although all tropane alkaloids are derived from ornithine
or arginine, some differences in intermediates and labeling
patterns have been observed. On introduction of [5- 14C]or-
nithine into plants of Erythroxylum, the activity was divided

stemonine (15) stemofoline (14)

stemospironine (13)

Fig. 29.4. Alkaloids of the Stemonaceae.


between C-1 and C-5 of the bridgehead of cocaine (16).
These studies indicate that a symmetrical intennediate (i.e.,
putrescine) is involved in the fonnation of tropane alkaloids
(Leete, 1983b, 1990). Incorporation of [1- 13C,methylamino-
"N]-N-methylputrescine into scopolamine (17) in Duboisia
provided evidence that free putrescine was not involved, at
least beginning with this intennediate, as only one 13C_15N
coupling was observed in the 13C_NMR spectrum (Mann,
1987). When [2-14C]ornithine is introduced into root cul-
tures of Hyoscyamus albus, hyoscyamine (18) labeled at
both bridgehead carbon atoms C-1 and C-5 is isolated. How-
ever, in similar experiments, in which the same precursor is
introduced into root cultures of Datura stramonium, hyoscy-
amine (18) labeled at only bridgehead carbon atom C-l is
isolated (Leete, 1990). Clearly, plants differ in whether sym-
metrical or unsymmetrical intennediates are involved in the
fonnation of tropane alkaloids.
Although it may appear that the double bond in the imi-
nium salt (3) can isomerize between the C-2 and the C-5
positions (which could lead to resultant scrambling of iso-
topic label at these positions), this does not occur in either
acidic or basic media (Leete, 1990). Furthennore, studies in
which appropriately labeled intennediate (3) is introduced
into plant cultures or intact plants indicate that incorporation
occurs in an unsymmetrical manner. For example, in biosyn-
thetic studies in which [2-14C]-I-methyl-,~.I-pyrrolinium
chloride (3) was fed to plants of Erythroxylum coca, the
resultant cocaine was labeled at the C-5 and not the C-1
position as suggested by previously proposed biosynthetic
schemes. The presence of the carboxyl group of the methyl
ester in cocaine indicates that the original attack is at C-2 of
the [2_14C]-I-methyl-A I-pyrrolinium chloride (3) precursor.
Attack by a methyl group (or a singly activated methylene
group) as previously proposed is without precedent, but the
presence of label in C-5 (and not C-l) of cocaine precludes
this mode of cyclization, in any case. In order to accommo-
date these data, Leete (1990) proposed that the initial attack
involves one molecule of malonyl-CoA, followed by exten-
sion by a second unit, to yield the required intennediate (19)
(Fig. 29.6). This saturated compound is then converted to
the corresponding iminium compound (24). Intramolecular
closure occurs between the methylene group of the side chain
(fonned by the sequential addition of two molecules of malo-
nate) and C-5 of the precursor.
The results of a number of feeding studies leading to
tropane alkaloids have been tabnlated (Leete, 1983a, 1990).
Tropinone (20) is a key intennediate in the synthesis of
many tropane alkaloids, for example, hyoscyamine (18) [an
ester of tropine (21) and (S)-tropic acid (22)] and scopolam-
ine (17) (Leete, 1990). Scopolamine is fonned from 613-
hydroxyhyoscyamine by a direct attack of the 6f3-hydroxyl
group at C-7, displacing the 7f3-hydrogen. The requisite en-
zyme, 6f3-hydroxyhyoscyamine epoxidase, requires 2-keto-
glutarate and oxygen as cofactors (Leete, 1990).
Many tropane alkaloids occur as esters of (S)-tropic acid
(22), a moiety derived from phenylalanine (Fig. 29.7) (Her-
Pyrrolidine. Tropane. Piperidine, and Polyketide Alkaloids 535
bert, 1988; Leete, 1984). The configuration of the f3-carbon
of phenylalanine is preserved in (S)-tropic acid (Herbert,
1988; Leete, 1984).
Large changes in the amounts of atropine [a mixture of
(R)- and (S)-hyoscyamine] present in Atropa belladonna
occur diurnally and seasonally (Waller and Nowacki, 1978).
The amount of atropine in leaves is greatest at about 6:00
P.M., whereas the atropine concentration of the froits peaks
at about 4:00 P.M. The smallest amount of atropine in the
leaves occurs at 10:00 A.M. (Waller and Nowacki, 1978).
Although undifferentiated calli of this species do not produce
hyoscyamine (18), production resumes when roots fonn on
the callus. Thus, the accumulation of this alkaloid seems to
be developmentally regulated. Root cultures of Hyocyamus
niger also produce hyoscyamine (Flores et aI., 1987).
A series of polyhydroxylated tropane alkaloids have been
isolated from the leaves of Solanum tuberosum and from
both a sphingid moth and an ithomiine butterfly, the larvae
of which feed on Solanum species (Nash et al., 1993). These
alkaloids are potent glycosidase inhibitors, in a manner simi-
lar to certain hydroxypyrrolidine and indolizidine alkaloids
(see Chapter 30).
Hybrids of Datura ferox [virus susceptible and hyoscine
(23) producing] and D. stramonium [virus resistant and hyo-
scyamine (18) producing] produced vigorous virus-resistant
plants that produced hyoscine, an alkaloid important in med-
icine. The F 1 plants inherited the high alkaloid level of D.
stramonium, but the oxidative ability of D.ferox. The segre-
gation ratio in the F2 generation is 3 : 1 and hyoscine produc-
tion is dominant (Waller and Nowacki, 1978).
Cocaine
Probably the best known alkaloid of this group is cocaine
(16), derived from the coca plant (Erythroxylum coca, Eryth-
roxylaceae) (White, 1989). This polymorphic species is a
native of the Andes of nurthwestern South America. The
leaves of the plant, which contain 0.5-2% cocaine, are
chewed by many Andean Indians who are said to derive a
feeling of well-being and alleviation of hunger pangs
thereby. There is no concomitant hallucinogenic effect. Most
commercially cultivated coca for the pharmaceutical indus-
try comes from Peru and Bolivia (Boucher, 1991; Tyler et
al., 1981; White, 1989).
Cocaine binds and inhibits the dopamine uptake carrier
(Wink, 1993). This alkaloid currently is a drog of abuse in
many countries. The widespread method for illicit
extraction/processing of cocaine is an interesting example
of alkaloid isolation and properties. Leaves of the coca plant
are dried and then soaked in a mixture of water and kerosene.
The resulting paste is then mixed, in tum, with dilute sulfuric
acid, lime, potassium pennanganate, and more kerosene. Fi-
nally the crude alkaloidal paste is extracted with ether and
acetone to remove impurities (Anon., 1985; Boucher, 1991).
Cocaine (16) has been used medicinally as a local anes-
thetic. Although cocaine itself is not as widely used in medi-
cine as was fonnerly the case, the synthesis of a number of
 w- " -
536 Pyrrolidine, Tropane, Piperidine, and Polyketide Alkaloids

~ .(C"",-
CH, CH COSCOA(CO'H
COSCoA ''-..._

COSCoA HO,C
o

~.-~"
·
CoAS·CO

(24) 0 o OH

R.
tropinone (20) /
tropine (21)
I CH ,

-
N 2

,
H
,
OCOCH(CH,OH)C,H,

.p C,=~ .~
(. )-tropic acid (22) hyoscyamine (18)
<a)

.. ~ ~
~SCOA CH,
COSCoA

o o

~~.t;Jy~~
o o 0 0
(19)

/H, N
/CH,
N

~
CO'CH'
f r = - < C 0 2CH, _ _....
, 2

.~ ~OH • 4 OCOC,H,
H H'

(b)
methyl ecgonine cocaine (16)

Fig. 29.6 (a & b). Biogenesis of tropane alkaloids (modified from Leete, 1990; used with permission of the copyright owner, Georg Thieme Verlag,
Stuttgart).

H01C\
~
T
I~
"'" H H
(8)-(. )-tropic acid (22)
Fig. 29.7. Biogenesis of tropic acid (modified from Leete. 1990; used
with pennission of the copyright owner, Georg Thieme Verlag,
Stuttgart).
other local anesthetics was based on the structure of this
alkaloid (Tyler et aI., 1981). Cocaine is generally considered
too toxic for use by injection, but it is used as a 0.1 % solution
as a topical anesthetic and 10-20% solutions for other appli-
cations (Cordell, 1978). The LDso i.v. of cocaine is 17.5
mg/kg (Wink, 1993).
Biological Activity of Tropane Alkaloids
A number of Solanaceous plants have a long folkloric
history in many parts of the world. All are poisonous and
contain tropane alkaloids (Cutler, 1992). Among these are
Atropa belladonna, Mandragora officinarum, and species
of Hyoscyamus, Latua, Duboisia, Datura, Brugmansia, and
Brunjelsia. The juice of the fruits of belladonna was placed
in the eyes of women in former times in order to expand the
pupils and make the eyes darker. This lead to the name
"bella donna" or beautiful lady (Cutler, 1992). Mandrake
(Mandragora) was considered by many as a miracle drug.
The root of this plant was also considered an aphrodisiac.
Several of these species contain alkaloids that imparted a
feeling of flying and were involved in witchcraft in Europe
and in ritualistic uses in other parts of the world (Schultes
and Hoffman, 1973). Datura stramonium has been reported
to be used in Haiti in association with the catatonic state
associated with zombies (Anon., 1987). A number of plants
containing tropane alkaloids have been used in Chinese tra-
ditional medicine (Han et al., 1988).
These compounds possess potent physiological effects in
animals and have long been of interest in medicine. Many
have mydriatic activity (i.e., they cause dilation of the pupil
of the eye). Others, such as cocaine, are anesthetics (Leete,
1990).
Hyoscyamine (18) is produced in the roots of Datura
(Solanaceae), but not in the leaves. This is the most common
alkaloid in solanaceous plants (Cordell, 1978). This alkaloid
inhibits germination of certain seeds, inhibits radicle growth
in Linum, and is toxic to Lemna (Wink, 1993). Hyoscyamine,
usually obtained from Hyoscyamus species) is a powerful
anticholinergic drug. Hyoscyamine is a feeding deterrent for
several insects (Wink, 1993).
Atrnpine [a mixture of (R) and (S)-hyoscyamineJ, usually
obtained from Atropa belladonna or from Hyoscyamus or
Duboisia species (all Solanaceae), is formed from hyoscya-
mine in the process of extraction. Atrnpine is a potent anti-
cholinergic drug that is sometimes used as an antidote for
Pyrrolidine, Tropane, Piperidine, and Polyketide Alkaloids 537
cholineesterase inhibitors such as physostigmine or organo-
phosphate insecticides. Atropine binds to muscarinergic ace-
OH
tyl choline receptors (Wink, 1993). Scopolamine (17) has
similar properties. The LCso p.o. (per as, or oral) in rat is
750 mg/kg (Wink, 1993). Incorporation of atropine at 0.1%
into artificial diets is totally lethal to the larvae of Calloso-
bruchus maculatus (Janzen et al., 1977). Atropine is a feed-
ing deterrent for several insects (Wink, 1993).
The corresponding 6,7-epoxide, scopolamine (17), is pro-
duced only in young leaves. This alkaloid inhibits germina-
tion of the seeds of several plants and inhibits growth of the
radicle in Lepidium and Lactuca. Scopolamine has been used
as a premedication prior to surgery and as a powerful hyp-
notic in the treatment of the delirium tremens (DTs) (Cordell,
1981). Scopolamine also is widely used to lreat motion sick-
ness (Tyler et al., 1981). This alkaloid is a feeding deterrent
for several insects (Wink, 1993).
Cocaine (16) inhibits germination of the seeds of certain
plants and is a feeding deterrent for the insect Leptinotarsa
(Wink, 1993).
Distribution of Tropane Alkaloids
Tropane alkaloids are common in the Solanaceae, but are
found in several other plant families. Tropane alkaloids are
found in the tribes Ceslreae, Datureae, Nicandreae, Salpig-
lossideae, and Solaneae (Evans, 1979). These alkaloids also
are found in the Convolvulaceae, which most systematists
consider to be related closely to the Solanaceae (Waterman
and Gray, 1987). Other families that contain tropane alka-
loids are the Brassicaceae (Cochlearia), Dioscoreaceae,
Elaeocarpaceae, Erythroxylaceae, Euphorbiaceae (Phyllan-
thus), Orchidaceae, Proteaceae, and Rhizophoraceae (Dahl-
grenetal., 1981; Romeike, 1978; Waterman and Gray, 1987;
Wooley, 1993). Because other types of alkaloids are found
in several of these families, many reports should be con-
firmed (Romeike, 1978).
FIPBRlDIl'IE ALKALOIDS
Piperidine alkaloids arise from lysine in much the same way
that pyrrolidine alkaloids arise from ornithine. A total of
about 700 alkaloids of these two groups are known (Ver-
poorte et al., 1991). The product of decarboxylation of ly-
sine, cadaverine, generally seems to be incorporated as an
unsymmetrical intermediate, but, in some instances, a sym-
metrical intermediate may be involved. This has been inves-
tigated by feeding [6_I5NJ-Iysine and [2_1SNJ-Iysine (Fig.
29.8). A pathway involving a bound form of cadaverine (25)
to pyridoxal that accounts for most observed chemical data
has been proposed (Spenser, 1970) (Fig. 29.8). Decarboxyl-
ation occurs with retention of configuration.
The results of a number of feeding studies and the forma-
tion of piperidine alkaloids have been tabulated (Leete,
1983a).
Piperidine alkaloids of the Apiaceae, such as coniine, and
S38 Pyrrolidine. Tropane, Piperidine, and Polyketide Alkaloids

~ L·lysine ~
H,N) H~~H~O'H H,N) H~~·CO'H

IXH
CHO
"
CH "
CH

~OH ~H
ll.,A
)\
N N / N

.~f:\N CH .J l
I Ie
~I OH H,N NH,
S-aminopentenal

o-
l1l>.ru~ cadaverine (25)

O
+
N:m'l face ('i H 0

00
N ~ ~NH~
l\,!.piperideine
~ from Fe face 2(R).a1ka1oids
(for example, (lR)-pelletierine)

H2N~( l .HA
O.NH

CO,H
2
NH ,::v
2(S)-aIkaloids
I (for example, (2S)·anabasine)
D·lysine ~

H'N~CO'H 6,1.piperideIne carboxylic acid (30) pipecolic acid (29)

Fig. 29.8. Biogenesis of piperidine alkaloids (modified from Leistner and Spenser, 1973; used with pennission of the copyright owner, the American
Chemical Society, Washington, DC).

those of coniferous gymnosperms are derived from polyke-
tide pathways (see below).
In the tobacco aIkaloids anabasine (26) and anatabine
(27), a lysine derivative is condensed with a derivative of
nicotinic acid to yield a system reminiscent of nicotine (Fig.
29.9) (Leete, 1977, 1983a).
Anabasine (26) has antisinoking properties similar to lo-
beline (see below) (Cordell, 1978). Structurally similar com-
pounds are known from ants and other animals (Nahrstedt,
1982). Anabasine is insecticidal and serves as a feeding de-
terrent for several insects and is teratogenic (Wink, 1993).
A number of other compounds with similar structures
[e.g., ammodendrine (28) from Ammodendron conollyii, Fa-
baceae] are not derived from nicotinic acid, but wholly from
lysine derived units (Fig. 29.10) (Herbert, 1988).
L-Pipecolic acid (29) occurs in many species that synthe-
size piperidine alkaloids. However, it is derived from D-
lysine rather than L-Iysine and probably via 6,'-piperideine
carboxylic acid (30) (Fig. 29.8) (Leete, 1983a; Strunz and
Findlay, 1985).
Alkaloids of Piper Species
Several representatives of the genus Piper (Piperaceae)
are of economic importance. Some of these plants [e.g.,
Piper nigrum (black pepper)] include alkaloids that are par-
tially responsible for the desirable pungent and preservative
properties of the plant. Other species are P. betle (widely
used as a masticatory), P. methysticum (widely used in the
South Pacific as a soporific drug), and P. guineense (ashanti
pepper). Most of these plants contain compounds that com-
bine phenylpropanoid compounds (see Chapter 8) and pyr-
 Pyrrolidine, Tropane, Piperidine. and Polyketide Alkaloids 539

D -
HaN .........
H02 T

L.[2.3Hllysine
NHCH3
HaN ""'~_
H
~
T
~ --0- TD
NHCH3 0
T NHCH3
7+
CH3

- +nicotinic

acid

anabasine (26) anatabine (27)

Fig. 29.9. Biogenesis of anatabine and anabasine (modified from Gupta and Spenser, 1970; modified and used with pennission of the copyright owner,
Elsevier Science Ltd., The Boulevard, Langford Lane, Kidlington OXS 1GB. UK),

rolidine alkaloid units. The pungent principle of black pep-
per, piperine (31), has an all E (trans) structure (Fig. 29.11).
Chavicine (32), another component important in the taste
properties of pepper, has aZ (cis) structure. Piperlongumine
(33) and piperlonguminine (34) occur in Piper longum or
long pepper.
A number of Piper species, e.g., Piper longum, have been
used in Ayurvedic medicine in India. This drug seems to
increase the bioavailability of other drugs. Piperine (31) is
similar in action to many central nervous system depressants
(Fodor and Colosanti, 1985).
produce a homologous series of alkaloids by intramolecular
cyclization. Internal cyclization produces alkaloids corre-
sponding to the tropane alkaloids, but with a 6-membered
ring system (Fig. 29.12). Many of these alkaloids have been
isolated from Punica granatum L. (Punicaceae, pomegran-
ate). Compounds analogous to hygrine and cuscohygrine
also are known. Examples are anaferine (35) and anahygrine
(36) from Withania somnifera Dunal. (Solanaceae).
Pseudopelletierine (37) (similar to hygrine in structure)
is an active taeniacide and anthelminthic for tapeworm and
roundworm (Fodor and Colosanti, 1985).

Piperine Alkaloids Involving Condensation Sedum Alkaloids

with Acetate/malonate
The reaction of piperideine precursors, homologous to
the N-methyl-.1 I-pyrrolinium cation (3) involved in tropane
alkaloid formation, with acetyl-CoA or ma10nyl-CoA can
A number of other piperidine alkaloids do not involve
condensation with acetate or malonate (previously consid-
ered to occur as addition of acetoacetate). Several that occur
in the genus Sedum (Crassulaceae) involve condensation of

o OI -- a,. I Q-
N NH NH aD N

- - cP )=0
N

ammodendrine (28)

Fig. 29.10. Biogenesis of ammodendrine (modified from Geissman and Crout, 1969).
S40 Pyrrolidine, Tropane. Piperidine. and Polyketide Alkaloids

o o
~~~OCH'
O ~O
~) ~O YOCH,
OCH,
piperine (31) piperlongumin (33)

piperlonguminine (34) chavicine (32)

Fig. 29.11. Piperine, piperlongumin, and piperolonguminine.

both lysine and phenylalanine moieties (Fig. 29.13). Label
is nonrandomly incorporated into sedamine (38), suggesting
the presence of an unsymmetrical intennediate. When cadav-
erine (25), chirally labeled with tritium at C-I, is used, the
I-pro-R hydrogen of the diamine is retained at C-2 of N-
methylpseudopelletierine and the I-pro-S hydrogen is lost
(Strunz and Findlay, 1985).
LobeOa AJkaIoids
Another series of lysine derived alkaloids occurs in the
genus Lobelia (Campanulaceae). One of these compounds,
lobeline (39) (Fig. 29.13) (from Lobelia inflata, Indian to-
bacco), has been used in antismoking preparations. Both lo-
beline and nicotine are classed as ganglionic stimulants.
Therapeutically, lobeline is hardly used today (Fodor and
Colosanti, 1985). Poisoning of cattle because of ingestion
of Lobelia berlandieri has occurred in Texas and Mexico
(Williams et al., 1987). Lobeline is a feeding deterrent for
several insects. The alkaloid is toxic to Lemna and inhibits
radicle growth of Lepidium (Wink, 1993).
Lycopodium Alkaloids
Approximately toO alkaloids are known from the genus
Lycopodium. These primitive seedless vascular plants, often
known as club mosses, are unusual among primitive plants,
as they contain alkaloids.
Two molecules of lysine and acetate are incorporated into
lycopodine (40). It has been suggested that isopelletierine
(41) plays a central role in the fonnation of these alkaloids
(Fig. 29.14) (Blumenkopf and Heathcock, 1985; MacLean,
1986).
Piperidine Alkaloids in Insects
In addition to a number of pyrrolidine alkaloids, many
piperidine alkaloids have been reported from secretions of

Qyr
- CH·CO,H

~ -- ~y- \OSCOA
~d
r
COSCoA
) __ )'·.COH -+ CH·CO,H
H,N HNH,' I -----.. N
I
'-...- --+ --+-
CH, COSCoA CH, CO,H

~COSCOA

('i
~CH,

<:? ~
--COASOC~
c~ QClJvO
o
,
CH,

l..NH~HN,)
anaferine (35)0 pseudopelletierine (37) anagyrine (36)

Fig. 29.12. Biogenesis of pseudopelletierine.

 Pyrrolidine, Tropane, Piperidine, and Polyketide Alkaloids 541

lysine
0.
Vk.
OR o

u-
CO'R ~CO'R
~
CO'R

I ~
:::,... NR, I~-

o OR

N
I
CR,

(-)-sedamine (38) (-)-Iobeline (39)

Fig. 29.13. Biogenesis of sedamine (modified from Geissman and Crout, 1969),

0{)
~NR~
isopelletierine (41)

ro ~R

C)6; ~F ~~~H-
OR

~-~"~~"
j~ .<9-
~ N NR N 0
+- ~.OR OR

I N+ 0
CR, 0 - I
a-obscurine lycopodine (40)
• label from (2_14CJ-lysine

Fig. 29.14. Lycopodium alkaloids (modified from Geissman and Crout, 1969).
542 Pyrrolidine, Tropane, Piperidine, and Polyketide Alkaloids

H H

coccinelline (42) precoccinelline (43) convergine (44)

\f.
H

hippodemine (45) myrrhine (46) propyleine (47)

Fig. 29.15. Coccinellines.

thief ants and fire ants of the genera Solenopsis and Mono-
morium. In general, these compounds occur in minute
amounts (50 fLglant) (Jones and Blum, 1983; Massiot and
Delaude, 1986). The alkaloids often are components of the
venom, but they also serve as a repellent for other ant species
and possibly as trail pheromones (Jones and Blum, 1983;
Numata and Ibuka, 1987).
Other lysine-derived alkaloids known as coccinellines
(42-47) occur in many members of the family Coccinellidae
(ladybugs or ladybird beetles) (Fig. 29.15). Many of these
insects are also warningly colored. Cryptic members of the
same groups usually do not contain the alkaloids (Jones and
Blum, 1983). These alkaloids also have been isolated from
a soldier beetle, Chauliognathus and from the boll weevil
Anthonomus grandis. Coccinellines are highly repellent to
ants and may be involved in deterring predation by other
animals as well (Jones and Blum, 1983). Structurally similar
compounds have been reported from the genus Poranthella
of the Euphorbiaceae (Nahrstedt, 1982; Numata and Ibuka,
1987).
POLYIillTIDE-DERIVBD ALKALOIDS
A number of polyketide-derived alkaloids are known to
occur. Probably best known among these are coniine (48)
and related compounds, found primarily in the Apiaceae
(mostly in the genus Conium) (Leete, 1971). Other alkaloids
with similar origin are pinidine (49) from pines, the Galbuli-

HO,O
" ~, . . NH", (CH,JIOCOHCH,

cassine carnavaline prosopine

Cassia excelsa Cassia spec/obi/is Prosopis ajricaIUJ

H:Q NH (CH')12COCH,

isoprosopinine A julifloridine spectaline

Prosopis africana Prosopis juliflora Cassia spectabilis

Fig. 29.16. Piperidin-3-o1s from Cassia and Prosopis.

 Pyrrolidine. Tropane, Piperidine. and Po/yketide Alka/oids 543

[l.14C].acetate _ _ ('l __ ( ' l --+ H ('I --+

HO,t ~ HO,t o~ ;j o~

~~ N4
-----'>
~ • N •
H •

'Y~coniceine (51)
coniine (48)

r'l H . •OH

/~NH~
plnidine (49) pinidinol (50)

Fig. 29.17. Biogenesis of coniine and related alkaloids (modified from Cordell, 1981; used with consent of the author).

mina alkaloids from the family Himantandraceae, and alka-
loids from the genus Elaeocarpus of the Elaeocarpaceae.
Alkaloids are uncommon in the Pinaceae. ( - )-Pinidine
(49) from Pinus sabiniana and P. jeffreyi is an example of
piperine alkaloids from this gymnospennous group. (-)-
Pinidinol (50) occurs in Picea engelmanii, as well as other
species of spruce (Stennitz et al., 1990). The biosynthesis of
these compounds from acetate has been demonstrated (Fodor
and Colosanti, 1985; Schneider and Stermitz, 1990; Stermitz
et al., 1990; Strunz and Findlay, 1985).
A series of substituted piperidine alkaloids have been iso-
lated from the legume genera Cassia (subfamily Caesalpini-
oideae) and Prosopis (subfamily Mimosoideae) (Fig. 29.16).
(Strunz and Findlay, 1985). Based on the structures of these
compounds, it seems possible that they are derived from
acetate-malonate precursors. These compounds are quite
similar in structure to the venoms of fIre ants (Nahrstedt,
1982). Indolizidine alkaloids also have been isolated from
Prosopis species (Howard and Michael, 1986).
Coniine
Although the alkaloids coniine (48) and 'Y-coniceine (51)
bear a structural resemblance to the piperidine alkaloids,
these compounds are derived from a polyketide pathway
(Fig. 29.17). Lysine is a poor precursor, and early attempts
to show incorporation of this compound resulted in failure.
guinea pig is 150 mg/kg. Coniine and coniceine are terato-
genic (Wink, 1993).
Both diurnal and seasonal variations in the content of
coniine and 'Y-coniceine in Conium maculalum have been
observed (Waller and Nowacki, 1978). The half-life of coni-
ine (48), 'Y·coniceine (51), andN-methylconiine is 1-4 days.
Coniine (48) is a feeding deterrent for several insects
(Wink, 1993).
Polyketide Alkaloid Pbytotoxins
Several compounds such as fnsaric acid (52) and a-picoli-
nic acid (53) (Fig. 29.18) (from the pathogenic fungi Fu·
sarium oxysporum and Pyricularia oryzae, respectively) are
phytotoxins. Both are probably involved in chelation of fer-
ric and zinc ions (Stoessl, 1981).
Polybydroxy Piperidine Alkaloids
A series of piperidine alkaloids with hydroxyl substitu-
tions have been isolated from a number of higher plants
(54-56) (Fig. 29.19) (Herbert, 1986, 1988). Among these
plant species are Lonchocarpus sericeus, L. coslaricensis
and Derris elliplica (Fabaceae), Morus species (Moraceae),
F agopyrum esculenlum (Polygonaceae), and a fern of the

~CO'H
Acetate is a much better precursor. Coniine is a highly toxic
alkaloid and is one of the toxic components of poison hem-
lock (Conium maculalum, Apiaceae) (Cutler, 1992). Other-
wise, alkaloids are very uncommon in the Apiaceae. Coniine
does occur in several other plants, for example, Sarracenia
(Sarracenia). 'Y-Coniceine is found in several species of Aloe fusarie acid (52) a~picolinle acid (53)
(a~pycolic acid)
(LiJiaceae) (Dring et al., 1984). Coniine is toxic to the
aquatic plant Lemna (Wink, 1993). The LDlOo p.o. in the Fig. 29.18. Fusaric acid and a~picolinic acid.
544 Pyrrolidille, Tropane, Piperidine, and Polyketide Alkaloids
oo'(:c 00, Ceo"CH20~NH~CH20H
OH
NH
A~OH 00)::(
CH20H
OH
NH
deoxymannojirimycin (54) deoxynojirimycin (55)
Fig. 29.19. Polyhydroxy plant alkaloids.
Aspidiaceae (FeJlows et aI., 1986; Janzen et aI., 1990). These
compounds are similar in some regards to coniine (48), a
nonhydroxylated piperidine alkaloid. In some legumes,
polyhydroxy piperidine alkaloids make up as much as 2%
of the dry weight of the plant. These compounds are similar
structuraJly to sugars and are potent inhibitors of glycosidase
activity. Specificity varies and some compounds of this se-
ries inhibit mannosidases, others fucosidases, and so forth.
No glucosidase inhibitor has been reported to present (Fel-
lows et aI., 1986) (also see Chapter 15).
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30
Pyrrolizidine, Quinolizidine, and
Indolizidine Alkaloids
Introduction
Pyrrolizidine Alkaloids
Biosynthesis
Distribution of Pyrrolizidine Alkaloids
Pyrrolizidine Alkaloids in Animals
Pyrrolizidine Alkaloids and Parasitic Plants
The Role of Pyrrolizidine Alkaloids in Livestock
Poisoning
Human Poisoning by Pyrrolizidine Alkaloids
Medicinal Uses of Pyrrolizidine Alkaloids
Quinolizidine Alkaloids
Biosynthesis
Complex Quinolizidine Alkaloids
Systematic Usefulness of Quinolizidine Alkaloids
Biological Activity of Quinolizidine Alkaloids
Medicinal Uses of Quinolizidine Alkaloids
Quinolizidine Alkaloids and Livestock Poisoning
Mescal-Hallucinogenic Properties of Quinolizidine
Alkaloids
Indolizidine Alkaloids
Biosynthesis
Biological Activity of Indolizidine Alkaloids
Indolizidine Alkaloids in Insects
Elaeocarpaceae Alkaloids
Phenanthroindolizidine and phenanthroquinolizidine
Alkaloids
Biosynthesis
Biological Activity of Phenanthroindolizidine Alkaloids
References
INI'KODVCTlOI'l
Pyrrolizidine, quinolizidine, and indolizidine alkaloids are
chemically diverse and restricted in distribution. Some simi-
larities in structures and biosynthesis exist, but as the path-
ways become more clear, these three major groups of alka-
S46
loids defmitely are of distinct origins. Pyrrolizidine alkaloids
are derived from arginine or ornithine and possess two fused
5-membered rings that share a nitrogen atom. Quinolizidine
alkaloids are derived from lysine and have two fused 6-
membered rings that share a nitrogen atom. Indolizidine
rings have a 5-membered ring fused to 6-membered ring
and share a nitrogen atom. Pyrrolizidine, qninolizidine, and
indolizidine alkaloids are involved in many plant-herbivore
interactions, but are of anthropocentric importance chiefly
because of their involvement in livestock poisoning, al-
though several have antitumor activity and others are used
medicinally. The phenanthroindolizidine alkaloids are a
major subgroup of indolizidine alkaloids.
Both the 'H- and "C-NMR (nuclear magnetic resonance)
spectra for several of the groups of alkaloids above have
been reviewed (Crabb, 1982).
PYRKOLIZIDIl'IE ALKALOIDS
Pyrrolizidine alkaloids are derived from ornithine and char-
acteristically have two fused 5-membered rings with a nitro-
gen at one of the common positions (Fig. 30.1). At least 560
alkaloids of this type are known (Verpoorte et al., 1991).
Pyrrolizidine alkaloids rarely occur in the free form and are
found as complex esters and N-oxides. Although pyrroliz-
idine alkaloids occur in all plant parts, the concentration
in at least one example, Senecio vulgaris, is highest in the
inflorescence (Hartmann, 1991).
Cells of Senecio vulgaris in tissue culture lack the ability
to synthesize pyrrolizidine alkaloids, but retain the ability
to take up and accumulate the corresponding N-oxides. The
translocation of exogenous N-oxides into the vacuole by car-
rier-mediated transport has been demonstrated; cells of non-
alkaloid-producing plants do not take up pyrrolizidine N-
oxides (Hartmann, 1991).
Pyrrolizidine alkaloids are synthesized in the roots and
 Pyrrolizidine, Quinolizidine, and Indolizidine Alkaloids 547

~
H 14 \ HO HO ..fHO

:"'6)00
...",
~O
"

0~to160'-
, jO~
heliotridine H II H II
7 ; ~
i ~
N
N
senecionine (5) monocrotaline (8)
(retronecine + (retronecine +
senecic acid) monocrotalic acid)
retronecine (1)

CH30.
~(
/ ~O
-< H
~'''/
HO,fHO

ct5
heliotrine (15) heliosupine
(heliotridine + angelic
~~tt5,100
H

trichodesmine
(retronecine +
II;

and echimidinic acids) trichodesmic acid)

HO~
lr1'"
d5 toO to'
_ H
[0 HO ".•'HO ..,,,CH,OH o
'. 0 19
0
H

H '! II
i '\ o H II o H 0

N+
; ~ 6 7 ~ 1~ ,

I N
5 4
O'

indicine N-oxide (16) junceine gynuramine

Fig. 30.1. Some typical pyrrotizidine alkaloids.

transported to other parts of the plant. Because of the ready
uptake of these compounds by parasitic plants (see below),
transport probably occurs in the phloem (Hartmann, 1991),
Root cultures of Senecio vulgaris synthesize pyrrolizidine
alkaloids and accumulate them as N-oxides (Herbert, 1988),
This synthesis parallels that of intact plant roots, Senecionine
is synthesized and converted to the N·oxide and transported
throughout the plant. Plants of many species contain only
N·oxides of pyrrolizidine alkaloids (Hartmann et aI., 1989),
A sensitive method for the detection and quantitation of
pyrrolizidine alkaloids based on stoichiometric reaction of
protonated alkaloids with methyl orange may be useful, as
these alkaloids sometimes give poor tests with Dragendorff's
reagent (Birecka et aI., 1981), Most give good tests with
iodoplatinate or Ehrlich's reagent. Important modifications
have been introduced by Mattocks and Jukes (1981),
Biosynthesis
Although most pyrrolizidine alkaloids have been re-
garded as coming from ornithine by the intermediacy of pu·
trescine, arginine probably is the actual precursor in most
instances (Hartmann, 1991), High incorporations of argi·
nine, isoleucine, putrescine, and spermidine were obsetved
in many pyrrolizidine-alkaloid-containing plants (Herbert,
1988), In some Heliotropium species (Boraginaceae), pu·
trescine is derived from arginine through an alternate path·
way (see Chapter 28), In contrast, no arginine decarboxylase
activity could be shown in species of Senecio and Crotalaria
S48 Pyrrolizidine. Quinolizidine. and lndolizidine Alkaloids

that were examined (Birecka et aI., 1988). Most nonalkaloi-
dal plants have high arginine decarboxylase activity and al-
most no ornithine decarboxylase activity.
Most pathways leading to the biosynthesis of pyrroliz-
idine alkaloids involve a symmetrical intermediate (see
Chapter 29 for additional discussion of symmetrical versus
unsymmetrical intermediates) (Fig. 30.2). [1-Amino- 15N-
!3Clputrescine was incorporated into retronecine (1) that was
isolated following hydrolysis of retrorsine (3) (Fig. 30.4).
Homospermidine (2) was suggested as a symmetrical inter-
mediate and also was shown to be incorporated into retronec-
ine (1). By means of l4C-Iabeled intermediates [such as
HzN(CH3hNHI4CHz(CHzhI4CHzNHz)], it was demon-
strated that homospermidine was incorpomted as a symmet-
rical intermediate (Khan and Robins, 1985a, 1985b; Spenser,
1985; Wrobel, 1985). [1,9-1 3CzlHomospermidine (2) is in-
corporated intact into retronecine (1). Introduction of [1,4-
zH.l-putrescine followed by zH_NMR revealed that the ma-
jority of 2H-Iabel was located at C-3, C-5, C-8, and C-9
(Fig. 30.3). The pattern was consistent with the proposed
biosynthetic pathway including homospermidine (Khan and
Robins, 1985a, 1985b). The formation of (9S)-retrorsine (3)
with 9_zH indicates that a stereospecific addition (of lH from
the re face to the carbonyl group of the aldehyde precursor)
has occurred. When putrescine (4) labeled at the (R)-[l-
zHl- or (S)-[I-zH]-positions was introduced, equal label, at

arginine or
ornithine
~ putrescine
- bomospermidine (2) (1)

'.
I
Hs +
lossof

di N
HO ~HO~ CO yHsH
. :. . - rl----.-
~N:)
R' H

NH

* loss of HR or Hs
0

~
*'" attack from re-face

retronecine (1)
Fig. 30.2. Biogenesis of pyrrolizidine alkaloids (Spenser, 1985; used with peIll1ission of the copyright owner, the International Union of Pure and
Applied Chemistry, Oxford).

~'"' --
DH
(R)-[l.'HI·putrescine
(4)
Fig. 30.3. Biogenesis of retrorsine from (R)-[1- 2H]putrescine (Wrobel, 1985; used with pennission of the copyright owner, Academic Press, Orlando,
FL).
positions 3/3, 50<, 80<, and 9-pro·S by the (R) precursor,
whereas only the 30<- and 5/3 was found positions were la-
beled by the (S) precursor (Fig. 30.3). These results suggest
that the oxidation of putrescine to 4-aminobutanal requires
the loss of the pro'S hydrogen, reduction of the intermediate
imine to homospermidine (2) occurs at the si face, two oxida-
tion steps leading to an aldehyde proceed with removal of
pro-S hydrogens, cycIization of the iminium ion to 8o<-pyr-
rolizidine proceeds at the re face of the ion, and reduction
of the aldehyde occurs via attack on the re face of the car-
bonyl group (Wrobel, 1985) [see Leete (1983) for a review
of the biosynthesis and feeding studies of labeled precursors
leading to pyrrolizidine a1kaloidsl.
Pyrrolizidine alkaloids usually occur as complex esters
of unique monobasic or dibasic acids called necic acids.
Senecionine (5) is composed of both the necine base, retro-
necine (1), and senecic acid (6) (Fig. 30.4).
Senecic acid (6) is produced by condensation of two mol-
ecules of isoleucine. The formation of the lO·carbon necic
acid (7) is accompanied by loss of C-4-pro-R hydrogen from
both isoleucine components (Wrobel, 1985). In retrorsine
(3), two hydrogen atoms of (2S)-isoleucine at C-13 and one
of the C-15 ethylidine group are derived from C-4 methylene
hydrogen atoms of (2S)-leucine. These were later shown to
arise by loss of 4-pro-S hydrogen (or that the atoms above
at C-13 and C-15 were derived from the 4-pro-R hydrogen
of L-isoleucine) (Wrobel, 1985).
Distribution of PyrroIizidine Alkaloids
These alkaloids are found mostly in the Asteraceae (tribes
Senecioneae and Eupatorieae), the Boraginaceae, Fabaceae
(Croralaria, Lotononis, and Buchenroedera), and a few
Pyrrolizidine, Quinolizidine, and Indolizidine Alkaloids 549
--
retrorsine (3)
other families. Of these plants, the genus Senecio, with about
1200 species worldwide and about 50 species in the United
States and Canada, is particularly important. The macrolide-
type pyrrolizidine alkaloids, such as senecionine (5), are
found in the Asteraceae (Senecioneae) and the Fabaceae
(Crotalaria) (Waterman and Gray, 1987). Compounds with
pyrrolizidine ring systems also have been found in the Apo-
cynaceae, Celastraceae, Convolvulaceae, Euphorbiaceae,
Linaceae, Orchidaceae, Poaceae, SantaIaceae, and Sapota-
ceae (Culvenor, 1978; Jenell·Siems et aI.,. 1993; van Wyk
and Verdoom, 1988; Waterman and Gray, 1987). There also
are reports from the genus Caltha (Ranunculaceae) and from
Castilleja (Scrophulariaceae) (see below). 1-Aminopyrroliz-
idine derivatives are known from the Poaceae, the Fabaceae
(Papilionoideae: Genisteae), and Rhizophoraceae. Despite
these occurrences, however, pyrrolizidine alkaloids are only
characteristics of the genus Parsonia (Apocynaceae), the
Asteraceae, Boraginaceae, and Crotalaria (Fabaceae) (Cul-
venor, 1978).
Study of the pyrrolizidine alkaloids of the Fabaceae, tribe
Crotalarieae, suggest that these data are useful for systematic
and phylogenetic study of this complex group of legumes
(van Wyk and Verdoom, 1990).
Pyrrolizidine Alkaloids in Animals
Although most of the toxic effects of pyrrolizidine a1ka·
loids probably are produced by alkylation of DNA and pro-
teins, heliotrine inhibits cholinesterase, and monocrotaline
(8) modulates pulmonary Na+/K+ pumps. Many pyrroliz-
idine alkaloids are mutagenic in Drosophila (Wink, 1993b).
Pyrrolizidine alkaloids of most plants occur primarily as
the N-oxides. Conversion to the corresponding bases yields
550 Pyrrolizidine, Quinolizidine, and lndolizidine Alkaloids
~ HO ! HO (2S)-isoleucine
="~0ttS'o~/: ~TIN'
CLJ~:~ ~"'-"J
i '\ 0 OH
8
N
rn~.lHrn~;,~,
C, HNH, CH,C,H _ 0 tt5°~H
+ OH
CO,H CHNH,
isoleucine I '
+ CO,H
retronecine (1)
Chap. 30,Fig. 4
Fig. 30.4. Biosynthesis of the necic acid of senecionine (Davies and Crout, 1974; Devlin and Robins, 1984; modified and used with permission of the
copyright owner. The Royal Society of Chemistry, London).
forms that can passively penetrate membranes (Hartmann,
1991).
Pyrrolizidine alkaloids are feeding deterrents and insecti-
cida
for many species of insects (Schneider, 1987; Wink,
1993b). Some insects, such as Melanchra persicariae and
Spodoptera littoralis feed on Senecio vulgaris, which con-
tains pyrrolizidine alkaloids, but do not sequester the alka-
loids. The larvae are cryptically colored (Schneider, 1987).
Certain insects appear to be able to excrete these alkaloids
without harm. For example, senecionine (5), its N-oxide, and
hydrolytic products, including retronecine (1), were found
in the honeydew of the aphid Myzus persicae when this in-
sect fed on Senecio vulgaris (Molyneux et aI., 1990).
On the other hand, pyrrolizidine alkaloids are sequestered
and have important ecological roles in a number of insects
(Harborne, 1982; Nahrstedt, 1982; Schneider, 1987; Wink,
1993b). The two main orders involved are the Danainae of
Nortb America and the Ithomiinae of South America (Har-
borne, 1989). Both larvae and adults of the Danainae may
consume plant materials with pyrrolizidine alkaloids, but the
Ithomiinae are unable to obtain these alkaloids at the larval
stage (Harborne, 1986). The nectar of some plants in the
Asteraceae (mostly of the tribe Eupatorieae) contains 2-4%
of the dry weight as alkaloids that can serve as a reward
for pollination (Harborne, 1989) for ithomiine and danaine
butterflies, but inhibit feeding by general feeding insects
(Masters, 1991). Adults of at least three genera of arctiid
moths visit plants that produce dehydropyrrolizidine attrac-
tants, such as (- )-(R)- (9) and ( + )-(S)-hydroxydanaidal in
H '.. HO
t
0
_ ~o
° Htt5~0
~ ; "
'\ N
N
the nectar (Krasnoff and Dussourd, 1989). Some moths store
Senecio alkaloids without modification. The larvae of the
cinnabar moth, Tyria jacobaea and related species, accumu-
late such alkaloids in their tissues by feeding on groundsel
or ragwort, both rich in pyrrolizidine alkaloids and, thus,
become distasteful to predators (Fig. 30.5) (Harborne, 1982;
Mann, 1987). All stages of these moths are brightly colored
and are not eaten by most insectivores (Schneider, 1987).
Ithomiine butterflies, widely known as distasteful, show
warning coloration and are usually rejected by both verte-
brate and invertebrate predators. The Ithomiine larvae con-
sume plants of the Solanaceae, but do not accumulate the
alkaloids from those plants (see Chapter 36). However, adult
ithomiine butterflies feed on plants of the Asteraceae and
Boraginaceae that contain pyrrolizidine alkaloids. By a pro-
cess of ejecting fluid through the proboscis onto the surface
of the plant and subsequently taking it up again, they acquire
pyrrolizidine alkaloids from the plants (Schneider, 1987).
Adult males may contain as much as 10% dry weight pyrrol-
izidine alkaloids, such as dehydropyrrolizidine alkaloid
monoesters and their N-oxides. These compounds also are
implicated in reproduction of the insect (Brown, 1984). The
males of some species of Ithomiidae secrete a lactone on
the hairs of hind wing fringes that serves as an aphrodisiac for
the female and/or as a male recognition signal. This lactone
probably is derived from the acid moiety of pyrrolizidine
alkaloids (Boppre, 1978).
Despite the defenses that older adults have, freshly
emerged adults (that presumably lack these defenses) are

eaten by various predators (e.g., the giant tropical orb spider,
Nephila clavipes).
Dead shoots of Heliotropium indicum (Boraginaceae) act
as a powerful attractant for male ithomiine and danaine but-
terflies. The butterflies use alkaloids obtained from these
plants for the production of chemicals with pheromonal ac-
tivity. Baiting with alkaloids and the esterifying necic acids
indicated that a volatile product derived from the necic acids
attracts males to the plants, whereas the intact alkaloids then
act as phagostimulants (Pliske et aI., 1976).
Moths of the families Ctenuchidae and Arctiidae also are
attracted to plants containing pyrrolizidine alkaloids. In par-
ticular, larvae of Nyctemera annulata (the magpie moth)
ingest pyrrolizidine alkaloids from a variety of Senecio spe-
cies. Larvae that feed on Senecio spathulatus are able to
store pyrrolizidine alkaloids. The alkaloids subsequently ap-
peared in the adult moths and their eggs and in a parasite
of the larvae of this species (Benn et aI., 1979; Goss, 1979;
Schneider, 1987; Specialist Periodic Reports, Alkaloids,
1978).
The moth Utetheisa ornatrix consumes plants of the
genus Crotalaria that contain pyrrolizidine alkaloids. Al-
though adults normally are not eaten by the spider Nephila
c/avipes, moths raised in the laboratory were consumed.
Males of this species also produce two pyrrolizidines that
are closely related to danaidal (10) and three hydrocarbon
pheromones. The pyrrolizidines are passed from the male to
the female and deposited in the eggs (Eisner and Meinwald,
1987).
The aposematic grasshopper Zonocerus variegatus se-
HO
senecipbyJlin N-oxide (12)
Fig. 30.5. Compounds derived from pyrrolizidine alkaloids found in insects (modified from Harborne, 1982).
Pyrro/izidine, Quinolizidine, and lndolizidine Alkaloids 551
questers monocrotaline (8) obtained from its food plant Cro-
talaria retusa (Bemays et aI., 1977).
In addition to the use of pyrrolizidine alkaloids as protec-
tive chemicals, a number of species of three groups of Lepi-
doptera (Danainae, Ithomiinae, and Arctiidae) biosynthesize
pheromones from these compounds thatthey acquire by phar-
macophagy or larval feeding (Schneider, 1987).
Danaid butterflies can metabolically alter pyrrolizidine
alkaloids without apparent harm. Individuals of the Ameri-
can monarch butterfly, Danaus plexippus, captured in the
field were found to contain pyrrolizidine alkaloids that were
present in food plants at the capture sites. Adults of D. plex-
ippus were able to store alkaloids for several days. Unlike
certain other species, however, these male butterflies do not
secrete alkaloid-derived substances on their hairpencils, nor
do the hairpencils figure prominently in courtship. It has
been suggested that the alkaloids may contribute to the lack
of palatibility of the butterflies to potential predators (Edgar
et aI., 1976; Pliske, 1975).
Male butterflies of several other species of the genus Da-
naus (17 out of 23 tested) ingest pyrrolizidine alkaloids and
convert them into pheromones such as danaidone (11), da-
naidal (10), and hydroxydanaidal (9) that are released from
the abdominal hairpencil organs during courtship behavior
(Fig. 30.5) (Boppr", 1978; Schneider, 1987). Certain male
danaid butterflies feed on plants in the Senecioneae (As-
teraceae) and utilize pyrrolizidine alkaloids as a source for
compounds such as (9-11). Compounds such as danaidone
(11) are used by the male butterflies of the queen butterfly
(Danaus gilippus) (of Africa and Australia) as female flight
toxic form bound
to liver
pyrrole I
(R)-hydroxydanaidal (9)
CO,H
(14)
552 Pyrrolizidine, Quinolizidine, and lndolizidine Alkaloids
arrestants or as aphrodisiacs and thus play a vital part in
the prelude to mating. The male deposits .. dust" of this
compound and a viscous material on the antennae of the
female butterfly, and mating usually ensues (Eisner and
Meinwald, 1987; Scbneider, 1987). Danaus chrysippus
males must dip their hairpencils into the wing pockets (scent
organs) before pheromones (such as 14) are produced (Bop-
pre et aI., 1978; Scbneider, 1987; Specialist Periodic Re-
ports, The Alkaloids, Vol. 8,9, and to). When the butterflies
are raised in the laboratory away from the host plants, they
lack the pyrrolizidine alkaloids and have limited reproduc-
tive success (Boppre, 1978; Schneider, 1987).
It has been hypothesized that the ancestral food plants of
these butterflies were plants that contained both pyrroliz-
idine alkaloids and cardiac glycosides (Edgar et al., 1974);
however, few plants today meet these criteria. A few species
of apocynaceous plants have both types of compounds but
have not been reported to serve as hosts for the insects.
Clearly, we lack sufficient information to explain the origin
of such complex pheromonal, reproductive, mimicry, and
protective systems.
In the case of species of the arctiid moth, Creatonos, not
only are the pyrrolizidine alkaloid metabolites involved in
courtship, but they are also involved in the growth and devel-
opment for the pheromone-producing organ in the pupa
(Scbneider, 1987).
The stems and leaves of Castilleja rhexifolia (Scrophula-
riaceae) contain senecionine (5) and its N-oxide (obtained
from Senecio triangularis) as their main alkaloids. The
major alkaloid of the blossoms and seeds is rhexifoline, an
iridoid-monoterpene-derived alkaloid, which is found in
many Castilleja species. These plants serve as a host for the
plume moth, Platyptilia pica. The larvae primarily eat the
green seeds. Both the larvae and the adults of this insect
contain rhexifoline (Roby and Sterrnitz, 1984). Plants of C.
hispida contain quinolizidine alkaloids, and occasional
plants of C. sulphurea contain quinolizidine alkaloids,
whereas those of C. occidentalis do not contain alkaloids
other than rhexifoline. The iridoid monoterpene content of
all these alkaloids is similar. The larvae were found to ex-
crete the monoterpene iridoids (Stermitz et al., 1986).
Larvae of the chrysomelid beetle Oreina cacaliae pro-
duce seniciphylline N-oxide (12) as a part of their defensive
secretions. This pyrrolizidine alkaloid probably is derived
from the alkaloids of the host plant Adenostyles leucophylla
(Asteraceae: Senecioneae) (Pasteels et al., 1988).
Larvae of the arctiid moth Creatonotos transiens accumu-
late pyrrolizidine alkaloids when they feed on plants contain-
ing these compounds. Other types of alkaloids tested were
excreted in the frass (Wink and Scbneider, 1988). Pyrroliz-
idine alkaloids act as precursors for pheromones, but also
as morphogens for the development of the male scent organ
(Wink and Schneider, 1988).
Larvae of Gnophaela latipennis consume plant material
of Hackelia californica (Boraginaceae), butlarvae and emer-
gent adults contain a pyrrolizidine alkaloid with a different
necie acid than that of the host plant (L'Empereur et aI.,
1989). The alkaloids of the plant occurred primarily as N-
oxides.
Aphids that feed on Senecio species sequester pyrroliz-
idine alkaloids. A ladybird beetle that feeds on the aphids,
in tum, sequesters these compounds (Hartmann, 1991).
Pyrrolizidine alkaloids also have been found in amphib-
ians. Certain of these amphibian alkaloids also occur in in-
sects. For example, the venom of the thief ant, Solenopsis
xenovenenum, is an amphibian pyrrolizidine (Daly et al.,
1993).
Pyrrollzidine Alkaloids and Parasitic Plants
Members of the genus Castilleja are hemiparasites that
attack many species of host plants, especially those in the
Asteraceae and Fabaceae. Plants of Castilleja linariifolia
that utilize sagebrush (Artemisia species which lack alka-
loids) are devoid of alkaloids. Several species that parasitize
quinolizidine-containing legumes also contain similar alka-
loids, although not in identical concentrations. Other species
that attack Senecio species contain pyrrolizidine alkaloids.
The variability of alkaloid content in Castilleja species is
linked to that of the host plant (Stermitz and Harris, 1987).
Plants from five species of Pedicularis (Scrophularia-
ceae) take up alkaloids from their host plants. Those of Pe-
dicularis groenlandica and P. bracteosa take up senecionine
(5) from the host Senecio triangularis. Those of Pedicularis
crenulata contain anagyrine (Fig. 30.1) (a quinolizidine al-
kaloid) from the host Thermopsis divaricarpa. Plants of Pe-
dicularis racemosa contain quinolizidine alkaloids from a
Lupinus argenteus hybrid (Scbneider and Stermitz, 1990).
lbe Role of Pyrrolizidine Alkaloids
in Livestock Poisoning
Many pyrrolizidine-alkaloid-containing plants are poi-
sonous to livestock (Hartmann, 1991). Over 300 plants from
at least 30 genera and 6 families that contain this group of
alkaloids are responsible for livestock poisoning. Probably
the mOSt important of these are plants of the genera Crota-
laria, Heliotropium, Senecio, and Symphytum (Soffness and
Cordell, 1985). Pyrrolizidine alkaloids produce hepatotoxic
effects; the action tends to be cumulative. As little as 1-5%
of the animal's weight in plant material is enough to be fatal.
The LOsos of a variety of pyrrolizidine alkaloids range from
about 50 to 1100 mg/kg. Monocrotaline (8) has an LOso i.p.
in rat of 175 mg/kg; retronecine (1) has an LOso i.p. of 634
mg/kg in mouse; senecionine (5) has an LOso i.p. of 50
mg/kg in mouse (Wink, 1993b). The toxicity of the N-oxides
of these alkaloids may be about the same or less as the
alkaloids themselves (Suffness and Cordell, 1985). How-
ever, N-oxides do not have the bitter taste associated with
the alkaloids (Wrobel, 1985).
The toxicity may be due to the formation of pyrrole esters
that have potent alkylating properties (Fig. 30.6). Hydroxy-
danaidal (9) has been suggested as a major hepatotoxic com-

Fig. 30.6. Pyrrole esters (modified from Suffness and Cordell, 1985; used with pennission of the copyright owner, Academic Press, New York).
pound (Harborne, 1986). These esters are produced by me-
tabolism of pyrrolizidine alkaloids in the mammalian liver
and are able to bind to· certain sites in the liver as well as
with macromolecules such as DNA. Some studies suggest
that the toxicity of pyrrolizidine alkaloids lies not in their
own structures but in the one major metabolite (13) to which
they are converted. This dehydrogenation product produced
by mammals is much more toxic. Hydrolysis of the complex
ester groups of these compounds yields retronecine, which is
then dehydrogenated. More recently, however, a breakdown
product, E-4-hydroxyhex-2-enal (14), has been suggested to
be the actual reactive metabolite that binds to DNA in the
liver (Harborne, 1986).
Human Poisoning by Pyrrolizidine
Alkaloids
Human health problems have been attributed to the acci-
dental consumption of plant materials that contain pyrroliz-
idine alkaloids (Beier and Nigg, 1992). The consumption of
wheat containing seeds of H eliotropium popovii has caused
a large outbreak of veno-occlusive disease in Mghanistan.
The main alkaloid present was heliotrine (15). In India, simi-
lar problems have occurred with Crotalaria species.
Pyrrolizidine alkaloids also occur in honey made from
Senecio jacobaea (tansy ragwort) and in milk of cattle that
feed on this plant.
Herbal teas are responsible for poisoning problems as
well (Beier and Nigg, 1992). In Arizona, a number of cases
of veno-occlusive disease have been attributed to the con-
sumption of tea from Senecio longilobus, whereas a similar
poisoning in West Germany is thought to have arisen from
senecionine in a Petasites species (Robins, 1993). Tea from
comfrey leaves (Symphytum spp., Boraginaceae) has long
been used (Schneider, 1987); however, comfrey leaves and
roots cause tomors when fed in the diet to rats. Pyrrolizidine
alkaloids have been identified as one of the causes of primary
liver cancer in countries of central Africa, where the inci-
dence of this cancer is the highest in the world. Many pyrrol-
izidine alkaloids are carcinogenic and have been demon-
strated to induce tumors in a number of different animal
systems.
Medicinal Uses of Pyrrollzidine Alkaloids
The medicinal uses of pyrrolizidine alkaloids and pyrrol-
izidine-alkaloid-containing plants bave been questioned, be-
Pyrrolizidine, Quinolizidine, and Indolizidine Alkaloids 553
):.AoeOR ~eHO
~!J 80
E-4-bydroxy-1-enaI(4)
cause of the cumulative toxic effects of these compounds
(Roder, 1992). Although the toxicity of specific compounds
varies, the use of many herbal remedies involving plants of
the Asteraceae and Boraginaceae that may contain pyrroliz-
idine alkaloids should be avoided.
A variety of pyrrolizidine alkaloids and their N-oxides
have antitumor activity (Wink, 1993b). Herbal material of
Senecio vulgaris (Asteraceae) has been used for hundreds
of years as a treatment for cancer. The active compounds
have been shown to be senecionine (5) and senecionine N-
oxide. Indicine N-oxide (16) from Heliotropium indicum
(Boraginaceae) has pronounced antitumor activity. Mono-
crotaline (8), from several Cratalaria species (Fabaceae),
has similar activity (Blasko and Cordell, 1988; Suffuess and
Cordell, 1985). Alkylation seems to be involved in the antito-
mor activity. As the N-oxides cannot serve as enamines and
hence cannot be directly involved in alkylation, these com-
pounds should only be active to the extent they are converted
to the free bases. At least in the case of indicine N-oxide
(16), this does not appear to be the case (Suffness and Cor-
dell,1985).
Senecionine (5) and senecionine N-oxide have been iden-
tified as the antifertility agents from Senecio vulgaris (Tu
et a1., 1988).
QUII'IOLJZlDII'IE ALKALOIDS
Quinolizidine alkaloids are derived from lysine and have
two fused 6-membered rings that share a nitrogen atom. In
contrast to the pyrrolizidine alkaloids, quinolizidine alka-
loids usually occur free. At least 570 quinolizidine alkaloids
are known (Verpoorte et a1., 1991).
This group of alkaloids primarily is found in the subfam-
ily Papilionoideae of the family Fabaceae; quinolizidine al-
kaloids are the most commonly encountered alkaloids in this
family (Howard and Michael, 1986; Kinghorn and Ba-
landrin, 1984). Quinolizidine alkaloids have been reported
from all plant parts, but in most plants, they are synthesized
in young photosynthetic tissues (Wink, 1987).
Lupine alkaloids are among the simplest representatives
of this group; they are common in the genus Lupinus (Fig.
30.7) (Aslanov et aI., 1987; Wink, 1984b).
Studies with cell suspension cultures have established
that alkaloid biosynthesis undergoes a diurnal rhythm (Kin-
554 Pyrrolizidine, Quinolizidine, and Indolizidine Alkaloids
oY
(-)-sparteioe (17) angustifoline (21)
/OH
CO'
'<::: NH H i
I N
° N
(-)-anagyrine (29) (+)-17-oxosparleine (25)
Fig. 30.7. Some representative quinolizidine aIkaloids.
ghorn and Baiandrin, 1984; Wink and Witte, 1984). Maxi-
mum alkaloid synthesis occurs during the day and dimin-
ishes at night. This confirms suggestions that lupine alkaloid
biosynthesis undergoes light-dependent regulation (Kingh-
orn and Balandrin, 1984; Wink and Witte, 1984). The alka-
loids are synthesized in the leaves and transported to the
seeds, pods, and roots. Ready uptake of quinolizidine alka-
loids by parasitic plants suggests that this transport occurs
via the phloem (Hartmann, 1991). During senescence of
leaves, the concentration of alkaloids drops by as much as
90% (Kinghorn and Balandrin, 1984).
The level of quinolizidine alkaloids in seeds decreases
greatly during germination, suggesting utilization of the al-
kaloids as a uitrogen source. Yoimg plants with fully devel-
oped leaves are able to synthesize these compounds. Lupin
cell cultures can survive and grow on media that contain
sparteine (17) as the only nitrogen source (Wink and Witte,
1985).
Cutting up leaflets of Lupinus polyphyllus induces a rapid
increase in quinolizidine alkaloids of up to 400% within
2.5-4.0 h. This response occurs under a variety of conditions
and is neither a constitutive defense nor the usual type of
induced response (Wink, 1983a).
Certain other groups of alkaloids that coincidentally have
a quinolizidine ring system are discussed in other chapters.
For example, the alkaloids of the Lythraceae are discussed
in Chapter 37 and those of the genus Nuphar are discussed
in Chapter 36. Yet other quinolizidine alkaloids (18 and 19)
are known from the Ericaceae (Vaccinium myrtillus) and
the Euphorbiaceae (Poranthera corymbosa) (see Piperidine
rhombifoline (28) matrine (26)
lamprobine
Alkaloids in Chapter 29) (Fig. 30.7) (Howard and Michael,
1986).
Most of the legume species that have been introduced into
tissue culture produce only small amounts of quinolizidine
alkaloids (Ellis, 1988).
Techniques for analysis (Kinghorn and Balandrin, 1984;
Wink, 1987, 1993a) and NMR and mass spectra (Aslanov
et al., 1987; Wink, 1987) of quinolizidine alkaloids have
been reviewed.
Biosynthesis
Quinolizidine alkaloids are derived from lysine. Studies
with labeled precursors indicate that a symmetrical interme-
diate, cadaverine (20), is involved in their formation (Her-
bert, 1988; Kinghorn and Balandrin, 1984; Leete, 1983;
Spenser, 1985), although no intermediate comparable to the
dimeric form plays a role in the formation of pyrrolizidine
alkaloids is involved (Spenser, 1985). Much recent informa-
tion is based on cell suspension cultures of Lupinus polyphyl-
Ius, Baptisia australis, and Sarothamnus scoparius (all Faba-
ceae). Lysine decarboxylase is localized in leaf chloroplasts
(Wink 1987; Wink and Hartmann, 1982, 1984); the presence
of a diamine oxidase does not appear to be involved. Lysine
decarboxylase is found in all parts of Lupinus plants.
[3,3-2H21 Cadaverine is incorporated into ( + )-Iupanine
(21) and (+ )-13a-hydroxylupanine (23) in Lupinus pol-
yphyllus andL. angustifolius, respectively, into (+ )-angusti-
foline (22) in L. angustifolius and into (- )-Iupinine (24),
and (- )-sparteine (17) in L. luteus (Fig. 30.8). The labeling
patterns were determined by 2H_NMR spectroscopy. Car
 Pyrrolizidine, Quinolizidine, and Indolizidine Alkaloids 555

bon-3 of cadaverine remains unaffected by events during
condensation. Retention of deuterium at position 13 of 13a-
hydroxylupanine indicates that the introduction of oxygen
at this site cannot involve keto or enol intermediates. Further,
the labeling of C-13 of angustifoline (22) by deuterium indi-
cates that the allylic moiety comes from cadaverine (Herbert,
1988; Spenser, 1985).
(IR)-[1-2HIlCadaverine afforded sparteine (17) that was
labeled with deuterium at C-2a, C-6J3, C-lla, C-15a, and
C-17a, whereas (IS)-[1-2HIlcadaverine gave sparteine that
was labeled with deuterium at C-2J3, C-lOa, and C-17a
(Fraser & Robins, 1987). The appropriate results were also
obtained for lupanine and angustifoline. These results were
compatible with the hypothesis that these alkaloids are modi-

C - D5P:
(a)
lysine cadaverine (20)

D NH, D N

D 3 D D. D
NH, N A D

(-)-sparleine (17)

~ ~
D'N DN
D D D
D D,,, D
N ~ D N Ii OH

°(+)-lupanine (21) ° (+)-13a-hydroxylupanine (23)

:ro'
CH,OH
D~D'NH
D n
N ~ D

(-)-lupinlne (24)
° anguslifoline (22)
D H

('-'NH'

yNH'
D H
(R)-[I-'Hlcadaverine

~
('-'NH'
'xNH,
H D
(S)-[l-'H]cadaverine
- D H D
(b)

Fig. 30.8 (a & b). Labeling studies for quinolizidine alkaloid biosynthesis (modified from Herbert. 1988 and Spenser. 1985; used with pennission of
the copyright owners, The Royal Society of Chemistry, Cambridge and the International Union of Pure and Applied Chemistry, Oxford. respectively).
556 Pyrrolizidine, Quinolizidine. and Indolizidine Alkaloids

£:)
C:B'~ Q~. -
o

si attack at C-2 from the face tbat is si

cadaverine (20)

~
.HR atC-3

Hs
~ ~N~ NH
N~ -

loss of lO(pro-1OR)-proton

l~~~ -
~~--~-
l~HV ·.··k!!' il
--........" ~
re-attack at C-ll from the face
that is si at C-9

H
re attack ofH- at ColO and C-17 sparteine (17)
Fig. 30.9. Proposed biosynthesis of quinolizidine alkaloids (Spenser, 1985; modified and used with pennission of the copyright owner, the International
Union of Pure and Applied Chemistry, Oxford).

fied trimers of a I-piperideine. [2-2HJ-a l-Piperideine gave
labeling at C-613, C-ll"', and C-17", (Herbert, 1986). Be-
cause lupanine and sparteine retain deuterium from (lR)-[I-
2Hdcadaverine and from [2-2H]-a 1-piperideine at C-17", at
a similar level to that at positions 11", and 613, both 17-
oxosparteine (25) and the 1,2-didehydrospartenium ion are
excluded as intermediates (Fraser and Robins, 1987 Herbert,
1986). Similar evidence excludes lO-oxosparteine or 1,2-
didehydrosparteniurn ion as intermediates and excludes the
possibility that lupanine is a direct precursor of sparteine
(Herbert, 1986). The results of feeding studies leading to
the formation of quinolizidine alkaloids have been tabulated
(Leete, 1983).
In whole plants, leaf chloroplasts convert cadaverine di-
rectly into lupanine (21) without releasing free intermediates
in a channeled process involving membrane-associated en-
zymes (Kinghorn and Balandrin, 1984). It is possible that
matrine (26) and other related types of quinolizidine alka-
loids are synthesized by a similar channeled process (King-
horn and Balandrin, 1984; Wink, 1987).
Cytisine (27), the second most widely distributed quino-
lizidine alkaloid (after sparteine), is derived from sparteine
(17) in Lupinus luteus by loss of ring D (Fig. 30.9). Interme-
diate compounds in this process such as angustifoline (21)
and rhombifoline (28), which are intermediate in this pro-
cess, are known also.
 Pyrrolizidine, Quinolizidine. and Indolizidine Alkaloids 557

Quinolizidine alkaloids are accumulated in the epidermal Systematic Usefulness of QuinoIizidine

cells of leaves, petioles, and stems. These plant parts often
contain as much as 5-6 mg/g fresh weight. Although the
alkaloids are accumulated in the epidermis, they are synthe-
sized in chloroplasts of mesophyll cells. Specific mecha-
nisms for movement of the alkaloids into the vacuoles of
the epidermal cells appear to involve carrier proteins (Mende
and Wink, 1987; Wink, 1985b).
Complex QulnoIizidine Alkaloids
Complex quinolizidine alkaloids are found in other leg-
ume genera, such as those in the genus Omwsia (tribe So-
phoreae) (Fig. 30.10). In view of recent biosynthetic findings
on the biosynthesis of other quinolizidine alkaloids, it seems
possible that these alkaloids may be synthesized directly
from four cadaverine units (Kinghom and Balandrin, 1984).
Alkaloids
Quinolizidine alkaloids occur in 10 of the most primitive
tribes of the Papilionoideae (Fabaceae) (Kinghorn and Ba-
landrin, 1984). They are especially common in the Sopho-
reae, Podalyrieae sensu lato, and the Genisteae (Wink,
1987). Isolated occurrences have been reported from Anaba-
sis aphylla (Chenopodiaceae), Caulophyllum thalictroide,
Leontice spp. (Berberidaceae), Chelidonium majus (Papav-
eraceae), Castilleja miniata (Scrophulariaceae), Orobanche
rapum-genistae (Orobanchaceae), Osyris alba (Santala-
ceae), Solanum lycocarpum (Solanaceae), and in species of
the Ranunculaceae (Wink, 1987).
Cell suspension cultures of Lupinus polyphyllus produce
quinolizidine alkaloids when foreign alkaloids are added to
the cultures (Brooks and Watson, 1985), or with a number of
other "disturbances." Quinolizidine alkaloid accumulation

-
OH
OH /OH /

CO-D
1( ~~!0 ~ii0
fJ
N .......,,'"
N ~ N+ _.""",,, HN
~) HN_ ~ UN -- ~-.. -
NH+ N~- H~_
H~.". -

H~ HOO H
H ;~/"-,

~ j !j.""'~.J
H,~ ...
NJiN - H ......~
NH

ormosanine
H H

penamine
Fig. 30.10. Biogenesis of Ormosia alkaloids (Geissman and Crout, 1969).
SS8 Pyrrolizidine, Quinolizidine, and Indolizidine Alkaloids
sparteine (17) lupaolne (21)
~~l ~ll
~k~OH ~N~'OH ~N~
o o
18-hydroxysparteine baptifolene
Fig. 30.11. Quinolizidine alkaloids from Baptisia.
also was demonstrated in cell cultures of Atropa belladonna,
Chenopodium rubrum, Conium maculatum, Daucus carota,
Spinacia oleracea, and Symphytum officinale. Nonnally,
these plants produce other types of alkaloids or none at all.
This suggests that the genes for the production of quinolizi-
dine alkaloids are not restricted to the Fabaceae, but are
more widely distributed among higher plants. Nonetheless,
quinolizidine alkaIoids are accumulated to measurable levels
only in legumes under most conditions (Wink and Witte,
1983).
Alkaloids of the genus Baptisia (Fabaceae) have been
studied by Mabry and co-workers (Mears and Mabry, 1971;
Waller and Nowacki, 1978). These compounds are highly
variable within this genus, which contains about 16 species
and occurs widely in the eastern half of North America.
Hundreds of populations of these species have been studied.
Several quinolizidine alkaloids are found in Baptisia species
(Fig. 30.11).
Ten plants of Baptisia leucophaea from two populations
approximately 120 miles apart proved to be similar in alka-
loid chemistry at a given developmental stage, but differ-
ences did occur during development of the plant. As the
plants matured, the amount of cytisine (27) decreased and
that of anagyrine (29) (Fig. 30.1) increased. The amount of
total alkaIoids decreased from 1.02 to 0.65 to 0.08% dry
weight of the plant. Differences in individual plants also
were observed. The inheritance of alkaloids in hybrid plants
was complex but did clearly indicate that hybridization was
taking place within the populations studied. Under the same
situations, the inheritance of flavonoids in hybrids tended
to be additive. In many of the hybrids, anagyrine (29) or
thennopsine (30) was dominant, whereas the parental types
contained a tricyclic-type alkaloid such as cytisine or N·
methylcytisine (31) (Mabry and Mears, 1970). Variations
were observed in different parts of plants as well. The most
striking changes were observed in reproductive parts (i.e.,
buds, flowers, fruits, and seeds).
The widespread occurrence of the same alkaloids within
the genus precluded separation of the species into phyletic
groups. In all but one species, cytisine (27) or N-methylcyti-
thermopsine (30) N·methylcytislne (31)
~j
cytisine (27)
sine (31) or a combination was dominant. The presence of
almost the same alkaloids in the genus Thermopsis suggests
a close relation of these two genera.
The distribution of many of the same alkaIoids in the
genus Lupinus correlated closely with taxonomic groupings.
The patterns of inheritance of many quinolizidine alkaloids
have been examined (Waller and Nowacki, 1978). In gen-
eral, these patterns are simple and easily explainable by
means of genetics.
The presence of quinolizidine alkaIoids in the African
genus Camoensia suggests that this genus belongs to the
subfamily Papilionoideae, rather than to the Caesalpini-
oideae (Watennan and Gray, 1987).
Biological Activity of Quinolizidine
Alkaloids
A variety of quinolizidine alkaloids inhibit phenylalanine
tRNA binding to ribosomes or aspects of translation (Wink,
1993b). These effects probably explain most of the pro-
nounced toxicity of this group of alkaloids. Anagyrine (29)
and cytisine (27) are teratogenic. Angustifoline (22), 13-
hydroxylupanine (23), lupanine (21), sparteine (17), and 13-
tigloyloxylupanine have activity against gram-positive bac-
teria. Lupanine, sparteine, and 13-tigloyloxylupanine have
antifungal activity against the fungus Erysiphe graminis
(Wink, 1993b).
Quinolizidine alkaloids strongly inhibit gennination of
lettuce seeds. Alkaloid esters, for example, 13-tigloyloxylu-
panine, inhibited gennination completely at a concentration
of 6 tuM (Wink, 1983b). Sparteine (17) and cytisine (27)
inhibit radicle growth in Lepidium (Wink, 1993b).
The importance of quinolizidine alkaIoids for protection
of plants against pathogens and herbivores has been re-
viewed (Wink, 1988). Incorporation of sparteine (17) sulfate
at 0.1 % into artificial diets is totally lethal to the larvae of
Callosobruchus maculatus (Janzen et aI., 1977).
A number of quinolizidine alkaloids have been demon-
strated to serve as feeding deterrents (or to be lethal to var-

ious insects). Others are nematicidal and molIuscicidaI
(Wink,1993b).
The quinolizidine alkaloids lupanine (21), sparteine (17),
lupinine (24), 13-hydroxylupanine (23), and 17-hydroxylu-
panine are toxic to and inhibit the growth of the hemipterous
aphid Acyrthosiphon pisum that normally feeds on quinolizi-
dine-free peas and beans (Harborne, 1986; Kinghorn and
Balandrin, 1984). Lupinine (24) has been shown to be a
feeding deterrent and growth inhibitor for the two-striped
grasshopper Me/anop/us bivittatus (Orthoptem). In general,
aphids avoid feeding on plants that contain quinolizidine
alkaloids, but some phloem-feeding aphids were also found
to contain these alkaIoids (Kinghorn and Balandrin, 1984).
Sparteine (18) in Sarothamnus scoparius acts as a feeding
stimulant for the specialized aphid Acyrthosiphon spartii.
Larvae of the blue Iycaenid butterfly, Plebejus icarioides,
are obligate feeders on several alkaIoid-rich Lupinus species.
The butterfly readily tolemtes the alkaIoids, but these com-
pounds do not appear to be essential for the diet of the adult
insect (Kinghorn and Balandrin, 1984). The larvae, however,
will not accept other types of plants and succumb without
lupines in their diet (Waller and Nowacki, 1978).
In the aphid genus Aeyrthyosiphon, two closely related
species feed on legumes. Individuals of one species, A. pisii,
develop well only when they feed on plants lacking quinoliz-
idine alkaloids. Those of the second species, A. spartii, only
develop when they feed on plants containing these alkaloids.
This aphid actually appears to be a!!mcted by sparteine (17)
(Waller and Nowacki, 1978).
The aphid Macrosiphon albifrons is attracted to Lupinus
species with a chamcteristic alkaloid pattern. Individuals that
had low alkaloid content were not attacked, nor were plants
with different quinolizidine alkaloid composition. This aphid
excretes a portion of the alkaloids in the honeydew and re-
tains a portion in its body (Wink and Romer, 1986). Another
aphid, Aphis cytisorum, which infests broom plants (Cytisus
scoparius), accumulates up to 0.5 mg alkaloid per gram fresh
weight. The alkaloids are similar in composition to those of
the host plant, 17-oxosparteine (25), sparteine (17), 12,13-
dehydrosparteine, and iupanine (21) (Wink et al., 1982).
Some plants of the genus Castilleja are hemiparasitites
that attack many species of host plants, especially those in
the Asteraceae and Fabaceae (McCoy and Stemitz, 1983).
Plants of Castilleja linariifolia that ntilized sagebrush (Arte-
misia species which lack alkaIoids) were devoid of alkaIoids.
Several species that parasitized quinolizidine-containing leg-
umes contained similar alkaloids, although not in identical
concentrations. Other Castilleja species that attacked Sene-
cio species contained pyrrolizidine alkaIoids. The variability
of alkaloid content in Castilleja species is linked to that of
the host plant (Stermitz and Hams, 1987).
Plants from five species of Pedicularis (Scrophularia-
ceae) were found to take up alkaloids from their host plants.
Those of Pedicularis groenlandica and P. bracteosa took
up senecionine from the host Senecio triangularis. Those of
Pedicu/aris crenulata contained anagyrine (29) (a quinolizi-
Pyrrolizidine, Quinolizidine, and lndolizidine Alkaloids 559
dine alkaloid) from the host Thermopsis divaricarpa. Plants
of the parasite Pedicularis racemosa contained quinolizidine
alkaIoids from a Lupinus argenteus hybrid (Schneider and
Stermitz, 1990). Plants of Pedicularis semibarbata from
California were shown to contain quinolizidine alkaloids that
they obtained via root pamsitism from Lupinus fulcratus.
Other plants were alkaloid free (Stermitz et al., 1989).
Plants of the parasite Cuscuta reflexa (Cuscutaceae or
Convolvulaceae) acquire quinolizidine alkaloids from the
host Spartiumjunceum (Hartmann, 1991). The species Cus-
cuta reflexa and C. platyloba take up alkaloids from a variety
of legume host plants, including Cytisus praecox, Chamae-
cytisus hirsutus, Petteria ramentacea, andSpartiumjunceum
(Baumel et aI., 1994).
Polyphagous molluscs such as Helix pomatia and Arion
rufus generally do not feed on plants containing alkaloids.
These species avoided the alkaloids cytisine (27) and N-
methylcytisine (31) more than lupanine (21). The molluscs
clearly preferred alkaIoid-free artificial diets (Wink, 1984a).
The presence of these alkaloids also has been shown to in-
hibit feeding of mammals and insects and to inhibit growth
of bacteria and fungi (Wink, 1985a). The ranges of alkaIoids
in the plants tested were higher than those shown to be active
in the labomtory.
lIIedicinal Uses of Quinolizidine Alkaloids
Both matrine (26) and cytisine (27) have established ame-
bicidal activity (Phillipson and O'Neill, 1987). Matrine has
antitumor activity against Ehrlich ascites tumor (Wink,
1993b).
Quinolizidine Alkaloids and Livestock
Poisouing
Alkaloids of this class have long been known for their
toxicity to range animals (Hartmann, 1991; Kinghorn and
Balandrin, 1984). Sheep seem to be especially susceptible.
Poisoning with quinolizidine alkaloids does not appear to
be cumulative. Most problems occur in the fall when seeds
(which often accumulate the alkaloids in large quantities)
are produced (Hartmann, 1991). Cytisine (27) and anagyrine
(29) are particularly poisonous and have temtogenic activity
in higher animals (Kinghorn and Balandrin, 1984). LDso
values (i.p.) range from about 10 to 600 mg/kg. The LDso
i.p. for cytisine (27) in mouse is 9.3 mgikg, that for lupanine
(21) 80 mg/kg, and that for sparteine (17) 55 mg/kg (Wink,
1993b).
lIIescal-Hallucinogeuic Properties of
Quinolizidine Alkaloids
The seeds of Sophora secundiflora, the mescal bean or
colorin, have long been considered hallucinogenic by Indi-
ans of Mexico and the southwestern United States (Schultes
and Hofmann, 1973). The main alkaIoid in these seeds is
cytisine (27). Genista canariensis also has been considered
to be mildly hallucinogenic (Kinghorn and Balandrin, 1984).
560 Pyrrolizidine, Quinolizidine, and Indolizidine Alkaloids
Il'IDOLIZIDIl'IE ALKALOIDS
This group of bicyclic alkaloids has a fused 5- and 6-memb-
ered ring system and is intermediate in that regard to the
pyrrolizidine and quinolizidine alkaloids (Fig. 30.12). At
least 170 indolizidine alkaloids are known (Verpoorte et al.,
1991). In contrast to those groups, however, these alkaloids
usually have not been identified clearly as a distinct group
of alkaloids (Blbein and Molyneux, 1987; Molyneux, 1993).
Indolizidine alkaloids often do not react with Dragendorff
reagent or with ninhydrin and have often been missed in
screening programs.
The techniques for isolation, purification, and characteri-
zation of indolizidine alkaloids have been reviewed (Moly-
neux, 1993).
Other groups of alkaloids that coincidentally have this
ring structure will be discussed under better known group-
ings [e.g., the alkaloids of Aspidosperma (indole alkaloids,
Chapter 34), Erythrina (benzylisoquinoline alkaloids, Chap-
;lU
~-,)J-OO
swainsonine (35)
s1aframine (38)
Fig. 30.12. Some representative indolizidine alkaloids.
ter 32), Amaryllidaceae (alkaloids derived from both phenyl-
alanine and tyrosine, Chapter 33), and certain steroidal alka-
loids of the Solanaceae (alkaloids derived from terpenes,
Chapter 36).
Amphibians (probably best known are frogs of the genus
Dendrobates and toads of the genus Melanophryniscus) are
known to produce a number of indolizidine alkaloids. Some
representative alkaloids of this origin are illustrated in Fig.
30.13 (Daly, 1982; Daly and Spande, 1986; Daly et al., 1993;
Howard and Michael, 1986; Witkop and Gossinger, 1983).
Subcutaneous doses of pumiliotoxin B as low as 20 ,...g cause
death in mice. Pumiliotoxin B (32) interacts with voltage-
dependent sodium channels. Although pumiliotoxin A (33)
type class alkaloids originally were thought to be unique to
dendrobatid frogs, they are now known to occur in a variety
of amphibians (Dalyet al., 1993).
Several indolizidine alkaloids are known from Dendrob-
ium (Orchidaceae). Dendroprimine (34) is representative of
these compounds (Howard and Micheal, 1986).
ep
HO H
N+
O·
I
yH _.•, OH
swainsonine N-oxide (37) castanospermine (36)
'Cb '.c:±> ,
i
dendroprimine (34)
5
J
~'
julisporine (39)

\\ .S?
~
pPllllliDtoxin23'1A
Lt;
gephyrotcWnWAB
OR
OH
pumillotoxlnU7C allopumlllotoxln3J9A
~~
H
OR
OU N H OR
pumlllotonlnB('u)
pumilioloxinA (J3)
Fig. 30.13. Simple indolizidine alkaloids from amphibians (modified
from Howard and Michael, 1986; used with pennission of the copyright
owner, Academic Press. Orlando. FL).
The two most studied hydroxy indolizidine alkaloids are
swainsonine (35) and castanospennine (36). Swainsonine
occurs in Swainsona canescens (of Australia) and Astragalus
and Oxytropis (western United States) at levels of about
0.001-0.003%. These plants have long been known to pro-
duce characteristic livestock poisoning, both in the United
States and Australia (Elbein and Molyneux, 1987; Harris
et aI., 1987; Hartmann, 1991; Howard and Michael, 1986;
Molyneux and James, 1982). The similarity in chemistry of
Castanospermum and a South American genus Alexa sug-
gest that the two are closely related (Fellows et aI., 1989).
The symptoms of this intoxication are similar to those of
mannosidosis. Swainsonine (35), along with. another alka-
loid of this type, is found in the fungus Rhizoctonia legumini-
cola which is pathogenic on red clover. Swainsonine N-
oxide (37) occurs in Astragalus lentiginosus in addition to
swainsonine. Castanospennine (36) occurs in the Moreton
Bay chestnut or black bean (Castanospermum australe, Fa-
baceae). Castanospermine occurs at about 0.3% in mature
seeds and has also been detected in the leaves and bark of
the tree. Consumption of these seeds causes severe gastroin-
testinal pain. As is true for locoweed poisoning, some ani-
mals develop a preference for them, despite the often fatal
gastroenteritis that develops. Both swainsonine and casta-
nospennine are soluble in water, but are not highly soluble
in nonpolar solvents (Elbein and Molyneux, 1987; Fellows
et aI., 1989).
Castanospennine (36) is a component of the honeydew
of mealybugs (Pseudococcus longispinus) living on Casta-
nospermum australe (Molyneux et aI., 1990).
Pyrrolizidine. Quino/izidine, and Indolizidine Alkaloids 561
The alkaloid slaframine (38) is produced by cultures of
Rhizoctonia leguminocola grown on nontoxic red clover ex-
tract. This alkaloid is responsible for a series of characteris-
tics such as slobbering (excessive salivation) and lacrima-
tion. This .. disease" has been detennined to result from
consumption of the fungal mycelia (Elbein and Molyneux,
1987; Fellows et aI., 1989; Howard and Michael, 1986).
Several hydroxypiperidine alkaloids share properties with
hydroxyindolizidine alkaloids. These compounds are dis-
cussed in Chapter 29 in the section Piperidine Alkaloids.
Biosynthesis.
The discovery of the indolizidine alkaloid swainsonine
(35) and its N-oxide (37) in the leguminous genera Astraga-
lus, Oxytropis, and Swainsona suggests a biosynthetic route
somewhat resembling those of pyrrolizidine and quinolizi-
dine alkaloid biosynthesis (Harris et aI., 1987; Kinghorn and
OK Balandrin, 1984). The similarity of certain indolizidine alka-
N H
loids to coniine-related compounds, such as 8-coniceine (not
naturally occurring) has been observed.
The biosynthesis of slaframine (38) and swainsonine (35)
in Rhizoctonia leguminicola involves lysine and proceeds
via the intennediacy of pipecolic acid. Carbon atoms 2 and
3 have been demonstrated to come from acetate via malonate
(Fig. 30.14). The biosynthesis of swainsonine and related
compounds in plants does not appear to have been investi-
gated (Elbein and Molyneux, 1987; Harris et aI., 1987; How-
ard and Michael, 1986).
Differences in configuration of swainsonine (35) and sla-
framine (38) appear to arise by involvement of an iminium
ion similar to the situation involved in conversion of ( + )-
reticuline to (- )-reticuline in the benzylisoquinoline alka-
loid series (see Chapter 32) (Harris et aI., 1987).
Biological Activity of IndoIizidine Alkaloids
G1ycosidases are important in life processes in all organ-
isms. These compounds catalyze the hydrolysis of the sugar
moieties of numerous types of glycosides (see Chapter 1
and 15). The glycosidases of animals, fungi, and bacteria
degrade large molecules to prepare them for uptake by the
organism. Glycosides also are involved in cells as compo-
nents of catabolic systems. In many organisms, these en-
zymes are thought to be involved in the production of new
cell wall materials and expansion of existing cell walls. Fur-
thennore, glycosidases are important in the fonnation and
processing of glycoproteins (Elbein and Molyneux, 1987;
Howard and Michael, 1986).
Castanospennine (36) is a potent inhibitor of almond em-
ulsin l3-glucosidase. This alkaloid gives almost complete in-
hibition at 50 fLg/ml. At five times that level, castanosper-
mine did not inhibit a-glucosidase, a- or l3-galactosidase, a-
mannosidase, l3-glucuronidase, I3-N-acetylglucosaminidase,
or a-fucosidase. Castanospennine proved to be a competi-
tive inhibitor of amyloglucosidase and almond emulsin 13-
glucosidase. This alkaloid also inhibited glycoprotein pro-
cessing. Castanospennine inhibits plant root elongation, cy-
tomegaloviruses, and retroviruses (Wink, 1993b).
562 Pyrrolizidine. Quinolizidine. and lndolizidine Alkaloids

O
OH

--
H
i CO,H

NH ......:m;;:.;;:I.;;:D;;:.t;;:e_ ( ) - \ ..•"'OH
~~J
!

65-
OCOCH,

~d) 00

slaframine (38)
swainsonine (35)

Fig. 30.14. Biosynthesis of slaframine and swainsonine in Rhizoctonia leguminocola (modified from Howard and Michael, 1986; used with pennission
of the copyright owner, Academic Press, Orlando, FL),

Castanospennine (36) (1,6,7 ,8-tetrahydroxyoctahydroin-
dolizine) is a potent phytotoxin for dicotyledonous plants
at 300 ppb, and for monocotyledonous plants at 200 ppb.
Swainsonine is ineffective as an inhibitor of root elongation.
(Stevens and Molyneux, 1988).
Animal systems contain three distinct types of a-mannos-
idases. Swainsonine (35) inhibits one of these completely at
concentrations as low as 20 11m. At much higher levels (more
than 50 times), this compound did not exhibit inhibitory
activity toward \3-mannosidase, a- or \3-glucosidase, a- or \3-
galactosidase, \3-N-acetylhexosaminidase, or a-L-fucosidase
(Elbein and Molyneux, 1987). The alkaloid also alters nor-
mal processing of N-linked oligosaccharides and biosyn-
thesis of glycoproteins.
These compounds promise to be of great value for the
examination of the structure activity relationship of glyco-
tasis, intracellular transport, and viral infectivity. Both casta-
nospennine (36) and swainsonine (35) have been of interest
for study of mV-l (AIDS) (Fellows, 1988).
Castanospennine (36) is a feeding deterrent for aphids
and greenbugs (Wink, 1993b). Castanospennine is lethal tu
the larvae of the bruchid beetle Callosobruchus maculatus
and the flour beetle Tribolium confusum at 0.03% and 0.1 %
in the diet (Fellows et al., 1986).
The unusual indolizidine alkaloid julisporine (39) from
Prosopis juliflora (Fabaceae) possessed in vitro activity
against several dennatophytic fungi (Clark and Hufford,
1992).
Indollzldine Alkaloids In Insects
Indolizidine alkaloids are produced by the Pharaoh ant,

9&
proteins and their role in the immune response, cancer metas- Monomorium pharaonis. This tropical ant is now a common

HO=OHOH (bH ,:Y

(b: ,:Y

N N N

elaeocarplne (42) (+)-Isoelaeocarplne (43) (+)-elaeokanine (-)-e1aeokanlne B

(-)-elaookanine C isoelaeocarpine elaeokanine E peduncularine (44)

Fig. 30.15. Alkaloids of the Elaeocarpaceae,

 Pyrrolizidine, Quinolizidine, and Indolizidine Alkaloids 563

pest in North America and Europe where it has been intro-
duced. The alkaloids monomorine VI (40) and monomorine
I (41) are found in the poison gland and in the Dufour's
gland of the insect (Fig. 30.12). These alkaloids act as attrac-
tants for the Pharaoh ant (Howard and Michael, 1986).
Elaeocarpaceae Alkaloids
The primarily tropical family Elaeocarpaceae contains
about 350 species in 7 genera. The genus Elaeocarpus con-
tains indolizidine alkaloids almost exclusively, for example,
elaeocarpine (42) and isoelaeocarpine (43) (Fig. 30.15).
Another genus, Aristotelia, contains indole alkaloids
[e.g., peduncularine (44)], but these appear to be, at most,
only distantly related to those of Elaeocarpus (Bick and Hai,
1985). This genus is found in the temperate regions of the
southern hemisphere (Argentina, Australia, Chile, and New
Zealand). Although little biosynthetic work has been done,
the precursors have been suggested to be tryptamine and a
monoterpene such as nerol. The alkaloids of a third genus,
Aceralium, have not been studied.
PbenantbroindoUzidine Alkaloids
This group of about 20 alkaloids, best known of which
is tylophorine (45), are primarily found in the genus Tylo-
phora, but also occur in the genera Cynanchum (Vinceloxi-
cum), Anlitoxicum, and Pergularia of the family Asclepi-
adaceae. Some representatives of these alkaloids possess
simple indolizidine structures. Both these simple types and
phenanthroindolizidine alkaloids are also known to occur
in the Moraceae (Ficus), Urticaceae (Boehmeria), and the
Lauraceae (Cryptocarya) (Bick and Sinchai, 1981; Herbert,
1985; Howard and Michael, 1986).

~
I
""
-
.I ~
~"----£-.l
&'
CO,R
n 0 ,R

°
OCR,
!
.
CR,O
--

JQ7 " (46)

~ I
0) RN
,(CO,R

•
CR,O "" °
OR t
~NR'

RO
~ CO,R

CR,O
~ OR OCR,
tylophorine (45)
OCR,
CR
C R ' °' Z m °
I""
,6

1 N

CR,O
OR OCR,
CR,O :'
tylophorinlne (47) cryptopleurine (48)

Fig. 30.16. Proposed biogenesis of tylopborine (Bick and Sinchai. 1981; used with pennission of the copyright owner, Academic Press, Orlando, FL);
cryptopleurine.
564 Pyrrolizidine, Quinolizidine, and Indolizidine Alkaloids
Biosynthesis
In terms of biosynthesis, these alkaloids are derived front
tyrosine, phenylalanine, and ornithine (Fig. 30.16). Phenyl-
alanine appears to be converted to cinnamic acid before in-
corporation. Phenacylpyrrolidines (such as 46) are defined
as key intermediates. Doubly-labeled compounds of this type
were incorporated intact into tylophorinine (47). Oxidative
coupling steps yield tylophorine (45) and tylophorinine (47)
(Bick and Sinchai, 1981; Herbert, 1985; Specialist Periodic
Reports, Alkaloids, 1978, 1979).
Biological Activity of
PhenanthroindoUzidlne Alkaloids
Ty10phorine (45) has anti-inflammatory properties. Leaf
extracts of Ty/ophora species have been used to treat asthma
and rheumatism (Wagner and Proksch, 1985). Several alka-
loids of this group have pronounced antitumor activity
(Blasko and Cordell, 1988; Gellert, 1982). The activities of
tylocrebrine, tylophorine (45), and cryptopleurine (48) (a
phenanthroquinolizidine aIkaloid) (Fig. 30.16) are all less
than those of emetine, which they resemble in observed ac-
tivity (Blasko and Cordell, 1988). Tylophorine is toxic to
Paramecium caudatum at 1: 50,000 dilution, but has low
toxicity to mice and gninea pigs. Tylophorine is more than
twice as potent against cultured Entamoeba histo/ytica as is
emetine, a common drug for treating amebic dysentery
(Borris and Schaeffer, 1992).
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31
Alkaloids Derived from Anthranilic Acid
Introduction
Quinazoline and Pyrroloquinazoline Alkaloids
Biosynthesis
Distribution of Pyrroloquinazoline Alkaloids
Biological Activity
Quinazolinocarboline Alkaloids
Quinoline, Furoquinoline, Acridone, and 4-Quinoline
Alkaloids
Chemosystematics and Phylogeny
References
Il'ITRODVCTlOI'l
Anthrauilic acid (1) is an intermediate in the biosynthesis
of tryptophan (see Chapter 7) (Fig. 31.1). A number of alka-
loids, best known from the family Rutaceae, are biosynthes-
ized from this important primary compound.
Small amounts of N-methylanthranilate occur in a num-
ber of essential oils (Grager, 1980). Another simple repre-
sentative, darnasceuine (2), is found in the seeds of Nigella
damascena L. (Ranunculaceae) (Fig. 31.2). This alkaloid has
been shown to come from shikimic acid via anthranilic acid
(Cordell, 1981). [I4CH3J-Methiouine is an efficient precur-
sor of all three bound methyl groups (Grager, 1980; Geiss-
man and Crout, 1969).
Dianthalexin (4) and related N-benzoylanthranilic acid
derivatives are formed in response to fungal attack in Dian-
thus (Caryophylaceae) (Ponchet et aI., 1984).
Other compounds apparently are derived from 3-hydrox-
yanthranilic acid (3), for example, several compounds from
Tecoma stans (Bignoniaceae), are catabolic products oftryp-
tophan (Grager, 1980; Geissman and Crout, 1969). 3-Hy-
droxyanthranilic acid is involved in the biosynthesis of sev-
eral fungal pigments and in actinomycins from strains of
Streptomyces. Actinomycin A was isolated soon after peni-
cillin, but it was too toxic for general use. Actinomycin D
568
completely blocks transcription from DNA, and as cancer
cells usually divide faster than normal body cells, they are
preferentially killed by this antibiotic. Actinomycin D is one
of the most potent antitumor agents known.
An additional group of alkaloids that arises from anthra-
nilic acid, the harman alkaloids, is discussed in Chapter 35.
Avenalumins, 2,4-dihydroxy-7-methoxy-I ,4-benzoxazin-3-
one (DIMBOA), and related compounds are treated in Chap-
ter 7.
Both the I H- and 13C_NMR (nuclear magnetic resonance)
spectra and techniques for the isolation and characterization
of several groups of alkaloids derived from anthrauilic acid
have been reviewed (Crabb, 1982; Gray, 1993). The results
of feeding studies leading to several alkaloids derived from
anthrauilic acid have been tabulated (Leete, 1983).
In addition to the relatively simple anthranilic-derived
metabolites mentioned above, several distinctive types of
alkaloids are derived from this amino acid. Most of these
are associated with the Rutaceae and related families of the
Rutales. Among these groups of alkaloids are the quinazo-
line, pyrroloquinazoline, quinazolinocarboline, quinoline,
furoquinoline, and acridone types.
QlJ1l'IAZOLIl'IE Al'ID FYRROLOQlJ1l'IAZOLIl'IE
ALKALOIDS
About 60 simple quinazoline alkaloids have been isolated
from several plant families, microorganisms, and auimals
(Grager, 1980). Arborine (5), from leaves of Glycosmis spe-
cies (Rutaceae), is an example of this group of alkaloids
(Fig. 31.3) (Johne, 1986).
The biosynthesis of quinazoline alkaloids is not resolved,
but anthrauilic acid, probably as N-acetylanthranilic acid, is
a precursor (Cordell, 1981, Grager, 1980). Both anthranilic
acid and phenylalanine serve as precursors for arborine (5)
in Glycosmis arborea (Cordell, 1981).
 Alkaloids Derived from Anthranilic Acid 569

HO,C)) HO,C))
, 1 ~
~CO,H .0 h

-0 -
~ HO~ 0 HN HO,PO N Amadori

"" NH, - ~~H rearrange;ent

OH OH HoN0 H
cbormlsmic acid anthranilic acid (1)

HO,C~ Q NH, NH,

HO'POWHN
)l) ~HO,Pol-ACO'H
<" OP~
!dH
CO,H

OPO,H <"
(Jc(t:
1 1
H

NH
CO,H

H - 1 "",I OooH - ~ NH '

HO ~ NH
H OH 0
indole-3-g1ycerol phosphate L-tryptophan

Fig. 31.1. Biosynthesis of anthranilic acid and tryptophan (Atta-or-Rahman and Basha, 1983; used with pennission of the copyright owner, Oxford
University Press, Oxford),

(XI
::,....
CO,H

NH,
- Y Y
::,....
OH
1
CO'H

NH,
- ::,....
OCH,
1
CO'H

-
NH,

anthranilic acid (3) damascenine (2) dianthalexin (4)

Fig. 31.2. Biogenesis of damascenine (Geissman and Crout, 1969); dianthalexin.

Quinazoline alkaloids are known from the Acanthaceae
(Adhatoda, Anisotes), Araliaceae (Mackinlaya), Arecaceae
(Daemonorops), Fabacea (Galega), Hydrangeaceae (Hy-
drangea, Dichroa), Malvaceae (Sida), Rutaceae [Euxylo-
phora, Glycosmis, Hortia, Tetradium, Zanthoxylum (Fa-
gara)], Scrophulariaceae (Linaria), and Zygophyllaceae
(Peganum) (Griiger, 1980).
Febrifugine (6) (from Dichroa and Hydrangea, Hydran-
geaceae) is a febrifuge and has antimalarial activity (Cordell,
1981; Johne, 1986). Although about 100 times more active
than quinine against some types of malaria, this compound
is too toxic for clinical use. Glomerin (7) has been isolated
from the millipede Glomeris marginata.
The pyrroloquinazoline-type alkaloids are represented by

o
~~ r?)~N ~N
UNAvV~N~ UN)
~NH
V~A,
I I I ~ 0
CH, CH, CH, CH,

arborine (5) g10merin (7) glyeorine glyco.smtcine glycosminine

0( 1~NH 0 NH ,r,
(J(:,OCW:~
: ,. . Y U~N-;:~
.J." N" OH "" N '" ""
OH
febrifuglne (6) chrysogine pegamine glycophymoline

Fig. 31.3. Some representative quinazoline alkaloids (Jaime, 1986; used with pennission of the copyright owner, Academic Press, Orlando, FL.).
570 Alkaloids Derived from Anthranilic Acid
(rI CO'H
-+
::::,.. NH,
anthranilic acid
vasicinone (9) deoxyvasicinone (10)
Fig. 31.4. Selected pyrroloquinazoline alkaloids and the biogenesis of vasicine (modified from Johne, 1986; used with pennission of the copyright
own6l", Academic Press, Orlando, Fl.).
vasicine (8), vasicinone (9), and desoxyvasicinone (10)
which occur together in Peganum harmala L. (Zygophylla-
ceae) (Fig. 31.9). Pyrroloquinazoline alkaloids co-occur with
alkaloids of the harmine type in this genus.
Biosynthesis
Although several proposals and studies of the biosyn-
thesis of vasicine (8) have been made, the complete bio-
synthetic route is not known with certainty. [carboxy
14C]Anthranilic acid is incorporated into vascicine in Adha-
toda vasica with incorporation of the carboxyl label (Johne,
1986). It is established that anthranilic acid, probably as the
N-acetyl derivative, also is incorporated. The acetyl portion
accounts for the origin of C-3 and C-lO. Aspartic acid may
explain the origin of the remaining portion of the molecule
(Johne, 1986) (Fig. 31.4).
Distribution of Pyrroloquinazoline
Alkaloids
Pyrroloquinazoline alkaloids have been reported from the
Acanthaceae (Adhatoda vasica, Anisotes), Araliaceae
(Mackinlaya), Fabaceae (Galega), Malvaceae (Sida), Scro-
phulariaceae (Linaria), and Zygophyllaceae (Peganum)
(Johne, 1986):
Biological Activity
Adhatoda vasica has long been used in medicine in India
(Johne, 1986). Vasicine (8), vasicinol (9), and desoxyvasi-
cine (10) are antifeedant to several insects (Wink, 1993).
QUINAZOLINOCARBOLIl'IE ALKALOIDS
More than 20 representatives of this group of alkaloids
(found only in the Rutaceae) are known (Fig. 31.5) (Berg-
man, 1983). These alkaloids primarily are found in a few
~HN-r-CO'H
~NHCOCH,Lco,H
aspartic acid
!
cc~ HO
vasicine (8)
(peganine)
species of the genera Araliopsis, Euxylophora, Hortia, Tet-
radium, Vepris, and Zanthoxylum (Fagara).
Feeding experiments with [3- 14C]tryptophan, [14C]for_
mate, [ 14CH3 jmethionine, and ['Hjanthranilic acid in the
plant Tetradium (Euodia) rutaecarpa, indicated that all la-
bels were incorporated into rutaecarpine (11) and evodia-
mine (12). The C 1 unit of methionine or formate was incor-
porated into the 13b position of both alkaloids and into the
N-methyl group of evodiarnine (Bergman, 1983; Cordell,
1981).
The dried fruits of Tetradium (Euodia) rutaecarpa have
long been used in Chinese medicine for the treatment of
headaches, abdominal pain, dysentery, postpartum hemor-
rhage, and amenorrhea (Bergman, 1983). The alkaloids from
these fruits have marked uterotonic effects (King et aI.,
1980).
QVIl'IOLOl'IE. FUKOQVIl'IOLIl'IE. ACRlDOl'lE. Al'ID
4-QVIl'IOLOl'IE ALKALOIDS
Alkaloids derived from anthranilic acid are represented com-
monly in the Rutaceae. The largest groups of these com-
pounds are the quinolone, furoquinoline, pyranoquinoline,
acridone, and 4-quinolone alkaloids. Quinolone alkaloids
arise by extension of the carboxyl group of anthranilic acid
with one acetate (malonate) group and subsequent cycliza-
tion. These compounds have a 2,4-dioxygenated quinoline
structure. Furoquinolines and pyranoquinolines are based on
prenylated quinolone nuclei. Both angular and linear pyrano-
quinoline alkaloids are known. Acridone alkaloids involve
extension of the carboxyl group of anthranilic acid by three
units of acetate (malonate) and cyclization. Anthranilic acid
also may be extended with acetate-derived chains or by
phenylpropanoids to yield 4-quinolone-type alkaloids.
 Alkaloids Derived from Anthranilic Acid 571

Quinolone Alkaloids
A number of alkaloids that possess the quinoline ring
system as part of their structure have been reported, primar-
ily from plants in the Rutaceae (Fig. 31.6) (Grundon, 1979;
1988).
Evidence from a number of incorporation studies indi-
cates that quinolone alkaloids are derived from anthranilic
acid and acetate or malonate. The structure of casimiroine
(13) requires only the usual processes of hydroxylation,
methylation, and closure of the methylenedioxy ring at ap-
propriate stages of the pathway.
Quinolone alkaloids are found most commonly in the Ru-
taceae, but occasionally are encountered in other families.
Alkaloids with a quinoline ring structure occur in four of
the seven subfamilies of the Rutaceae (Aurantioideae, Flin-
dersioideae, Rutoideae, and Toddalioideae) (in addition, a
pyranoquinolone, N-methylflindersine, occurs in the
Spathelioideae). Quinolone alkaloids are found in the
subfamilies Rutoideae, Toddalioideae, and Aurantioideae,
but also have been reported from Xyloearpus (Meliaceae).
In addition to quinine and related alkaloids (see Chapter
34), other quinoline alkaloids occurin Tylophora asthmatiea
(Asclepiadaceae) (see Chapter 30). Two quinoline alkaloids
have been reported from Meloehia (Sterculiaceae) (Special-
ist Periodic Reports 1978, 1979). An alkaloid isolated from
Broussonetia (Moraceae), 4-formyl-8-hydroxyquinoline,
may not be closely related to other quinoline alkaloids. An
additional quinoline alkaloid has been reported from Limon-
ium (Plumbaginaceae).
Furoquinoline and PyranoquinoHne
Alkaloids
Many quinolone alkaloids are subject to prenylation and
give rise to the furoquinoline or pyranoquinoline alkaloids.
The furan rings of furoquinoline alkaloids arise by a similar
process to thosli of furanocoumarins that have been previ-
ously discussed (Fig. 31.8). (see also Chapter 9) (Geissman
and Crout, 1969; Grundon, 1979, 1983).
Anthranilic acid is incorporated intact into the quinoline
portion of furoquinoline alkaloids, such as dictamnine (14),
in the same manner as for quinolone alkaloids. The biosyn-
thesis of furoquinoline alkaloids involves formation of the
quinoline ring system before introduction of the side chains.
4-Hydroxy-2-quinoline is a specific precursor of skimmi-
anine (15) in Ruta graveolens. The quinolone base is preny-
lated, the prenyl residue cyclized, and the isopropyl group
removed. The existence of furoquinoline alkaloids contain-
ing C, prenyl groups elsewhere in the molecule and the co-
occurrence of furoquinoline alkaloids and isopropyldihydro-
furoquinolines supports this proposed route. Alkaloids such
as lunasine (18) and lunacrine (16) co-occur with hydroxy
derivatives such as (17) in Lunasia amara and Pte/ea trifoli-
ata (Figs. 31.7 and 31.8). Epoxides may be intermediates in
the formation of isopropyldihydrofuroquinolines. The C-4

(J( CO,H
"'I
,... NH, (')--(l
(t:():
I I
<;;"
CO,H
S-adenosylmethionine~ ~ ____ ~NH~~'N0
'" NH NH, ~NH~~ COR N ~
~
P'p 2 ruta«arpiDe (11) "'" 1
~NHCH3

~ OQQ
' ";~ ~::c;
euxylophoriDe
YOCH,
OCH,
YOCH,
OCH, ~
O::Q/N~N~~/ CH, ""
0

~NH~N 0 evodiamiDe (12)

CHfl

I" N~:: CH'O~~N

I;ON'

14N
,0

'9' .N V
N:
0 NH lOCH,
t9

I 0 O::1)r.oN0
... I' CH, I CH ,;7
• "" "" ""I
hortiacine hortlamine paraensin rhetsinine

Fig. 31.5. Typical quinazolinocarboline alkaloids (modified from Bergman, 1983; used with permission of the copyright owner, Academic Press,
Orlando, FL).
572 Alkaloids Derived from Anthranilic Acid

((
V
CoO _

~ wO~H'
".. I '-:: CHCOSCoA
NH, to,H
U",~-"..I
NOHO NO
'-0 I
I DMAPP CH,
.. casimiroine (13)

~~OH~0c21
- -V~)lOJ<:: U"'~~.. ~
U",.:l~ ~ I
!
+- V

1
oc2
NHO OCH' NOH"..
'CR, NH 0
alanine (+ HR)-isobalfouridine (21) flindenine (22)

~
:H'h
"..
I
N O ' "
I 0
~O
I I
V
VI NO
,,,..
'"
CR, '- 0 OCH,CH, NH 0
N-methylatanine oxirine
iunacrine (16) ~ihYdroninderSine

~'OH
! OCR, """ OCH,

UNJlok ~~
U",.J.)
CH,OYN0. 0 "
CH, OCH, N 0

(-)-(S)-ribaiinine (20) lunacridine skimmianine (15) diciamnine (14)

Fig. 31.6. Quinoline, furoquinoline. and pyranoquinoline alkaloids (modified from Geissman and Crout, 1969).

o o o

~-,"~OH
y~A.!\
OCR,
-- ~R,
~-"'<
y~~j\
OCH, bR,
~"'-'"<
y~~j'H
OCR, bH,

(-)-(R)-iunacrine (16)

i
~ __ 9¢c( --
OCH'
0CR' OR

~
,;:r """
~ I """
.&
~I 'H
N 0 ::::". N 0
OCH, CH,
I I
OCH, CH, OCH, bR,

(-)-<R)-IUl188ine (18)

Fig. 31.7. Biogenesis of lunasine and lunacrine (modified from Grundon, 1979; used with pennission of the copyright owner, Academic Press,
Orlando, FL).

(X
""I
COlH CHCOSCoA
1- ~- ~
NH, CO,H
UNH~O I
cxn
;?'
""
1
OCH
'<::
NH
'
0
H
(+)-(R)-platydesmine (17)
~ ~
yN-:::-lO)J
OCH,
dictamnine (14)
evoxine
Fig. 31.S. Biogenesis of furoquinoline alkaloids (modified from Grundon. 1979; used with permission of the copyright owner, Academic Press,
Orlando, FL).
and C-5 of mevalonic acid is incorporated specifically into
to C-2 and C-3 of skimmianine (15) in Zanthoxylum (Fa-
gara) coco (Fig. 31.6) (Grundon, 1979; 1983). Furthermore,
3-prenylquinolones labeled at C-l' with 14C were good pre-
cursors of dictamnine (14) and skimmianine (15)
(3.6-4.8%). (±)-[14C]Platydesmine (17) was an excellent
specific precursor for dictamnine (14) (18.8% incorporation)
in Skimmia japonica. DictantOine is a specific precursor for
skimmianine in Choisya ternata (incorporation 1.3-6.6%).
The order of introduction of hydroxylation and methylation
is more complicated (Griiger, 1980; Grundon, 1979, 1983).
Furoquinoline and pyranoquinoline alkaloids primarily
are known from the Rutaceae and occur in four of the five
alkaloid-containing subfamilies (Aurantioideae, Flindersi-
oideae, Rutoideae, and ToddaIioideae). The most common
is skimmianine (15) (Grundon, 1979).
Although unusual, these alkaloids also are known from
unrelated plant families. For example, Tylophora asthmatica
(AscJepiadaceae) contains -y-fagarine (19) and skimmianine
(15) (Etherington et al., 1977). Skimmianine also has been
reported from Datura stramonium.
pyranoquinoline alkaloids, such as ribalinine (20) and
isobalfourodine (21), appear to arise from the same epoxide
intermediate involved in the formation of furoquinoline alka-
loids. However, differences in stereochemistry of the prod-
Alkaloids Derived from Anthranilic Acid 573
OH
9'
CH'
'" .&
::,.. NH 0
OCH,
CH,o¥N-:::-lO)J
OCH,
'Y~fagarine (19) skimmianine (15)
choisylne
ucts require that alternate mechanisms be involved (Grun-
don, 1983).
The antifeedant activity of extracts of Zanthoxylum (Fa-
gara) chalybaea, Z. holstii, andXylocarpus granatum (Meli-
aceae) has been shown by Kubo and Nakanishi (1977) to be
due to the presence of N-methylflindersine [flindersine (22)].
Both of these alkaloids are widespread in the Rutaceae.
Skimmianine intercalates with DNA and, as is true for
several furoquinoline alkaloids, undergoes photoaddition re-
actions with DNA as well (Wink, 1993). DictantOine is pho-
totoxic to both bacteria and fungi (Gray, 1993).
Dimers produced by Diels-Alder reactions between py-
ranoquinolone and dihydrofuroquinolone alkaloids occur in
a number of rutaceous species. These compounds are known
from Araliopsis, Euxylophora, Geijera, Oricia, Ptelea, and
Vepris (Waterman, 1986).
Acridone Alkaloids
Acridone alkaloids are formed by the addition of three
acetate (or malonate) units, followed by cyclization (Figs.
31.9 and 31.10) (Geissman and Crout, 1969; Griiger, 1980).
More than 100 alkaloids of this type are known (Gray, 1993).
Representatives of this group of alkaloids are widespread
in the Rutaceae, especially in the genera Acronycia, Atalan-
tia, Balfourodendron, Citrus, Euodia (which should be used
574 Alkaloids Derived from Anthranilic Acid

o OCR, o OR

~OCR'
~N~OCR' I
CR,

l,3-dimethoxy-N-methylacridone acronyclne (23) arborinine

o OR
o OCR, 0 OCR,

o(6)~O)
~fYO NR 0
CR, OCR,

rutacrldone epoxide (24)

o
evoxantbidine me1icopidine

Fig. 31.9. Some acridone alkaloids of the Rutaceae.

in preference to Evodia), Glycosmis, Melicope, Ruta, Teclea,
and Zanthoxylum (Fagara), as well as in other species of
the subfamily Toddalioideae (Groger, 1980) (Fig. 31.9).
Several acridone alkaloids have antitumor activity in a
number of cell lines; some are inhibitory to growth of Plas-
modium yoelii (Borris and Schaeffer, 1992; Wink, 1993).
Acronycine (23) (from Acronycia, an Australian and Asian
genus of the Rutaceae) has been shown to possess antitumor
activity (Gerzon and Svoboda, 1983; Suffness and Cordell,
1985). Acronycine (23) proved to possess the broadest ex-
perimental antitumor spectrum of any alkaloid isolated from
higher plants (Blasko and Cordell, 1988; Gerzon and Svo-
boda, 1983). The compound was active both interperitone-
ally and orally against 12 of 17 experimental tumor models
and appears to be active against long established tumors.
The LDso in mice as a single dose (orally) is from 350 to
680 mg/kg. The mechanism of antitumor activity appears to
be different than that of most other antitumor drugs. It has
been stated that' 'acronycine interfered primarily with struc-
ture, function andlor turnover of cell membrane compo-
nents." The effect involves nucleoside transport across
plasma membranes (Suffuess and Cordell, 1985). Acronyc-
ine (23) also has been reported to be carcinogenic (Gerzon
and Svoboda, 1983).
Rutacridone epoxide (24) from Ruta graveolens was
shown to possess antimicrobial activity against several or-
ganisms (Nahrstedt et aI., 1980; Wink, 1993). Cultures of
Ruta graveolens produced 50-fold more rutacridone epoxide
and hydroxyrutacridone epoxide when treated with fungi not
specific to the host (Brooks and Watson, 1985; Ellis, 1988).
4-Quinolone Alkaloids
4-Quinolones are rather rare alkaloids, known only from
Tetradium, Ruta, Vepris, and Ptelea (Ng et aI., 1987) (Fig.
31.11).

(X1 - - (XICO,R COSCOA

+ 3
CO,R
I ---.
"", NR, "", NR, CR,COSCoA

1,3-dihydroxyacridone

Fig. 31.10. Biogenesis of acridone alkaloids (Geissman and Crout, 1969).


from Galipea oJficinalis (Rutaceae)
OCR,
o
)
o
cusparine
Fig. 31.11. Representative 4-quinolone alkaloids.
CHEIIIOSYSTBMATICS AI'ID PHYLOGBNY
The Rutaceae has been subdivided into several subfamilies
by various workers (Da Silva et al., 1988; Watennan, 1983).
The subfamilies Aurantioideae, Flindersioideae, Rutoideae,
and Toddalioideae possess many common features and are
considered by most workers to be closely related. Three
other proposed subfamilies are more doubtful in relation-
ship. The Spathelioideae has been placed in the Simarou-
baceae but contains N-methylflindersine, an alkaloid charac-
teristic of the Rutaceae. The Dictylomatoideae also has been
transferred to the Simaroubaceae by some. Another, the
Rhabdodendroideae, probably is a close relative of the Phy-
tolaccaceae and should be transferred from the Rutaceae
(Airy-Shaw, 1973; Prance, 1968).
However, several workers have felt that the present
subfamilies are not in accord with all lines of evidence (e.g.,
floral anatomy and phytochemistry). A revised scheme of
classification has been proposed (Watennan, 1975, 1983).
The Rutaceae is one of the most interesting families in
regard to alkaloid chemistry as well as the fonnation of fla-
vonoids, mono-, sesqui-, and triterpenes, furocoumarins, and
other secondary compounds (Watennan and Orondon,
1983). Many chentical features support the view that the
Rutaceae is a distinct and homogenous group. Essential oils
and coumarins are found in at least four subfantilies. Furo-
quinoline alkaloids are essentially ubiquitous in the family,
and acridones are common.
Members of the family contain alkaloids based on several
major pathways such as benzylisoquinoline (tyrosine de-
rived), quinolone, furoquinoline, quinazoline (all from an-
thranilic acid), imidazole (histidine), indoloquinazoline
(tryptophan), and both simple aliphatic and aromatic amines.
In the tribe Ruteae (Rutoideae), no fewer than five types of
alkaloids are common to the three major genera. Quinolone,
furoquinoline, and acridone alkaloids are especially wide-
spread within the family, being found in four of the five
Alkaloids Derived from Anthranilic Acid 575
from Ruta graveo1ens
o>
o
eduleine
subfamilies from which alkaloids have been reported (Aura-
ntioideae, Flindersioideae, Rutoideae, and Toddalioideae).
Acridone alkaloids are not known from sources outside this
family. Most reports of quinolone and furanoquinoline alka-
loids also are from this family. In contrast, benzylisoquino-
line alkaloids are found in many plants of the Magnoliidae
and in the Rhamnaceae, Euphorbiaceae, Celastraceae, Sym-
plocaceae, and other families (Seigler, 1977; Watennan and
Grundon, 1983).
Alkaloids of the I-benzyltetrahydroisoquinoline type are
assumed to be primitive in the Rutaceae and the plants pro-
ducing them belong to the most printitive extant genera of
the family. As anthranilate-derived alkaloids are found in
some of the same genera, it appears that the evolutionary
trend was for direct replacement of one type with another
(Watennan and Khalid, 1981). The taxa that do not have 1-
benzyltetrahydroquinoline alkaloids [e.g., tribes Diosmeae
and Boronieae (Rutoideae) and the subfamily Auranti-
oideaej, appear to be relatively advanced.
Alkaloids of the benzylisoquinoline type occur mostly in
the genera Fagaropsis, Phellodendron, Tetradium, Toddalia
(Toddalioideae), and Zanthoxylum (Fagara) (Rutoideae); a
group of genera considered to represent the "proto-Ruta-
ceae" (Ng et ai., 1987; Watennan and Khalid, 1981).
Plants of subfamily Aurantioideae contain other types of
alkaloids. Members of the genera Merrillia and Micromelum
and several Murraya species contain indole alkaloids such
as yuechukene (see Chapter 35) (Kong et ai., 1986, 1988a,
1988b). Other Murraya species produce carbazole alkaloids
(Kong et al., 1986, 1988b). Carbazole alkaloids have been
reviewed (Bhattacharyya and Chakraborty, 1987; Chakra-
borty and Roy, 1991) (see also chapter 35).
Plants of the Rutoideae, tribe Diosmeae also contain quin-
olone and furoquinoline alkaloids (Campbell et ai., 1987).
The family Rutaceae has been regarded by most system-
atists as closely related to the Cneoraceae, Meliaceae, Ptaer-
oxylaceae, and Simaroubaceae. Although alkaloids largely
576 Alkaloids Derived from Anthranilic Acid
are lacking in the last three families, the biosynthetic path-
ways leading to limonoids, quassinoids, and related
triterpenes link the Rutaceae to the Meliaceae, Simarou-
baceae, and Cneoraceae. The presence of chromones and
coumarins link this group with the Ptaeroxylaceae (Water-
man and Khalid, 1981). It has been suggested that this last
family has links to Rutaceae, subfamily F1indersioideae. Af-
finities to the Burseraceae and Zygophyllaceae also have
been suggested. The latter relationship has been suggested
largely because of the genus Peganum. This genus has cer-
tain similarities to the Rutaceae and has been placed in that
family by some (Engler, 1896). Species of Peganum contain
alkaloids of the harmine and quinazoline types that resemble
those of some rutaceous plants.
As many of the primitive Rutaceae contain benzylisoqui-
noline alkaloids, it is probable that the ancestors of this fam-
ily possessed them. The presence of these alkaloids and a
variety of morphological features suggests that the Rutaceae
is derived from ancestors in the Magnoliidae, near the Ra-
nunculales or the PapaveraIes (Seigler, 1977; Waterman and
Khalid, 1981). The alkaloids produced by Fagaropsis ango-
lensis are completely typical of those produced by the Ra-
nales, in particular by the Papaveraceae (Waterman and
Khalid, 1981). Benzylisoquinoline alkaloids are uncommon
in the Rosidae and this group would not seem tu be probable
as ancestral to the Rutaceae.
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SPECIALIST 1'ERlODlC REPoRTS, Alkaloids, Vol. 8, Chemical Society,
London, 1978. Alkaloids, Vol. 9, Chemical Society, London,
1979.
Alkaloids Derived from Anthranilic Acid 577
SUFFNESS, M. and G. A. CORDELL, Antitumor alkaloids, in The
Alkaloids, Vol. 25 (A. Brossi, ed.), 3-355, Academic Press,
New York, 1985.
WATERMAN, P. G., Alkaloids of the Rutace..: Their distribution
and systematic significance, Biochem. Syst. Bcol., 3,149-180
(1975).
WATERMAN, P. G., Phylogenetic implications of the distribution
of secondary metabolites within the Rutales, in Chemistry and
Chemical Taxonomy of the Rutales (P. G. Waterman and M.
F. Grundon, eds.), 377-400, Academic Press, London, 1983.
WATERMAN, P. G., The dimeric alkaloids of the Rutace.. derived
by Diels-Alder addition, in Alkaloids: Chemical and Biological
Perspectives, Vol. 4 (S. W. Pelletier,ed.), 331-387, Wiley,New
York,1986.
WATERMAN, P. G. andM. F. GRUNDON, eds., Chemistry and Chemi-
cal Taxonomy of the Rutales, Academic Press, London, 1983.
WATERMAN, P. G. and S. A. KHALID, The biochemical systematics
of Fagaropsis angoiensis and its significance in the Rutales,
Biochem. Syst. Bcol., 9, 45-51 (1981).
WINK, M., Allelochemical properties or the raison d'elre of alka-
loids, in The Alkaloids, Vol. 43 (G. A. Cordell, ed.), 1-105,
Academic Press, New York, 1993.
32
Isoquinoline and Benzylisoquinoline
Alkaloids

Introduction Curare
Isoquinoline Alkaloids Erythrina Alkaloids
Biosynthesis Biosynthesis
Dimers and Oligomers of Isoquinoline Alkaloids Biological Activity
Cryptostyline Alkaloids Distribution of Benzylisoquinoline Alkaloids
Distribution of Isoquinoline Alkaloids Ipecacuanha Alkaloids
Biological Activity Biosynthesis
Interactions of Cactus Species, Yeasts, and Drosophila Distribution of Ipecac Alkaloids
Benzylisoquinoline Alkaloids Medical Uses of Ipecacuanha Alkaloids
Tetrabydrobenzylisoquinoline Alkaloids Other Biological Activity
Biosynthesis References
Biological Activity
Azafluoranthene and Tropoloisoquinoline Alkaloids
Aporphine Alkaloids
Biogenesis INTRODUCTION
Biological Activity
Aristolactams and Aristolochic Acid Alkaloids that possess an isoquinoline moiety in their struc-
Eupomatia Alkaloids ture are among the most common of all alkaloids. More
Proaporphine Alkaloids than 4000 compounds of many structural types but with this
Morphinandienone Alkaloids (Promorphinanes) structural feature are known (Verpoorte et al., 1991). Those
Hasubanan Alkaloids treated in this chapter are all derived from a 3,4-dihydroxyty-
Morphine Alkaloids ramine (dopamine) precursor that is linked to an aldehyde or
Biosynthesis ketone of several different origins. One series of isoquinoline
Pharmacological Activity alkaloids involves glyoxylic acid, pyruvic acid, and an a-
Other Biological Activity keto acid derived from leucine as the carbonyl portion. These
Protoberberidine Alkaloids compounds are largely, but not exclusively, found in the
Biosynthesis Cactaceae.
Biological Activity A second major structural type, commonly known as ben-
Protopine Alkaloids zylisoquinoline (BIQ) or tetrabydrobenzylisoquinoline
Benzophenanthridine Alkaloids (TBIQ), alkaloids constitute one of the two most numerous
Phthalideisoquinoline Alkaloids types of alkaloids. As is true for the simple isoquinoline
Rhoeadane Alkaloids alkaloids mentioned above, all are derived from a 3,4-dihy-
Dibenzopyrrocoline Alkaloids droxytyramine (dopamine) precursor condensed with a car-
Pavine and Isopavine (Argemone) Alkaloids honyl compound. In this case, the precursor of most, if not
Cularlne Alkaloids all, benzylisoquinoline alkaloids is 4-hydroxyphenylacetai-
Bisbenzylisoquinoline Alkaloids dehyde. Benzylisoquinoline alkaloids are found in a limited
Biological Activity group of plant families; some have great medical impor-

578
 lsoquinoline and Benzylisoquinoline Alkaloids 579

tance. The origins of several major subgroups occur are de-
scribed below.
A third major group, including emetine and a series of
structurally related alkaloids, involves condensation of the
same amine precursor (3,4-dihydroxyphenylethylamine or
dopamine) with a carbonyl group from secologanin-an iri-
doid monoterpene precursor. Most of these compounds have
been isolated from two families, the Rubiaceae and the Alan-
giaceae.
ISOQUIl'IOLIl'IB ALKALOIDS
About 130 alkaloids based on a 3,4-dihydroxytyramine (do-
pamine) precursor linked to an aldehyde or ketone of several
different origins are known (Guinaudeau and Bruneton,
1993). Among the usual origins of this carbonyl compound
are glyoxylic acid, pyruvic acid, and an ",-ketoacid derived
from leucine (Fig. 32.1).
The application of both 'H- and 13C-NMR (nuclear mag-
netic resonance) spectroscopy and other spectroscopic meth-
ods to the study of isoquinoline alkaloids has been reviewed
(Crabb, 1982; Guinaudeau and Bruneton, 1993; Hughes and
MacLean, 1981; Mata et aI., 1983).
Biosynthesis
Isoquinoline alkaloids are derived from tyrosine through
the intermediacy of 3,4-dihydroxyphenylethylamine (dopa-
mine) and a carbonyl unit of various origins. The genesis of
tyramine, and dopamine from tyrosine has been described
previously (see Chapter 28). In contrast to benzylisoquino-
line alkaloids (see below), the formation of isoquinoline al-
kaloids usually involves the amine and an ",-ketoacid instead
of an amine and aldehyde. However, several compounds can

CH"0:roJ _
1
CHJO~ ~ CH'OW

~ NH, CHj'O~ /'f~ CH,O "'- ' NH

CH,O COCO,H HO / 'CO,H HO CO,H
HO ,
CH,
peyoruvic acid (3)

~
CH'O~ CH'OW' CHJoy?

CH3 0 ::::....
, NH
CH,O
"'- N,
CH,
~ I "",N
2 CHJO
OCH, HO HO

mescaline (4) pellotine (2) 3,4·dihydro-6,7-dimefhoxy

-1-methyl-8-hydroxyisoquinoline

CH'O~,
~O "'- NH,-
CH,'O

HO
,y

~ I
+HCOCO H
2
CHJO
W HO COzH
g -+
CH"OW

CH,O
~l
HO
NH

SAM also is incorporated peyoxylic acid

anhalamine (1)

~
CH"0y) CHJOW
,yl CH','0:Q)
, N
~ N ..... ",-' NH
CH,'O CH, CH,O CH,-O ~ h
HO HO HO

anhalidine {IO} anhalonidine (11)

3,4-dihydro-6,7-dimethoxy
-8-hydroxyisoquinoJine

Fig. 32.1. Origin of some representative isoquinoline alkaloids (modified from Lundstrom. 1983; used with permission of the copyright owner,
Academic Press, Orlando, FL).
580 Isoquinoline and Benzylisoquinoline Alkaloids

serve as precursors in specific instances. In one case, closure
of the nitrogen-containing ring to produce anhalamine (1)
involves methionine (Fig. 32.1). A related alkaloid, pellotine
(2), is probably derived from pyruvate. A carboxylic acid
of similar structure, peyoruvic acid (3), suffers oxidative
decarboxylation and serves as a precursor for other isoquino-
line alkaloids (LundstrOm, 1983; Leete, 1983).
The order of methoxylation and oxidation steps varies.
In some instances, the 3,4-dihydroxyphenylethylamine (do-
pamine) precursor may be modified before condensation oc-
curs. Despite their structural similarity, pellotine (2) and an-
halarnine (1) are probably synthesized along distinct
pathways from mescaline (4). All three alkaloids co-occur
in Lophophora williamsii.
Lophocereine (5), a related compound with a five-carbon
unit inserted into the nitrogen-containing ring, is found in
another cactus species, Lophocereus schottii. The usual car-
bonyl precursor probably is 4-methyl-2-oxopentanoic acid
(6), an entity that probably arises by transamination of leu-
cine (Geissman and Crout, 1969) (Fig. 32.2). However, feed-
ing studies reveal that both leucine and mevalonic acid can
act as precursors. Previous studies indicate that leucine can
be converted into l'I-hydroxY-I'I-methylglutaric acid (7), a
probable precursor of mevalonic acid. Mevalonic acid can
be converted to the required aldehyde and condensed with
dopamine to afford lophocereine (Fig. 32.2).
The results of a number of feeding studies leading to
isoquinoline alkaloids have been tabulated (Leete, 1983).
Dlmers and OUgomers of Isoquinoline
AJkaIoids
In addition to simple monomeric units with isoquinoline
structures, a number of dimeric and oligomeric alkaloids of
this series are known. An example of this type, pilocereine
(8) (Fig. 32.3), known from Pachycereus, Pilocereus, and
Lophocereus (all Cactaceae), is derived by coupling of iso-
quinoline alkaloid units (probably by a free-radical mecha-
nism, although proof for this is lacking), much in the same
manner as the dimerization process leading to bisbenzyliso-
quinoline alkaloids, a topic discussed below.

:::(rlNH'~O~I :~,y
(22)
I NH~O
CHO HO HO HO

~ Y
n
lophocereine(S)

H CH30 '" CHy~H3

HO
--
CO,H HO
~I_NH+- CH,
I
_fHNH,
CO,H
mevalonic acid leucine

! \ decarboxylation

1 ?O,H 0
~NH- I I( -+
'~CO,H~
1 COSCoA - I""", COSCoA
~
leucine (6)

-
(
~
CO,H
~
COSCoA - +
X
CO,H
H
__
COSCoA

p.hydroxy·~.methylgl.laryl CoA
X
bO,H l
mevalonic acid
OH

(7)

Fig. 32.2. Biogenesis of lopbocereine (modified from Geissman and Crout, 1969).
 isoquinoline and Benzylisoquinoline Alkaloids 581

CHro~1 CH'-oX:Y CH'-O~

HO ~ NH 1 N 1
.CH,-O ~ . . . CH, CH,-O ~ NH

HO
lophocereine (17) carnegeine (18) anhalanine (ll)

~
OCH'CH'·°7Yr1
HN I""" HO ~ NH

& HN 1
"'"
""" OCH,
o

pllocereine (8l

CH'-O:yo CH'-OXPI CHrow

o ~I N . . . CH 0 ~ NH
0
~I N '- ./
'--0 ' Lo '--0 .......
lopbopborine (14) anhalonine (13) peyophorine (15)

Fig. 32.3. Biologically active isoquinoline alkaloids.

CryptostyUne Alkaloids Other families known to possess isoqninoline alkaloids

A small group of isoquinoline alkaloids, in which substi-
tuted benzaldehyde derivatives such as 9 appear to be in-
volved in the biosynthetic process, occurs in the genus Cryp-
tostylis (Orchidaceae) (Fig. 32.4). Dopamine serves as a
precursor for both aromatic rings of the system (LundstrOm,
1983).
DlSTRlBUI101'1 OF ISOQUIl'IOLIl'IE ALKALOIDS
Isoquinoline alkaloids are found primarily in the Cactaceae,
Chenopodiaceae, and Fabaceae (Guinaudeau and Bruneton,
1993; Mata and McLaughlin, 1982). The Cactaceae also
elaborate (3-phenylethylamines (see chapter 28) that co-
occur with tetrahydroisoquinoline alkaloids. The latter ap-
pear to have evolved by cyclization of variously substituted
phenylethylamines with suitable ring-closing units. A com-
prehensive listing of isoquinoline alkaloids in cacti has been
published (LundstrOm, 1983).
Peyote, Lophophora williamsii, appears to be the most
prolific cactus, in terms of alkaloid production. In addition
to mescaline and other (3-phenylethylamines, this cactus con-
tains anhalamine (1), anhaladine (10), anhalonidine (11),
pellotine (2), anhalanine (12), anhalonine (13), lophophorine
(14), and O-methylanhalonidine (Lundstrom, 1983).
include the Alangiaceae, Chenopodiaceae (a family related
to the Cactaceae), Fabaceae, Musaceae, Nymphaeaceae, and
Sterculiaceae (LundstrOm, 1983). At least four species of
the Chenopodiaceae contain isoquinoline alkaloids, whereas
other species contain (3-phenylethylamines. Many of the
plants that contain benzylisoquinoline alkaloids also contain
smaller amounts of isoquinoline alkaloids. Among these are
plants belonging to the Annonaceae, Euphorbiaceae, Puma-
riaceae~ Hernandiaceae, Menispermaceae, Monimiaceae,
Papaveraceae, Ranunculaceae, and Rharnnaceae (Lunds-
trOm, 1983). The distribution of benzylisoquinoline alka-
loids is discussed in more detail below.
BIOLOGICAL ACDVITY
In contrast to (3-phenylethylamines such as mescaline (4),
isoquinoline alkaloids do not have hallucinogenic activity.
These alkaloids are toxic to many animals and exhibit a
number of other physiological effects. Both peyophorine
(15) and camegeine (18) have positive inotropic effects and
modify heart action in mammals (Wagner, 1988). Other iso-
quinoline alkaloids have been reported to possess antitumor
activity (Lundstrom, 1983).
582 Isoquinoline and Benzylisoquinoline Alkaloids
HO~
CH,-O
~ NH,
4.0·methyldopamine
CH,-O
~NH,-tt-;H-O
po
A)I ' ~
00
3-0-melhyldopamlne
CH'_O~
~ I ",N
CH,O
""
l,b
o
0--.1
Fig. 32.4. Proposed biosynthesis of cryptostyline alkaloids (modified from Lundstrom, 1983; used with pennission of the copyright owner, Academic
Press. Orlando. FL).
Interactions of cactus Species. Yeasts.
and DrosopblJa
The interactions of certain Drosophila species and cacti
in the southwestern United States have been discussed in
cbapter 23. These insect species feed on rotting limbs of
cacti and have a requirement for scbottenol, a steroidal mate-
rial that occurs in the species involved (Kircher, 1982). The
saguaro cactus (Carnegiea giganfea) contains primarily two
isoquinoline alkaloids: dopamine and the phytosterols camp-
esterol and sitosterol. The senita cactus (Lophocereus schot-
tii) contains a number of unusual alkaloids and sterols. Lo-
phenol and schottenol are among the sterols, and
lophocereine (17) and pilocereine (8) are among the alka-
loids (Fig. 32.3). The organ pipe cactus, Sfenocereus thur-
beri, previously known as Lemaireocereus thurberi, con-
tains no alkaloids, but does possess large quantities of lipids
and triterpene glycosides. Cholesterol, campesterol, and si-
tosterol are among the sterols. The agria cactus, Stenocereus
gummasus (formerly known as Machaerocereus gummosus)
has not been as thoroughly analyzed, but contains no alka-
loids. The cina cactus. Sfenocereus alamosensis, formerly
known as Rathbunia alamosensis, is rich in triterpene glyco-
sides. A common species of prickly pear, Opuntia ficus-
indica, produces mucilage, but no alkaloids or saponic mate-
rials. The organ pipe, agria, and cina cacti all contain large
quantities (25-45%) of water-soluble triterpene glycosides
and lipids. The saguaro and senita cacti contain alkaloids
(1-10%) (Kircher, 1982).
Many species of Drosophila (fruit flies) show significant
dopamine (22)
~
CH'_O~
I H~O
NCH
, ~ I ""
I "" ~
~
OH
/ 0 OCH,
0-1 isovanillin
(+)-(S)-cryploslyline I
(9)
host specificity. For example, D. nigrospiracula is found
only in decaying tissues of saguaro (and one other closely
related cactus), whereas D. pachea occurs solely in the senita
cactus. D. mojavensis breeds in organ pipe cactus in Arizona
and Sonora, where the agria cactus is absent, but is found
preferentially in the agria cactus, in areas where both plants
exist. This insect species also occurs on other cactus species
on occasion (Kircher, 1982).
The restriction of D. pachea to the senita cactus is a result
of the strict 11.7 -sterol requirement of the fly and its tolerance
of the senita alkaloids. Although schottenol (7-stigmastenol)
and lophenol (4a-methyl-7-cholestenol) were the main ste-
rols present, the insect utilizes and requires 7-cholestenol,
which is present in smaller quantities (Kircher, 1982). Lo-
phocereine (17) and pilocereine (8) occur in the senita cactus
and act as feeding deterrents to other Drosophila species.
Only Drosophila pachea and D. mettleri are impervious to
their effects (Harborne, 1982; Meyer and Fogelman, 1987).
The last species typically breeds in soil beneath saguaro
cacti.
The close association of D. nigrospiracula with saguaro
(and another cactus, cardon) can be explained only in that
this fly is excluded frum other potential hosts. Compounds
(alkaloids and medium-chain fatty acids) frum other poten-
tial hosts are lethal to this insect (Kircher, 1982). The sagu-
aro cactus contains camegeine (18), which acts as a repellent
to D. pachea but not to D. nigrospiracula (a species that
feeds on saguaro) (Harborne, 1982)_
Individuals of D. mojavensis cannot breed in the senita
 /soquinoline and Benzylisoquinoline Alkaloids 583

cactus because of the alkaloids present. In the saguaro, this
species does not appear to be able 10 coexist with D. ni·
grospiracula (Kircher, 1982).
The above observations were based on the identification
of a relatively small number of alkaloids and terpenoids.
Recently, the diversification of plant compounds has been
discovered to be much greater than previously thought (Gib-
son et aI., 1986; Spencer, 1987). Early studies considered
the activity of the aglycones of the steroidal compounds, but
not that of the glycosides themselves. Cactophilic yeasts are
able to hydrolyze the glycosides and produce the correspond-
ing aglycones under certain conditions. Specific differences
in toxicity to mixtures (consisting of alkaloids, glycosides,
sugars, and aglycones) that had suffered hydrolysis by yeasts
have been observed. The three Drosophila species examined
showed consistent differences in tolerance toward given
plant species. It was concluded that the yeasts hydrolyzed
the glycosides to produce aglycones that are selectively toxic
to D. mojavensis, but that the alkaloids themselves are not
generally toxic to these Drosophila species at the levels en-
countered in the plants. Furthermore, is was noted that nona-
dapted insects do not exhibit selective tolerance toward any
given compound arrays and may suffer toxication by alka-
loids or aglycones or both. Triterpenoid glycosides may spe-
cifically affect Drosophila, whereas the alkaloids may be
more general toxins (Spencer, 1987).
Despite the fact that chemical factors are important in
defining the interactions of Drosophila cactus species, not

, ,
oo~
HO ",' :H
rn,o~
HO '"
~o~HO '"
• N , ,H N'CH,
HO "" , ,H 'CH,
CH,O CH,O
HO '" '
0 0

rn'02f,
(. HS)·norlaudanosoline (26) salutaridine (52) sinoaeutine (53)

HO~
",' rn,o~
HO "" 1 N'CH CH,'O '" "N
0 H '
CH,'O ""
"'. H N'CH, CH,'O cY
HO" h ""I CH,O '"
(+)-isolbebalne (49) papaverine (31)
0

<
0

<0 0

0 OCH,
) OCH,
0
0 prolopine (60) berberine (71)

<
CH,O
0
0 <0 HO
OCH,

OCH, OCH,
0 0 0
OCH, (+)·rhoeadine (59) -.../ eryptaustoline (92)

CH"O~
1CIb l "" OCH,
CH'01Jg:foH
-- c:?
CH,'O '" 'N '" I HO ~ "N'CH,:::,... \
OCH, 0 : D OCH,
(.).argemonine (93) (:;,.. 1 N
o thalielidine

CH,O a
erythraline (106)
Fig. 32.S. Some major types of benzylisoquinoiine alkaloids.
584 lsoquinoline and Benzylisoquinoline Alkaloids

all aspects of the story can be explained by chemical factors
(Kircher, 1982).
BEl'IZYLlSOQUIl'IOLIl'IE ALKALOIDS
Benzylisoquinoline alkaloids differ from isoquinoline alka-
loids in that a different carbonyl donor unit, 3,4-dihydroxy-
phenylacetaldehyde (19), is involved in their biosynthesis
(Herbert, 1988; Schumacher et al., 1983). The plants that
contain benzylisoquinoline alkaloids often are poisonous
(see references in Chapter I and Kingsbury, 1964). At least
4000 benzylisoquinoline alkaloids belonging to many
subgroups are known (Figs. 32.5 and 32.6) (Verpoorte et
al., 1991; Waller and Nowacki, 1978).
Both the IH_ and 13C_NMR spectra for benzylisoquino-
line alkaloids have been reviewed (Crabb, 1982; Janssen et
al., 1989). The results of a number of feeding studies leading
to benzylisoquinoline alkaloids have been tabulated (Leete,
1983).
TetrabydrobenzyUsoquinoline Alkaloids
The simplest alkaloids of this series are those in which
the nitrogen-containing ring of the isoqniuoline system is
completely saturated (Fig. 32.7). Quaternary bases also are
found. Tetrahydrobenzylisoquinoline alkaloids are wide-
spread and are found in almost all the families that possess
benzylisoquinoline alkaloids. About 100 alkaloids of this
type are known (Guinaudeau and Bruneton, 1993).

C~7¥'0 <:~,..
o
,...
'"
OCH3
: I N.CH
-
3
HO,...

CH30 ' "

I

I
H
N. CH

\
3
HO

O.
-
Ho~··rn,CH'O
r

:,..
I
CH30~
1
HO '"

1 1H
0
N· CH3

proaporphine. ~hines morphinane./ protomorphinanes

CH30h~oCH,
CH,O~ __
CH~:2?'" 1 N. CH
3
CH30
~7OH
OCH, HO".. -HO~/-CH \
pavines ,.,. 1 '-.J ,... OCH3
CH3 0 isopavines
(+)- and (-)-rellcu6ne (20 and 21)

CH,O OCH3
CH 0
3

~ '"

r
0 '
,
NTH
H '

/
CH,O ,.,.
OCH3 OCH3
benzophenanthridines protoberberines cularines
t
CH,<)

o HO
OCH3
o> OCH3
OCH3
OCH3
protopines pbtbalideisoquinolines dibenzopyrrocolines
t o ,...
<0 " I H
CH,O I
HN
"" OCH,
o OCH3

secophthaiideisoquinolines

Fig. 32.6. Biosynthetic relationships between alkaloids derived from reticuline (modified from Preininger, 1986; used with pennission of the copyright
owner, Academic Press, Orlando. FL).
 lsoquinoline and Benzylisoquinoline Alkaloids 585

CH,'O

C H ' . 012 7 CH'-027

HO:::'" NH :::,.. 1 N
2' CHr O 'CH
HO ,:? I'
H H 3

" 1 ,:71 ,:71

CH"O.,:::'" "
5' HO :::,.. HO :::,..

(+)-reticuline (2) (+)-(S)·coc:laurine (12) (-)-armepavloe (13)

.O~ rnro~ ~,o~

:::,.. 1
HO
N+-CH,
H .... CH,
HO:::'" HNH HO:::'" NH

HO ,:7 HO ,:7
CH,-O ,:7 1 H
1 :::,..1
HO :::,.. CH,-O
HO :::,..
(-)-norlaudanosoline (26) (+)-nororientallne tembetarine

CH~OW
HOW CHro:cQ
HO:::'" NH
1

d
HO :::,.. NH 1 N
! H HO:::'" , .... CH,
CH"O~ I H
,:71 H
HO :::,..
HO~
HO :::,..
HO :::,..

(R)-norcoclaurine (-)-nororientaline (27) 6-0-methylnorlaudanosoline (28)

<a> [(+)-(R)-demelhylcoclaurlne )

H
HO 0 2 1
NH ~ I HO~
~
HO
I N
H.... CH'

HO ~
~I I
HO ~ HO ~

demethylcoclaurine (l2) {+)-Iaudanosoline (33)

(b) (higenamine)

Fig. 32.7 (a & b). Some representative tetrahydrobenzylisoquinoiine alkaloids.

From the biogenetic point of view, the most important
tetrahydrobenzylisoquinoline alkaloids is undoubtedly ( + )-
reticuline (20). This alkaloid is the precursor of a number
of more elaborate compounds (Fig. 32.6) and is widely dis-
tributed. (+ )-Reticuline is ftrst synthesized and then con-
verted to ( - )-reticuline (21) in the plant (Fig. 32.8) (Bat-
tersby and Foulkes, 1965; Beecher and Kellelior, 1988).
Reticuline occurs in the ( + )-form in Annona reticulata (An-
nonaceae), Cinnamomum camphora (Lauraceae), and in
Phylica rogersii (Rbamnaceae). In the opium poppy, Pa-
paver somniferum, both enantiomers of reticuline occur with
the ( + )-enantiomer predominating. Morphine alkaloids are
derived from ( - )-reticuline (21).
Biosyntbesis
Benzylisoquinoline (BIQ) or tetrahydrobenzylisoquino-
line (THBIQ) alkaloids are formed by condensation of dopa-
586 lsoquinoline and Benzylisoquinoline Alkaloids

H HOm HOm
I I H-O~
'-.. '-AI
~
i COzH NH ,;;-'
I
-CC(22)CH~Od-
HO 0 z::::.... N ::::.... ..... NH+

HO ~ NHz H O i llJl
'<::: ,;;-' ,;;-' I
L-tyrosine I ::.. I ::..
HO ~ (19) HO HO

H.:J~~
CH3-027'
HO;:::"" NH HO
~ NH
H

~, ~I
HO ::,... HO ::::....
(S)-norcocJaurine (23)
(S)-coclaurine (124)

CH3::27'"
*I >:-rn:~",
I <,,,,,--':~;:::,...' :'CH3

,
3'~ HO ~ _ HO ~ _
, ;:::,... ;:::,... ,
HO ;:::,... HO CH3-O
(S)-N-methyl-(S)-coclaurine 3'-hydroxy-N-methyl c..laurine (25) (+)-(S)-reticuline (20)

CH 0 CH3-0~

3:0~::::"" , hN"!:"' CH3 HO~:'CH3

HO ~ ---" HOXY

CH3- 0 ;:::,... I 1,2-dehydroreticuline CH3- 0 (-)-(R)-reticuUne (21)

Fig. 32.8. Biosynthesis of (+ )-(S) and (- )-(R)-reticuline (modified from Franzel and Zenk, 1990b and used with pennission of the copyright owners,
Elsevier Science Ltd., The Boulevard, Langford Lane, Kidlington OXS 1GB, UK).

mine (22) (Fig. 32.9) and 4-hydroxyphenylacetaldehyde (19)
(Fig. 32.8) (Frenzel and Zenk, 1990b).
The lack of strict specificity for the enzymes involved
in the initial conversion to (S)-reticuline (20) suggests that
stereochemical control does not occur at this stage ofbiosyn-
thesis (Zenk, 1985). The use of plant cell cultures (both cal-
lus and suspension types) from different species of plants
that produce benzylisoquinoline alkaloids has proven to be
a powerful approach for the isolation of enzymes and inter-
mediates in the pathways leading to these compounds (Zenk
et al., 1985). For example, the use of cell-free extracts of
Berberis cultures permitted Zenk and co-workers to isolate
and characterize all eight enzymes involved in the conver-
sion of dopamine (22) and 4-hydroxyphenylacetaldehyde
(19) to (S)-reticuline and, subsequently, to berberine.
Several types of data based on feeding experiments, isola-
tion of intermediates and in vivo NMR experiments, indicate
that norcoclaurine (23) serves as a precursor to both coclau-
rine (24) and (S)-reticuline (20) (Stadler et al., 1987, 1989),
and that (S)-coclaurine (24) serves as a specific precursor
to other classes of benzylisoquinoline alkaloids, such as the
protoberberines, benzophenanthridines, and morphinandie-
nones, as well as for pavine and benzophenanthridine alka-
loids in intact plants (Stadler et al., 1987, 1989). The five
enzymes involved in the conversion of dopamine and 4-
hydroxyphenylacetaldehyde (19) to (S)-reticuline (20) have
been elucidated (Frenzel and Zenk, 1990b).
The first step of this biosynthetic sequence involves con-
version of the amine and aldehyde to (S)-norcoclaurine (23)
with (S)-norcoclaurine synthase. This condensation is fol-

£)tC~DJ~
H
i reticuline derived
HO
1 ~
b
NH
, HO
L-tyrosine tyramine
H o : c r t ; CO,H H o m
~
H
--I
1# NH, # NH,
HO HO
L-DOPA dopamine (22)
HO
D! '
I
//
'" 0
CO H H o x Y Y C 0 2 H these two compounds ~ve no~
4·hydroxyphenylpyruvate
Fig. 32.9. Fonnation of the precursors of benzylisoquinoline alkaloids (modified from Zenk et aI., 1985; used with pennission of the copyright owner,
the American Society of Phannacognosy Downers Grove, lllinois).
lowed by methylation at the 6 position in the presence of S-
adenosyl methionine, N-methylation, and hydroxylation at
C-3' to yield 3'-hydroxy-N-methylcoclaurine (25) (Fig.
32.8). The enzyme controlling the N-methylation has been
isolated and studied (Frenzel and Zenk, 1990a). The enzyme
controlling the 3'-hydroxylation was a phenolase also capa-
ble of hydroxy1ating tyrosine to dopa, and tyramine to dopa-
mine, in the presence of ascorbate and oxygen. It is proposed
that the phenolase plays a multiple function in Berberis sto-
lonifera cultures (Loeffler and Zenk, 1990). The fmal meth-
ylation reaction involves methylation of the C-4' hydroxyl
group of 3'-hydroxy-N-methylcoclaurine with S-adenosyl-
L-methionine (SAM): 3'-hydroxy-N-methyl-(S)-coc!aurine-
4'-O-methyltransferase and SAM to produce (S)-reticuline
(20) (Frenzel and Zenk, 1990b).
It has long been known that differential incorporation of
tyramine into the two portions of the molecule occurs (Bee-
cher and Kelleher, 1988). When DOPA (3,4-dihydroxyphe-
nylalanine) was fed to callus cultures of Berberis cana-
densis, 91 % was incorporated into the isoquinoline moiety,
whereas tyrosine was almost equally incorporated into both
portions of the molecule (Riiffer and Zenk, 1986), supporting
the pathway outlined above.
Although norlaudanosoline (26) (Fig. 32.7) was previ-
ously assumed to be the precursor of (S)-reticuline (20)
(based on the condensation of dopamine and 3,4-dihydroxy-
phenylacetaldehyde), this route of biosynthesis is no longer
considered to account for the formation of benzylisoquino-
line alkaloids. In previous reports, it was noted that an en-
Isoquinoline and Benzylisoquinoline Alkaloids 587
NH, alkaloids
4-hydroxyphenylacetaldehyde (10)
__ H0)CJ
I"'" CHO
HO #
3,4·dihydroxyphenylacetaldehyde
HO
1 ~
b
been shown not to be mtermed18tes
for the synthesis of benzylisoquinoline
0
alkaloids
3,4-dihydroxyphenylpyruvate
zyme, (S)-noriaudanosoline synthase, that catalyzes the for-
mation of (S)-norlaudanosoline (26) from dopamine (22)
and 3,4-dihydroxyphenylacetaceldehyde (19) was isolated
from the soluble protein fraction of Eschscholtzia tenuifolia
cell suspension cultures (Schumacher et aI., 1983), but no
reaction was observed with cell-free extracts and 3,4-dihy-
droxyphenylpyruvic acid. No apparent cofactor require-
ments were demonstrated (Schumacher et aI., 1983). The
enzyme consisted of four isoenzymes upon further elec-
trophoretic separation. A series of relatively specific methyl-
transferases have been isolated from cultures of Argemone
platyceras (Papaveraceae) and Berberis. In the presence of
SAM, the first enzyme was reported to convert norlaudano-
soline (26) to 6-0-methylnoriaudanosoline (28) (Zenk,
1985). A second enzyme was reported to convert 6-0-meth-
ylnoriaudanosoline to the corresponding 4,6-0-methyl de-
rivative, and another enzyme to methylate the 5'-position to
yield nororientaline (27) (Fig. 32.7). N-Methyltransferases
were found in cultures of several plants and in latex of Pa-
paver somniferum that produced compounds such as reticu-
line and orientaline (29) (Fig. 32.17) (Zenk, 1985).
Apparently, the reason that noriaudanosoline (which had
never been isolated from any plant source) is easily incorpo-
rated is because of the relative nonspecificity of the enzymes
of the reticuline pathway (Hartmann, 1991). This nonspecif-
icity contrasts with the high specificity found among the
enzymes involved in the synthesis of more complex struc-
tures (Hartmann, 1991).
Tetrahydrobenzylisoquinoline alkaloids such as lauda-
S88 Isoquinoline and Benzylisoquinoline Alkaloids

HO~
HOI ::::,.. :H
CH3"O~1
~HO NH
-- H
HO 9' HO ,;?
I ~I
HO ~ CH,-O

(-)·(S)·norlaudanosoline (26) (-)-norreticullne

+ +
CH'_O~I CH'_O~I CH'_O~I
~
HO::::'" NH CH,.O::::'" -",N
CH,.O::::'" NH
H --+
CH,-O 9'
CH,-O 9' I CH,-O 9' I H
I
~ CH,'O ~
HO CH,'O ~

(0 )onororientaline (-)-tetrahydropapaverine papaverine (31)

Fig. 32.10. Biogenesis of papaverine (Cordell, 1981; used with pennission of the author).

nosine (30) often are dehydrogenated to the corresponding
aromatic compounds, in this instance, papaverine (31) (Fig.
32.10).
Biological Activity
Tetrahydrobenzylisoquinoline and derived alkaloids have
physiological effects in most animals (Schiff, 1987).
In general, quaternary benzylisoquinoline alkaloids can·
not pass through membranes (Zenk, 1988). (S)-Reticuline
(2) and (S)-scoulerine (17) are transported into vacuoles of
Fumaria capreolata. This transport involves an active A TP-
requiring, stereospecific carrier system that transports only
the (S)-enantiomers and not the (R)-enantiomers (Zenk et
al., 1985).
An aromatized alkaloid of this derivation, papaverine (31)
is the most important alkaloid of the BIQ group from the
pharmacological point of view. Papaverine inhibits aldol re-
ductase, GABA and glucose response in chemosensory cells,
and phosphodiesterase (Wink, 1993). In vivo, this alkaloid
decreases the tonus of the smooth muscle, increases coronary
artery flow, and causes dilation. Papaverine has a beneficial
effect on angina pectoris. This aromatic isoquinoline alka-
loid is neither narcotic nor addictive (Cordell, 1981). Papav-
erine has an LDso Lv. in mouse of 27.5 mglkg. Demethylpa-
paverine inhibits aldose reductase (Wink, 1993).
Papaverine (31) inhibits root growth and induces poly-
ploidy in Allium. This alkaloid is a feeding deterrent to sev-
eral insects (Wink, 1993).
Azafluorantbene and Tropoloisoquinoline
Alkaloids
This group of alkaloids occurs in the genus Abuta (Men-
ispermaceae). Crude extracts of the plants are used as ingre-
dients of arrow poisons by the Juris of the Rio Japuras basin,
Amazonas, Brazil (Fig. 32.11) (Buck, 1984). Alkaloids of
this structural type from an African tree, Cleistopholis patens
(Annonaceae), had inhibitory effects on Candida.albicans
in concentrations as low as 1.56 ,...glml (Clark and Hufford,
1992).
APORPllll'lE ALKALOIDS
The simplest derivatives of the tetrahydrobenzylisoquinoline
alkaloids are the aporphine alkaloids (Fig. 32.12). Aporphine
alkaloids (about 650) are widespread and occur in almost the
same families as benzylisoquinoline alkaloids (Guinaudeau
and Bruneton, 1993; Kametani and Honda, 1985). Several
subgroups of aporphine alkaloids are known [noraporphines,
dehydroaporphines (34), oxoaporphines (35), dimeric apor-
phines, and phenanthrenes (36)] (Fig. 32.13) (Cave et al.,
1987). The aporphine alkaloids present in members of the An-
nonaceae and in the genus Thalictrum (Ranunculaceae) have
been reviewed (Cave et al., 1987; Schiff, 1987).
Biogenesis
Aporphine alkaloids may arise by an oxidative coupling
reaction that can occur at positions ortho or para to phenolic
groups (Fig. 32.14) (Battersby, 1967). Rotation about the
single bond by which the benzyl group is attached before
cyc1ization gives rise to two series of aporphine alkaloids,
as represented by bulbocapnine (32) on the one hand, and
glaucine (28) on the other. Methylation can reduce the num-
ber of possible coupling sites, as coupling only occurs ortho
 Isoquinoline and Benzyiisoquinoline Alkaloids 589

OCH,
OCH,
CH,-O

CH,-O

OCH, OCH,

imerubrine imeluteine

tropoloisoquinoline alkaloids azatluoranthene alkaloids

Fig. 32.11. Azafluoranthene and tropoloisoquinoline alkaloids.

(+)-bulbocapnine (37) (+)-glaucine (38) (+ )-ocotelne (40)

CH,-O
HO

CH,-O
CH,-O

HO

HO
HO
OCH,
OCH,

{+)-lirioferine (43)
(+)-liriotulipiferine (44)

H-stephanlne (47) laureline (48) (+).isothebaine (49)

Fig. 32.12. Some representative aporphine alkaloids.

590 /soquinoline and Benzylisoquinoline Alkaloids

""w CH,-O
CH'°Z?I
CH3~O ~ h ..... CH3 o

:?'I 00
CH,-O "'" OCH,
OCH,
oxoglaucine (35) taspine (41)
1,2-dihydroxy-7-oxoaporphine
(Iiriodendronine)
OH

HO~ 0
CH,-O "'" I .,..:'CH'<O

:?'I
CH,-O "'"
OH

boldine (42) dehydrothalicmine (34) N-methylthaliglucine (36) liriodenine (45)

Fig. 32.13. Subgroups of aporphine alkaloids.

or para to free hydroxyl (phenolic) groups. The methylation
pattern is of great importance in aporphine alkaloid biosyn-
thesis (Fodor, 1980).
The label from N-CH3 labeled ( + )-(S)-reticuline is incor-
porated into bulbocapnine (37) in Papaver somniferum at
high levels. Similar experiments with reticuline labeled in
several positions demonstrated that direct coupling of reticu-
line occurs to yield the aporphine skeleton. Furthermore,
reticuline is incorporated into isoboldine (39) (Kametani and
Honda, 1985; Santavy, 1979).

CH"O~I
o N'CH
CH'O~IN'CH HO "" CH'-OifN
. ~H ' 'H 'CH3-0 "" ' '''H 'CH3
-------"-
---+- "" ~
/ I I I"" :P I
CH,·o CH,O CH,-O ""
CH,O o OH
OCH,
HO isoboldine (39) (+ )-glaucine (38)

CH,H: : I 6'
(+).reticuline (20)
\CHJO~I 0
CH'Ogl
N . . . CH HO ~ N "CH
: 'H 3 "H 3

o ---+-HO ~ -+- ---...

I I
CH,- 0 "" CH,- 0 '"
(+ )-bulbocapnine (37)

Fig. 32.14. Biogenesis of aporphine alkaloids such as bulbocapnine and glaucine (modified from Geissman and Crout, 1969).

Biological Activity
Aporphine alkaloids exhibit several types of biological
activity in other organisms. For example, these compounds
display a variety of effects in mammals (Corde\1, 1981;
Schiff, 1987). Most are toxic; they often exhibit antagonistic
effects to dopamine (Castro, 1993). The anticonvulsant ac-
tion of several aporphines acting at dopamine receptors has
been documented. Glaucine (38) induces narcosis and con-
vulsions in mammals (Schiff, 1987). Ocoteine (40) (thalic-
mine) has antitussive, hypotensive, spasmolytic, and adreno-
lytic activity in cats and has been noted to produce
hyperglycemia in rats (Schiff, 1987). Bulbocapnine (37) in-
hibits peripheral dopamine receptors and has an LDso p.o.
in mouse of 413 mg/kg and glaucine (Lv.) of 98 mglkg.
Isoboldine (39) inhibits aldose reductase (Wink, 1993).
Other members of this group of alkaloids exhibit a variety
of activities. Taspine (41) is the active component of the sap
of Croton species used by the Jivaro Indians for its wound-
healing properties (Lewis, 1992). Demethylcoclaurine (hi-
genamine, norcoclaurine) (23) has positive inotropic activity
at a concentration of 10-7 g/ml (Wagner, 1988). Laudanoso-
loline (23) is antifeedant and exhibits growth inhibition to
larvae of Hyphantria. Spodoptera, and Lymantria. Lauda-
nosine (30) modulates glycine neurochemical activity
(Wink, 1993).
Several of these alkaloids are involved in plant-insect in-
teractions. Isoboldine (39) is known to be an inbibitor of insect
feeding (Cordell, 1981). Several aporphine alkaloids are re-
pellent or toxic to insects. Among these are boldine (42), a
feeding deterrent to polyphagous Syntomis larvae. glaucine
(38), which is a feeding deterrent and growth inhibitor for lar-
vae of Hyphantria. Spodoptera, and Lymantria, and isobol-
dine (39), which is a feeding deterrent for Prodenia and Orae-
sia (Wink, 1993). The pharmacological effects of many
aporphine alkaloids have been reviewed (Castro, 1993).
Two previously undescribed aporphine alkaloids, liriofer-
ine (43) and liriotulipiferine (44) as well as several other simi-
lar alkaloids were produced in the sapwood of Liriodendron
tulipifera (tulip tree, Magnoliaceae) upon injury to the tree.
Under normal conditions, only glaucine could be detected
(Chen et al., 1976). Liriodenine (45), from the same source,
has broad-spectrum antimicrobial activity, including activity
against Candida albieans. Aspergillus niger, and several
other fungi. Because of its relatively low toxicity and its good
in vivo efficacy, liriodenine may have potential as an antifun-
gal agent (Clark and Hufford. 1992). This compound also is
active against nasopharyngial tumors and is cytotoxic (Wink.
1993). Boldine is toxic toLemna (Wink, 1993).
Aristolactams and Aristolocbic Acid
This group of alkaloids is known primarily from the genus
Aristoloehia (Aristolochiaceae). Several of the compounds
contain nitro groups. Despite their unusual structures, aris-
tolochic acids are derived from benzylisoquinoline precur-
sors. Alkaloids from the genus Aristoloehia (Aristolo-
chiaceae) have been reviewed (Chen and Zhu, 1987).
Isoquinoline and Benzylisoquinoline Alkaloids 591
Aristolochic acids (46) and the related aristolactams are
thought to be derived from aporphine alkaloids, although
there is little experimental evidence to support this proposal.
Tyrosine. DOPA, and noradrenaline are precursors. A bio-
synthetic pathway has been proposed (Fig. 32.15) (Cordell.
1981).
Aristoloehia clematitis has been used to treat snakebites
and wound infections. One of the major alkaloids of this
plant is aristolochic acid (46). The plant extract is not directly
antimicrobial. but it produces an enbancement of phagocyto-
sis of leucocytes and peritoneal microphages. Aristolochic
acid is suspected to be carcinogenic (Pezzuto et al.. 1988;
Wagner and Proksch, 1985) and has been reported to have
antitumor activity. The LDso i.v. of aristolochic acid (46) in
mouse is 38-70 mg/kg (Wink. 1993).
Larvae of the butterfly, Paehlioptera aristoloehiae, which
feed exclusively on plants of the family Aristolochiaceae,
accumulate aristolochic acid (46) (Levinson, 1976). Aris-
tolochic acids have also been isolated from severallepidop-
teran caterpillars Md are transferred to the pupae. Imagos
of the swallowtail butterflies, Battus polydamas and B. phi-
lenor. contain aristolochic acid (Nahrstedt, 1982; Urzua et
al., 1987), but do not appear able to adjust the levels of
toxins, as do monarch butterflies (Harborne, I 986).
A mixture of aristolochic acids and inositol was found to
be an oviposition attractaot for an Aristolochiaceae-feeding
swallowtail, Atrophaneura alcinous. and induced a response
identical to that of the host plant (Nishida and Fukami.
1989).
Aristolochic acid is a feeding deterrent and produces
growth inhibition in the larvae of Hyphantria. Spodoptera.
and Lymantria (Wink, 1993).
Eupomatia Alkaloids
This small group of alkaloids is only known from the
genus Eupomatia (Eupomatiaceae). These compounds ap-
pear to be derived from oxoaporphine alkaloids, although
little experimental work has been done to establish this pro-
posal (Fig. 32.16) (Taylor, 1985).
Proaporpbine Alkaloids
Although the formation of most aporphine alkaloids is
straightforward, the formation of others, such as stephanine
(47), laureline (48), and isothebaine (49) (Fig. 32.17) is more
complicated (Mann, 1987). In this case. the ortho or para
oxygen function reqnired for direct oxidative coupling is
absent in the probable precursor. Formation of this type of
alkaloids involves the intermediacy of compounds called
proaporphine alkaloids, such as orientalinone (50). The for-
mation of aporphine alkaloids with apparently anomalous
structures has been postulated to occur by the biological
equivalent of the dienone-phenol and the dienol-benzene
rearrangement (Fig. 32.17) (Geissman and Crout, 1969).
Following coupling of the position para to the hydroxyl
of the benzyl group of N-methylcoclaurine (51) to produce a
592 Isoquinoline and Benzylisoquinoline Alkaloids
aristolocbic acid·U (46)
CHHi¥2~?":"" "Hi§9:
~ 9' : I N'CH3CH30R:9'
HO I N, CH3
0.&
OCH3 HO.&OCH -- :9':",. I OCH
orientalinone (50)
3 3
Fig. 32.15. Biogenesis of aristolochic acids and aristolactams (modified from Cordell, 1981; used by permission of the author).
5-membered ring, ring expansion occurs by dienone-phenol
rearrangement to yield laureline (48) (Fig. 32.17) (Geissman
and Crout, 1969).
In a similar manner, coupling and ring closure occur with
( - )-orientaline (29) to yield isothebaine (49). 10 this in-
stance, however, ring expansion occurs via a dienol-ben-
zene rearrangement (Fig. 32.17) (Geissman and Crout,
1969). Migration of the alkyl rather than the aryl group in
an intennediate leads to an aporphine from which stephanine
is readily derived (Fig. 32.17).
Although the mechanisms above were postulated before
compounds resembling the proposed intermediates were
known, compounds such as orientalinone (50) were later
isolated. Both (- )-orientaline (29) and (+ )-orientalinone
(50) (a proaporphine alkaloid) serve as precursors for iso-
thebaine (49) in Papaver orientale (Fig. 32.12) (Geissman
and Crout, 1969).
Proaporphine alkaloids are known from the Euphor-
biaceae, Lauraceae, Menispermaceae, Monimiaceae, Ne-
lumbonaceae, and Papaveraceae (Santavy, 1979).
l'fORPIIINAI'IDmI'lOl'lE ALKALOIDS
(PROl'fOKPHIl"lAl'lES )
Morphanandienone alkaloids are widely distributed in the
families Papaveraceae and Meuispennaceae. Alkaloids of
this structural type in the Papaveraceae and in the genus
&ristolocbic acid·I
t
Thalictrum (Ranunculaceae) have been reviewed (Santavy,
1979; Schiff, 1987).
The in vivo conversion of (R)-reticuIine to morphinandie-
nones such as salutaridine (52) (promorphinanes) has been
demonstrated (Santavy, 1979) (Fig. 32.18). An enzyme from
a cell-free extract of Papaver somniferum utilized H20 2 to
produce salutaridine in high yield. Morphine alkaloids (see
below) are derived from the morphinandienone alkaloid sa-
lutaridine.
Both enantiomers of the morphinan skeleton occur in na-
ture.
Hasubanan Alkaloids
Hasubanan alkaloids (about 40 in total), in which the ni-
trugen is attached at position C-14 (rather than C-9), are
derived from sinoacutine (Guinaudeau and Bruneton, 1993).
( + )-Reticuline (20) gives rise to sinoacutine (53). 10 Sino-
menium acutum, sinoacutine is the precursor of sinomenine
(54), a compound enantiomeric to morphine.
Hasubanonine-like alkaloids are known from the genera
Sinomenium and Stephania (Menispennaceae). A biogenetic
pathway leading to the fonnation of hasubanonine (55) and
protostephanine (56) has been proposed (Battersby et al.,
1974, 1977, 1981a, 1981b, 1981c) (Fig. 32.19).10 experi-
ments in which labeled precursors were fed into whole
plants, Battersby and co-workers found that simple tyramine
derivatives such as 2-(3,4-dihydroxy-5-methoxyphenyl)eth-
 Hte
lsoquinoline and Benzylisoquinoline Alkaloids 593

OOg2.
If. -
HO ::,... 1 "N oo 1h N
o 1 N
--+ --+ "
~ 1 0 ~ 1 0 ~ 1

~t2 -- 021:
0
::,... ::,... ::,...

o~ -
1'<::
HN I h
N N~ ~N
HN ""N
--+ ~
~ 1 0 ~ 1 0
~ 1 0
::,... ::,...
::,... 0
0

--
0

&2.
~
::,...
.0
1
""N

0
--
g1~
~.o N ~ 0

~ 1 0

~
OCH,
::,...

ci2J
eupolauramine
o ::,... N

l..,p ::,.. 1 1.0

"" 0
N
eupolauritline

Fig. 32.16. Eupomatia alkaloids (modified from Taylor, 1985; used with pennission of the copyright owner, Academic Press, Orlando. Fl.),

ylamine (57) were incorporated into hasubanonine and pro-
tostephanine, as were a series of l-benzyltetrahydroisoqui-
nolines that possessed two phenolic oxygens in one of the
rings undergoing oxidative coupling during the biosynthesis
(Battersby et aI., 1981a, 1981b, 1981c).
The role of alkaloids from the genus Stephania in Chinese
traditional medicine has been discussed (Han et aI., 1988).
The NMR spectra of hasubanan alkaloids have been re-
viewed (Matsui, 1988).
JIIOKPHll'lE ALKALOIDS
Poppies have long been used by man as a medicinal plant
and as a drug of abuse. The use of opium is mentioned by
several ancient writers; among them are Theopbrastus and
Dioscorides (Tyler et aI., 1981). Morphine-type aIkaIoids
are found in several members of the genus Papaver, but
morphine (58) itself is only known to occur in the opium
poppy, Papaver somniferum (Bisset, 1985). Another species,
P. bracteatum, synthesizes quantities of thebaine (59) that
can be converted chemically to morphine (Verpoorte et aI.,
1991).
Opium is produced by lacerating the immature capsules
of the plant. Care must be taken not to cut through the peri-
carp. Mter the latex has exuded and dried, the dark, resinous
material is collected. This crude opium, which contains as
much as 12-14% morphine, is then used directly or further
purified (Tyler et aI., 1981). The estimated legal world pro-
duction of opium is more than 1000 metric tons; from this,
about 660 metric tons of codeine and 200 metric tons of
morphine are prepared (Verpoorte et aI., 1991).
Because of the economic importance of morphine alka-
loids, many attempts to produce them in plant tissue cultures,
usually Papaver somniferum or P. bracteatum have been
made (Ellis, 1988; Verpoorte et aI., 1991). Cultures of both
S94 /soquinoline and Benzylisoquinoline Alkaloids

CH30~
I CH3 0 ' r3
HO '-' N' CH3 ',-,
H HO 1Z
CH3·O r CH3·O
1- 11 r
HO '-' 0 h

(-j.orientaline (29) (+ )-orienlalinone (50) dienol-benzene (+)-lsotbebalne (49)

rearrangement

N-methylcoclaurine (51)

CH30~
HO '-' N' 1 CH
H ....:.....
r l
HO '-'

dienone-phenol laureline (48)

rearrangement

N CH3-0
'CH3 HO '-'
1 » :N'
CH
<O~I
° '-' N.
H CH3
(+ )-orienlaline (29) H H 3_ r
- r I
'-' 1 '-' OCH3
OCH3 OCH3
stephanine (47)

Fig. 32.17. Fonnation of aporphine alkaloids via the intennediacy of proaporphine alkaloids (modified from Geissman and Crout, 1969).

species are excellent producers of sangninarine. In summary,
none of these attempts has successfully produced commer-
cially interesting amounts of morphine alkaloids. Radio-
tracer studies, however, suggest that the failure of these cul-
tures to accumulate morphine alkaloids may be due to high
turnover rather than to an inability to synthesize the com-
pounds of interest (Ellis, 1988). Other alkaloids from earlier
steps in the pathway are present. These include isothebaine
(49), orientaIidine (50), protopine (60), cryptopine, and, usu-
ally as the main product, sanguinarine (61). Treatment of
suspension cultures of Papaver somniferum with a homoge-
nale of the fungns Botrytis increased the amount of sanguina-
rine 150-fold. Tissue cultures have been extremely useful
for the isolation of key enzymes of this pathway (Hutchin-
son, 1986).
Although morphine has an extremely limited distribution
among plants, this alkaloid has been isolated in trace
amounts from the skin of a bufonid toad, Bufo marinus (Daly
et al., 1993). Morphine and thebaine have been reported from
mammals (Brossi, 1993). The biosynthetic pathway seems
to be similar to that of plants, although some differences
have been noted.
Biosynthesis
Robinson and Gulland (1925) were the first to observe
that the foonation of aporpine alkaloids was by oxidative
coupling of benzylisoquinoline precursors. They also
pointed out that by a different mode of coupling, the basic
carbon skeleton of the morphine alkaloids thebaine (59),
codeine (62) and morphine (58) could arise (Fig. 32.20).
(- )-(R)-Reticuline serves well as a postulated precursor be-
 Isoquinoline and Benzylisoquinoline Alkaloids 595

(-).(R)·reticuline (21)

salutaridine (52) morphinan system

CH30~
I
HO
?"
~ N 'CH
CH30~
HO
~ I CH30
0.
I 2t
__
"H ~ ......' \. ~ .......' ....
= ?" N N
HO P I ~ I H ' CH3 I I H ' CH3
CH3 0 ~ CH30 CH30
OH 0
(+ HS)·reticuline (20)

CH30~,
CHP~
HO ~
, 3

4
HO ~
.."
., ~"

, ......, H \'-;3- 5 16
H N'CH3
o h
CH3 0 OCH3
o
sinoacutine (53) hasubanan system sinomenine (54)

Fig. 32.18. Fonnation of motphinandienones from (+)- and (- )-reticuline (modified from Battersby, 1967; modified and used with pennission of the
copyright owner, Marcel Dekker, Inc., New York).

cause the methylation pattern precludes formation of unde-
sirable coupling modes and favors the desired pathway (Cor-
dell, 1981).
The results of numerous labeling and feeding studies and
other experimental results have established that the steps of
the pathway are as indicated (Fig. 32.20). 2-14C-Tyrosine
produces morphine labeled at C-9 and C-16. 1.1 4 C-Dopa-
mine gives morphine labeled at C-16. 3,4-Dihydroxyphenyl·
alanine is readily incorporated into morphine (58), thebaine
(59), narcotine (63), and papaverine (31) (Santavy, 1979).
(R,S)-Norcoclaurine (23) and (R,S)·coclaurine (24) (both lao
beled at C-I) were incorporated into thebaine and morphine
(labeled at position C-9) when fed to Papaver samniferum
plants (Loeffler et aI., 1987). Noriaudanosoline (26) (Fig.
32.5) is an efficient precursor of morphine. Studies of the
rates of incorporation of radioactivity demonstrated the se-
quence thebaine (59) to codeine (62) to morphine (58).
Quadruply-labeled (- )-reticuline (21) was specifically in-
corporated into thebaine. Tritium-labeled salutaridine (52)
also was specifically incorporated. Salutaradine first was dis-
covered in Croton salutaris (Euphorbiaceae) from Brazil,
but later was demonstrated to occur in Papaver somniferum
in low concentrations (Geissman and Crout, 1969). This
compound gives salutaradinol I (64) by reduction (Fodor,
1980). In the above study, it was demonstrated that the oxy-
gen bridge is formed by an SN2' displacement of the oxygen
on salutaradinol rather than by addition to the dienone sys-
tem of salutaridine (Fodor, 1980).
N-Demethylation is the most frequently observed step in
alkaloid catabolism (Waller and Nowacki, 1978). Not only
is morphine formed by this process, but morphine is con-
verted into normorphine quite readily.
Over 40 alkaloids are known from opium. Several of
these are of importance. Among them are morphine (58),
S96 Isoquinoline and Benzylisoquinoline Alkaloids

CH,-O
CH'-OW
CH'-0)QJ
I

--
N HO
HO
I "'" NH, HO ~ ,'CH,

""it
HO~H --

CH'-O~ CH,-O
o
HO

CH,-O CH,-O
CH'.O~
- --
I
HO

CH,-O OCH,
--
··"".::::::::'N+....... CH
3
HO

CH,- 0
""'-

I ······,·""."N ..... CH3

OCH,
CH,-O

o
o o OCH,

(0) hasubanonine (55)

CH'.O~OCH'
~I
17 N-CH, I
HO~~ NH,

~ I HO
CH,· 0 OCH, OCH,

(b) protostephanine (56) 2--(3,4-dihydroxy-5-methoxyphenyl)ethylamine (57)

Fig. 31.19. Proposed biosynthesis of basubanonine (Battersby et aI .• 1981c; used with pennission of the copyright owner, The Royal Society of
Chemistry, Cambridge).

codeine (67), thebaine (59), a-narcotine (noscapine) (Fig.
32.27) (63), and papaverine (11).
Two of the principal alkaloids of opium are morphine
(4-21 %) and a a-narcotine (noscapine) (4-8%) (63). These
alkaloids occur partially bound to meconic acid, which is
diagnostic for opium. Morphine (58) and its salts are classi-
fied as narcotic analgesics. Codeine (62) also occurs in
opium, in the concentration range 0.7-2.5%. Most codeine
(62) is prepared by methylation of morphine.
Morphine does not continuously accumulate in the latex
of P. somniferum. The isolated latex of the opium poppy
sustains alkaloid synthesis and further metabolizes morphine
in vivo to as yet unidentified products. The alkaloids are
synthesized in the vesicles and are translocated to the devel-
oping capsule by the upward movement of the latex. The
metabolites pass out of the latex into the pericarp and into
the ovules (Santavy, 1979). Translocation from the stem to
the developing capsule is well established. These transfers
are most rapid during the first days of capsule development,
at which time the pericarp volume is increasing rapidly.
When morphine was fed to the stem below the developing
capsules, 8% of the morphine was metabolized in a few
days. Diurnal changes in the content of alkaloids in Papaver
somniferum occur (Waller and Nowacki, 1978). The half-
life of morphine in several species of poppies is 7.5 h.
Pharmacological Activity
The pharmacological actions of morphine (58) are com-
plex. Some specific central nervous system functions are
depressed; others are stimulated. Typically, morphine pro-
duces analgesia, drowsiness, changes in mood, and mental
clouding. Analgesia occurs without loss of consciousness.
In humans, death from morphine poisoning is almost always
due to respiratory arrest. Morphine (58) and its analogs are
powerful depressants of the cough center (antitussives).

(-)-(R)-reticuline (21)
salutaridinol I (64) tbebalne (59)
codeinone codeine (62)
Fig. 32.20. Biogenesis of morphine (modified from Geissman and Crout, 1969).
Morphine has an LDso i.v. in mouse of 226-318 mglkg
(Wink, 1993). Codeine (62) is also an important analgetic
and antitussive drug. Codeine is the most widely used mor-
phine type aIkaloid; it has an LDso Lp. in mouse of 300
mg/kg (Wink, 1993). This aIkaloid is derived from opium
(0.2-0.7%) and synthesized by methylation of morphine
(Tyler et al., 1981). Heroin (65) (Fig. 32.21), a synthetic
diacelate of morphine, crosses the blood-brain barrier more
rapidly than morphine and is highly euphoric and analgetic.
The compound methadone (66) appears to have the struc-
tural features needed to bind to opiate receptors in the brain.
This compound is active orally. Naturally occurring peptides
called enkephalins (67 and 68) have been isolated from brain
tissues of certain animals, including man (Fig. 32.21). These
compounds are derived from larger peptides. Both have anal-
gesic effects and apparently act at the same receptors as
opiates. Morphine and related aIkaloids may also occur in
animal tissues (Kosterlitz, 1987).
Thebaine (59) is of special interest, as this alkaloid can
be converted into morphine. Thebaine is almost the sole
alkaloid (up to 26%) of the latex of Papaver bracteatum
Isoquinoline and Benzylisoquinoline Alkaloids 597
salutaridine (52)
neopinone
morphine (58)
(Cordell, 1978a). This substance has an LDso Lp. in mouse
of 20 mglkg (Wink, 1993).
otber Biological Activity
Although the biological properties of these alkaloids in
humans are well known, their role in other biological interac-
tions has been little studied. Morphine inhibits root growth
and induces polyploidy in Allium. Narcotine (63) inhibits
seed germination (Wink, 1993). Several morphine alkaloids
have activity in plant-insect interactions. Morphine (58) is
a phagorepellent for Pieris and Leptinotarsa. Codeine (62)
is a feeding deterrent for Phormia; narcotine (noscapine)
(63) is a feeding deterrent for polyphagous Syntomis larvae
(Wink, 1993).
PROTOBERBERINE ALKALOIDS
The protuberberine aIkaloids are one of the most widely
distributed groups of the benzylisoquinoline alkaloids (a
subgroup of these is called "berberine aIkaloids"). Approxi-
 %
598 lsoquinoline and Benzy/isoquinoline Alkaloids
o
"""
1
H
N(CH,h
~I
"""
methadone (66)
H,N·tyr·gly·gIy·pbe·met·CO,H (67)
H,N.tyr.gly.gly.pbe·leu·CO,H (68)
Fig. 32.21.
mately 100 alkaloids of this series are known (Beecher and
Kelleher, 1988; Guinaudeau and Bruneton, 1993) from at
least 10 plant families: Alangiaceae, Annonaceae, Berberi·
daceae, Fabaceae (Erythrina), Fumariaceae, Lauraceae,
Menispermaceae, Papaveraceae, Ranunculaceae, and Ruta·
ceae (Bhaknni and Jain, 1986). Berberine also has been reo
ported from the Juglandaceae and Rubiaceae (Suffness and
Cordell, 1985).
Berberine (71) is produced by several plant cell cultures
(Ellis, 1988). Suspension cultures of Coptis japonica pro·
duce large quantities (8% by dry weight) of berberine. Some
cultures excrete berberine directly into the culture medium
whereupon it crystallizes (Ellis, 1988). Cell cultures of some
Berberis species synthesize jatrorrhizine (69) and colum·
bamine (70) as the principal alkaloids, especially during the
exponential growth phase and stationary phase (Verpoorte
et al., 1991). Many of these same cultures produce berberine
as the major alkaloid during lag·phase growth.
Biosyntbesis
Based on work with cell·free extracts, the enzymology
of the biosynthesis of protoberberine alkaloids has been reo
solved to a great extent (Herbert, 1986). (S)·Reticuline (20)
is converted intu berberine (71). (S)·Coclaurine (24) is an
early precursor for protoberberine alkaloids (Stadler et al.,
1987). This compound gives rise to a later precursor of pro·
toberberines, (S)- or (+ )-reticuline (10), a major branch
point in the synthesis of many types of benzylisoquinoline
alkaloids. The additional methylene group of protoberberine
alkaloids has been demonstrated to come from methionine
(Fig. 32.22) and is called "the berberine bridge" in many
publications. The "berberine-bridge" enzyme converts (S)-
reticuline (20) into (S)-scoulerine (72) (Hartmann, 1991).
The N-methyl group is transformed into an iminium function
by oxidation and followed by ring closure (Beecher and Kel-
leher, 1988; Bhaknni and Jain, 1986; Geissman and Crout,
J-O~
"""I
o
• N
)-0....... Q Ii 'CH,
o
heroin (65)
enk:ephalins
Methadone and enkephalins.
1969). (S)-Scoulerine (72) is the first tetrahydroberberine
formed. This compound is subsequently methylated at the
hydroxyl group in position 9 (S-adenosyl methionine) to
yield (S)-tetrahydrocolumbarnine (73), which is then aroma-
tized to form columbarnine (70) (Hartmann, 1991). The
methyltransferase that reacts with (S)-scoulerine (72), S-ad-
enosyl-L-methionine: (S)-scoulerine 0-9-methyltransferase,
is highly specific (Herbert, 1986; Zenk et aI., 1985). Colum-
barnine (70) gives rise to berberine (71) by formation of a
methylenedioxy ring at ring A (Amann et al., 1988). A highly
specific Fe2+-containing enzyme with 32,000 MW converts
columbamine into the corresponding methylenedioxy deriv-
ative, berberine (49)(Herbert, 1986; Riiffer and Zenk, 1985).
The C-8 bridge of berberine is derived from the N-methyl
of the tetrahydrobenzylisoquinoline precursor. The results
of double-labeling experiments suggest that the process is
similar to the formation of methylenedioxy systems.
All of these enzymes are associated with specific vesicles,
most likely derived from smooth endoplasmic reticulum. Be-
cause of the charge of the quaternary protoberberine alka-
loids, the alkaloids do not leave the vesicles, but ultimately
end up in the vacuole when the vesicle membrane fuses with
the tonoplast (Hartmann, 1991).
Berberine biosynthesis in Coptis cultures involves forma-
tion of a methylenedioxy bridge into tetrahydrocolum-
barnine (73) to yield canadine (74) (Fig. 32.23). The pathway
differs in Berberis cultures. This should be a warning not
to generalize pathways of secondary metabolism unless the
enzymatic steps have been elucidated for each species (Hart-
mann, 1991). (- )-Canadine (SO) was efficiently incorpo-
rated into berberine in Hydrastis canadensis (Bhaknni and
Jain, 1986).
An enzyme, (S)-tetrahydroprotoberberine oxidase, from
suspension-cultured cells of Berberis wilsoniae catalyzes the
removal of four hydrogen atoms from a number of tetrahy-
droprotoberberine alkaloids in the presence of oxygen
(Amann et al., 1988).
 Isoquinoline and Benzylisoquinoline Alkaloids 599

-
CH3·O

HO

OCH3

(+)-(S)-reticuline (20)

CH30~
I CH30~
I CH3 0

~ ~ ~OCR'
'"
HO'" N HO'" N ~ ",I N 3
H __ H HO-
o ",OH H OCH
I I '" 3
OCR, OCR,

(S)-scoulerine (72) (S)-tetrahydrocolumbamine (73)

<
CH3 0 CH3-O o
4
HO -0
OCH3

OCH3

columbamlne (70) berberine (71)

1: berberine bridge enzyme, 50,000 daltons, pH optimum 8.9, Oz

2: (S)-scoulerine-9-Q-metbyltransferase, 60,000 daltons, pH optimum 8.8, SAM
3: (S)-tetrahydroproloberberine oxidase, 100,000 daftoos, pH optimum 8.9, 0,
4: berberine synthase, 52,000 daltons, pH optimum 8.9, O2

Fig. 32.22. Proposed biosynthesis of berberine (modified from Amann et aI., 1988; used with pennission of the copyright owner, Springer-Verlag.
Berlin).

It has been demonstrated that berberine is incorporated
into jatrorrhizine (69) (Beecher and Kelleher, 1983). Cul-
tures of Berberis aggregata also yielded a specific methyl-
transferase that converts tetrahydrocolumbamine (73) to tet-
rahydropalmatine (75) and an oxidase that converts
tetrahydroberberine (76), tetrahydrocolumbamine (73), and
tetrahydropalmatine (75) to their quaternary counterparts
(Beecher and Kelleher, 1984).
Biological Activity
Berberine (71) inhibits growth of radicle in Lepidium and
Lactuca (Wink, 1993).
The phannacological activity of berberine and protober-
berine alkaloids has been reviewed (Schiff, 1987). Berberine
has a wide range of interesting biological activities. Berber-
ine has general antimicrobial, trypanocidal, antiamebic, anti-
fungal, anthelminthic, leishmanicidal, and tuberculostatic
properties. This alkaloid inhibits the growth of Trypanosoma
cruzi (Wink, 1993). It inhibits reverse transcriptase, interca-
lates with DNA, and inhibits aldose reductase, acetylcholin-
esterase, alcohol dehydrogenase, aldehyde reductase, di-
amine oxidase, tyrosine decarboxylase, and RNA synthesis
(Wink, 1993). This alkaloid is widely used for the treatment
of malaria, amoebiasis, and leishmaniasis. The ICs• against
Plasmodiumfalciparum is from 0.14 to 0.36 ILg/mi. How-
ever, berberine lacks in vivo activity in mice (Borris and
Schaeffer, 1992; Phillipson et al., 1993). The LDso of berber-
ine in mice (intraabdominal) is 27.5 mgikg. Further, berber-
ine has antitumor properties (Schiff, 1987; Suffness and Cor-
dell, 1985). Berberine is sold in India as an antidiarrheal and
600 lsoquinoline and Benzylisoquinoline Alkaloids
RO
CR,-O
jatrorrhizine (69)
canadine (74)
Fig. 32.23. Biologically active protobererine alkaloids.
has been shown to be effective for this pwpose (Beecher
and Kelleher, 1988). 1n Japan, berberine and the rhizomes
of the plant Coptis japonica are widely consumed as a stom-
ach tonic (Ranunculaceae). Berberine contracts the uterine
muscle and is used to stop uterine bleeding (Verpoorte et
al., 1991). Berberine (71) is a feeding deterrent and is toxic
to a number of insects (Wink, 1993).
Jatrorrhizine (69) and palmatine (78) are active against
Plasmodium Jalciparum. Jatrorrhizine inhibits butyrylchol-
inesterase (Wink, 1993). Palmatine inhibits reverse tran-
scriptase, aldose reductase, and acetylcholinesterase (Wink,
1993).
Columbamine iodide and certain other protoberberine al-
kaloids are active inhibitors of the mv-1 reverse tran-
scriptase system (Tan et al., 1991). Columbamine (70) also
inhibits butyrylcholinesterase (Wink, 1993).
Canadine inhibits aldose reductase (Wink, 1993).
PROTOPIl'IE ALKALOIDS
Berberine or protoberberine alkaloids [such as stylopine
(79) j may be converted into alkaloids of the protopine type
(60) (Fig. 32.24) (Geissman and Crout, 1969; Hartmann,
1991). Highly specific microsomal cytochrome P-450-de-
pendent enzymes from cells of Eschscholtzia californica
(and other species of the Papaveraceae and Fumariaceae)
introduce two methylenedioxy bridges into (S)-scoulerine
(72) to form (S)-stylopine (79), which is, in tum, an impor-
tant precursor of the protopine, phthalideisoquinoline, and
benzophenanthridine groups (Hartmann, 1991).
Allocryptotine (80) produces antiarrhythmic effects in
humans in doses of 60-120 mglpatient. This alkaloid in-
:::~:~71 N
OCR "'" OCR,
, I
OCR, h OCR,
tetrahydroberberine (76) tetrahydropalmatine (75)
palmatine (78) tetrahydrojatrorrhizine (77)
creased the amplitude of uterine contractions in rabbits and
guinea pigs and appears to be useful as an oxytocic. Proto-
pine (60) has smooth-muscle relaxant, hypotensive, and anti-
microbial activity against Gram-positive bacilli as well as
oxytocic properties (Schiff, 1987). Protopine has an LDso
i.p. in mouse of 36-102 mg/kg (Wink, 1993).
BENZOPHEI'IANTHRIDIl'IE ALKALOIDS
The benzophenanthridine skeleton is encountered in approx-
imately 30 alkaloids, principally of the family Papaveraceae
(Cordell, 1978a).1n contrastto the biosynthesis of protopine
alkaloids, phenanthridine alkaloids are synthesized in the
cytoplasm (Hartmann, 1991). This type of system arises
from a protoberberine precursor by fission of the C-6-N
bond and recyclization. The biogenetic sequence leading to
chelidonine (SO) biosynthesis in Chelidonium majus has
been supported by feeding experiments with multiply-la-
beled (+ )-reticuline [(S)-reticulinej (20) and with labeled
stylopine (79) (Fig. 32.25) (Hutchinson, 1986; Simanek,
1985; Tanabashi and Zenk, 1988). (S)-Z-N-Methylstylopine
and protopine (60) have been shown to be metabolites in
this pathway. Reticuline is oxidatively cyclized to (-)-
scoulerine (72). Formation of two methylenedioxy groups
results in the formation of stylopine (79) (Hartmann, 1991).
Oxidation of the methylene group at C-6 to the aldehyde
(81) involves stereospecific removal of the pro-S hydrogen.
A microsomal cytochrome P-450 NADPH-dependent en-
zyme which hydroxylates C-6 of protopine (60) and leads
to 6-hydroxyprotopine (S2) has been discovered. This en-
zyme is dependent on NADPH and molecular oxygen and
probably is a P-450-linked monooxygenase (Tanabashi and

stylopine (79)
allocryptopine (80)
Fig. 32.24. Biogenesis of protopine alkaloids (modified from Geissman and Crout. 1969).
Zenk, 1990). 6-Hydroxyprotopine (82) spontaneously rear-
ranges to dihydrosanguinarine (83) (Tanahashi and Zenk,
1988, 1990). Another enzyme (dihydrobenzophenanthridine
oxidase) has been isolated from elicited cell suspension cul-
tures of Eschscholtzia californica that catalyzed the oxida-
tion of dihydrobenzophenanthridines to the quaternary alka-
loids in the presence of oxygen (Schumacher and Zenk,
1988; Tanahashi and Zenk, 1988, 1990). The pro-R hydro-
gen at C-13 is retained in chelidonine (80) (Simanek, 1985).
Although protopine (60), sanguinarine (61) and a number
of related alkaloids were found in callus cultures of certain
papaveraceous plants, chelerythrine (84) and protoberberene
alkaloids (that occur in intact plants) were not produced (Si-
manek, 1985). Treatment of suspension cultures of Papaver
somniferum with a homogenate of the fungus Botrytis in-
creased the amount of sanguinarine 150-fold (Ellis, 1988;
Flores et al., 1987), and polypeptide antibiotics induced for-
mation of sanguinarine (61), chelerythrine (84), chelirubrine,
chelilutine, and macarpine in cell cultures of Eschscholtzia
california (Schumacher et al., 1987). Sanguinarine, cheler-
ythrine, and macarpine (85) (Fig. 32.26) also were formed
after treatment of suspension cultures of this species with a
yeast elicitor. The relative proportions of the three alkaloids
in this last study depeuded on the growth stage of the cells
when elicited (Collinge and Brodelius, 1989).
Benzophenanthridine alkaloids occur in five plant fami-
lies: Fumariaceae, Papaveraceae, Rutaceae, Caprifoliaceae
(Symphoricarpos), and Meliaceae (Kyiocarpus) (the last
two reports should be confirmed). Most alkaloids of this
series occur in the first three of these families (Simanek,
1985).
Chelidonine (S4) and sanguinarine (61) inhibit growth of
the radicle in Lepidium (Wink, 1993).
lsoquinoline and BenzyJisoquinoline Alkaloids 601
protopine (60)
OCR,
OCR,
11
Some benzophenanthridine alkaloids possess a wide
range of biological activity, including antifungal, antibacte-
rial, anti-inflammatory, and antitumor effects. Chelerythrine
and sanguinarine are used in human medicine (Simanek,
1985). Chelythrine (84) has an LDso s.c. in mouse of 95
mgikg, chelidonine (SO) (i. v.) of 35 mgikg, and sanguinarine
(61) (i.v.) of 16 mglkg. Chelythrine has antitumor activity,
intercalates with DNA, and inhibits reverse transcriptase and
alanine and aspartate aminotransferases; chelidonine (SO) in-
hibits reverse transcriptase and microsomal monooxygen-
ases and is cytotoxic (Wink, 1993). Both dehydrocheler-
ythrine and dehydrosanguinarine inhibit reverse
transcriptase. Nitidine (86) intercalates with DNA and inhib-
its reverse transcriptase, DNA polymerase, !RNA methyl-
transferase, and (Na+,K+)-ATPase (Wink, 1993). Nitidine
(S6), sanguinarine (61), and chelerythrine (S4) have been
shown to possess antitumor properties (Suffness and Cor-
dell, 1985). Chelidonium majus (papaveraceae) has folkloric
use for the treatment of cancer. The alkaloid chelidonine
sulfate, isolated from this plant, has been used for gastric
cancer (Cordell, 1978b). Both fagaronine (S7) and nitidine
(S6) (Fig. 32.26) are active in the P-388 and L-1210 tumor
cell lines (Blasko and Cordell, 1988; Cordell, 1978b). Fagar-
onine is a potent inhibitor of RNA-directed DNA polymerase
in several viral systems and binds to DNA (Pezzuto et al.,
1983). Both of these alkaloids inhibit reverse transcriptase
and have potent activity in the mv-1 reverse transcriptase
system (Tan et al., 1991).
Bloodroot (Sanguinaria canadensis, Papaveraceae) has
been used as a plant drug. The active ingredients are sanguin-
arine (61) (about 1%), chelerythrine (84), protopine, and
allocryptopine (SO). The salts of these compounds are col-
ored, hence, the name bloodroot. The roots of the plant serve
602 /soquinoline and Benzylisoquinoline Alkaloids

CH30

HO

(+ HS)-reticullne (20)
protopine (60)

o o

<o < o

o
)
-- 0

)
dihydrosangulnarine (83)

;;
o OCH3

OCH3
HO 11

chelidonine (80) sanguinarine (61) chelerythrine (84)

Fig. 32.25. Biogenesis of benzophenantbridine alkaloids (modified from Tanahashi and Zenk, 1988; modified and used with pennission of the
copyright owner, Elsevier Science Ltd., The Boulevard, Langford Lane, IGdlington, OXS 1GB, UK).

OCH3
o
CH3-O ) CH3-O
o
CH;-O

nitidine (86) fagaronine (87) macarpine (85)

Fig. 32026. Biologically active benzophenanthridine alkaloids.


CH3 0 CH3 0
HO HO
OCH3
(+)·(S)·reticuline (20)
--
OH
Fig. 32.27. Biogenesis of pbthalideisoquinoline alkaloids (modified from Geissman and Crout, 1969).
as a stimulating expectorant and have emetic properties
(Tyler et al., 1981). This alkaloid uncouples respiration and
oxidative phosphorylation in mitochondria and photosyn-
thetic photophosphorylation, inhihits reverse transcriptase,
and intercalates with DNA (Wink, 1993). Sanguinarine has
tuberculostatic, antifungal, antiyeast, and antimicrobial ac-
tivity against gram-positive and gram-negative bacteria and
has been reported to have antitumor activity (Verpoorte et
al., 1991; Wink, 1993). Because of its antiplaque properties,
sanguinarine has been included in some toothpastes (Water-
man, 1993). Sanguinarine (61) exhibits deterrency to several
insects and growth inhibition to larvae of Hyphantria,
Spodoptera, and Lymantria (Wink, 1993).
Species of the genus Argemone have been introduced
from the New World into the Old World. Seeds of some
of these species (in particular, A. mexicana) often contami-
nate oil seeds and produce outbreaks of poisoning in India.
This poisoning has various symptoms, but a primary high-
tension glaucoma that leads to permanent blindness often
has been observed (Bisset, 1985). The alkaloids are soluble
in the oil expressed from the seeds. Sanguinarine (61)
seems to be the principal alkaloid involved (Bisset, 1985).
Sanguinarine also exhibits a positive inotropic action by
inhibition of (Na+,K+)-ATPase (Steinegger and Hiinsel,
1992; Waguer, 1988).
Chelidonine (80) is a feeding deterrent to polyphagous
Syntomis larvae (Wink, 1993).
mTIfALIDEISOQUINOLIl'IE ALKALOIDS
Phthalideisoquinoline alkaloids are frequently observed
in the Papaveraeeae and occasionally in the Berberidaceae
and the Ranunculaceae. The pathway established for ( - )-a-
lsoquinoline and Benzylisoquinoline Alkaloids 603
CH30
HO
(-)-(S)..coulerine (72)
OCH3
OCH3 OCH3
Darcotine (63) (-)-~.hydrasdne (88)
narcotine (63) biosynthesis in Papaver somniferum involves
(+ )-(S)-reticuline (20) and (- )-(S)-scoulerine (72) (Fig.
32.27) (Geissman and Crout, 1969; MacLean, 1985). Scoul-
erine is a precursor of a-narcotine in Papaver somniferum.
Only 14-S-scoulerine is incorporated and the H -14(C) retains
its stereochemical integrity. The 13-pro-S hydrogen of scoul-
erine is removed in the conversion to narcotine (MacLean,
1985).
The major alkaloid of this series is narcotine (63). This
alkaloid possesses antitussive activity, depresses smooth
muscles, and, in spite of its name, is not a narcotic (Cordell,
1978a).
The active principle of goldenseal (Hydrastis canadensis,
Ranunculaceae) is (- )-(3-hydrastine (88), a phthalideisoqui-
noline alkaloid. Hydrastis has long been used as a medicinal
plant and is used to treat inflammation of the mucous mem-
branes (Tyler et al., 1981).
A second series of phthalideisoquinoline alkaloids, the
secophthalideisoquinoline alkaloids, involves additional
cleavage (Fig. 32.28). These compounds are found only in
the Papaveraceae and Fumariaceae (MacLean, 1985).
RHOEADAl'IE ALKALOIDS
This group of about 40 alkaloids is known only from the
Papaveraceae (Guinaudeau and Bruneton, 1993; Ronsch,
1986). These compounds probably are derived from proto-
berberine precursors (Santavy, 1979). (13R)- and (13S)-
scoulerine (72) are converted in plants of Papaver rhoeas
into rhoeadine (89) (Fig. 32.29). This alkaloid had lost 79%
of the tritium label from the (13S) precursor, whereas the
alkaloid retained 74% of the label from the (13R) precursor.
Although the starting materials were not completely confor-
604 Isoquinoline and Benzylisoquinoline Alkaloids

CH,O r N(CH,J,

CH,O ~

5,OCH3
"o OCH, OCH,
OCH,

narceineimide N·methylhydrastine fumaramidine

Fig. 32.28. seco-PhthalideisoquinoIine alkaloids.

(S)-reticuline (20) -+- CH'O~ I

<o
HO ~ _., N -+ --+- 0----"
H'

o>
'" 0"
I
h OCH,

(S)-scoulerine (72) protopine (60)

o o o
~<
<o
---
~O ___ 0

o
>
o

o
<o
o o
OH 0-1 OCH,O---l

.
{+)·rhoeadine (89)

• CH,-O
•
~CO,H

r --
HO~ NH,

.
CH,SCH,CH,CHCO,H
H2

alpigenine (90)

Fig. 32.29. A biogenetic sequence for rhoeadine alkaloids (modified from Ronsch, 1986; used with permission of the copyright owner, Academic
Press, Orlando, FL).

HO HO
HO - - -....
·'HO
OH
OH
CH,'O
CH,'O
HO
OCH,
cryptaustoline (91)
Fig. 32.30. Biogenesis of dibenzopyrrocoline alkaloids (modified from Geissman and Crout, 1969).
mationally pure, these values suggest that a stereospecific
loss of the pro-S hydrogen occurs from C-13 of scoulerioe
(Santavy, 1979). By introduction of I'C-Iabeled muramine,
it was shown that a protopine (60) (rather than a phthalidei-
soquinoline) alkaloid is the precursor of alpinigenine (60)
in Papaver bracteatum (Ronsch, 1986). A biogenetic
scheme that accounts for most of the available labeling data
has been proposed (Ronsch, 1986).
OmEI'IZOFYRKOCOLIl"IB ALKALOIDS
Early attempts to simulate the synthesis of the aporphine
and morphine alkaloids often met with failure. Efforts to
oxidize laudanosoline (30), for example, did not give the
desired type of coupling, but resulted in the formation of
dibenzopyrrocoline structures (Fig. 32.30) (Elliott, 1987;
Geissman and Crout, 1969). Alkaloids of this general struc-
ture were discovered in the Australian plant Cryptocarya
bowiei (Lauraceae). Among these were cryptaustoline (91)
and cryptowolline (92).
PAYII'IE AI'ID ISOPAYII'IE (ARGEMOIm)
ALKALOIDS
Various species of Argemone and Eschscholtzia (papavera-
ceae) and Thalictrum (Ranunculaceae) contain pavine alka-
loids (about 20) and isopavine alkaloids (about 10) with a
tetracyclic nucleus derived from benzylisoquinoline alka-
loids (Gozler, 1987; Guinaudeau and Bruneton, 1993;
Schiff, 1987). The formation of argemouine (93) and related
alkaloids is rationalized as follows (Fig. 32.31) (Geissman
and Crout, 1969). An alternate mode of cyclization also has
been observed in the formation of ( - )-eschscholtzine (94)
and ( - )-muuitagine (95).
Systematic applications of pavine and isopavine alkaloids
/soquinoline and Benzylisoquinoline Alkaloids 605
HO
HO
OH
OH
HO
cryptowolline (92)
to the genera Papover and Argemone have been investigated
(Stermitz, 1968). The phannacological effects of certain
pavine and isopavine alkaloids have been reviewed (Gozler,
1987; Schiff, 1987).
CULARII'IE ALKALOIDS
So far only C-C bond formation has been considered. A
number of alkaloids also are known in which C":'O bond
formation occurs. Among the compounds of this type are
the cularine alkaloids [such as cularine (96), which occur in
species of Corydalis, Dicentra, and other genera of the fam-
ily Fumariaceae (Fig. 32.32). This faruily is sometimes
merged with the Papaveraceae (Castedo and Suau, 1986;
Preininger, 1986; Santavy, 1979).
BISBEI'IZYLISOQVIl'IOLIl"IB ALKALOIDS
Intermolecular coupling of benzylisoquinoline units is
known to occur, as well as intramolecular coupling. An ex-
tensive series (about 400) of alkaloids formed by intermolec-
ular coupling of different monomeric units, of the benzyliso-
quinoline, tetrahydroisoquinoline, aporphine, and pavine
series, are known (Battersby, 1967; Guinaudeau and Bru-
neton, 1993; Schiff, 1987). One major group involves ben-
zylisoquinoline and tetrahydroisoquinoline subunits. These
dimers are called bisbenzylisoquinoline alkaloids (Fig.
32.33) (Geissman and Crout, 1969). The parts of these alka-
loids often are linked by one or two diphenylether bridges.
The majority of bisbenzylisoquinoline alkaloids appear to
be derived from norcoclaurine (23) or a suitably methylated
derivative. Tubocurarine (97), a constituent of South Ameri-
can tube curare, exhibits a type of "head-to-tail" coupling.
Only a few bases arise by C-C coupling. Ocotine (98) from
Ocotea rodiaei (Lauraceae) is one of these. Bisbenzylisoqui-
606 lsoquinoline and Benzylisoquinoline Alkaloids

CH,O CH,O
'"
CH,O
'" H"-
N· CH, _CH,O C H ' ° nH
CH" Ittc
"" OCH,
V CH,O::"" N::,...
I o
'" OH
OCH,

--+-
CH'O~
CH,O::""
I CH,,'
._", N
'"
'" I
OCH, <
0"
r
2 ::,...
OCH, 0
11

(. )-argemonine (93) (-)-eschscholizine (94) (-)-munatagine (95)

a pavine alkaloid

12 11

thalictidine
an isopavine alkaloid

Fig. 32.31. Biogenesis of pavine and isopavine alkaloids (modified from Geissman and Crout, 1969),

noline alkaloids occur in many of the same families as ben-
zylisoquinoline alkaloids.
Biological Activity
The pharmacological activity of certain bisbenzylisoqui-
noline alkaloids has been reviewed (Buck, 1987; Schiff,
1987). Many of these compounds have weak to moderate
antimicrobial activity. Two types of bisisoquinoline alka-
loids possess antitumor activity. These are bisbenzylisoqui-
noline and aporphine-benzylisoquinoline alkaloids [e.g.,
tetrandrine (99) and thalicarpine (100), respectively]. Both
have pronounced side effects (Cordell, 1978b).
(+ )-Tetrandrine (99) is a component of the Chinese drug
plants Stephania tetrandra and Menispermum dauricum, as
well as other plants. This alkaloid interacts with the plasma
membrane and is highly cytotoxic to KB cells (EDso 0.1
mg/kg). In clinical trials, the drug proved to be quite toxic
and to lack significant antitumor properties (Suffness and
Cordell, 1985). This alkaloid also had blood pressure lower-
ing and anti-inflammatory effects. Thalicarpine (100) also
has hypotensive and antitumor properties (Suffness and Cor-
dell, 1985). Thalidasine (101) also has pronounced antimi-
crobial and antitumor activity. The crude extract of Thalic-
trum faberi (Ranunculaceae) has been used to treat stomach

CH,-O CH,-O

--
CH,-O

CH,-O CH,-O
CH,-O
OR OCH,
OH

cularine (96)

Fig. 32.32. Cularine alkaloid biogenesis (modified from Geissman and Crout, 1969),

CH::27:::,..
I N'CH,
17 --
I
HO :::,..
(+)- and (-)-N-methylcoclaurine
OCH, HO
oondrodendrine (102)
isochondrodendrine (103)
(a)
Fig. 32.33 (8 & b). Bisbenzylisoquinoline alkaloids.
cancer in China (Schiff, 1987). Chondrodendrine (curine,
bebeerine) (102) inhibits growth of Leishmania, whereas
isochondrodendrine (103) is active against nasopharyngial
carcinoma (Wink, 1993). Five bisbenzylisoquinoline alka-
loids from Triclisia patens (Menispermaceae) bad ICso val-
ues against Plasmodium Jalciparum at levels of 0.15-1.43
IJ.g1ml (chloroquine phosphate has an ICso of 0.14 IJ.g/ml
under the same conditions) (Borris and Schaeffer, 1992;
Phillipson and Wright, 19911; Phillipson et aI., 1993).
Phaenthine, also from a Triclisia species, was twice as potent
against a cbloroquine-resistant strain as against a chlo-
roquine-sensitive strain with 50% inhibitory concentrations
of 360 nM (Ekong et al., 1991). The bisbenzylisoquinoline
alkaloid tetrandrine (99) and structurally related alkaloids
are more active against chloroquine-resistant strains that
against chloroqnine-sensitive strains. These alkaloids are ef-
fective in reversing resistance in chloroquine-resistant Plas-
modium Jalciparum. When used in combination with arte-
/soquinofine and BenzyJisoquinoline Alkaloids 607
magnoline
misinin (see Chapter 21), tetrandrine is said to provide long-
acting and synergistic activity (Phillipson et aI., 1993).
Curare
Curare is a mixtore of plant products that is used to poison
the tips of arrows for hunting and sometimes for warfare.
The peoples that made these combinations of ingredients
used many types of plants, but several of these plants contain
BIQ and bisbenzylisoquinoline alkaloids (Bisset, 1985; Cor-
dell,1981).
So-called tobe curares (because they are stored in bamboo
tubes) often are prepared from the menispermaceous plant
Chondrodendron tomentosum. These extracts are prepared
and used in localized areas of the upper Amazon and Colom-
bia. Most of the active alkaloids are bisbenzylisoquinoline
alkaloids. The major alkaloid is tubocurarine (97), a quater-
nary species.
Injection of tubocurarine rapidly blocks neuromuscular
608 /soquinoline and Benzylisoquinoline Alkaloids
CH,O
CH,O
CH,O
thalicarpine (100)
(b) (+ )-tetrandrine (99)
Fig. 32.33.
action, causing respiratory failure and death. A paralyzing
dose for man is in the range 3-7 mg; the LDso p.o. (per as. or
oral) in mouse is 33.2 mg/kg (Wink, 1993). The compound
has been used in small doses to enhance the action of anes-
thetics because it causes paralysis of the abdominal muscles
without stopping the natural movement of the intestines. Tu-
bocurarine is also used to control convulsions of strychnine
poisoning and of tetanus (Tyler et a1.. 1981). The drug is inac-
tive orally. The di -O-methy1 ether of tubocurarine is interest-
ing as it has three times the skeletal-muscle relaxant activity
but does not cause respiratory depression (Cordell, 1981).
ERYTJIRIlVA ALKALOIDS
A series of at least 60 complex alkaloids derived from ben-
zylisoquinoline alkaloid precursors is found in the genus
thalidasine (101)
tubocurarine (97)
(continued)
Erythrina (Fabaceae) and in Cocculus (Menispermaceae)
(Fig. 32.34). Alkaloids of this type have been reported from
a Dysoxylum species (Meliaceae), but some question about
the identify of the plant material exists (Waterman, 1993).
Seeds of Erythrina species typically contain about 0.1 % of
the alkaloids, but these compounds are also known from the
leaves, stalks, stems, bark, roots, pods, and flowers (Dyke
and Quessy, 1981).
Biosynthesis
Erythrina alkaloids are the products of a lengthy pathway
involving a dienone-phenol rearrangement and several rear-
rangement steps (Fig. 32.34) (Geissman and Crout, 1969).
Labeled erysodiene (104), erysopine (105), erythraline
(106), and erysodienone (107) are converted to a- and 13-
erythroidine (Fodor, 1980). Label from [2-14C]tyrosine was
found to be incorporated equally into C-8 and C-lO of 13-
 Isoquinoline and Benzy/isoquinoline Alkaloids 609

H02Y
-
CH•. O "" 1 NH

CH.·O
'"""I
OH
N~normethylprotosinomenine (108)

_CH'O~;~~~C::
OH

CH'O~
""I

CH.O
"'I
""
NH

CH.O
1 1
CH.O
o
-
OH
o /
(110) erysodienone (107)

- o

::X(),
OH
erythratine

fX),
'CH.O'v CH.OrJLll"'"U
CH.O"'"
erisodiene (104) erysoplne (lOS) cocculidlne (109)

Fig. 32.34. Biogenesis of Erythrina alkaloids (modified from Dyke and Quessy, 1981; used with pennission of the copyright owner, Academic Press,
Orlando, FL).

erythroidine (Dyke and Quessy, 1981). (+ )-(S)-Norprotosi-
nomenine (108) was incorporated 100 times more effectively
than the enantiomeric compound, suggesting that this com-
pound is a specific precursor of erythraline. TIte intennedi-
acy of compound 110 was also established. Further, eryso-
diene (104) has heen isolated from some of the species that
synthesize these alkaloids. Introduction of [14C]4'-methoxy-
norprotosinomenine in Erythrina christa-galli produced
erythraline (106) in which the methoxyl and methylenedioxy
group carbon atoms were equally labeled, confrnning the
presence of a symmetrical intennediate such as (111) (Dyke
and Quessy, 1981). (- )-(5S)-Erysodienone (107) is a pre-
cursor of erythraline and both Cl- and /3-erythroidine (105,
106).
Biological Activity
Many Erythrina alkaloids possess curare-like action and
interact with acetylcholine receptors. Extracts of many
Erythrina species are used in indigenous medicine, particu-
larly in India. Cocculine and cocculidine nitrates have been
reported to show hypotensive action in dogs (Dyke and
Quessy, 1981). The insecticidal alkaloid cocculolidine (109)
has been isolated from Cocculus trilobus and C. carolinus
610 !soquinoline and Benzylisoquinoline Alkaloids
(Dyke and Quessy, 1981; Wink, 1993). IncOlporation of
Erythrina flabelli/ormis seed alkaloids at 0.1 % into artificial
diets is totally lethal to the larvae of Callosobruchus macu-
latus (Janzen et al., 1977).
DlSTRIBVTIOl'l OF BEl'IZYLlSOQUIl'IOLIl'IE
ALKALOIDS
The distribution of benzylisoquinoline alkaloids is restricted
among higher plants (Guinaudeau and Bruneton, 1993;
Seigler, 1977; Waterman, 1993; Waterman and Gray, 1987).
Most of these alkaloids occur in certain families of the Mag-
noliales and Ranunculales, although sporadic occurrences
are known among related plant groups and from others that
are only distantly related. Among the families that have been
reported to have these alkaloids are Annonaceae, Aristolo-
chiaceae, Berberidaceae, Eupomatiaceae, Hemandiaceae,
Fabaceae (Erythrina, Andrachne), Fumariaceae, Lauraceae,
Magooliaceae, Menispermaceae, Monimiaceae, Nelum-
bonaceae, Papaveraceae, Ranunculaceae, Winteraceae, Eu-
phorbiaceae (Croton), Rhamnaceae (Rhamnus, Phylica,
Colletia, Colubrina, Discaria, Retanilla, Talguenea, andZi-
zyphus), Phellinaceae (Phelline), Symplocaceae (Sym-
plocos), Rutaceae, Combretaceae, Araliaceae (Hedera),
Apiaceae (Heracleum), Caprifoliaceae (Symphoricarpos),
Rubiaceae (Cephaelis), and Araceae (Lysichiton) (Bisset,
1985; Dahlgren et al., 1981).
Most botanists agree that the orders and families of the
Magooliidae (sensu Cronquist) are related and derived from
common ancestors. This conclusion is based on both mor-
phological and chemical data. The families Annonaceae,
Aristolochiaceae, Berberidaceae, Eupomatiaceae, Hernandi-
aceae, Fabaceae (Erythrina, Angrachne), Fumariaceae,
Lauraceae, Magnoliaceae, Menispermaceae, Monimiaceae,
Nelumbonaceae, Papaveraceae, Ranunculaceae, and Win-
teraceae contain benzylisoqninoline alkaloids and their de-
rivatives. The families Himantandraceae, Myristicaceae, Ca-
lycanthaceae contain other types of alkaloids. Some other
families such as the Degenariaceae, Austrobaileyaceae, Tri-
meniaceae, Lardizabalaceae, Corynocarpaceae, and Coria-
ceae have been tested and shown (at least usually) not to
contain alkaloids. Several other smaller families have appar-
ently not been tested. The statos of the non-alkaloid-contain-
ing families within the group is unclear. Probably many of
these families have lost the ability to synthesize benzyliso-
quinoline alkaloids and, in some instances, gained the ability
to synthesize other types of alkaloids (Seigler, 1977).
The placement of the families Fumariaceae and Papavera-
ceae near the Magooliales, Piperales, Ranuncnlales, and so
forth has become generally accepted in recent years (Seigler,
1977; Waterman and Gray, 1987). Alkaloids of these two
families are rather similar and are similar to those of other
families of the order Ranunculales. These two families are
especially close to the families Berberidaceae, Menisperma-
ceae, and Ranuncnlaceae, in terms of the types of alkaloids
they possess.
There also has been considerable discussion concerning
whether the Fumariaceae should be included in the Papaver-
aceae. The two families share many types of alkaloids (e.g.,
the protoberberine, benzophenanthridine, and protopine
groups). Characteristic for the Fumariaceae are the spiroben-
zylisoquinoline, indenobenzazene, secophthalideisoqnino-
line, phthalideisoquinoline, and cularine alkaloids (Preinin-
ger, 1986).
The Rutaceae is one of the more interesting and complex
families with regard to alkaloid chemistry (see Chapter 31).
The family contains alkaloids derived from several different
pathways, such as acridine, benzylisoqninoline, furoquino-
line, imidazole, indoloqninazoline, quinazoline, quinoline,
and both simple aliphatic and aromatic amines. Furoquino-
line and quinoline alkaloids are especially widespread within
the family and are found in four of the five subfamilies from
which alkaloids have been reported. The Rutaceae appears
to be a relatively homogeneous group by both morphological
and chemical criteria. Alkaloids of the benzylisoquinoline
type are found in the genera Fagaropsis, Phellodendron,
Tetradium, Toddalia, and Zanthoxylum (including Fagara),
three closely related genera (Waterman, 1993). Alkaloids of
the I-benzyltetrahydroisoqninoline type are assumed to be
primitive within the family, and the genera that produce them
appear to be primitive within the family as well. These alka-
loids appear to have been lost in relatively advanced taxa
and to have been replaced by other types of alkaloids
(Seigler, 1977; Waterman and Gray, 1987). If this assump-
tion is true, the family is likely derived from benzylisoquino-
line-alkaloid-containing ancestors. The alkaloids and many
morphological features of the Rutaceae are similar to such
families as the Berberidaceae, Menispermaceae, and Papav-
eraceae (Seigler, 1977; Waterman and Gray, 1987). Benzyl-
tetrahydroisoquinoline-derived alkaloids have been studied
as systematic markers (Rezende et al., 1975).
IPECACVAl'IHA ALKALOIDS
Various groups of South American Indians used ipecac root
long before their contact with Europeans. Ipecacuanha was
brought to Europe late in the 17th century. This preparation
is derived from the root of Cephaelis ipecacuanha (Rubia-
ceae). Ipecac (from Brazil) consists of about 2% alkaloids,
60-70% of which is emetine (111) and about 25% cephae-
line (112) (Fig. 32.35).
Despite the importance of this material, work on cell and
plant tissue culture of this plant is limited. Callus, root, and
root suspension cultores contain emetine (111) and cephae-
line (112) at low levels. Root suspension cultures had ap-
proximately the same amount on a dry weight basis as the
parent plant (Verpoorte et al., 1991).
A series of related compounds are found in several other
plants of the Rubiaceae. The compounds differ from emetine
in that one or both of the dopamine-derived portions are
replaced with tryptamine. These compounds are discussed
in Chapter 34.
 Isoquinoline and BenzyJisoquinoline Alkaloids 611

tO~H OH ~ I strictosidine

~1"'~~oH~ NHH ", P

",HH OH
CH,02C HO 0N~ NH2
"""O~OH
o HO 0
seCOllogani~~~~ • CH,02C o

Ho0 ~H2 ~ indole alkaloids

dopamine (22) HO
deacetylisoipecoside (116)
HO NHp
HO

NHp ""HH OH
HO
""O~OH
"",HH OH o HO HO
"""O~OH
H"
'" 0 HO HO \
desacetylipecoside
CH'O~ '"

jH
CH'O~ ~ I"
\
protoemetine CH,O N

HO "" IH N '" 0 HO~ H" ,,~/

H HO~ NH2 CHO
o
I H ""H OH

alangiside(llS) ~~OH CH'O~

CH,o~HO CH,O '" IH" N H

CH . 0 : I N H'" ""./
HO , H" H \H
H" ''''./ HN~OCH'
HO
• H ~OH
"",HH OH C o ' OCH,
H'" '''''O~OH HN I '"
cephaeline (ll2)
CH,O,C '" 0 HO HO '"" OCH,
ipecoside (ll4) emetine (lll)

Fig. 32.35. Proposed biogenesis of emetine (modified from Geissman and Crout, 1969).

Biosynthesis graphic methods and by correlation with known compounds

Ipecacuanha alkaloids arise by pathways similar to those
previously discussed for the origin of isoquinoline and ben-
zylisoquinoline alkaloids with the exception that a different
aldehyde moiety is involved. In this case, the condensation
involves dopamine (22) and secologanin (113). The origin
of secologanin was discussed previously in Chapter 20, Em-
etine (114) and an alkaloidal glycoside, ipecoside (114), co-
occur in Cephaelis ipecacuanha (Kapil and Brown, 1979),
The presence of ipecoside, an acetylated derivative of the
first proposed intermediate, lends credence to the proposed
biogenetic pathway (Fig, 32.36). The absolute stereochemis-
try of ipecoside has been determined by x-ray crystallo-
(Kapil and Brown, 1979),
Feeding experiments with [2-14C]geraniol and [0-
methyl-'H,6-'Hzlloganin showed that the C IO unit of ipeco-
side and the C9 unit of cephaeline were of iridoid monoter-
pene origin, Furthermore, [0-methyl-'H,6-'H2 1secologanin
and [3'-14C]deacetylipecoside served as specific precursors
for ipecoside (114) (Kapil and Brown, 1979) and alangiside
(115) (Fujii and Ohba, 1983). Contrary to some earlier re-
ports, however, deacetylisoipecoside (116) (Fig, 32.37)
(with a la-H configuration) is the precursor of cephaeline
(112) and emetine (111) (Fujii and Ohba, 1983),
Alkaloids with both types of stereochemistry at C-I are
known to occur. For example, alangiside (115) (from Alan-
612 Isoquinoline and Benzylisoquinoline Alkaloids

CH,O CH,O

CH,O CH,O

OCH, OCH,
CH,O
OCH, OH
CH,O

OCH,

OH

CH,O

HO

OH
HO

HO CH'O~I
CH,O::"" N
H H

ipecoside (114) protoemetine CHO

Fig. 32.36. Ipecacuanha and related alkaloids (modified from Fujii and Ohba, 1983; used with permission of the copyright owner, Academic Press,
Orlando. FL).

gium lamarckii) has a C-II3-proton (Fig. 32.36). This glyco-
side was found in the unripe fruit, roots, and leaves of the
plant (Kapil and Brown, 1979).
Distribution of Ipecac Alkaloids
Most ipecac alkaloids are found in the family Rubiaceae,
often in the genus Cephaelis but they are known to occur
in other genera as well. These alkaloids have been found in
the genera Borreria. Bothriospora, Capirona, Ferdi-
nandusa, Hillia, Psychotria and Uragoga (synonyms of
Cephaelis), Remija, and Tocoyena (Rubiaceae).
According to the classification of Leeuwenberg (1980),
the Rubiaceae may be divided into four subfamilies: the Rub-
ioideae, Cinchonoideae, Guettardoideae, and Hillioideae.ln-
dole alkaloids of the corynanthean type are the most common
in the family. The tribe Cinchoneae of the subfamily Cincho-
noideae is the only group to contain alkaloids with a noorear-
ranged secologanin moiety as well as quinoline and isoqui-
noline alkaloids. Isoquinoline alkaloids [such as emetine
(114)] are also found in Pogonopus (Rondeletieae), Toco-
vena (Gardenieae), some members of the Rubioideae, for
example, Psycho tria and Cephaelis of the Psychotrieae,
Bothriospora (Hamelieae), Borreria, Spermacoce, Richard-
sonia (Spermacoceae), and Manettia (Hedyotideae). Within
the Hillioideae, Hillia species contain only emetine-type al-
kaloids.
These alkaloids also have been found in the Alangiaceae
(Alangium lamarckii) and Araliaceae (Hedera helix) (Fujii
and Ohba, 1983). The last report should be confirmed, as it
is from a most unusual source.
Medical Uses of Ipecacuanha Alkaloids
Emetine (114) was first demonstrated to be toxic to the
microorganism Entamoeba histolytica in 1912; today, eme-

HO
HO
,:r
H -
H OH
""O~O~OH
OHO~
HO
deacetylisoipecoside (116)
HO
HO
Fig. 32.37. Emetine and related biologicany active alkaloids.
tine (114) and tubulosine (118) are used widely to treat ame-
bic dysentery caused by Entamoeba histolytica (Borris and
Schaeffer, 1992; Phillipson and O'Neill, 1987; Phillipson et
aI., 1993). World consumption of plant material of Cephaelis
ipecacuanha plant material is 10-100 metric tons (Ver-
poorte et aI., 1991). Emetine has an LDso i.v. in mouse of
135 mg/kg, but 12.1 mg/kg in rat, and is an active inhibitor
of protein biosynthesis (Wink, 1993). This compound also
has been used to treat schistosomiasis, leishmaniasis, and
malaria (Borris and Schaeffer, 1992). Emetine has many
toxic side effects: among these are cardiotoxicity, muscle
weakness, and gastrointestinal problems as diarrhea, nausea,
and vomiting. Toxic effects often are observed at therapeutic
doses. This alkaloid has a profound reversible effect on DNA
synthesis and produces essentially total inhibition at concen-
trations of 1 fLM. The aIkaloid does not, however, penetrate
the cell wall of yeast or bacteria. Both emetine (114) and
tubulosine (118) inhibit protein biosynthesis (Borris and
Schaeffer, 1992; Wink, 1993).
Emetine also has some antitumor activity but is quite
toxic and does not appear highly promising (Suffness and
Cordell, 1985). Psychotrine (117) and O-methylpsychotrine
are selective inhibitors of mv-1 reverse transcriptase (Tan
et aI., 1991a, 1991b). Alangium lamarkii has long been used
in Indian medicine (Fujii and Ohba, 1983).
Other Biological Activity
Emetine is toxic to Lemna and is a feeding deterrent to
polyphagous Synromis larvae (Wink, 1993).
lsoquinoline and Benzylisoquinoline Alkaloids 613
-
HO
HO
CHO CHO
protoemetine
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1. T. Romeo, and H. A. Stafford, eds,), Recent Advances in
Phytochemistry Vol. 27), 203-233, Plenum Press, New York,
1993.
WATERMAN, p, G, and A. I. GRAY, Chemical systematics, Nat.
Prod. Rep., 4, 175-203 (1987).
WINK, M., Allelochemical properties or the raison d'etre of alka-
loids, in The Alkaloids, Vol. 43 (G. A. Cordell, ed.), 1-105,
Academic Press, New York, 1993.
ZENK, M, H., Enzymology of benzylisoquinoline alkaloid forma-
tion, in The Chemistry and Biology ofIsoquinoline Alkaloids (1.
D. Phillipson, M. F. Roberts, and M. H. Zenk, eds.), 241-256,
Springer-Verlag, Berlin, 1985.
ZENK, M. R" M. RUFFER, M, AMANN, and B. DEUS-NEUMANN,
Benzylisoquinoline biosynthesis by cultivated plant cells and
isolated enzymes, J. Nat. Prod., 48, 725-738 (1985).
33
Alkaloids Derived from Both Tyrosine
and Phenylalanine
Introduction
Colchicine and Other Tropolonic Alkaloids
Biosynthesis
Biological Activity of Colchicine
Medicinal Uses of Colchicine
Use of Colchicine in Horticulture
Amaryllidaceae Alkaloids
Biosynthesis
Biological Activity
Medicinal Uses of Amaryllidaceae Alkaloids
Mesembryanthemum and Sceletium Alkaloids
Cephalotaxus and Homoerythrina Alkaloids
Biosynthesis of Cephalotaxus Alkaloids
Biosynthesis of Homoerythrina Alkaloids
Systematic Value of Cephalotaxus and Homoerythrina
Alkaloids
Antitumor Activity
References
INTRODUCTION
The biosynthesis of several types of alkaloids involves both
phenylalanine and tyrosine. These alkaloids occur in the
closely related families Amaryllidaceae and Liliaceae and
in the Cephalotaxaceae and Mesembryanthemaceae. The last
two families are not closely related to each other, nor to the
ftrst two families.
Both the IH_ and 13C_NMR (nuclear magnetic resonance)
spectra for several of these alkaloids have been reviewed
(Crabb, 1982). The results of feeding experiments leading
to colchicine, Amaryllidaceae, and Cephalotaxus alkaloids
have been tabulated (Leete, 1983).
COLCHICJl'IE AND Ol'HEK TKOPOLOl'IIC
ALKALOIDS
Colchicum is one of the most ancient plants known to man
both as a drug and as a poisonous plant. Colchicine (1) is
found in the leaves and mature seed. At least 19 species of
Colchicum and 10 other genera (including Androcymbium,
Bulbocodium, Gloriosa, Iphigenia, Kreysigia, and Merend-
era) contain colchicine and related alkaloids. These genera
belong to the subfamily Wurmbaeiodeae, with the exception
of the Australian genus Kreysigia (Capraro and Brossi,
1984).
The amide nitrogen of colchicine is not basic, and some
have argued that colchicine is not a true alkaloid. However,
as the precursors and the pathway leading to this compound
are typical for those of alkaloids, colchicine is considered
an alkaloid for present purposes. Although this compound
is the best known of the group, more than 30 other tropolonic
alkaloids occur in Colchicum autumnale and related plants
(Capraro and Brossi, 1984). The physical constants and spec-
tral data of colchicine and related alkaloids have been tabu-
lated (Tojo, 1989).
Natural (7S)-( - )-colchicine (1) displays molecular sym-
metry derived from a noncoplanar arrangement of the tropo-
Ionic ring C and the benzenoid ring A (Fig. 33.1). These
rings are twisted out of the plane with a torsion angle of
about 53°. This feature proves to be critical for the binding
of colchicine to tubulin (Boye and Brossi, 1992). Natural
colchicine has the two aromatic moieties arranged in a coun-
terclockwise helicity, which implies an (as) absolute con-
ftguration (Boye and Brossi, 1992; Geissman and Crout,
1969).
Biosynthesis
Colchicine (1) is derived from both tyrosine and phenylal-
anine (Fig. 33.1). One of the major steps in unraveling the
biosynthetic sequence leading to colchicine was the isolation
and recognition that androcymbine (2) is related to an inter-
mediate in the pathway (Fig. 33.2). [1- 13C]Autumnaline (3)
is incorporated into colchicine. Androcymbine is the de-
methylated form of the intermediate O-methylandrocymbine
(4) in the pathway. Attack on the bridged system occurs,
617
618 Alkaloids Derived from Tyrosine and Phenylalanine

OCH,

'Ok",
CH,O

I '
'CO,H
+-- HO'C~O
.~. NHl ~ 1~1H2 ~
o OH

phenylalanine tyrosine

o
colchicine (1)
Fig. 33.1. Colchicine (modified from Boye and Brossi, 1992; used with pennission of the copyright owner, Academic Press, New York).

followed by ring expansion of the aromatic tyrosine-derived
nucleus. Inclusion of the first carbon atom of the side chain
(C-12 of colchicine) generates the tropolone ring. This
scheme was established by introduction of [3- 14C]tyrosine
and degradation studies of the colchicine obtained (Capraro
and Brossi, 1984; Geissman and Crout, 1969).
Biological Activity of Colchicine
The ability of colchicine to interfere with microtubule-
dependent cell functions and to bind to tubulin (the subunit
of microtubules) has long been known (Capraro and Brossi,
1984). Colchicine binds to tubulin <limers of 100,000 molec-
ular weight in a 1: 1 stoichiometry at the same site as podo-
phyllotoxin (Boy" and Brossi, 1992). Treated cells are ar-
rested at metaphase because microtubules are essential for
moving chromosomes during mitosis. The transport of vesi-
cles also is affected. Colchicine inhibits the incorporation
of uridine into RNA. This alkaloid has many other types of
activity in animal systems (Capraro and Brossi, 1984).
Colchicine is a feeding deterrent for Locusta, polypha-

OCB, OH
(S)-autumnaUne (3) O-mefhylandroeymblne (4)

CH.lO~HO) CH30~~
CHiO HO
NHCH I ') NHCH, I -<.cno
n ~ 'l! H--+ CR~O ~ 'I ~ H ---+
,---+
CH3 0 'CH,O
OCR) OCH ~ 0
o '~r 0 OCR;
~3 cn, CH,O

CH;JO

o
c:oIdddne(1) o democolclne OCR,

Fig. 33.2. Biogenesis of colchicine (modified from Capraro and Brossi, 1984; used with pennission of the copyright owner, Academic Press, New
York).
 Alkaloids Derived from Tyrosine and Phenylalanine 619

gous Syntomis larvae, and Agelaius (red-winged blackbird)
(Wink, 1993). Incorporation of colchicine at 0.1 % into artifi-
cial diets is totally lethal to the larvae of Collosobruchus
maculatus (Janzen et aI., 1977). This alkaloid is insecticidal
for Leptinotarsa (Wink, 1993).
Medical Uses of Colchicine
Colchicum autumnale has long been used to treat gout,
for which it is efficacious, although the drug exhibits toxic
manifestations. The colchicine content of Colchicum autum-
nale (Liliaceae) is about 0.25-0.6%. At a dose of 1 mg every
2 h for 8 hours and a maintenance dose of 500 ILg twice a
day, colchicine is still an effective treatment for gout. Colchi-
cine has an LDso i.v. in mouse of 4.11 mglkg (Wink, 1993).
This alkaloid also may be useful for the treatment of cirrhosis
of the liver, amyloidosis, and familial Mediterranean fever
(Brossi, 1992). Colchicine is an anticancer agent (Blasko
and Cordell, 1988; Brossi, 1992), but without practical im-
portance because of its toxicity. The inhibition of cell divi-
sion is not specific for malignant cells.
Use of Colchicine in Horticulture
Colchicine is used to introduce polyploidy in plants and
plants. This effect has been useful in many studies of plant
genetics. A number of plant varieties of economic impor-
tance have been produced by use of this alkaloid.
AlllARYLLIDACEAE ALKALOIDS
The approximately 100 alkaloids of this series occur in the
family Amaryllidaceae. This family is considered closely
related to the Liliaceae and some taxonomists (e.g., Cron-
quist, 1981) have merged the two into one large family. The
alkaloids of the Amaryllidaceae are similar to colchicine and
other related alkaloids of the Liliaceae in that both phenylala-
nine and tyrosine are involved in their synthesis. AIl Amaryl-
Iidaceae alkaloids, however, are derived from a single inter-
mediate, norbelladine (4). The three major structural Iypes
are found at times in individuals of the same species.
Biosynthesis
Amaryllidaceae aJkaJoids are derived from both iyrosine
and phenylalanine. The adduct of these two amino acids,
norbelladine (5), is an intermediate in the three major Iypes
of Amaryllidaceae aJkaJoids (Fig. 33.3). This adduct arises

·.'
causes doubling or increase in the chromosome number of by prior conversion of phenylalanine to 3,4-dihydroxybenz-

•m
• ::,...
I •
NH,
CO,H

-+
H{:N0"
HO'-'HN~
~ 1· . ' U OH + -
HO,C
~•
NH,
•

'~OH
•

phenylalanine norbelladine (5) tyrosine

VTu
,
;,.. I NH,-
CO,H
~:;,.. CO,H
~
I -+
HO~:;'"
HO ~
1 __
COH
, HO:oCHO

HO
~I
,...

phenylalanine
/ (6)

norbelladine (5)

Fig. 33.3. Biogenesis of norbelladine and the origin of the three major types of AmarylIidaceae alkaloids (modified from Geissman and Crout. 1969).
620 Alkaloids Derived from Tyrosine and Phenylalanine

.;=;
OR H+

HO ~
~ NH~ ;,
OH
CH,-O
~~
Q
'" C
fi

norbelladine (5) ~ HO, 4 1.& HN '-....

11 7 1"HO CH,-O H
CH,-OjCG'"" .. / I"'"
1 "''' I
HO • .& HN HO
• 7

O-methylnorbelladine (13) OH

norpluviine (9) Iycorine (8)

CH,-O.
!~;W _ ~HO'"
HO
H I! H 1 CH,-O
I"'"
H
N
1
CH,-O

CH,-O
QT.) CH,-O'&
Cor -
CH,-O
H~ \
CH,s-
pluviine (17)

~
o OCH,

CH,-O
CH,-O '" I
-+-
CH,-O 1.& N
CH,-O
o
Iycorenine (10) homolycorine (11) galanthine (12)

Fig. 33.4. Biogenesis of lycorine and structurally related alkaloids (modified from Geissman and Crout, 1969).

aldehyde (6) and conversion of tyrosine to tyramine (7),
followed by Schiff-base fonnation and reduction.
Synthesis of alkaloids of the first structural type [such as
lycorine (8), norpluviine (9), lycorenine (10), and homoly-
corine (11)1 in various daffodil varieties may occur as indi-
cated (Fig. 33.4). Radioactively labeled norbellidine (5) is
incorporated into norpluviine (9).
[3H1Norpluviine (9) is incorporated into lycorine (8) in
daffodils (Fuganti, 1975; Martin, 1987). Feeding studies
with [8-3H1norpluviine to Narcissus psewionarcissus (King
Alfred daffodils) afforded mostly lycorenine (10) and homo-
lycorine (11), although there was some incorporation into
pluviine (17), galanthine (12), and methylpseudolycorine. In
other experiments with Narcissus poeticus, norpluviine was
incorporated into lycorine (8), galanthine (12), methylpseu-
dolycorine, and narcissidine, but no label was incorporated
into lycorenine (10) (Martin, 1987).
Tyrosine with 'H label ortho to the hydroxyl group and
with 14C in position 2 in the side chain (which should pro-
duce norbelladine labeled in positions 2 and 4) was incorpo-
rated into norpluviine and into lycorine with loss of one-
half of the 'H label. The 'H atom retained in lycorine was
located at C-2. Thus, it appears that all of the 3H was retained
in the derived lycorine (8). This suggests a stereospecific
course in both protonation to fonn the allylic methylene of
norpluviine (9) and hydroxylation to form lycorine (8). The
'H atom in norpluviine at C-2 has a ~-configuration. Proton-
ation of the aromatic precursor of norpluviine (9) at C-2
takes place from the ( l side of the molecule and hydroxyla-
tion of C-2 of norpluviine occurs with inversion to fonn
lycorine (Fuganti, 1975).
Incorporation of [4-'H;~-I4C]cinnamic acid into norpluv-
iine resulted in 50% loss of the 'H label. The same loss was
observed with the [3,5-2H2;4-'H;~-I4C]-isomer. It appears
 Alkaloids Derived from Tyrosine and Phenylalanine 621

that para-hydroxylation involves complete migration and re-
tention of tritium and a second hydroxylation at one of the
two equivalent positions causing loss (without migration) of
half the remaining tritium. The 3H atom retained is at posi-
tion 11 of norpluviine (9). Enzymatic control appears to be
involved in the elimination (Fuganti, 1975).
The genesis of the second structural type is illustrated by
the pathway leading to haemanthamine (14) (Fig. 33.5). 1n
this case a para-para instead of an ortho-para coupling is
observed. The framework is completed by nitrogen addition
to the dienone system, as before. Haemanthamine (14) may
then be converted into pre-tazettine (15).
The stereochemistry of protonation involved in the incor-
poration of protocatechualdehyde (3,4-dihydroxybenzalde-
hyde) into haemanthamine (14) and the stereochemical
course of the hydrogen removal during the hydroxylation Ol
to the nitrogen atom in the conversion of norpluviine (9)
and haemanthamine into lycorenine (10) and haemanthidine
(16), respectively, have been examined. [6_3H~-!4C]Hae­
manthamine (14) was converted into haemanthidine (16)
(Fig. 33.5) without 3H loss in Spreckeliaformosissima. [7-
3H-5-!4C]Norpluviine (9) was incorporated into lycorenine
(10) (Fig. 33.4) without loss of 3H. O-Methylnorbelladine
(13) randomly labeled in the benzylic positions, was incorpo-
rated into pluviine (17) (Fig. 33.4) without loss of tritium
and into lycorenine (10) with loss of half the tritium. 1n
similar experiments, haemanthamine (14) and haemanthid-
ine (16) lost approximately half the activity (Fig. 33.5).
These experiments indicate that incorporation of protoca-
techualdehyde (6) (3,4-dihydroxybenzaldehyde) into the
C.-C! unit of the alkaloids and both the protonation to form
the benzylic methylene of norbelladine (5) [and hence of
norpluviine (9) and haemanthamine (14)] and the subsequent
hydroxylation of norpluviine (9) and haemanthamine (14)
are stereospecific processes. The hydrogen introduced in the
process or formation of norpluviine (9) and haemanthamine

HO~
- NH

norbeUadine (5)
v6 ~
"-...
h
OH

OH

elf ____
OH CH,- 0
HO
-03
,r
"'" I C
"(

NH
~H+
1.0

--
CH,-O~ ~
HO~NH
O-methylnorbelladine (I3)

, OCH,

CH'-O~
9" H 9"
O @ OOH 11 ---l_'-I--OH

<
CH,-O 9" ___ 0 109"

HO ""
1 N
-- HO ""
1 NO,"'"
• 7
haemanthamine (14)

~
OCH' ~OCH'
<~ <::
OCH'
H 9" OH H 9" 1 CH,
o

o '::,T[: (if ~
9"
""I
o
~
N

H
--+

CH,S-
I
oY
I
0'-
H
haemanthidine (16) pretazzettine (15)

Fig. 33.S. Biogenesis of haemanthamine, pre-tazettine. and tazettine (modified from Geissman and Crout, 1969).
622 Alkaloids Derived from Tyrosine and Phenylalanine

(14) is the same as that removed in the oxidation step
(Fuganti, 1975). In the oxidation process a pro-R hydrogen
at C-7 is removed (Martin, 1987). These results establish
that in the incorporation of protocatechualdehyde (6) into
the aromatic C6 -C I unit of the alkaloids, protonation takes
place from the re face of the molecule and that oxidation
of the amine proceeds with the stereospecific removal of
an a-hydrogen from the benzylic position (Fuganti,
1975).
Hydroxylation of the methylene at position 6 (13 to the
nitrogen atom) to form haemanthamine (14) occurs late in
the sequence, once the ethanophenanthridine skeleton has
been constructed from O-norbelladine (5) [O-methyInorbel-
ladine (13)]. O-Norbelladine stereospecifically labeled at po-
sition 6 (mixed with identical 14C-labeled samples) was fed
to daffodil plants. High tritium retention was observed in
haemanthamine (14) when the (6S)-isomer of O-norbellidine
was administered, whereas loss of tritium was observed with
the (6R)-isomer. Thus, 3H loss from position 13 to the nitro-
gen atom in haemanthamine takes place during the hydroxyl-
ation and, because the absolute stereochemistry of haema-
nthamine (14) is known, must proceed with retention of
configuration (Fuganti, 1975).
Biosynthesis of the third type of Amaryllidaceae alka-
loids is represented by the formation of galanthamine (18)
(Fig. 33.6).
In daffodil plants, galanthamine is biosynthesized from
compounds 19-21, but not from norbelladine (5) [which is
a good precursor of haemanthamine (14) and Iycorine (8) in
the same plants] (Fig. 33.6). These experiments suggest a
definite order of methylation of norbelladine (5) during the
biosynthesis of galathamine. In feeding experiments with
the plant Leucojum aestivum, [2,4-3H2 ; '4C_O_methyl]O_
methylnorbelladine (13) is a precursor of galanthamine (18)
that retains the same 3H114C ratio as in the precursor. There
is a 50% loss of tritium in the biosynthesis of Iycorine (8).
The tritium labels were found in positions 2 and 4 of galan-
thamine (18) (Fuganti, 1975).

OH CH+

HO~NH~OH OH CH30mH'~ 0

...... OHg 7 --+

norbelladine (5) CH3o'(C' ___ ::,... I N,

::,...' N CH3

m
\
CH,
N,O-metbylnorbelladine (20)

o 0
CHJ 0 -:9' CHjO 10

::;,.. I ~
N
, CH,
17
.::;,..

narwedine galanthamine (18) crinine (27)

HO

CH'-0:cG IJ CH~O~ ~.
HO

10 . ; ; ) HO~'
7 H0
72, ;

HO CH,
(19) (20)

"",
HO,()

HO~.~)
narcicJasine (22) H02;
HO~ :.

HO~I HO~
CH,
(21) norbelladine (5)

Fig. 33.6. Biogenesis of galanthamine (modified from Geissman and Crout, 1969),

Iycoricidine (23)
Fig. 33.7. Biologically active Amaryllidaceae alkaloids.
Biological Activity
Lycoricidine (23) and Iycoricidinol (24) are antifeedant
and galanthamine (18) is insecticidal to the yellow butterfly,
Eurema hecabe mandarina (Lepidoptera) (Fig. 33.7) (Mar-
tin, 1987). An extract of the bulbs of Lycoris radiata was
found to exhibit antifeeding activity when tested against the
yellow butterfly, Eurema hecabe mandarina (Martin, 1987).
Medicinal Uses of Amaryllidaceae Alkaloids
Galanthamine (18) has been of interest, as it has powerful
cholinergic activity and is reputed to have analgesic activity
comparable to morphine. This alkaloid was used in the for-
mer Soviet Union for the treatment of myasthenia gravis,
myopathy, and diseases of the nervous system (Cordell,
1981). Galantharnine inhibits cholinesterase, causes brady-
cardia and atrioventricular conduction distorbances, and has
an LDso Lv. in mouse of 8 mg/kg (Wink, 1993).
A number of AmaryUidaceae alkaloids are of interest as
potential antitumor agents. The most important are lycorine
(8), narcic1asine (22), and pretazettine (15). Lycorine is
widely distributed in the family and is known from at least
30 genera. Pretazettine is not so widely distributed but is
found in at least 18 genera. Narciclasine (22) is known from
only a few species of the family (Martin, 1987; Suffness and
Cordell, 1985).
Lycorine (8) inhibits ascorbic acid synthesis (Robinson,
1979) as well as plant cell division and cell elongation (Mar-
tin, 1987). This alkaloid also inhibits DNA polymerase, pro-
tein synthesis, Rauscher virus NIHl3T3, and herpes simplex
virus (Wink, 1993).
Narciclasine (22) halts protein synthesis by blockage of
peptide-bond formation on the 60-S ribosomal subunit. The
effect is specific for eucaryotic cells. Narciclasine inhibits
Rauscher virus NIHl3T3 (Wink, 1993). Lycorine (8) blocks
mitosis in the broad bean (Vidajaba). The mechanism ap-
pears to be related to inhibition of protein synthesis (Suffness
and Cordell, 1985). Pretazettine (15) has been used in combi-
nation with DNA-binding and alkylating agents in the treat-
ment of the Rauscher leukemia virus (Cordell, 1981; Martin,
1987). This alkaloid inhibits purified RNA-dependent DNA
polymerase (reverse transcriptase) from avian myelo-
Alkaloids Derived from Tyrosine and Phenylalanine 623
pseudolycorine (26)
narclclasine (24)
Oycoricidinol)
blastosis virus, a typical C-type virus, by binding with the
polymerase itself (Martin, 1987). Pretazettine inhibits
Rauscher virus NIHl3T3 and herpes simplex virus (Wink,
1993).
The LDso Lv. of tazettine (25) in mouse is 100 mg/kg
(Wink, 1993). Lycorine (8), haemanthamine (14) and pseu-
dolycorine (26) are toxic to Rauscher virus NIHl3T3 cells
and inhibit protein biosynthesis (Wink, 1993).
/fIBSBMBBYAJYTIIEMlJM Al'ID SCELETIlJIII
ALKALOIDS
A novel group of alkaloids is found in a number of species
of the genus Mesembryanthemum (Mesembryanthaceae or
Aizoaceae). Many taxonomists have now subdivided this
genus into a number of segregates. Alkaloids are found in
many of these species, but especially in those plants now
considered to comprise the genus Sceletium. This group of
plants is characteristic of a number of regions of South Af-
rica, especially the South-West Cape Province. A number
of species were used by the Hottentots and Bushmen of Na-
maqualand for preparation of a drug called' 'channa" (Jeffs,
1981; Schleiffer, 1979).
The approximately 25 compounds of this group possess
several types of ring systems; the mesembrine alkaloids are
major among these.
Biosynthesis of this group of alkaloids appears to involve
p-coumaric acid andlor cinnamic acid, although a number
of related compounds apparently can serve as precursors.
The proposed pathways of origin are similar to those for
crinine (27), an AmaryUidaceae alkaloid. Both phenylala-
nine and tyrosine, when administered to Sceletium strictum,
gave rise to labeled mesembrine (28) and mesembrenol (29).
Radioactive label from DL-[2-14C] and DL-[3- 14C]phenyl-
alanine was not incorporated into mesembrine, in agreement
with the general proposal of biosynthesis. Ring-labeled
pheylalanine was incorporated, as was label from [2-14C]tyr-
osine. Norbelladine (5) and its two O-methyl derivatives also
were incorporated, but a number of experiments demon-
strated that these compounds are not involved in the pathway
leading to Mesembryanthenum and Sceletium alkaloids. Ty-
rosine is converted to tyramine and then to N-methyltyra-
624 Alkaloids Derived from Tyrosine and Phenylalanine

mine (30) during the biosynthesis of mesembrine alkaloids
(Fig. 33.8). Furthermore. the aromatic ring and the CH2 -N
side chain is incorporated as an intact unit. Incorporation
of phenylalanine has been shown to involve conversion to
cinnamic acid and to p-coumaric acid (31). Reduction prod-
ucts of the latter compound may be involved in additional
steps (Jeffs. 1981).
A major pathway to mesembrenol (29) by cinnamic acid.
p-coumaric acid (31). and the corresponding dihydro-p-
coumaric acid involves sceletenone (32). an efficient precur-
sor for mesembrenol (29) (Fig. 33.8). This suggests that hy-
droxylation of the aromatic ring occurs at a late stage of
biosynthesis.
CEFIIALOTAXUS AI'ID HOIIIOERYTHRIl'IA
ALKALOIDS
The gymnospermous genus Cephalotaxus (Cephalotaxa-
ceae) (the only genus in the family) is native to Asia and is
generally considered to have eight species (Huang and Xue.
1984). Several of these species are cultivated as ornamental
shrubs in various parts of the world. Alkaloids from species
of Cephalotaxus have antitumor activity. Of the compounds
present. about 20 are unique to the genus (such as com-
pounds (33) and (34) and belong to an unusual structural
type. whereas another 10 are homoerythrina alkaloids (Fig.
33.9). Homoerythrina alkaloids are found in other groups

~
OH ~C02H

"" HOV NH2

HO~

U.: :,. .
phenylalanine I I h
¥
/" tyrosine

C02H ..-J' hi"" ~0~H3

~ I .,/
~ 1:
C02H NHCH3 HO " '"
::,... (31) (30) ---

clnnamicacld _0 ~N'CH

0"
~ OG~h
70
OO~"'/.
"".;::

I / - . ,__
o . N)
~

N --
'CH
~

I N' CH
%

3
3

~.'CH3 3 0 \
H • 0 . 0

C-:'bo
~, ~~'
CH3
I
:'bo
H
o~~ _
I
CH3
H
RO 0

seeletenone (32)
J

f~' r~~'
:'bo
IH
CH3
:·bOH
I
CH3
H

mesembrine (28) memembrenone mesembrenol (29) Scelelium~

Fig. 33.8. Biogenesis of Mesembryanthemum and Sceletium alkaloids (modified from Jeffs. 1981; used with pennission oftbe copyright owner,
Academic Press, New York).

HO~
o
<o
CH,o
CH,O
schelhammeridine (39)
harringtonine (33) deoxyharringtonine (36)
homoharringtonine (34)
Fig. 33.9. Cephalotaxus and homoerythrina alkaloids.
of plants such as Schelhammera (Liliaceae) and Phelline
(Phellinaceae or sometimes Aquifoliaceae) (Pusset et aI.,
1989). More than 20 homoerythrina alkaloids are known.
Homoerythrina alkaloids usually make up only a very minor
proportion of the alkaloids present in most Cephalotaxus
species, although, in the species Cephalotaxus wilsoniana,
these alkaloids are major constituents (Dyke and Quessy,
1981; Powell et aI., 1972a).
Homoharringtonine (33) is an inhibitor of chloroquine-
resistant Plasmodium jalciparum in vitro and P. yoelii in
mice (Borris and Schaeffer, 1992). Both homoharringtonine
and harringtonine (34) inhibit protein synthesis (Wink,
1993).
Biosynthesis of CephaJotaxus Alkaloids
Biosynthetic studies of Cephalotaxus alkaloids indicate
that ring A of the cephalotaxine molecule is derived from
tyrosine, and rings C and D are derived from phenylalanine.
Alkaloids Derived from Tyrosine and Phenylalanine 625
'" 1 NH
I'"
.&
OH
(38) schelhammerine
cephalotaxine (35)
< o
OH H'....
~····"rrO
OCH,
, HO~~OCH
H2'
isoharringtonine (37)
A biogenetic pathway has been suggested (Fig. 33.10) (Hud-
licky et aI., 1987).
Cephalotaxine (35) occurs esterified to a series of some-
what unusual hindered acids. In deoxyharringtonine (36), L-
leucine appears to be the precursor of the acidic moiety as
indicated by labeling studies. The following pathway has
been suggested (Fig. 33.11) (Dyke and Quessy, 1981). 13C_
NMR data for several Cephalotaxus alkaloids have been re-
ported (Weisleder et al., 1980).
Callus cultures of Cephalotaxus harringtonii produce
cephalotaxine (35), and the antitumor esters harringtonine
(33), isoharringtonine (37), and homoharringtonine (34) in
both callus tissue and the medium. Deoxyharringtonine (36)
was found in the medium but not in the callus (Delfel, 1980;
Delfel and Rothfus, 1977; Spec. Per. Rep., 1975, 1979).
Biosynthesis of Homoerythrina Alkaloids
Homoerythrina alkaloids that occur in the genus Cephalo-
taxus appear to be derived from phenylalanine and tyrosine
626 Alkaloids Derived from Tyrosine and Phenylalanine

o •

OR OR
\
b'-..
0 o •
0
0
(
0
(
0 <O~I
o ""
N.( 0
...- be~id O. II
rearrangement
o OR
o
cephalotaxlne (35)

Fig. 33.10. Proposed biogenetic pathway for the synthesis of cephalotaxine (modified from Huang and Xue, 1984; used with pennission of the
copyright owner, Academic Press, Orlando. FL).

by way of a phenethyJisoquinoline precursor such as (38)
(this type of intennediate also is involved in the fonnation
of Cephalotaxus alkaloids) (Dyke and Quessy, 1981). The
intennediacy of such a compound has been demonstrated
for schelhammeridine (39). Lahel from ring-Iaheled tyrosine
is incorporated almost entirely into the A ring. Phenylalanine
is incorporated into rings C and D. Lahel from C-I (ofphe-
nylalanine) appears mostly at C-8 of the alkaloid.
Systematic Value of Cepbalotaxus and
Homoerthrina Alkaloids
The relationships of the gymnospennous family Cephalo-
taxaceae have heen viewed in a number of ways in the past.
There are about eight species in the only genus of the family,
Cephalotaxus (Huang and Xue, 1984). Some workers have
considered the family to he closely related to the Taxaceae,
whereas others have even placed the family in its own order,
the order Cephalotaxales.
The genus Taxus (Taxaceae) is noted for the presence
of diterpenes and diterpene alkaloids such as taxine (see
Chapters 22 and 36). There is a complete dichotomy in the
types of alkaloids present in the two groups. These data do
not support union of the two families.
Antitumor Activity
Only the four esters harringtonine (33), homoharring-
tonine (34), isoharringtonine (37), and deoxyharringtonine

OH

YLCO'~ ~O C~ ytCO'H --+ YlCO'H _

NH, I II CO,H CO,H
leucine

yxCO'H --+ yyCO,:... '-- ~ ~CO'H _ '-- ~ ~CO'H

HO CO,H I O~CO'H T ~ T ~ .
~ homoleucine

-
OH
the chain can be
extended further by
a similar series of !'{CO'H
reactions
CO,H
Fig. 33.11. Proposed biogenesis of the acid portion of Cephalotaxus alkaloids (modified from Huang and Xue. 1984; used with pennission of the
copyright owner. Academic Press. Orlando, FL).

(36) show significant antitumor activity (Cordell, 1978;
Powell et al., 1969, I 972b, 1974). Alkaloids of this type
generally inhibit the synthesis of DNA and protein synthesis
(Blasko and Cordell, 1988; Wink, 1993). These compounds
significantly prolong the life spans of mice with lymphocyte
leukemia. Harringtonine is effective in treating both acute
and chronic myelocytic leukemia in human subjects (Spe-
cialist Periodic Reports, Alkaloids 1975, 1979).
REFERENCES
BLASKO, G. and G. A. CORDELL, Recent developments in the chem-
istry of plant-derived anticancer agents, in Economic and Me-
dicinal Plant Research, Vol. 2 (H. Wagner, H. Hikino, and N.
R. Farnsworth, eds.), 119-191, Academic Press, London, 1988.
BORRIS, R. P. and J. M. SCHAEFFER, Antiparasitic agents from
plants, in Phytochemical Resources for Medicine and Agricul-
ture (H. N. Nigg and D. S. Seigler, eds.), 117-158, Plenum
Press, New York, 1992.
BOYE, O. and A. BROSSJ, Tropolonic Colchicum alkaloids and a110
congeners, in The Alkaloids, Vol. 41 (A. Brossi and G. A.
Cordell, eds.), 125-176, Academic Press, New York, 1992.
CAPRARO, H. and A. BROSSI, Tropolonic Colchicum alkaloids, in
The Alkaloids, Vol. 23 (A. Brossi, ed.), 1-70, Academic Press,
New York, 1984.
CORDELL, G. A., Anticancer agents from plants, in Progress in
Phytochemistry, Vol. 5 (L. Reinhold, J. B. Harborne, and T.
Swain, eds.), 273-316, Pergamon, London, 1978.
CORDELL, O. A., Introduction to Alkaloids, A Biogenetic Approach,
Wiley-Interscience, New York, 1981.
CRABB, T. A, Nuclear magnetic resonance of alkaloids, in Annual
Reports on NMR Spectroscopy, Vol. \3 (G. A. Webb, ed.),
59-2\0, Academic Press, London, 1982.
CRONQUIST, A., An Integrated System for the Classification of
Flowering Plants, Columbia University Press, New York, 1981.
DELFEL, N. E., Alkaloid distribution and catabolism in Cephalo·
taxus harringtonia, Phytochemistry 19, 403-408 (1980).
DELFEL, N. E. and J. A. ROlHFUS, Antitumor alkaloids in callus
cultures of Cephalotaxus harringtonia, Phytochemistry, 16,
1595-1598 (1977).
DYKE, S. F. and S. N. QUESSY, Erythrina and related alkaloids, in
The Alkaloids, Vol. 18 (R. H. F. Manske and R. G. A. Rodrigo,
eds.), 1-98, Academic Press, New York, 1981.
FUGANTI, C, The AmaryJlidaceae alkaloids, in The Alkaloids, Vol.
15 (R. H. F. Manske, ed.), 83-164, Academic Press, New York,
1975.
GElSSMAN, T. A. and D. H. G. CROUT, Organic Chemistry of Sec-
ondary Plant Metabolism, Freeman Cooper, San Francisco,
1969.
HUANG, L. and Z. XUE, Cephalotaxus alkaloids in The Alkaloids,
Vol. 23 (A. Brossi, ed.), 157-226, Academic Press, New York,
1984.
Alkaloids Derived from Tyrosine and Phenylalanine 627
HUDLICKY, L., L. D. KWART, and J. W. REED, Synthesis ofCephalo-
taxine alkaloids, in Alkaloids: Chemical and Biological Per-
spectives, Vol. 5 (S. W. Pelletier, ed.), 639-690, Wiley, New
York, 1987.
JANZEN, D. H., H. B. JUSTER, and E. A. BELL, Toxicity of secondary
compounds to the seed-eating larvae of the bruchid beetle Callo-
sobruchus maculatus, Phytochemistry, 16, 223-227 (1977).
JEFFS, P. W., Sceletium alkaloids, in The Alkaloids, Vol. 19 (R. H.
F. Manske and R. G. A. Rodrigo, eds.), 1-80, Academic Press,
New York, 1981.
LEETE, E., The biosynthesis of alkaloids, Specialist Periodic Re-
ports, Biosynthesis, 102-223, The Royal Society of Chemistry,
London, 1983.
MARTIN, S. F., The Amaryllidaceae alkaloids, in The Alkaloids,
Vol. 30 (A. Brossi, ed.), 252-376, Academic Press, New York,
1987.
POWELL, R. G., R. V. MADRIGAL, C. R. SMTIH, JR., and K. L.
MIKOLAJCZAK, Alkaloids of Cephalotaxus harringtonii var. dru·
pacea, J. Org. Chern., 39, 676-680 (1974).
POWELL, R. G., K. L. MIKOLAJCZAK, D. WEISLEDER, and C. R.
SMITH, JR., Alkaloids of Cephalataxus wi/saniana, Phytochem-
istry, 11, 3317-3320 (1972a).
POWELL, R. G., D. WEISLEDER, and C. R. SMITIl, JR., Antitumor
alkaloids from Cephalotaxus harringtonii: Structure and activ-
ity, J. Phann. Sci., 61, 1227-1230 (1972b).
POWELL, R. G., D. WEISLEDER, C. R. SMITH, JR., and I. A. WOLFF,
Structure of cephalotaxine and related alkaloids, Tetrahedron
Lett., 4081--4084 (1969).
PUSSET, J., S. LA BARRE, N. LANGLOIS, and J. HAMON, Alkaloids of
Phelline comasa var. robusta, Phytochemistry, 28, 1298-1300
(1989).
ROBINSON, T., The evolutionary ecology of alkaloids, in, Herbi-
vores. Their Interaction with Secondary Plant Metabolites. (C.
A. Rosenthal and D. H. Janzen, eds.) 413-448, Academic Press,
New York, 1979.
Sl>ECIALlST PERIODIC REPORTS, Alkaloids, Vol. 5 Chemical Society,
London, 1975.
SPECIALIST PERIODIC REpORTS, Alkaloids, Vol. 9, Chemical Society,
London, 1979.
SUFFNESS, M. and G. A. CORDELL, Antitumor alkaloids, in The
Alkaloids, Vol. 25 (A. Brossi, ed.), 3-355, Academic Press,
New York, 1985.
ToJO, E., The homoaporphine alkaloids, J. Nat. Prod., 52,909-921
(1989).
WALLER, G. R. and E. K. NOWACKI, Alkaloid Biology and Metabo-
lism in Plants, Plenum Press, New York, 1978.
WEISLEDER, D., R. G. POWELL, and C. R. SMITH, JR., Carbon-13
nuclear magnetic resonance spectroscopy of Cephalotaxus alka-
loids, Org. Magn. Res., 13, 114--1\5 (1980).
SCHLEIFFER, H., Narcotic Plants of the Old World, Lubrecht, Monti-
cello, NY, 1979.
WINK, M., Allelochemical properties or the raison d'etre of alka-
loids, in The Alkaloids, Vol. 43 (G. A. Cordell, ed.), 1-118,
Academic Press, New York, 1993.
34
Indole Alkaloids

Introduction leqnin et aI., 1993; Verpoorte et aI., 1991). Several types of

The Biosynthetic Pathway Leading to Key Intennediates alkaloids have an indole nucleus included in the strncture;
Strictosidine (Isovincoside) the ones considered in this chapter are those based on the
Subsequent Reactions of Strictosidine condensation of secologanin with trYptamine.
Classification and Strnctoral Types of Indole Alkaloids Methods for the chromatographic separation and purifica-
Fonnation of the Major Indole Alkaloid Types tion of indole alkaloids (TilJequin et aI., 1993; van der Heij-
Summary of Pathways Leading to Major Types of den et al., 1987a, 1987b, 1988) and both the 'H- and 13C_
Monoterpene-Derived Indole Alkaloids NMR (nuclear magnetic resonance) spectra of indole alka-
Chemosystematic and Phylogenetic Application loids have been reviewed (Cordell, 1979; Crabb, 1982; TiI-
Monoterpenoid Indole Alkaloids of Phannacologic lequin et aI., 1993). The results of feeding stodies leading to
Significance the fonnation of indole alkaloids have been reviewed (Leete,
Vincamine 1983).
Ajmalicine and Related Compounds
Ajmaline
Yohimbine
11m BIOSYl'lTHE11C PATHWAY LEADIl'IQ
Reserpine
TO KEY II'ITERMEDIATES
Picralima Alkaloids
StrYchnine and Its Relatives
Biogenesis Indole alkaloids are derived mechanistically in a manner
Curares from Strychnos Species similar to that discussed for ipecacuanha alkaloids in Chapter
Olivacine and Ellipticine 32. Schiff-base fonnation occurs between a carbonyl com-
Bisindole Alkaloids pound and an amine, but in this case, the amine is tryptamine
Catharanthus Alkaloids (I) (instead of 3,4-dihydroxyphenylethyl amine), and the
Gelsemium Alkaloids carbonyl-containing terpenoid unit is secologanin (2). The
Alkaloids from Tabernanthe iboga stereochemistrY of the condensation products is identical to
Camptothecine that of the ipecacuanha alkaloid series. The initial product
Biogenesis of the condensation of secologanin (2) and tryptamine (1)
Distribution of Camptothecine Among Higher Plants in most, if not all, plants that produce monoterpenoid indole
Biological Activity alkaloids is strictosidine (3) (Fig. 34.1) (fonnerly known as
Cinchona Alkaloids isovincoside).
Biogenesis
Biological and Medicinal Activity strictosidine (l!iovincoside)
Cinchophylline and Related Alkaloids
References Although there has been considerable debate conceming
the stereochemistrY of the initial precursor of indole alka-
loids, it is now finnly established that all naturally occurring
INTRODUCTION
monoterpenoid indole alkaloids are derived from strictosid-
Indole alkaloids (at least 4100 known) are among the most ine (3) (Battersby et al., 1978; Brown et aI., 1978; Scott,
numerous and complex of all secondary compounds (TiI- 1981; Stiickigt and Zenk, 1977). This alkaloidal glycoside

628
 Indole Alkaloids 629

0~
H'0. H O-glucosyl
O-glucosyl

CH30 2C
H.p'·

CH30 2C
: :,. . °
secologonin (2) strictosidine (3) viocoside (4)

11
3 :::,...2 (1_0) 'C02CH3
OH 0

(1.O)··X·- OH
'. I 4
··(1.0)
2109
-<:::,3. 3
5,9- H-Ia~lled
71 •• (1.0)
o ( 5) _
-HO
7105 H 0 secologamD
HOCH 2 IC02H
•
Ito I both (1.0)
!
10geraniol O-glucosyl
[4-3H,2-14C]_(3R,4R)_mevalooate [4-3H,2-14C]-(3R,4S)-menlonate, no tritium label introduced

X
11
C02CH3
.... OH ::::"'2
(1.0),.3. 4
'<:::: H'(I.O)
• 3 ,
4 2 -+-6 H 3 _ 3,7-3H-labeUed
HOCH2 I C02H 71 secologanin
•
10 9 .(1.0) loganin (11) O-gluoosyl
[2-3H,4-14C]-(2R,3R)-mevalonate •

-
H lto21
3to17
Sto15
O-glucosyl 7 to3
9islostlnajmalaclne
lito earbomelhoxy

CH30 2C
11 CH,O;C
..cologaoin (2) 'IImalicioe (7)
Fig, 34.1. Origin of monoterpenoid indole alkaloids.

possesses 3-(S) or 3-0l stereochemistry (Kapil and Brown,
1979; Cordell, 1981). It was demonstrated to he the precursor
by Stiickigt and Zenk (1977), and subsequently confirmed
by Battersby et aI. (1978) and Brown et al. (1978) in work
with cell-free systems from Catharanthus roseus (Apocyna-
ceae). Strictosidine is accumulated by Rhazya stricta (Apo-
cynaceae), the source from which it was first isolated (Smith,
1968).
When tryptamine and secologanin were incubated with
an enzyme preparation from a Catharanthus cell culture in
the presence of a f3-glucosidase inhibitor (D-d-gluconolac-
tone), only strictosidine (3) was formed. The reaction clearly
was enzyme dependent. The enzyme, strictosidine synthase,
a single polypeptide with 30,000 MW (Hampp and Zenk,
1988; Stiickigt and Zenk, 1977), is found in the plant vacu-
ole. The specific glucosidase occurs in the cytosol (Deus-
Neumann and Zenk, 1984). This enzyme has been isolated
from Catharanthus roseus plant tissue cultures at more than
500 times the level that occurs in the plant itself (Hutchinson,
1986). The cDNA clone for strictosidine synthase from Rau-
volfia serpentina has heen sequenced and its expression in
Escherichia coli examined (Kutchan et al., 1988). A similar
clone from Catharanthus roseus has been introduced into
Nicotiana tabacum plants along with the CaMV 35S pro-
moter. These plants produced levels of enzyme 3-22 times
greater than Catharanthus roseus plants (McKnight et at,
1991). Furthermore, evidence was found for the production
of strictosidine.
Strictosidine (3), and not the 3f3-epimer vincoside (4),
is the precursor of a numher of indole alkaloids, including
630 Indole Alkaloids
yohimbine (5) (Fig. 34.11), camptothecine (6) (Fig. 34.18),
ajmalicine (7), serpentine (8) (Fig. 34.2), vindoline (9) (Fig.
34.3), catharanthine (10), reserpiline, and mitragynine. Al-
though it has been suggested that vincoside (4) is the precur-
sor of certain 3(3-CorynantM alkaloids, it has been shown
that these compounds also are derived from strictosidine
(Kapil and Brown, 1979; Riiffer et aI., 1978).
Subsequent Reactions of Sbictosidlne
The formation of the monoterpenoid indole alkaloid aj-
malicine (7) and its isomers from tryptamine (1) and secolo-
ganin (2) involves the formation of four key intermediates
(Fig. 34.2) (Hutchinson, 1986). Ajmalicine represents the
first major stage in the synthesis of most major groups of
monoterpenoid indole alkaloids (see below). Stereoselective
strictosidine (3)
(isovincoside)
~
-.;---
NAD'
OK
4,21-dehydrogeissoscbiziae (18)
(a)
Fig. 34.2 (a & b). Proposed biogenesis of ajmalicine and serpentine (modified from Hutchinson. 1986 and Stockigt. 1980; used with pennission of the
copyright owners, the Royal Society of Chemistry, Cambridge and Academic Press, London, respectively).
retention of tritium from loganin labeled at positions I, 5,
7, and 8 occurs in positions 3, 15, 19 and 21 of Cory-
nantM-Strychnos-type alkaloids, respectively. For exam-
ple, [1-3H]-loganin (11) is incorporated into ajmalicine (or
class I, see Fig. 34.5) with retention of tritium at C-2!. Thus,
any mechanism invoked to explain the formation of ajmali-
cine (7) must explain the retention of tritium at both positions
C-21 and C-3 (Fig. 34.1). An enzyme preparation from Cath-
aranthus roseus has been shown to convert tryptamine (1)
and secologanin (2) into ajmalicine (7), 19-epi-ajmalicine
(12) and tetrahydroalstonine (13) in the presence ofNADPH
(Griiger, 1980). The initial step is viewed as hydrolysis by (3-
glucosidase, followed by opening of the hemiacetal to yield a
dialdehyde (14). A (3-glucosidase highly specific for stricto-
sidine has been isolated from a number of indole-alkaloid-
producing plants. Attempts to trap the dialdehyde have been
I
(14)
CK,O,C
O'K
4,21-dehydrocorynantbeine
aldehyde (15)
OK

OH
4,21.dehydrogeissoschizine (18)
CH,O,C
ajmalicine (7)
~ NADPH
serpentine (8) 19-epi-ajmalicine (12)
(b)
Fig. 34.2.
unsuccessful (Blasko and Cordell, 1990). Such an intermedi-
ate should recyclize and dehydrate to produce 4,21-dehydro-
corynantheine aldehyde (15). However, subsequent experi-
ments do not support the intermediacy of this aldehyde (15).
Cathenamine (20,21-dehydroajmalicine) (16), in its iminium
form (17), has been established to be an intermediate in the
formation of tetrahydroalstonine (13) (StOckigt, 1980), and
an NADPH-dependent enzyme that specifically hydrogen-
ates the iminium form of cathenamine (17) at C-21, called
cathenamine reductase, has been isolated (StOckigt, 1980).
This enzyme has a molecular weight of about 81,000
(Hemscheidt and Zenk, 1985). Strictosidine (3) is converted
into the same compounds (Fig. 34.2). In the absence of
NADPH, cathenamine (16) is accumulated (Fig. 34.2) (Atta-
ur-Rahman and Basha, 1983; Groger, 1980).
Other cell suspension cultures of Catharanthus roseus
synthesize and accumulate substantial amounts of both ser-
pentine (8) and ajmalicine (7). Serpentine (8), the principal
alkaloid of some cell cultures of Catharanthus roseus, is
derived from ajmalicine (7); in contrast to some other indole
alkaloids, serpentine is located inside the vacuole (Deus-
Neumann and Zenk, 1984; Zenk et aI., 1985). Serpentine
Indole Alkaloids 631
CH,O,C
cathenamine (16)
CH,O,C
~
tetrahydroalstonine (13)
(continued)
(8) accumulates inside the vacuoles against a concentration
gradient, and the uptake system is specific for alkaloids in-
digenous to the plant from which the vacuoles have been
isolated (Deus-Neumann and Zenk, 1984; Zenk et al., 1985).
This uptake requires energy and probably ATP. In other
experiments, vindoline (9) (Fig. 34.3) did not occur as a
salt within the vacuoles and could exchange with excess
vindoline in the medium (Zenk et al., 1977). Ajmalicine (7)
represents the first major branching point in the synthesis
of other groups of alkaloids. These alkaloids are sometimes
called heteroyohimbine types (Stockigt, 1980).
Proposed biogenetic pathways and mechanisms by which
relatively simple indole alkaloids such as ajmalicine are con-
verted into the subgroups of Corynanthti-Strychnos-type al-
kaloids are reviewed by Atta-ur-Rahman and Basha (1983).
Classification and structural Types
of Indole Alkaloids
The most important classification schemes are based on
biosynthetic relationships of the alkaloids involved. In 1971,
Kompis et al. proposed a new approach to the classification
632 Indole Alkaloids
ajmalicine (7)
Class 1
vindoline (9)
Class 3
Fig. 34.3. Biogenetic classification of indole alkaloids (Cordell, 1981; used with pennission of the author; Kompis et al., 1971).
of indole alkaloids that will be used in this work. These
workers divided monoterpene-derived indole alkaloids into
five classes, and, further, divided each class into subclasses.
The main classes are subdivided as shown in Fig. 34.3 [based
on a condensed version prepared by Cordell (1981)]. The
rationale for this system is shown in Fig. 34.4. Importantly,
the numbering system used is internally consistent. The sys-
tem of numbering was devised by Taylor and Le Men (1965)
and is now used by almost all workers in the field. Carbon
3 of one skeleton is carbon 3 of any other skeleton within
the monoterpenoid portion of the alkaloids.
A bewildering number of subgroups of monoterpene-de-
rived indole alkaloids occur [see, for example, the discussion
in Kisakiirek et al. (1983) and Cordell (1981)]. Because of
the vague lines delineating these groups and because of the
resultant confusion among those lacking intimacy with this
group of complex alkaloids, several classification schemes
have been proposed. In the past, many alkaloids discussed
below as Group 1 (Type A) were sometimes referred to as
"Corynanthe-Strychnos alkaloids," those of Group 3 (Type
B) as "Aspidosperma alkaloids," and those of Group 5
(Type C) as "iboga alkaloids." To further complicate things,
older literature is oriented toward discussion of the alkaloids
of a particular genus. As will be observed, many genera
contain divergent groups of monoterpene indole alkaloids
as well as other types of alkaloids. Several plants are known
to contain representatives of more than one of the five groups
outlined above. For example, Catharanthus rose us contains
members of classes 1,2,3, and 5.
Formation of the M~or Indole Alkaloid
Types
Ajmalicine (7) was formerly considered a key intermedi-
ate in the synthesis of many classes of alkaloids. This alka-
i
""'"
17 IS
18
secodine (29) vincamine (35)
Class 2 Class 3
(f-r\1
~N~
COlCH)
OH
fruticosine catharanthine (10)
Class 4 Class 5
loid is derived from 4,21-dehydrogeissoschizine (18), now
known to be the Ime intermediate. This last alkaloid is con-
verted to preakuammicine (19) and akuammicine (20). Prea-
kuammicine (19) is subsequently converted to stemmade-
nine (21) and alkaloids of classes 2, 3,4, and 5 (Fig. 34.5).
In feeding studies, it was shown that [O-methyl-3H,Ar-
3H]geissoschizine (22) can serve as a precursor for class 1,
3, and 5 alkaloids (Groger, 1980). Geissoschizine (22) also
can be converted to an intermediate related to preakuammic-
ine (19) and stemmadenine (21). Geissoschizine has been
shown to be incorporated into ajmalicine (7), serpentine (8),
akuammicine (20) stemmadenine (21), the Aspidosperma al-
kaloid vindoline (9) and coronaridine (17) (Fig. 34.7)
(Groger, 1980; Hutchinson, 1986). Although geissoschizine
(22) appears to be an important compound in indole alkaloid
pathways, this alkaloid probably is not an intermediate; it
appears to enter the pathway by an NADP+-dependent reac-
tion (Hutchinson, 1986; Stockigt, 1980).
Preakuammicine (19) serves as an efficient precursor of
akuammicine (20) (a class 1 Strychnos alkaloid) and vindo-
line (9) (an Aspidosperma alkaloid). When labeled stemma-
denine (21) (a Strychnos alkaloid) (class 1) was fed to Cath-
aranthus roseus plants, labeled tabersonine (24) (class 1),
vindoline (9) (class 3), and catharanthine (10) (class 5) were
produced. Thus, preakuammacine (19) and stemmadenine
(21) serve as key intermediates of both class 3 and 5 alka-
loids. It has been proposed that incorporation of stemmade-
nine (21) into vindoline (9) and catharanthine (10) proceeds
via dehydrosecodine (25). A Diels-Alder reaction could lead
to the formation of tabersonine (24) and catharanthine (10),
respectively (Fig. 34.5).
Catharanthus raseus and Stemmadenia pubescens are
most unusual in that each of these two species contain four
 Indole Alkaloid, 633

R
I
NH
b
- - . . Class 1, e.g., ajmalicine (7)

17 15
14
---. Class 3
e.g., vincamine (35)
19
18

Class 2, e.g., secodine (29)

3 18

14

15 14

18
\
Class 5
e.g., catharanthine (10)

Class 3
/ 18

e.g., vindoline (9)

Class 4
fruticosine
Fig. 34A. Biogenetic classification of indole alkaloids (Cordell, 1981; used with pennission of the author; Taylor and Le Men. 1965).
634 Indole Alkaloids
.strictosidine (3) 4,21-debydrogeissoschizine (18) 0 . . . . "
+
geissoschizine (22)
~_~~~_ ~<?
I IL.,~
H
CO, CH3
VHN~0 HOCH, CO,CH3
stemmadenine (21)
N
,~~~~
akuammicine (20) catharanthine (10)
C.... S
Fig. 34.5. Fonnation of other major indole alkaloid types.
major types of indole alkaloids. Becanse of the diversity
of alkaloids produced in various cultures and the medicinal
importance of several of these, Catharanthus roseus has
been the plant of choice for biosynthetic studies. In one set
of experiments with Catharanthus roseus seedlings, geis-
soschizine (22) and preakuammacine (19) were detected in
seedlings within 28-40 h, the Strychnos alkaloids stemma-
denine (21) and akuammicine (20), and the Aspidosperma
alkaloid (classes 3 and 5) tabersonine were detected after
40-50 h of growth, whereas the iboga alkaloid (class 5)
catharanthine (10) was formed after 100 h.
These feeding experiments seem to suggest that As-
pidosperma-Hunteria alkaloids (classes 3 and 5) arise by
prior formation of Corynanthi and then Strychnos alkaloids
(class 1) (Atta-ur-Rahman and Basha, 1983).
Preakuammicine (19) and stemmadenine (21) (both class
1) are converted to tabersonine (24) (class 3), probably via
CH30 1
8jmalicine (7)
Class 1
HN " ~
CO,CH3
/
!
debydrosecodine (25)
ClassZ
tabersonine (24)
CO,CH3
Class 3
the intermediacy of dehydrosecodine (25), a class 2 monoter-
pene-derived indole alkaloid (Fig. 34.6).
When seeds of Catharanthus roseus are germinated in
the dark, the young seedlings first accumulate tabersonine
(24). In the subsequent 5-10 days, the cotyledons accumu-
late vindoline (9) and its inunediate precursors (Balsevich
et aI., 1986). Transfer of 5-day-old seedlings to the light
results in the rapid loss of vindoline precursors, gradual loss
of tabersonine (24), and accumulation of vindoline (9).
Assuming that tabersonine (24) is a direct precursor of
vindoline (9) (this assumption is based on whole plant feed-
ing data), tabersonine first appears to be oxygenated to yield
16-hydroxytabersonine (26). That compound is then hydrox-
ylated to yield 16-methoxytabersonine (27). The next inter-
mediate produced is 16-methoxy-2,3-dihydro-3-dihydroxy-
N(I)-methyltabersonine (i.e., desacetoxyvindoline) (28),
which is, in turn, converted to desacetylvindoline and vindo-
 Indole Alkaloids 63S

line (9) (Balsevich et aI., 1986). The scheme suggested by
Blasko and Cordell (1990) probably is not correct.
Both antipodes of several Aspidosperma and Hunteria
alkaloids are known to occur, but it is uncommon to find
more than one in a single plant.
Iboga alkaloids occur only in the Apocynaceae and are
most common in the tribe Tabemaemontana. This group of
alkaloids is derived by the same biogenetic pathway as the
class 3 (Aspidosperma-Hunteria) alkaloids, at least in the
early stages. Strictosidine (3), geissoschizine (22), stemma-
denine (21), 16,17-dihydrosecodin-17 -01, secodine (29) (Fig.
34.3), and tabersonine (24) all are incorporated into iboga
alkaloids, which lie at the end of the biosynthetic pathway
(Fig. 34.7). On one branch, class 1 (Strychnos alkaloids)
give rise to class 3 (Aspidosperma) alkaloids and, on an-
other, class 5 (iboga) alkaloids. A common secodine inter-
mediate appears to be involved.
When seeds of Catharanthus roseus are germinated,
iboga alkaloids do not appear for 100-160 h. Only class 1
(CorynantM and Strychnos) alkaloids are found during that
time. Vindoline (9) (a class 3 or Aspidosperma alkaloid)
does not appear until 200 h after germination (Atta-ur-Rah-
man and Basha, 1983).
Within the iboga alkaloids, two antipodal series are pro-
duced. (+ )-Catharanthine (10), (+ )-ibogarnine (30), and
( + )-coronaridine (23) belong to one, whereas (- )-coro-
naridine (31) and (- )-ibogamine (32) belong to the other
(Alta-ur-Rahman and Basha, 1983). The occurrence of both
( + ) and ( - ) forms of both series of alkaloids [such as ( + )-
quebrachamine (33) and ( - )-quebrachamine (34)] suggests
that the pathway is closely linked and possibly occurs at the
stage of cyclization of a secodine precursor (Atta-ur-Rahman
and Basha, 1983).
Although plants of Voacanga africana normally produce

C\:qOv --
"" I HN I
COaCH3

dehyd....ecodine (25)

~I~
VHN\=~~
22C01CH3
COaCH3
tabersonine (24)

HO
~
HN ,;?"
"" I ~CH3-0
HI~ --
~HI
,;?
I
"" N
I
CH3
""
COaCH3
--

COaCH3
16-methoxytabersonine (27)
16-hydroxytahersonine (26)

CH3-O
~
I
HI
,;?

"" N
OH
. OH
~
CH3-O
I i
CH3 COaCH3
vindoline (9)
desatetylvindoline (28)

Fig. 34.6. Proposed biosynthesis of vindoline (modified from DeLuca et aI., 1986; used with pennission of the copyright owner, Gustav Fischer
Verlag, Stuttgart).
636 Indole Alkaloids
catharanthine (10)
(+)·coranaridine (23)
Fig. 34.7. Representative iboga or class 5 alkaloids.
iboga-type alkaloids, cell cultures produce a much simpler
pattern, mostly alkaloids of the class I (Aspidosperma) type
(Ellis, 1988).
Summary of Pathways Leading to Migor
Types of "'onoterpene-Derlved Indole
Alkaloids
As observed above, there are numerous subgroups of mo-
noterpene-derived indole alkaloids. Unfortunately, various
authors have not always agreed or been consistent in placing
monoterpene-derived alkaloids into subgroups. Many
subgroups and the distributional patterns of alkaloids be-
longing to those groups are discussed and reviewed in Kisa-
kiirek et al. (1983) and in Atta-ur-Rahman and Basha (1983)
(Fig. 34.8).
CHE"'OSYSTElIIADC Al'ID PlIYLOGEl'IEDC
AFFLICADOI'l
Data from alkaloid chemistry and biochemistry have been
applied to a chemosystematic stody of three closely related
families: Apocynaceae, Loganiaceae, and Rubiaceae (Kisa-
kiirek et aI., 1983). In this stody, eight types of indole alka-
loids were utilized: aspidospermatan, corynanthean, ebur-
nan, ibogan, plumeran, strychnan, vallesiachotaman, and
vincosan. Those skeletal types with a non-rearranged skele-
ton have the same absolute configuration as secologanin it-
self. On the other hand, alkaloids with a rearranged secolo-
18
(+)·ibogamine (30) (-)·ibogamine (32)
(l---i;~
~HN'~
17 ~15
(-)·quebrachamine (34) (+)-quebrachamine (33) 18
ganin component (ebuman, plumeran, and ibogan types) can
occur with either absolute configuration. These skeletal
types were subdivided according to increasing "chemical
complexity" compared to the basic type of each group. Skel-
etal types with a rearranged secologanin moiety (ebuman,
plumeran, and ibogan types) occur exclusively in the
subfamily Plumerioideae of the Apocynaceae. Alkaloids of
the aspidosperman and strychnan types are found only in
the Apocynaceae and Loganiaceae. Alkaloids of the cory-
nanthean, vincosan, and vallesiachotaman types are found
in all three families, although those alkaloids of the corynan-
thean type that are found in all three families were simply
derived representatives of the group; more complex alka-
loids were restricted in distribution.
The corynanthean type represents the most extensive
class of indole alkaloids. At least 41 skeletal variations of
this type are known and these alkaloids are distributed
widely in all three families. Vincosan alkaloids apparently
are of two independent biosynthetic origins. One type occurs
in the Apocynaceae and a second occurs primarily in the
Rubiaceae, but also are found in some plants of the Logania-
ceae. Strychnan alkaloids are extremely numerous; II skele-
tal types are recognized. Many occur in the Apocynaceae,
but the majority of skeletal variations are encountered in the
Loganiaceae. As preViously mentioned, the ebuman,
plumeran, and ibogan types are only found in one SUbfamily
of the Apocynaceae; that is, only plants of the Apocynaceae
have the ability to rearrange the secologanin moiety of these
alkaloids. The authors of this stody conclude that the Rubia-
ceae are comparable to the Apocynaceae in regard to their
 Indole Alkaloids 637

ability to produce indole alkaloids with modified structures,
and that both families are evolutionarily more developed
than the Loganiaceae.
Within the family Apocynaceae, only four of seven tribes
contain indole alkaloids. These are the Carisseae,
Plumerieae, Rauvolfieae, and Tabemaemontaneae. All
major skeletal types occur in the Carisseae. Within this
group, the simpler alkaloids are more widely distributed than
the more derived types. Alkaloids of the most complicated
skeletal type are found only in one species of Hunteria. The
Tabemaemontaneae represent a rather uniform tribe in com-
parison to the Plumerieae. The genus Tabernaemontana is
quite complex; many other genera that were formerly recog-
nized have been placed in this group. Among these are Anar-
tia, Bonafusia, Capuronetta, Conopharyngia, Ervatamia,
Gabunia, Hazunta, Pagiantha, Pantiaca, Peschiera, Rejoua,
Sarcopharyngia, Stenosolen, and a number of less well-
known genera (Danieli and Palmisano, 1986; Leeuwenberg,
1980). Only two of the eight genera studied do not contain
alkaloids of the ibogan type. Otherwise, iboga alkaloids
occur only in Alstonia, Catharanthus (Plumerieae), and Mel-
odinus (Carisseae). Plumeran alkaloids are distributed
widely within the tribe. Some of these are known only from
the Tabemaemontaneae. The Plumerieae probably are the
most thoroughly studied tribe of the Apocynaceae. Alkaloids
of all skeletal types are known to occur in members of this

slriclosidine (3) corynantheine vallesiachotamine

stridosidine group corynantheine group vaUesiachotamine group

adifoline talbotine stemmadenine (21)

adifoline group talbotine group stemmadenine group
CHlOH
COl CH3

H
CHlOH
mavacurine cinchonamine (70) sarpagine
mavacurine group cinchonamine group sarpagine group
H

~ perakine
H ,
CHO
H
i
corynine
akuammiline
perakine group picraJine group corynine group
<a>
Fig. 34.8 (a-d). The major classes of iridoid derived indole alkaloids and representatives of the major subgroups of each (subgroups based on Atta-ur-
Rahman and Basha. 1983; modified and used with pennission of the copyright owner, Oxford University Press, Oxford),
638 Indole Alkaloids

cvgg
HO

H I I N
.•• OH"" HN
H. 0
H Ii

ajmaline (37)
peraksine rauvoxine
ajmaline group
peraksine group oxindole group

CO,CH,

condylocarpine akuammicine (20)

pseudoxindole group condylocarpine group akuammicine group

Q
~
~HNy
CO,CH,

strychnine (45)
secodine (29)
strychnine group
(b) Class 2

Fig. 34.8. (continued)

group. Corynanthean and plumeran alkaloids are the most
commonly encountered. The Plumerieae have the greatest
variety of each of these two types. The genera Catharanthus
and Vinca have many affinities with the tribe Tabemaemon-
taneae, but are often placed in the Plumerieae. With the ex-
ception of the ibogan types, all other major stmctural types
occur in the Rauvolfieae.
According to the classification of Leeuwenberg (1980),
the Rubiaceae may be divided into four subfamilies: the
Cinchonoideae, Guettardoideae, Hillioideae, and Rubi-
oideae. Altogether, about 7000 species and 500 genera make
up this family (Hemingway and Phillipson, 1980). Onlyal-
kaloids with a non-rearranged secologanin portion occur in
these plants. Alkaloids of the corynanthean type are the most
common. Most indole alkaloids of the comyanthean, vinco-
san, and vallesiachotaman types occur in the tribes
NaucIeeae and Cinchoneae of the subfamily Cinchonideae.
The tribe Cinchoneae of the subfamily Cinchonoideae is the
only group to contain alkaloids with a non-rearranged seco-
loganin moiety as well as quinoline and isoquinoline alka-
loids. Isoquinoline alkaloids (such as emetine) also are found
in Pogonopus (Rondeletieae), Tocovena (Gardenieae), some
members of the Rubioideae, Psychotria and Cephaelis of
the Psychotrieae, Bothriospora (Hamelieae), Borreria,
Spermacoce, and Richardsonia (Spermacoceae), and Manet-
tia (Hedyotideae). Within the Hillioideae,Hillia species con-
tain only emetine-type alkaloids.
Only two tribes of the Loganiaceae, the Gelsemieae and
Strychneae, contain indole alkaloids (Bisset, 1980; Leeu-
wenberg, 1980). Corynanthean-type alkaloids are the sole
type known from the Gelsemieae. The genus Gardneria of
the Strychneae contains only corynanthean-type alkaloids.
Members of the genus Strychnos (about 200 species) contain
aspidospermotan, corynanthean, strychnosan, vallesiacho-
maman, and vincosan types. Strychnosan types are the most
abundant (11 skeletal variations) (Kisakiirek et aI., 1983).
Although the majority of monoterpene-derived indole al-
kaloids occur in the Apocynaceae, Loganiaceae, and Rubia-
 Indole Alkaloids 639

~059
H
, I 07
H~~'
N

""'HN 07, CH,·O HN HN

. ::,... HN "'"
I ~
........ CO,CH,
CO,CH,

(+)-quebrachamine (33) vincaditTormlne schizophylline

quebrachamine group aspidospermine group schizophylline group

~
H

(~:7,
H

o N
j N 07,
::,... HN
o A

vincamine (35) schizozygine tuboxinine

vincamine group schizozygine group vindolinine group

aspidofractinine kopsine vincatine

(0)
pleiocarpine group kopslne group oxindole group

fruticosine catharanthine (10) rupicoline

catharanthine group pseudooxlndole group
(d)
Class 4 Class 5

Fig. 34.8. (continued)

ceae, indole alkaloids also have been reported from the Alan-
giaceae, Annonaceae, Euphorbiaceae, Icacinaceae, and
Sapotaceae (Grager, 1980). Reports from the Annonaceae,
Euphorbiaceae, and Sapotaceae should be confinned, as
other alkaloids are known from those families, and the pres-
ence of indole alkaloids would be quite unusual in a chemo-
systematic sense. Further, it is difficult to distinguish many
specimens of the Sapotaceae and Apocynaceae which could
lead to misidentification of materials.
1II01'l0TERPEl'IOID Il'IDOLE ALKALOIDS OF
PHAKJIIACOLOGICAL SIGl'IIFICAl'ICE
Many of the alkaloids of this series have pronounced physio-
logical properties in animals, and some are of great medici-
nal importance (Cordell, 1981). The pharmacology and cer-
tain other biological properties of alkaloids from the genus
Tabernaemontana (Apocynaceae) have been reviewed
(Danieli and Palmisano, 1986).
640 Indole Alkaloids
Vincamine
Eburnamine-vincamine alkaloids (about 70 in number)
occur in a number of genera of the Apocynaceae (Lounasmaa
and Tolvanen, 1992). One of the best known representatives
of these groups of alkaloids, ( + )-vincamine (35) (Fig. 34.3),
the major aIkaIoid of Vinca minor, is used to treat headache
and vertigo. This compound has central nervous system ac-
tion and produces a fall in blood pressure. Its principal activ-
ity is to moderate cerebral vasodilation (Oanieli and Palmi-
sano, 1986; Lounasmaa and Tolvanen, 1992; Neuss, 1980).
This alkaloid has proven useful in treatment of patients with
advanced arteriosclerosis. Vincamine has an LOso i.v. in
mouse of75 mglkg and quenches singlet oxygen. Vincamine
is a feeding deterrent to polyphagous larvae of Syntomis
(Lepidoptera) and to bees (Wink, 1993).
JijmaJicine and Related Compounds
Ajmalicine (7) was first isolated from yohimbe bark and,
later, from Rauvolfia species. This compound is one of the
principal alkaloids of Catharanthus roseus. Ajmalicine is
found in members of both the Apocynaceae and Rubiaceae.
Approximately 3600 kg are produced each year at a market
price of about $2000lkg (Verpoorte et aI., 1991).
Ajmalicine has been used for the treatment of circulatory
disorders and 10-methoxyajmalicine (44) (Fig. 34.9) ex-
hibits hypotensive and vasodilator actions (Cordell, 1981;
Neuss, 1980; Verpoorte et aI., 1991).
A number of species of Alstonia (Apocynaceae) are used
in traditional medicine throughout Southeastern Asia for the
treatment of malaria and dysentery (Phillipson et aI., 1993).
Alstonine (36) (Fig. 34.9) is used for the treatment of dysen-
tery (Phillipson and O'Neill, 1987). Examination of several
of the aIkaIoids from Alstonia angustifolia revealed that they
had relatively low activity against Plasmodium [alciparum
and Entamoeba histolytica (Phillipson et aI., 1993; Wright
et aI., 1995). Ajmalicine (7) is a feeding deterrent to polypha-
gous Syntomis larvae (Lepidoptera) (Wink, 1993).
Jijmaline
Ajmaline (37) is derived from the sarpagine alkaloid po-
Iyneuridine aldehyde (Fig. 34.10). This alkaloid has power-
ful coronary dilating and antiarrhythmic effects. Neoajma-
line, a derivative of ajmaline, is a central nervous system
stimulant, a vasodilator, and uterine stimulant. This com-
pound lowers blood pressure, and, in high doses, causes
death by respiratory arrest. Although ajmaline has been used
to treat heart ailments, it is currently not used because of
toxicity problems (Tillequin et aI., 1993).
Yohimbine
The bark of the tree Corynanthe yohimbe (Rubiaceae),
indigenous to the Cameroons and the Congo Republic (for-
merly French Congo), has been used in the treatment of
arteriosclerosis and is said to be an aphrodisiac. The princi-
pal alkaloid is yohimbine (5) (Fig. 34.11). The yohimban
system contains three asymmetric carbon atoms: C-3, C-15,
and C-20. Only compounds with an a-configuration at C-
15 are known in nature (Atta-ur-Rahman and Basha, 1983).
This aIkaIoid also has been isolated from Amsonia, As-
pidosperma, Catharanthus, Rauvolfia, and Vallesia (all
Apocynaceae), Ladenbergia (Rubiaceae), and Gelsemium
and Strychnos (Loganiaceae) and has been reported from the
Euphorbiaceae (Alchornea).
Yohimbine is an a-adrenergic blocking agent and a sero-
tonin antagonist. It depletes catecholamines from the mouse
brain (Neuss, 1980). Yohimbine derivatives exhibit hypoten-
sive and cardiostimulant activities (Cordell, 1981; Szantay
et aI., 1986).
Yohimbine (5) is a feeding deterrent to Phormia, Syn-
tomis larvae, and bees and is toxic to Lemna (Wink, 1993).
Reserpine
The genus Rauvolfia (about 150 species from the tropics
and subtropics) has long been used medicinally. Authenti-
cated reports of the use of R. serpentina as a medicine date
back to 1000 B.C. The hypotensive activity of the drug was
reported in 1933. As indigenous supplies became depleted
in India, the development of R. vomitoria, an African spe-
cies, and R. tetraphylla, a Central American species, was
carried out (Cordell, 1981; Tyler et aI., 1981). Because the
root of Rauvolfia serpentina contains more than 50 aIkaIoids,
it is not surprising that the crude drug differs in activity from
isolated reserpine (39) (Fig. 34.11) (Tyler et aI., 1981). The
crude drug contains from 0.15% to 0.20% aIkaIoids.
Tissue and cell cultures of Rauvolfia serpentina synthe-
s~ze a plethora of alkaloids, dominated by yohimbine (5),
a)maline (37), and ajmalidine, which differed from that of
any plant part and from undifferentiated cultures (Ellis,
1988).
The central nervous system effects of reserpine are due to
catecholamine and 5-hydruxytryptamine depletion in the
brain. This alkaloid acts to produce sedation and tranquiliza-
tion and is useful in the treatment of hypertension (Cordell,
1981; Neuss, 1980; Szantay et aI., 1986). Reserpine (39)
causes depletion of both 5-hydroxytryptamine and norepi-
nephrine (Neuss, 1980), is a stimulator of prolactin release (it
may be carcinogenic in women) (Cordell, 1981; Mann, 1987),
and inhibits oxidative phosphorylation and uptake ofCa2+, se-
rotonin, and dopamine (Robinson, 1979). This aIkaIoid also
quenches singlet oxygen and inhibits noradrenaline transport.
Reserpine is antimicrobial against Gram-negative bacteria
and cytotoxic to Walker 256 carcinosarcoma. The oral LOso
in Agelaius is 100 mglkg (Wink, 1993). Incorporation ofre-
serpine at 0.1 % into artificial diets is totally lethal to the larvae
ofCallosobruchus maculatus (Janzen et aI., 1977). This alka-
loid is a feeding deterrent to polyphagous Syntomis larvae at
the 1% level in the diet (Wink, 1993).
PicraJima alkaloids
Several Picralima aIkaIoids also have interesting pharma-
cologic activity. Aknamrnine (40) augments the hyperten-
 Indole Alkaloids 641

akuammine (40) akuammidine (41)

cimiciphytine, R=CH3 (42)

norclmiciphydne, R=H (43)
CH.... O

10-methoxyajmBliclne (44) alstonine (36)

Fig. 34.9. Bioactive monoterpenoid indole alkaloids.

sive effects of adrenaline and has local anesthetic action
almost equal to cocaine. The seeds of Picralima nitida (Apo-
cynaceae) have been used by natives of West Africa as an
antipyretic. Akuammidine (41) is about three times as active
as cocaine as a local anesthetic (Fig. 34.9) (Cordell, 1981).
Another alkaloid, akuammine (40), has been isolated from
Picralima species.
An extract of Haplophyton crooksii (Apocynaceae) is
said to be an effective poison for such insects as cockroaches,
flies, mosquitoes, fleas, and lice (Correll and Johnston,
1970). This plant contains yohimbine and norcimiphytine
(Mroue and Alam, 1988). Cimiphytine (42) and norcimiphy-
tine (43) are two minor, lactonic alkaloids isolated from
Haplophyton cimicidum (Fig. 34.10) (Specialist Periodic Re-
ports 1981).
Strychnine and Its Relatives
The poisonous properties of Strychnos nux-vomica (Lo-
ganiaceae) have been known in Europe since the 16th cen-
tory, when the seeds of this plant were introduced into Ger-
many as a rat poison. These seeds contain about 1.5-5%
alkaloids, consisting mainly of strychnine (45) and brucine
(10,n-dimethoxystrychnine) (46) (Fig. 34.12) (Tyler et a1.,
1981). To humans, these alkaloids have an intensely bitter
taste; most persons can detect 1 part strychnine to 500,000
parts water.
Alkaloids of this type belong to class I and have an un-
rearranged secologanin skeleton, but have a C-12-C-16
bond (Tillequin et a1., 1993).
Both strychnine and brucine (as well as other optically
active alkaloids) are used to effect the resolution of racemic
mixtures of acids in synthetic organic chemistry.
Strychnine inhibits growth of the radicle of Lepidium and
is toxic to Lemna (Wink, 1993). Strychnine (45) and brucine
(46) are feeding deterrents to polyphagous Syntomis, Pieris,
and Bombyx larvae (Lepidoptera) and a variety of other or-
ganisms. Both alkaloids are insecticidal to bees (Wink,
1993).
642 Indo/e A/ka/oids

CH,02C

striclosidine (3) 4,21·dehydrogeissoschizine (18) OH polyneuridine aldehyde vinorine

H06

18
19

vomilinene norajmaline ajmaline (37)

Fig. 34.10. Biosynthesis of ajmaline (modified from Herbert, 1985, 1988; used with permission of the copyright owner, The Royal Chemical Society,
Cambridge).

Strychnine (Fig. 34.12) excites all portions of the central
nervous system and binds to the glycine receptor (Robinson,
1979). The alkaloid is a powerful convulsant; death results
from asphyxia. As little as 60-90 mg may be fatal to humans;
the LOso i.v. in rat is 0.9 mg/kg (Wink, 1993). Strychnine
currently has no therapeutic uses in Western medicine (Cor·
dell, 1981; Tyler et aI., 1981). Incorporation of strychnine
at 0.1 % into artificial diets is totally lethal to the larvae of
Callosobruchus maculatus (Janzen et aI., 1977).
Brucine (46), the dimethoxy derivative of strychnine, has
an oral LOso in rat of 1 mg/kg. Both strychnine and brucine
quench singlet oxygen, bind to glycine receptors, and inhibit
muscle lactate dehydrugenase (Wink, 1993).
Biogenesis
Feeding studies have demonstrated that both geissoschi·
zine (22), probably as 4,21·dehydrugeissoschizine (18), and

CH,02C

yohimbine (5)

12 H
o
I8~OCH'
o ~ I
~ OCH,
OCH,
reserpine (39)
Fig. 34.11. Yohimbine and reserpine (modified from Cordell, 1981; used with pennission of the author),
 Indole Alkaloids 643

OH

striclosidine (3) 4,21-dehydrogeissoschizine

~71
;:". HN

CHO -
I
HO J H+

QC-CHz-COOSCOA

strychnine (42)

~'\
U~V.) / 0 CHO HO

diaboline Wieland-Gumlich aldehyde (44) vomicine

Fig. 34.12. Biogenesis of stryclurine (Heimberger and Scott, 1973; modified and used with pennission of the copyright owner, the Royal Society of
ChemislIy, Cambridge).

the Wieland-Gumlich aldehyde (47) are involved in the bio-
synthetic pathway leading to strychnine (Fig. 34.12) (Bisset,
1980; Kapil and Brown, 1979).
Curares from Strychnos Species
Most curares derived from Strychnos species in South
America are known as calabash curares because they are
stored in a calabash or small gourd. Curares of this type are
regarded as the most paralytic natural or synthetic neuromus-
cular blocking agents. At least seven alkaloids have been
isolated that are more active than d-tubocurarine (see Chap-
ter 32). For example, C-toxiferine (48) is about 10 times as
active, and C-alkaloid G (49) and E (50) are 100 times more
active, being active at I fLg per kg (Cordell, 1981).
The most potent curarizing alkaloids have little effect on
blood pressure (in cats), with some exceptions. Toxiferine
(48) at a dose of 2 mg intravenously produced paralysis for
50-160 min in a 70-kg human and is probably the most
useful specific curarizing agent. The LDwo of toxiferine i.p.
is 0.03 mglkg. Toxiferine binds to the acetylcholine receptor
(Wink, 1993). There is no depression of blood pressure, no
histamine liberation, and an absence of bronchoconstrlction.
The diallyl his-nor-derivative has more reproducible activity
and is shorter-acting (Cordell, 1981).
The dimeric curare alkaloids are derived from monomeric
units such as Wieland-Guntlich aldehyde (47) (Fig. 34.13)
(Bisset, 1980), a compound first derived in 1932 from degra-
dation of strychnine.
644 Indole Alkaloids

OH
Wieland·Gumlich aldehyde (47)
(Nb-methyl, curacurine Vll)

HO
CHO
16-dihydronorfluorocurarine

venecurine (51)
caracurine V

OH
HO HO

C·alkaloid E (50) C·alkaloid G (49)

Fig. 34.13. Biogenesis of C-toxiferine I and similar alkaloids (modified from Cordell, 1981; used by pennission of the author).

CH,-O

olivacine (52) ellipticine (53) 9-methoxyellipticine (54)

Fig. 34.14. Olivacine, ellipticine, and 9-methoxyeIlipticine.


Although alkaloids with curarizing activity usually are
dimers, a monomeric alkaloid with curarizing activity, vene-
curine (51), has been isolated from the curare prepared by
the Hoti tribe of Venezuela (Quetin-Leclercq et al., 1989).
Olivacine and Ellipticine
Olivacine (52) occurs in the bark of several Brazilian
trees of the genera Aspidosperma and Tabernaemontana
(Apocynaceae); ellipticine (53) and 9-methoxyellipticine
(54) have been isolated from species of Ochrosia (Apocyna-
ceae) (Neuss, 1980). Similar alkaloids have been isolated
from Strychnos dinklagei (Gribble, 1990). Both ellipticine
and 9-methoxyellipticine (54) have been isolated at low lev-
els from callus cultures of Ochrosia elliptica (Gribble,
1990).
Olivacine (52) and ellipticine (53) are antileukemic
agents in mice, and derivatives of ellipticine are used clini-
cally in Europe (Fig. 34.14) (Cordell, 1978; Gribble, 1990).
The principal mechanism of action is related to the planar
structures of this group of alkaloids. Ellipticine and its deriv-
atives appear to inhibit topoisomerase IT; they also are muta-
genic and clastogenic at the tk locus of mouse lymphoma
cells. The major mechanism of action appears to be chromo-
somal cleavage (Borris and Schaeffer, 1992; Gribble, 1990).
These alkaloids inhibit DNA synthesis by intercalation into
DNA. 9-Methoxyellipticine and ellipticine inhibit mitochon-
drial respiration and cytochrome c oxidase (Wiuk, 1993).
Both ellipticine and olivacine are active against cultures
of Crithidiafasciculata (a flagellate) and Trypanosoma cruzi
(the causative agent of Chagas' disease) (Gilbert, 1977). EI-
Iipticine has an LDso i.v. in mouse of 19-22 mg/kg (Wink,
1993).
Bisindole Alkaloids
Numerous bisindole alkaloids, fonned by dimerization of
monomeric monoterpenoid-derived indoles, have been iso-
lated. Probably the best source of these alkaloids is Cathara-
nthus roseus; bisindole alkaloids from this source have been
tabulated (Blasko and Cordell, 1990). Several of these alka-
loids antitomor activity (Blasko and Cordell, 1988); most
important in this regard are vincristine (55) and vinblastine
(56) from Catharanthus roseus (Fig. 34.15). Certain other
dimeric indole alkaloids known as curares have paralytic
effects in animals (see the subsection Curares from
Strychnos species, above).
Nuclear magnetic resonance and mass-spectral data for
bisindole alkaloids have been reviewed (Blasko and Cordell,
1990).
Catbarantbus Alkaloids
Two clinically useful bisindole alkaloids, vincristine (55)
and vinblastine (56), are among the most expensive of all
plant-derived drugs (as much as $23,000 per gram), because
of their low abundance in the source plant Catharanthus
roseus (fonnerly placed in the Vinca by some workers) and
Indole Alkaloids 64S
their efficacy as anticancer agents (Fig. 34.15) (Cordell,
1978; Cordell and Saxton, 1981; Endo et al. 1988). Because
these alkaloids occur at extremely low levels in the plant,
enonnous quantities are required for commercial production.
Nearly 500 kg of plant material are needed to produce I g
of the active alkaloids (Tyler et al., 1981). Vincristine occurs
at 0.0003% by weight in the source plant. Vinblastine also
is known from Catharanthus ovalis, C. longifolius, and C.
trichophyllus (Blasko and Cordell, 1990). These antimitotic
agents inhibit cancer cell growth and are the treatment of
choice for several types of leukemia and Hodgkin's disease
(Miura et al., 1987). The pharmacology and therapeutic use
of these alkaloids has been reviewed (McConnack, 1990;
Neuss and Neuss, 1990). Synthetic strategies leading to the
monomers vindoline and catharanthine and routes to couple
them have been developed (Cordell, 1981; Miura et al.,
1987).
Vincristine (56) and vinblastine (57) bind to and dimerize
tobulin, and inhibit protein synthesis and DNA-dependent
RNA polymerase. Both inhibit intracellular transport. Vin-
blastine (57) inhibits growth of Trypanosoma cruzi, the caus-
ative agent of Chagas' disease. The LDso i.p. in mouse of
vinblastine is 9.5 mg/kg; that of vincristine is 5.2 mg/kg
(Wink, 1993).
Although the seeds of Catharanthus roseus lack alka-
loids, young seedlings contain several dozen alkaloids.
These alkaloids disappear after about 3 weeks and reappear
at 8 weeks (Robinson, 1974); in the intennediate period,
alkaloids are absent from the plants.
The products of cell culture of Catharanthus roseus are
many and varied (Ellis, 1988); bisindole alkaloids and other
products from cultures of this plant have been reviewed
(Blasko and Cordell, 1990). Some lines fail to produce any
of the alkaloids nonnally found in the whole plant. Ajmali-
cine (7) and serpentine (8) (class I or Corynanthe-type alka-
loids) often are the principal alkaloids produced in Catha-
ranthus roseus tissue cultures (Blasko and Cordell, 1990;
Ellis, 1988; Knobloch et al. 1982, Kurz et al. 1980). Taber-
sonine (24) (a class 3 or Aspidosperma alkaloid) and cathara-
nthine (10) (a class 5 or iboga alkaloid) have been found in
relatively low yields in tissue cultures (DeLuca et al. 1986).
Vindoline (9) (a class 3 or Aspidosperma alkaloid), a major
alkaloid in Catharanthus roseus plant material, has never
been found in plant tissue cultures. The pathways leading
to vindoline appear to occur in the shoots of Catharanthus
roseus plants, but are not known to occur in roots (DeLuca
et al., 1986).
Both vindoline (9) and catharanthine (10) are of great
importance, as coupling of these two compounds (possibly
via an iminium intennediate) leads to 3',4'-anhydrovinblas-
tine (57), a direct precursor to both vinblastine (57) and
vincristine (56) (Fig. 34.15) (Blasko and Cordell, 1990;
Stuart et ai., 1978). Enzymes from cell-free systems of Cath-
aranthus roseus have been demonstrated to carry out this
coupling (Endo et al., 1988). The reaction also can be cata-
lyzed by horseradish peroxidase (Goodbody et al., 1988) or
646 Indole Alkaloids

vindoline (9)

tabersonine (24)

r~ COlCH,

catbaranthine (10)

CH,O

iminium intermediate

OH
/ CH,O
COlCH,

3' ,4'·aohydrovinblastine (57)

vincristine (55), R = CHO

<a)
vinblastine (56), R = CH,

(b)

Fig. 34.15 (a & b). Proposed biosynthesis of vincristine and vinblastine (modified from Goodbody et aI., 1988; used with pennission of the copyright
owner, Georg Thieme Verlag, Stuttgart).

carried out synthetically (Kutney et al., 1976). Others have
suggested that vinblastine (57) and vincristine (56) are not
found in cell cultures because these cultures do not synthe-
size vindoline (9) (Goodbody et al., 1988).
Gelsemium Alkaloids
A number of highly toxic alkaloids is found in members
of the genus Gelsemium (Loganiaceae). One species, Gelse-
mium sempervirens or yellow jessamine, is extremely COffi-
mon in the southeastern United States and has been involved
in poisoning of children. The major alkaloid is gelsemine
(58) (Fig. 34.16), but another alkaloid, gelsemicine (59)
(MLD 0.05-0.06 mg/kg in rabbits), probably is responsible
for most of the toxicity. Gelsemine modulates glycine neuro-
chemical activity (Wink, 1993). A similar species, G. eleg-
ans, occurs in China and has been used in traditional medi-
cine (Liu and Lu, 1988). A crude mixture of Gelsemium
alkaloids has been used as an analgesic and antispasmodic
drug. Strictosidine is converted to gelsemine (58) in G. sem-

--
strictosidine (3) akuammidine (41)
(koumicine)
vobasindiol / anhydrovobasindiol
gelsenidine
humantienine type
CH,-O
gelsemicine (59)
Fig. 34.16. Proposed biosynthesis of gelsemine (Liu and Lu, 1988; modified and used with permission of the copyright owner, Academic Press,
Orlando, FL).
pervirens in 0.47% yield. Structurally similar alkaloids
apparently occur in the related genus Mostuea (Bisset,
1980).
Alkaloids from Tabemantbe /boga
The roots of the West African plant Tabernanthe iboga
(Apocynaceae) are used to combat fatigure, sleep, and hun-
ger (central nervous system stimulation), and are associated
with secret societies and religious practice (Schultes and
Hofmann, 1973). lboga, when used in small quantities, is a
stimulant used to combat fatigue, whereas, in larger quan-
tities, it is hallucinogenic (Schleiffer, 1979). In Gabon,
where this practice is widespread, iboga may be derived from
either Tabernanthe iboga or from T. subsesselis. Although
the roots of the plant are usually used, the leaves have more
pronounced physiological activity (Raymond-Hamet, 1941).
Extracts of this plant also are used while stalking game; the
Indole Alkaloids 647
CO~~:~~CH'OH
9" H
I I N
---+ "" HN H --
"'" "'"
koumidine
koumine
use of plant extracts enables the hunters to remain motionless
for as long as 2 days while retaining mental alertness (Dan-
ieli and Palmisano, 1986; Thompson, 1974).
The principal alkaloid, ibogaine (50) (lO-methoxyibo-
gamine), was first obtained at the tum of the century and is
regarded as the principal hallucinogenic agent of Tabernan-
the iboga root. Several iboga alkaloids are central nervous
system stimulants, as evidenced by their antagonism to reser-
pine catalepsy. Ibogaine (60) is a cholinesterase inhibitor
(Schultes and Hofmann, 1973). A number of alkaloids of
this type cause hypotension and bradycardia. Ibogaline (61)
is the most active of these (Fig. 34.17).
Iboga alkaloids are found in other genera [e.g., Conopha-
ryngia, Ervatamia, Hazunta, Melodinus, Pagiantha, Pan-
daca, Tabernaemontanae, and Voacanga (Apocynaceae).
Catharanthine (10) possesses hypoglycaernic activity
(Neuss, 1980).
648 Indole Alkaloids
CH,O
CH'0'O:W~N
"'" I IN"", I
HN
·...'H
ibogaine (60)
(10-methoxyibogamine)
CH,O ~
IIN
rn,o--J,,~
"'" HN
tabernanthine
Fig. 34.17. Alkaloids from Tabernanthe iboga.
Camptotbecine
Camptothecine (6) was fIrst isolated from the Chinese
tree Camptotheca acuminata (Nyssaceae). Extracts of this
plant were shown to possess very high antitumor activity
(Cai and Hutchinson, 1983; Cordell, 1978; Suffness and Cor-
dell, 1985). Derivatives of camptothecine are now in clinical
trials in the United States.
Camptothecine (6) does not give positive alkaloid tests
with Dragendorf's reagent or other similar reagents. Further,
this alkaloid does not form salts with mineral acids (Cai and
Hutchinson, 1983).
Biogenesis
Feeding experiments have demonstrated that strictosidine
(3), tryptamine (1), and secologanin (2) all serve as precur-
sors for camptothecin (6) (Fig. 34.18) (Cai and Hutchinson,
1983; Kapil and Brown, 1979). Feeding studies with [5-
14C,14-3H]strictosamide (63) indicate that this compound is
incorporated efficiently into camptothecine.
Distribution of Camptotbecine Among
Higher Plants
In addition to Camptotheca acuminata (Nyssaceae), cam-
ptothecine (6) has been found in Nothapodytes (Mappia)
joetida and Merilliodendron megacarpum (Ieacinaceae),
Ophiorrhiza mungos (Rubiaceae), and Ervatamia heyneana
(Apocynaceae) (Cordell, 1981). This distribution is of con-
siderable interest to plant systematists and phylogenists, as
it reflects the same dichotomy seen in the distribution of
other types of monoterpene iridoids.
Biological Activity
Plant extracts containing camptothecine (6) were shown
to possess very high antitumor activity (Suffness and Cor-
o
I
HN
'. . H
ibogamine (30) iboluteine
CH'°lrl?F _
"H
ibogaline (61)
dell, 1985; Wall et al., 1966). Camptothecine is a potent
cytotoxic agent that acts by inhibiting nucleic acid synthesis.
In certain cell lines, DNA and RNA synthesis are inhibited
reversibly about 50% by 5 J.LM camptothecine (Cordell,
1981). Camptothecine exerts its action on DNA topoisomer-
ase I, an enzyme that relaxes supercoiled DNA. IO-Hydroxy-
camptothecine (64) has a better therapeutic index than camp-
tothecine and has been subjected to clinical study. This
compound is used widely in China for treatment of liver
cancer, leukemia, and gastric cancer (Blasko and Cordell,
1988). The 20(R,S)-9-amino derivative of camptothecine
has been found effective in treating immunodefIcient mice
carrying three different lines of human colon cancer without
toxic effects (Kinghorn, 1992).
Camptothecine (6) inhibits replication of DNA vimses
such as adenovims, vaccinia vims, and herpes vims, but has
no effect on RNA vimses. Camptothecine inhibits 45 S
rRNA transcription (Wiuk, 1993) and is a strong inhibitor
of n\lcleic acid synthesis in mammalian cells (Blasko and
Cordell, 1988). IO-Methoxycamptothecine (65) is abo\lt
eight times more active against herpes vims than campto-
thecine (Cai and H\ltchinson, 1983).
Camptothecine exhibits selective plant growth inhibition.
The growth of tobacco and com were retarded, whereas no
effect was noted on beans and sorgh\lm when a spray of 1
X 10-4 ppm was applied. Growth inhibition appeared to
be limited to the rneristomatic areas of the plant (Cai and
Hutchinson, 1983).
Camptothecine (6) has been \lsed topically for the treat-
ment of psoriasis (Cai and Hutchinson, 1983).
Cinchona Alkaloids
Alkaloids from plants of the genus Cinchona (Rubiaceae)
have been used in Western medicine for more than 300 years.
The use of Cinchona bark to treat malaria was first recorded
 Indole Alkaloids 649

in 1633; South American Indians do not appear to have used Biogenesis

it for this purpose. Quinine (66), isolated from this plant,
Despite the fact that quinine (66) and related alkaloids
was the first effective drug to treat Plasmodium falciparum
have quinoline skeleta; biogenetically, they are indole ~a­
and related organisms (Phillipson and Wright, 1991). As the
loids. Radioactivity from labeled loganin (11) and stnctosld-
medicinal properties of quinine became known, substantial
ine (3) is incorporated into quinine. The indole nitrogen be-
supply problems from South America developed and cultiva-
comes the quinoline nitrogen (Fig. 34.19). Loganin (11),
tion of Cinchona was initiated in other parts of the world.
corynantheal (69), and probably cinchonarnine (70) have
The Dutch introduced Cinchona into Java and, today, that
been shown to be key intermediates in the biosynthesis of
island is the world's major supplier. Before World War n,
qninine (66), cinchonine (67), and cinchonidine (68) (Kapil
quinine (66) was the major drug used to control malaria.
and Brown, 1979).
When the Japanese occupied the Dutch Indies, a major
Feeding experiments with doubly-labeled [1-3H2 , 1-
search was initiated to find substitutes. Several antimalarial
14C]tryptamine (1) showed that 50% of the tritium at C-I
drugs were developed and are still used.
of tryptamine was lost during the formation of Cinchona
At least 40 alkaloids have been isolated from various
alkaloids. This indicates that the cleavage between C-5 and
species of Cinchona (Cordell, 1981; Tyler et aI., 1981). An
N-4 in corynaltheal (69) is a stereospecific process. The ring
average yield of alkaloids from the bark is about 6-7%,
expansion to the quinoline nucleus must occur via opening
although up to 18% is occasionally found (Tyler et aI., 1~8.1).
of the N-containing ring and recyclization of (68) to furnish
Although first isolated in 1820, the structure of qmrune
cinchonidinone (71), which has been determined tu be a
was determined in 1909, and the first synthesis was carried
natural product in Cinchona ledgeriana (Kapil and Brown,
out in 1944 (Cordell, 1981). Quinine is used as a standard
1979). The specific incurporation of [11-3H21cinchonidinone
for bitterness.
(71) in cinchonine (67) and quinine (66) has been observed
Despite extensive searches, quinine and related alkaloids
(Kapil and Brown, 1979).
have been found only in Cinchona and a few closely related
The structure of guettardine (72), isolated from Guettarda
genera of the Rubiaceae, especially the genus Remijia.
heterosepala, suggests that this alkaloid may represent an
Because of the value and the widespread use of Cinchona
intermediate between the Corynanthe and cinchonamine
alkaloids, many attempts to produce alkaloids in plant tissue
types of alkaloids (Herbert, 1986). If so, cl~avage of the .13-
cultures and cell cultures from this group of plants have been
carboline system must precede the formation of the qum-
made (Verpoorte et aI., 1991). Trees require about 10 years
uclidine ring (Fig. 34.20) (Herbert, 1986).
before they can be harvested. Cell cultures of Cinchona ledg-
eriana and C. succirubra produce largely cinchonine (67)
Biological and JIIedicinal Activity
and cinchonidine (68), although small quantities of quinine
and quinidine were produced. Only small amounts of total Quinine forms a complex with haemin that seems to be
alkaloids were produced (Ellis, 1988). an essential part of the receptor for both quinine and chlo-

O-glucosyl
strictGsidine (3) strictosamlde (63) camptotheclne (6)

HO CH,-O

10-hydroxycamptothecine (64) lO.methoxycamptothecine (65)

Fig. 34.18. Biogenesis of camptothecine (modified from eai and Hutchinson, 1983; used with permission of the copyright owner, Academic Press,
Orlando. FL).
650 Indole Alkaloids

(Jc(1:' COzH
OH
I I
'>-. HN
NH
z
N

;5
tryptophan
+

CHO ~ O-gIU-:::-

'>-. 0
CH30 Z corynantheal (69) cinchonamine (70)

seoologanin (2)

quinamine

u
quinine (66) cinchonidine (68) cinchonine (67)

Fig. 34.19. Biogenesis of quinine (modified from Leete, 1969; modified and used with pennission of the copyright owner, the American Chemical
Society, Washington, DC),

roquine, Quinoline antimalarials are toxic preferentially to
the mature stages of the parasite (Borris and Schaeffer,
1992).
Quinine (66), cinchonidine (68), cinchonine (67), and
quinidine (73) are toxic to Cinchona cells in culture and to
Lemna. Cinchonine and quinidine inhibit growth of the radi-
cle of Lepidium and Lactuca (Wink, 1993).
Several alkaloids of Cinchona species [e.g., quinine (66),
quinidine (73), cinchonidine (68), and cinchonine (67)] serve
as feeding deterrents to Syntomis larvae (Lepidoptera), bees,
Leptinotarsa (Coleoptera), Locusta, Agelaius, and a variety
of other organisms (Wink, 1993). The presence of quinine
sulfate or chloride at 4 X 10-7 or 1.5 X 10-6 M reduced
larval food consumption by Pieris brassicae by approxi-
mately 75% (Levinson, 1976).
Certain insects that feed on Cinchona species appear to
accumulate the alkaloids in their bodies. For example, a Hel-
opeltis species and Attacus atlas both accumulate cinchonine
(67) or cinchonine-like alkaloids (Waller and Nowacki,
1978).
Qninine (66) is toxic to many bacteria and unicellular
organisms. This alkaloid is active against Trypanosoma
cruzi (Wink, 1993). Quinine is a local anesthetic and has
cardiovascular effects, oxytocic effects, curarizing effects,
and an analgesic effect comparable to salicylate. Quinine is
not commonly used alone as an antimalarial today (Cordell,
 Indole Alkaloids 651

OH 1981}. This alkaloid has the ability to supress. but not cure.
vivax malaria. However. quinine has regained importance
in the treattnent of chloroquine-resistant falciparum malaria
(Tyler et al .• 1981).
Quinine (66) intercalates with DNA. modulates ion chan-
nels. and inhibits glucose response in chemosensory cells
(Wink. 1993). Cinchonidine (68) has an LDso i.p. in rat of
206 mglkg; cinchonine (67) an LDso i.p. in rat of 152 mglkg;
quinidine (64) has an LDso Lv. in rat of 30 mglkg; and qui-
nine has an LDso p.o. (per os. oral) in Agelaius of 100 mglkg.
OH All of these organisms produce growth inhibition in Plasmo-
dium Jalciparum (Wink. 1993). Cinchonidine inhibits the
guettardine (70) potato X virus (Wink. 1993).
Quinidine (73). another alkaloid found in Cinchona. is
Fig. 34.20. Guettardine.
used to treat certain heart conditions; in partiCUlar. this alka-
loid is used to inhibit auricular fibrillation (Fig. 34.19) (Cor-
dell. 1981; Tyler et aI.. 1981).

(75) CHO

OH
(76)
4'
usambarenslne (77)
CH,-O

CH,-O

OH

tubulosine (74) OH
3,4·dihydroxyusambarenslne (78)

Fig. 34.21. Cinchopbylline alkaloids.

652 Indole Alkaloids
Cinchophylline and Related Alkaloids
The cinchophyllines, a series of alkaloids that structurally
resemble emetine, cephaeline, and other isoquinoline alka-
loids, except that they are formed from tryptamine and seco-
loganin, are found in the leaves of certain Cinchona species
(Fig. 34.21). Somewhat similar alkaloids occur in Ochrosia
and Dyera species (Apocynaceae) and in Strychnos species
(Loganiaceae) (Borris and Schaeffer, 1992; Phillipson et al.,
1993). Another structurally related alkaloid, tubulosine (74),
has been isolated from a Pogonopus species (Rubiaceae)
(see Chapter 32) (Hemingway and Phillipson, 1980).
Strychnos usambarensis (Loganiaceae), the source of several
of these alkaloids, is used as an arrow poison by the Ban-
yarnbo tribe on the border of Tanzania and Rwanda (Phil-
lipson and Wright, 1991). These alkaloids probablY arise
via precursors such as (75) and (76) that are derived from
strictosidine (3) (Bisset, 1980).
Several cinchophylline and related alkaloids have pro-
nounced arnebicidal and cytoxic activity. The alkaloids
usarnbarensine (77) and 3',4'-dihydroxynsarnbarensine (78)
from Strychnos usambarensis have ICso values against a
multiple-drog-resistant strain of Plasmodium Jalciparum of
0.38 and 0.01 IJoglml, respectively (phillipson and Wright,
1991). Usurnbarensine (77) has an ICso value of 1.40 IJoglml
against Giardia intestinalis, 3',4'-dihydroxynsarnbarensine
(78) of 0.023 IJoglml against Plasmodium Jalciparum, and
usarnbarine (79) 1.02 IJog/m1 against Entamoeba histolytica
(compared to emetine with 2.04 IJog/ml) (Pbillipson et al.,
1993).
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BALSEVICH, J., V. DELUCA, and W. G. W. KURZ, Altered alkaloid
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BATIERSBY, A. R, N. G. LEWIS, and 1. M. 'fIpPETI, The basic
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CAl, J. and C. R. HUTCHINSON, Camptothecine, in The Alkaloids,
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CORDELL, G. A., The biosynthesis of indole aIkaIoids, Lloydia, 37,
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CORDELL, O. A .. Anticancer agents from plants, in Progress in
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35
Ergot and Other Indole Alkaloids
Introduction
Ergot Alkaloids
Biosynthesis
Biosynthesis of Peptide-Containing Ergot Alkaloids
Distribution of Ergot Alkaloids
Ergotism
Biological Properties
Endophytes
Lysergic Acid Diethylamide
Medicinal Properties
Commercial Production of Ergot Alkaloids
Harmane or [:I-Carboline Alkaloids
Biosynthesis
Distribution of Harmane Alkaloids
Biological Activity
Biosynthetically Related Alkaloids
Cantbin-6-one and Related Alkaloids
Carbazole Alkaloids
Alkaloids of Physostigma venenosum
Alkaloids of the Calycanthaceae
Polyindolenines
Other Alkaloids with Indole Skeleta
References
INTRODVcnOI'l
Many aIkaloids contain an indole nucleus as a part of their
structure. Monoterpene-derived indole aIkaloids (see Chap-
ter 34) are the most important of these compounds, but sev-
eral other significant types of indole aIkaloids exist. Ergot
alkaloids fonned from tryptamine and a mevalonate-derived
hemiterpene unit are of medical importance. Others, such as
harmane aIkaloids, physostigmine and a series of structurally
similar aIkaloids, Calycanthus alkaloids (Calycanthaceae)
and related compounds (principally from the Rubiaceae),
and relatively minor types of aIkaloids from the Ascelpiada-
ceae, Sterculiaceae, and Verbenaceae are summarized in the
present chapter.
ERGOT ALKALOIDS
Indole alkaloids involving a hemiterpene unit have long been
known as mycotoxins and pharmaceutical products. Al-
though these alkaloids are best known from the fungal genus
Claviceps, they also are found in several genera of the higher
plant family Convolvulaceae. ReCently, ergot alkaloids also
have been found in certain groups of endophytic fungi (An-
tkowiak and Antkowiak, 1991). Ergot alkaloids may be di-
vided into three major groups: clavine alkaloids, simple lys-
ergic acid alkyl amides, and peptide derivatives of lysergic
acid amide. Two of the most important ergot aIkaloids are
lysergic acid (1) and agroclavine (2). Alkaloids of the
agroclavine type have a CH20H or methyl group at C-8 and
lysergic acid types have a carboxyl or carboxamide group
at that center (Fig. 35.1) (Antkowiak and Antkowiak, 1991;
Geissman and Crout, 1969; Mann, 1987). Free lysergic acid
usually is not accumulated by Claviceps species, although
the simple amide ergine (3) has been isolated from Claviceps
paspa/i and from Ololiuqui, a hallucinogenic preparation
from seeds of Ipomoea violacea and Rivea corymbosa (An-
tkowiak and Antkowiak, 1991). Cell-free extracts from
Claviceps species that synthesize clavine aIkaloids have
been obtained.
Analytical methods for the detection and analysis of ergot
alkaloids by high-perfonnance liquid chromatography
(HPLC) and tandem mass spectrometry (Yates and Powell,
1988), and both the IH_ and I3C-NMR (nuclear magnetic
resonance) spectra for these compounds have been reviewed
(Crabb, 1982). The results of feeding studies leading to the
fonnation of ergot alkaloids have been tabulated (Leete,
1983).
IiSS
656 Ergot and Other Indole Alkaloids
17 H
Ho2e
agroclavine (2) lysergic acid (1)
HO HO
elymoclavlne (5) chanoclavine-J (7)
Fig. 35.1. Lysergic acid and agroclavine.
Biosynthesis
The biosynthesis of ergot alkaloids is initiated by prenyla-
tion of tryptophan with dimethylallyl pyrophosphate
(DMAPP) to yield 4-dimethylallyltryptophane (DMAT) (4)
(Fig. 35.2) (Floss, 1980). This alkylation step is believed to
be rate limiting, and the enzyme that catalyzes this reaction,
DMAT synthetase, has been purified more than 60 times
(Maier and Groger, 1976; Waller and Dermer, 1981). The
enzyme appears to be specific for L-tryptophan and is inhib-
ited by agroclavine (2) and elymoclavine (5) the end prod-
ucts of the reaction.
Mixed-function oxidase enzymes from ergot are capable
of converting DMAT (3) to the corresponding hydroxy de-
rivative (HODMAT) (6) have been studied (Maier and
Groger, 1976; Waller and Dermer, 1981).
Cyclization of a 4-dimethylallyltryptophan (4) intermedi-
ate yields chanoclavine (7). Many of the same mixtures of
enzymes also produced chanoclavine I (7), the precursor for
several ergot alkaloids with two rings as well as the agroclav-
ine and lysergic acid series. The synthesis of rings C and D
has been studied with multiply-labeled mevalonic acid and
related precursors in work done primarily by Floss (1976,
1980). The reaction is mediated by the chanoclavine-I cy-
clase enzyme complex. The enzyme is reasonably specific,
requires ATP, a pyridine nucleotide, and Mg2+ for activity.
Several cyclases of this type probably exist: one produces
agroclavine (2) and another elymoclavine (5) (Waller and
Dermer, 1981). Mevalonate-2- 14C specifically labels the C-
17 methyl group of chanoclavine I (7). The pro-4R hydrogen
of mevalonate is retained during alkaloid formation. This
ergotamine (9)
4-dimethylallyl- ergine (3)
tryptophan (4)
indicates that a ZoE (cis-trans) isomerization must occur
in the formation of chanoclavine I (Floss, 1976, 1980). By
feeding 4-(-y;y-dimethylallyltryptophan)-(Z- 14CH3 ) and de-
grading chanoclavine I (7), agroclavine (2), and elymoclav-
ine (5), it was established that a ZoE isomerization occurs
(Floss, 1976). Additional evidence indicates that methyl
group hydroxylation occurs before the closure of ring C,
formation of an epoxide may be involved in this oxidation
(GrOger, 1978). Chanoclavine I (7) is oxidized to the corre-
sponding aldehyde (8) and this is cyclized to produce
agroclavine (2). Another ZoE isomerization· is involved at
this stage. This rearrangement involves addition to the dou-
ble bond followed by elimination of the original vinyl proton
(Fig. 35.3). However, in subsequent addition steps, the en-
zyme-proton complex (that now bears the original vinyl
proton) can be added across the double bond of another mol-
ecule of the aldehyde (8). This "recycling" of protons has
been confirmed by double-labeling experiments (Floss,
1980). If ttitium is incorporated into the hydroxymethyl
group of chanoclavine I (7), half of the label is lost in the
subsequent formation of tetracyclic ergolines.
Agroclavine is converted into elymoclavine (5) and ulti-
mately into lysergic acid (1). An enzyme preparation that
catalyzes the aerobic conversion of agroclavine to ely-
moclavine (in addition to several other types of activity) has
been studied. Feeding experiments with mevalonate-3-D3
established that both methylene hydrogens at C-17 of cha-
noclavine I (7), but only one (at C-7) of elymoclavine (5)
comes from C-3 of mevalonate. The hydrogen that remains
was shown to be the pro-7S hydrogen.
 Ergot and Other Indole Alkaloids 657

Biosynthesis of Peptide-Containing diate Iysergyltripeptide is linked to the enzyme and subse-

Ergot Alkaloids quently cyclized (Floss, 1980).

The structure of ergotamine (9) is a peptide alkaloid in

which a lysergic acid moiety is linked to alanine, phenylal-
anine, and proline. The manner of attachment of the amino
acids is not clear. Neither dipeptides or tripeptides are
added in the synthesis. Lysergylalanine does not appear
to be incorporated as an intact unit. Although the amino
acids were incorporated, the peptides appear to have been
broken down and the component amino acids used. A
crucial step seems to be the hydroxylation of the amino
acid directly linked to lysergic acid (Groger, 1978). Other
major problems involve the formation of the cyclic struc-
ture of the final product, ergotamine. Floss et aJ. (1974)
proposed that peptide chain formation takes place in a
concerted fashion on a mUltienzyme complex. The interme-
Distribution of Ergot Alkaloids
Although best known from Claviceps species, these alka-
loids also are known to occur in other fungi, including Peni-
cillium, Aspergillus, and Rhizopus species. Ergot alkaloids
are also known to occur in certain higher plants, notably
in the seeds of Argyreia, Convolvulus, Cuscuta, Ipomoea,
Operculina, Rivea, Strictocarpia, and Turbina (Convolvula-
ceae), but also in the leaves, stems, and roots of some species
(Amor-Prats, personal communication). Ololiuqui is a hallu-
cinogenic drug used by the Indians of Mexico, made from
Ipomoea violacea and Rivea corymbosa. These seeds contain
elymoclavine (5), chanoclavine-I (7), and lysergic acid
amide (10), the principal hallucinogenic constituent of ololi-

~ 'criNH2C02H

opp

~ I ~
~ NH

4-dimethylallyl. N.methyl-4-dimethyl-
tryptophan (4) allyltryptophan

o
HO

hydroxydimethylallyl chanoclavine-I (7) chanoclavine-I

-tryptophan (6) aldehyde (8)

CH H
HN' 3 H02C~1
N/CH3
H H
~

-+ ---+

c? I ~
~ NH

agroclavine (2) elymoclavine (5) lysergic acid (1)

Fig. 35.2. Biogenesis of lysergic acid (modified from Floss, 1980).

658 Ergot and Other Indole Alkaloids

-
H H

enzX

--
X-enz

--
Fig. 35.3. Isomerization of the double bond in the conversion of chanoclavine I to ergolines (modified from Floss, 1976; used with pennission of the
copyright owner, Elsevier Science Ltd., The Boulevard, Langford Lane, Kidlington OXS 1GB, UK).

uqui (Fig. 35.4). In general, the yield of ergot alkaloids from
higher plants is much less than from fungi.
Ergotism
Ergot has been responsible for poisoning of both human
and domestic animals for thousands of years. Accounts are
known from the ancient Chinese, Greeks, Romans, and oth-
ers. Ergot was not recognized as a fungus until 1764 by von
Munchhausen. In humans, poisoning usually occurred by
consumption of bread prepared from infested grain, typically
rye. In the Aquitane region of France in A.D. 944, about half
of the popUlation died of ergot poisoning. Ergotism was a
problem in Europe through much of the Middle Ages, but
it has been largely eliminated by better grain-handling tech-
niques, inspection of grain, and pooling of grain supplies.
Some alkaloids of ergot possess potent vasoconstricting
abilities; these were largely responsible for one of the effects
of ergotism called SI. Anthony's Fire, a gangrenous condi-
tion of the extremities which often resulted in loss of limbs.
Other related alkaloids produced delirium and hallucina-
tions, and, in more severe cases, convulsions.
Ergotism is still an important disease of domestic animals.
Cattle that feed on infested fields are regularly poisoned by
the sclerotia of Claviceps (Thomas and Basset, 1970).
Biological Properties
Ergocryptine (11) has an LOso Lv. in rabbit of 1.1 mg/kg,
ergocornine (12) of 1.2 mgikg, ergometrine (13) in mouse
of 0.15 mg/kg, and ergotamine (9) of 62 mg/kg (Fig. 35.5)
(Yates et aI., 1989).
Ergonovine (13), ergotamine (9), ergocryptine (11),
agroclavine (1), and elymoclavine (5) reduced larval weights
and amount of com leaf disks eaten by larvae of the fall
armyworm, Spodoptera /rugiperda, compared to controls
(Clay and Cheplick, 1989). Ergocryptine (11), ergometrine
(13), and ergotamine (9) are feeding deterrents to Syntomis
larvae (Lepidoptera) or are toxic to Oncopeltus (Hemiptera)
(Wink, 1993).
Endophytes
Although many plants are infected by fungal parasites,
others are infested with endophytic fungi. These fungi live

o NH,

HO

lysergic acid (1) lysergic acid amide (10) lysergic acid diethylamide (14) 8~hydroxylysergic acid (15)
(LSD)

Fig. 35.4. Biologically active ergot aIkaloids.


'/:~~
0 0
H H 0 0
H H
~ b
ergotamlne (9)
,/:f~
0 0
H H 0 0
H
ergocornine (12)
FIg. 35.5. Peptide-containing ergot alkaloids.
entirely within the leaf and stem tissues of the plant. Endo-
phytes of grasses (Poaceae) and sedges (Cyperaceae) are
especially common and important (Clay, 1989). The fungi
are members of the family Clavicipitaceae (Ascomycetes),
tribe Balansiae. Five genera are especially common: Atkinso-
nella, Balansia, Balansiopsis, Epichloi!, and Myriogen-
osporae. A few species are epiphytic; however, none pro-
duce the haustoria common to parasitic fungi. Most of these
fungi produce fruiting bodies on the leaves or aborted inflo-
rescences of host species, although others grow into the re-
productive tissues of the plant and are maternally transmit-
ted. Many endophytes are transmitted through seeds of their
hosts. As is true for Claviceps infections of grasses, poison-
ing of herbivores by endophytes is well known. The cause
of many livestock poisoning problems of this narure was
long mysterious, as obvious infection was not readily seen.
Poisoning by tall fescue (Festuca arundinacea), orchard
grass (Dactylis glomeratus), perennial ryegrass (Lotium per-
enne), annual ryegrass (Lotium tementulum), and species of
Stipa and Metica (often called "sleepy" or "drunk" grass)
is now known to involve endophytes (Clay, 1989; Petroski
et al., 1992; Powell and Petroski, 1992; Powell, and Yates
1988).
Many endophytic fungi produce alkaloids; uninfected
host plants lack these compounds. The alkaloids of most of
these grasses (presumably produced by the endophytes) are
similar to those of Claviceps species described above. Those
Ergot and Other Indole Alkaloids 659
"/:,l~
H H 0 0
ergocryptine (11)
ergometrine (13)
(ergonovine)
of tall fescue, however, are of an unusual pyrrolizidine type
(Clay, 1988).
Infected individuals of several grass species are more re-
sistant to a number of insect herbivores (Clay, 1988). Fur-
ther, seeds of infected species are more resistant to herbivore
attack (Cheplick and Clay, 1988). Lysergic acid amide (10),
isolysergic acid amide, 8-hydroxylysergic acid (15), ergono-
vine, chanoclavine 1(7), andN-fonnylloline all were isolated
from Stipa robusta infected with an Acremonium endophyte
(Petroski et al., 1992; Powell and Petruski, 1992).
Lysergic Acid Diethylamide
Lysergic acid diethylamide (LSD = Lysergsiiurediethy-
lamid) (14) was first syuthesized by A. Hoffman in 1943.
This compound, which is not naturally occurting, is well
known for its hallucinogenic effects. These effects are proba-
bly due to an inhibition of a basic brain stem mechanism that
integrates sensory input. LSD apparently occupies serotonin
receptor sites and potentiates noradrenaline systems (Cor-
dell, 1981).
Medicinal Properties
Ergot alkaloids are adrenergic blocking agents. These
compounds also inhibit lactation in animals by inhibition
of prolactin release, a mammalian hormone responsible for
mammary and milk production (Fliickiger, 1980; Stadler and
660 Ergot and Other Indole Alkaloids
Stiitz, 1975). As prolactin is necessary for induction and
growth of certain tumors in mice, ergocryptine (11) and er-
gocornine (12) significantly reduced the size and incidence
of these tumors. Ergometrine (13) and ergotamine (9) are
used as uterine-contracting agents following childbirth.
These uses are based on the well-established vasoconstric-
tion action of these alkaloids. Both are amides of lysergic
acid (Cordell, 1981).
Jivaro women seem to control family size by determining
the time they become pregnant. They do this by ingesting
infusions of Cyperus species at specified times. Women also
use a decoction made from the fungus Balansia cyperi to
aid in parturition or postpartum contractions and to reduce
bleeding following childbirth. In both instances, the presence
of fungi related to ergot may be involved (Lewis, 1992).
Commerdal Production of Ergot Alkaloids
Ergot has been used medicinally since the 1500s. Most
of that used is from cultivated ergot. About 12,000 kg per
year is produced for a total value of about $50 million. Ergot
alkaloids are produced parasitically on rye, in saprophytic
culture (usually with Claviceps paspali), or by partial or
total chemical synthesis.
HARIIIAI'IE OK ~·CAKBOLII'III ALKALOIDS
Alkaloids based on the tetrahydro-f3-carboline system are
not common, but occur in a number of families. Several of
these harmane or f3-carboline alkaloids occur in Peganum
iulrmala (Zygophyllaceae). AIta-ur-Rahman and Basha,
1983.
Heterotrophic cultures of Peganum iulrmala accumulate
about 0.1 % of their dry weight as harmine (16), harmaline
(17), harmol (18), and harmalol (19) (Berlin and Sasse, 1988;
Ellis, 1988).
The results of feeding studies leading to the formation of
harmane alkaloids have been tabulated (Leete, 1983).
Biosynthesis
The formation of harmine (16) is similar to the formation
of pellotine (see Chapter 32), except that a tryptamine pre-
cursor is utilized (Fig. 35.6). Tryptophan has been shown to
be an effective precursor of eleagnine (20) and harmane (21)
in Eleagnus angustifolia and Passiflora edulis. The incorpo-
ration of [f3_ 14C- 1SN]_tryptamine into harmane (21) with
retention of isotopic ratio in Peganum iulrmala (Zygophylla-
ceae) suggests that a three-carbon pyruvate unit undergoes
condensation with tryptamine and subsequent cyclization.
Also, in the formation of eleagnine in Eleagnus angustifolia,
the additional two carbon atoms come from pyruvic acid
(Fig. 35.6). The key intermediate (22) serves as a more effi-
cient precursor than either tryptophan or pyruvic acid (Hus-
son, 1985). However, in Passiflora edulis, N-acetyltrypto-
phan, N-acetyltryptamine, harmalan (23), and
tetrahydroharman are all incorporated into harman. These
results suggest that a second pathway involving N-acetyl-
tryptamine is involved in the formation of harmane alkaloids
(Fig. 35.6).
Distribution of Hannane Alkaloids
Harmane or f3-carboline alkaloids have been reported
throughout the family Rubiaceae (Hemingway and Phil-
lipson, 1980). These alkaloids also occur in the Acanthaceae
(Adhatoda), Apocynaceae (Aspidosperma, Alstonia, Pi-
crasma), Eleagnaceae (Eleagnus), Fabaceae (Petalostylis,
Gastrolobium), Loganiaceae (Strychnos), Malpighiaceae
(Banisteriopsis caapi), Passifloraceae (Passiflora), Ranun-
culaceae (TiullictrumJoetidum), Rutaceae (Murraya, Clau-
seno), Simaroubaceae (Ailanthus), Solanaceae (Vestia), and
Zygophyllaceae (Peganum) (Cordell, 1979; Faini et aI.,
1978; Husson, 1985; Joshi et aI., 1977; Schiff, 1987).
Many of these plants also are known to contain other
alkaloids; reports of f3-carboline alkaloids should be con-
firmed in some cases. Species of Ailanthus also contain can-
thine derivatives (see below) (Cordell et aI., 1978).
BiologiCal Activity
Harmane alkaloids inhibit membrane transport and act at
serotonin receptors (Robinson, 1979). Harmine (16) inhibits
monoamine oxidases and binds to DNA. Harmaline (17)
inhibits (Na+,K+)-ATPase, Na+ transport, and monoamine
oxidase (Wink, 1993).
Alkaloids of this type are responsible for the hallucino-
genic activity of a number of plants. Among these are Pega-
num harmala (Zygophyllaceae) and Banisteriopsis caapi or
(ayahuasca or yage) (Malpighiaceae), a plant used as a hallu-
cinogenic drink by Indians in Amazonian and Andean South
America. At oral doses of 4 mg/kg, harmaline (17) produces
psychotomimetic activity in humans. High intravenous doses
of harmine (16) also produce hallucinogenic effects (Neuss,
1980); harmine has an LDso i.v. in mouse of 38 mglkg
(Wink, 1993). The seeds of Peganum iulrmala are 2-3%
alkaloids. Certain alkaloids of this group have pronounced
hypotensive activity (Husson, 1985; Nuess, 1980).
Harmine (16), harmol (18), and harmaline (17) are active
against the epimastigotes of Trypanosoma cruzi at 1.9-5
fl.g/ml (Borris and Schaeffer, 1992; Phillipson and Wright,
1991). Harmaline (17) shows activity against Leishmania
mexicana amazonensis at 24 fl.g/ml, whereas 6-methoxy-N-
methyl-l,2,3,4-tetrahydro-f3-carboline (24) from Nectandra
megapotamica (Lauraceae) inhibits the growth of Crithidia
Jasciculata. 4-Methoxy-I-vinyl-f3-carboline (25) and the
corresponding 6-hydroxy derivative (26) from Picrasmia ja-
vanica (Simaroubaceae) inhibit multidrug-resistantPlasmo-
dium Jalciparum in vitro (Fig. 35.7) (Borris and Schaeffer,
1992).
Harmaline (17), harman (21), norharman (27), and har-
mine (16) elicit phototoxicity in larvae of Trichoplusia (Lep-
idoptera), and serve as feeding deterrents to larvae of the
 Ergo/ and Other Indole Alkaloids 661

~H:­
~N) ~
~-
~~)'\~~
I 'CO,H

(Ir-llH
~NH")<:'
s:cY
"""
-- (In()HI
NH
I
0
N
~NHI'

e:y""
CO2"
(22) eleagnine (20)
/ harmalan (23)

I I N
CH,-O """ NH 0

harmine (16)

Fig. 35.6. Biogenesis of harrnane.

CH,-O
N=:C? ~
I

harmaline (17)
NH
I
h
N

harman (21)
Q:O
~
I NH
I
~
N

norharman (27)
h

~
~
~
I I N I I N
HO ~ NH h HO ~ NH h

harmol (18) harmalol (19)

OCH,
CH,-O
CH'-On9 n
4 ;, ?'

7 ~
I NH
I N'
'CH
~
8 1 '

6~methoxy-N-methyl-l,2,3,4- 4-methoxy-l-vinyl- 6-methoxy-l-vinyl-

tetrahydroxy-p-carboline (24) p -carboline (25) p-carboline (26)

Fig. 35.7. Biologically active hannane alkaloids.

662 Ergot and Other Indole Alkaloids

borreverine (29) isoborreverine borrerine (28)

Fig. 35.8. Borrerrine and related compounds (modified from Saxton. 1981; used with pennission of the copyright owner. the Royal Chemical Society,
Cambridge).

polyphagous lepidopteran Syntomis (Wink, 1993). Both har-
mine (16) and harmalol (19) are reputed to bind to insect
synapses (Wink, 1993).
BiosyntbeticaUy Related AIkaloids
Borrerine (28), a compound probably analogous in syn-
thesis to lophocereine but belonging to the (3-carboline series
of alkaloids, has been found in Borreria verticil/ata (Rubia-
ceae), along with a dimeric compound borreverine (29) (Fig.
35.8). This alkaloid has also been found in Flindersia four-
nieri (Rutaceae) (Cordell and Saxton, 1981; Saxton, 1981).
CAl'I11UN·6·0NE Al'ID RELATED ALKALOIDS
Canthin-6-one (30) and a series of related alkaloids are found
in one species of Pentaceras, several species of Zanthoxylum
(Rutaceae), and several species of the Simaroubaceae (Fig.
35.9) (Waterman and Khalid, 1981). These alkaloids also
have been reported from the Malvaceae, Caryophyllaceae,
and Amaranthaceae (Tillequin, 1993). Similar compounds
occur in the Leitoeriaceae (K. Readel and D. Seigler, unpub-
lished data).
Some of the plants that contain canthin-6-one (30) and
its relatives are used medicinally. I-Methoxycanthin-6-one
(31) is found in Hannoa klaineana (Simaroubaceae) roots.
This plant is used to treat fever and intestinal diseases in
Zaire (Lumonadio and Vanhaelen, 1984). Brucea javanica
is used to treat malaria and dysentery as well as being an
insecticide. Another simaroubaceous plant, Eurycoma longi-
folia, also is used to treat dysentery, glandular swelling, per-
sistent fever, and tertian malaria (Kardono et al., 1991). The
major alkaloids of this plant were 9-methoxycanthin-6-one
(32), 9-hydroxycanthin-6-one, and the corresponding N-ox-
ides (Kardono et al., 1991). The canthin-6-one derivatives
were active against both KB and P-388 cell lines (Kardono
et al., 1991).
Cultores of Ailanthus altissima and Brucea javanica pro-
duced canthin-6-one (30) and 1-methoxycanthin-6-one (31)
as well as a number of minor, related alkaloids (Ellis, 1988;
Liu et al., 1990).
1-Methoxycanthin-6-one (31), lO-hydroxycanthin-6-one
(33), and lO-methoxycanthin-6-one are cytoxic against car-

'59"
""
I
o
N
I
.&
-<
N

'59
""
1

o
N
IO~:'
.&
-<

canthinoo6..one (30) I-methoxycanthin-6-one (31)

CH,-O
~"" ""
1

o
N
1

.&
-<
N

10-hydroxycanthin-6-one (33) 9-methoxycanthin-6-one (32)

Fig. 35.9_ Canthin-6-one and related alkaloids.

 Ergot and Other Indole Alkaloids 663

"'" 000"'"
CCJY
OH

:::,...
I NH
I ~:::,...
I I ~
OCH, NH

1·methoxy·3·hydroxymethylcarbazole (37) girinimhin (34) 3-methylcarbazole (36) carbazole (35)

(koenoline)

Fig. 35.10. Carbazole alkaloids.

cinoma of the nasopharynx (KB) (Liu et al., 1990; Wink, ity (Chakraborty and Roy, 1991). Oxidative demethylation
1993). also appears to occur.
Koenoline (l-methoxy-3-hydroxymethylcarbazole) (37)
has been isolated from the root bark of Murraya koenigii, a
tree widely used in India to flavor foodstuffs (Fiebig et aI.,
CARBAZOLE ALKALOIDS 1985). This alkaloid has cytotoxic activity toward KB cells.

Carbazole alkaloids are found in the genera Clausena, Gly-

cosmis, Micromelum, and Murraya of the Rutaceae. There
is a single report from the genus Ekebergia of the Meliaceae
(Bhattacharyya and Chakraborty, 1987; Chakraborty and
Roy, 1991).
Girinimbin (34) (Fig. 35.10) is a common alkaloid in
several species of Murraya sect. Bergera (Kong et al.,
1988a). The distribution of these alkaloids and 3-prenylin-
doles and 8-prenylated coumarins strongly supports division
of this group into two genera, Murraya and Bergera (Kong
et al., 1986, 1988a,b) (see Chapter 31).
The isolation of several 3-methylcarbazole derivatives
from higher plants and the isolation of carbazole (35) shows
that the aromatic methyl group can be eliminated from the
key compound 3-methylcarbazole (36) via oxidation to the
alcohol, the aldehyde, and, subsequently, the acid functional-
ALKALOIDS OF P/lYSOSTIG/I1A VEl'IElYOSUM
The calabar bean (the seed of Physostigma venenosum, Fa-
baceae) was formerly used for "trial by ordeal" in Eastern
Nigeria in an area known as the Calabar Coast (Holmstedt,
1972). By this method, the guilt or innocence of the accused
is determined by whether that person survives after ingesting
extracts or concoctions prepared from the plant. The seeds
of the calabar bean contain a number of indole alkaloids
derived from tryptamine and S-adenosyl methionine. A con-
certed ring closure and nucleophilic attack on S-adenosyl-
methionine appears reasonable, but neither this mechanism
nor the origin of the carbamate group have been well studied
(Fig. 35.11).
Physostigmine (38), with a pyrrolo[2,3b lindole system,

(O~CH'_S'-

I I NH
/ ~ NV 2

(Jc)'1:
CH3
C02H
CH'NHCO-O~

I I NH
~ NH 2
~NAN)
I I
tryptophan CH] CH]

(O~ (o~CH3/ physostigmine (38)

/ U~) NH
~H2--
~
I
NHNH

Fig. 35.11. Biogenesis of physostigmine (modified from Geissman and Crout, 1969),
664 Ergot and Other Indole Alkaloids

the principal active ingredient from the seed of Physostigma
venenosum, Fabaceae, is a reversible cholinesterase inhibitor
used in the treatment of glaucoma. It is employed in ophthal-
mology after administration of atropine to return the pupil to
its normal size (Neuss, 1980; Tillequin, 1993). This alkaloid
causes accumulation of acetylcholine and continuous stimu-
lation of the cholinergic receptors. As is true for most other
cholinesterase inhibitors, physostigmine also stimulates se-
cretions such as saliva and perspiration and increases tone
and peristalsis of the gastrointestinal tract (Cordell, 1981).
Physostigmine has an oral LOs. in mouse of 4.5 mg/kg
(Wink,1993).
Physostigmine is a feeding deterrent to polyphagous Syn-
tomis larvae (Wink, 1993).
Somewhat similar alkaloids have been isolated from skin
secretions of Australian frogs (~aly et al., 1990).
ALKALOIDS OF THE CALYCAm1IACEAE
A number of highly complex, multinuclear indole alkaloids
(indolenines) are found in the family Calycanthaceae (Ca/y-
canthus and Chimonanthus) (Cordell and Saxton, 1981).
This family is closely related to several benzylisoquinoline-
alkaloid-producing families, but lacks the characteristic al-
kaloids of that group (see Chapter 32). Similar compounds
have been found subsequently in the genera Bhesa (Celastra-
ceae) and Palicourea (Rubiaceae). Both calycanthioe (39)

O:::():
I I
CO.H

QJ()HCH~ ~-
7

~N~ NHCH,
~ NH.~
NH

tryptophan

calycantbine (39)

ofI})
CH,
I H

",... HN i N
HI
CH,
meso-chimonanthine meso-calycanthine
Fig. 35.12. Biogenesis of Calycantbaceae alkaloids (modified from Geissman and Crout, 1969),
 Ergot and Other Indole Alkaloids 665

CH, CH,

NNI:
~
,... I """'--_L-_
N N
CH, CH,
folicanlhine (40) qnadrigemine B quadrigemine A (42)
(+ diastereomer)

psycholridine (11)
hodgkinsine (41)
Fig. 35.13. Complex oligomers of tryptophan-derived precursors.

and chimonanthine also occur in Palicourea lentileri (Fig.
35.12) (Hemingway and Phillipson, 1980).
Labeled tryptophan is incorporated into calycanthine (39)
and folicanthine (40) in Calycanthus florida (Cordell and
Saxton, 1981).
POLYIl'IDOLENIl'IES
Alkaloids similar to those of the Calycanthaceae have been
found in several other plants. Hodgkinsoniafrutescens (Rub-
iaceae) contains such compounds as hodgkinsine (41), in
which three tryptophan units are involved, and quadrigemi-
nine A (42). The latter contains four tryptophan units linked
into a tetrameric structure (Fig. 35.13). Psychotridine (43),
the major alkaloid of Psychotria beccarioides, is a pentamer
based on similar precursors (Cordell and Saxton, 1981). In
addition to the simple harman-type alkaloids, species of the
genus Borreria (Rubiaceae) also contain dimeric forms of
tryptamine-derived alkaloids (Hemingway and Phillipson,
1980).

OCH,
~10Wo
olf "
melosatin A (44) melosatin B (45) cryptolepine (47)

trichotomine (46) trichotomine G.

Fig. 35.14. Miscellaneous indole alkaloids.

666 Ergot and Other Indole Alkaloids
Ol1IER ALKALOIDS WITH Il'IDOLE SKELETA
Melochia tomentosa, a tumorigenic plant of the Sterculia-
ceae, has been shown to contain the alkaloids melosatin A
and B (44, 45) that contain an indole nucleus and are quite
unusual in structure (Kapadia et al., 1977).
The bright blue color of fruits of Clerodendron trichoto-
mum (Verbenaceae) is due to the presence of bisindole alka-
loids such as trichotomine (46). The blue color of these alka-
loids is uncommonly encountered in nature (Fig. 35.14)
(Cordell and Saxton, 1981).
Cryptolepine (47) from the roots of Cryptolepis sanguin-
olenta (Asciepiadaceae), is highly active against Plasmo-
dium Jalciparum. The in vitro IC50 value for this alkaloid
is 0.03 11g!m1, compared to 0.07 l1g!ml for chloroquine, a
common antimalarial drug (phillipson et al., 1993). Extracts
of the roots of the plant also are used to treat patients in
some Southeast Asian countries.
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36
Alkaloids of Terpenoid Origin
(excepting indole alkaloids and ergot
alkaloids)

Introduction cally arise via the pathways leading to the various groups
Monoterpenoid Alkaloids of terpenes.
Biological Activity Some do not consider these compounds to be alkaloids,
Medical Uses of Monoterpenoid Alkaloids but prefer to call them "pseudoalkaloids" (Hegnauer, 1964;
Sesquiterpenoid Alkaloids Roddick, 1980). Many of these compounds are related
Dendrobium Alkaloids closely to non-uitrogenous plant metabolites, and, biosyn-
Nuphar and Castor Alkaloids thetically, are more related to those groups of terpenes from
Alkaloids of the Celastraceae and Hippocrateaceae which they are derived than to many groups of alkaloids
Khat (Gross et al., 1985). However, because of the many proper-
Miscellaneous Types of Sesquiterpenoid Alkaloids ties they share with other alkaloids, such a distinction will
Diterpenoid Alkaloids not be followed in this work.
Diterpenoid Alkaloids Derived from Kaurene Many spectral data for terpene-derived alkaloids have
Alkaloids from the Garryaceae been reviewed (Pelletier and Mody, 1979, 1981). Both the
Alkaloids of Delphinium and Aconitum 'H- and I3C-NMR spectra for several diterpene alkaloids
Erythrophleum Alkaloids have been discussed (Crabb, 1982). The results of feeding
Taxus Alkaloids studies leading to the synthesis of several alkaloids of this
Steroid and Triterpenoid Alkaloids group have been tabulated (Leete, 1983).
Solanum Alkaloids
Biosynthesis
Biological Activity of Solanum Alkaloids MONOTERPENOID ALKALOIDS
Solanum Alkaloids in Potatoes
Teratogenic Properties A number of important alkaloids are derived from several
Veratrum Alkaloids structural types of monoterpenes. Some involve substitution
Biosynthesis of nitrogen into ordinary monoterpene structures. Among
Biological Activity these compounds are simple monoterpene alkaloids in which
Steroidal Alkaloids in the Apocynaceae uitrogen is added to an existing monoterpene and more com-
Buxus Alkaloids plex structures, in which secologanin serves as a carbonyl
Daphniphy//um Alkaloids compound much as do the precursors for isoquinoline and
References benzylisoquinoline alkaloids. Alkaloids involving condensa-
tion of secologanin and tryptamine units are treated in Chap-
ter 34; those involving condensation of secologanin and tyra-
mine-derived units are included in Chapter 32. For
INTRODUCTION information concerning the precursor secologanin, the reader
should consult Chapters 19 and 20.
A large number of alkaloids are based on terpenoid struc- Both the 'H- and I3C_NMR spectra for several of the
tures. In most instances, the source of the nitrogen is not groups of alkaloids presented below have been reviewed
established, but the remaining portions of the molecule typi- (Crabb, 1982).

668
 Alkaloids of Telpenoid Origin 669

A number of alkaloids are known in which nitrogen is
incorporated into monoterpenes. The source of the nitrogen
is not known. These alkaloids possess relatively simple
structures. Several common alkaloids of this type are derived
from secologanin (1) or other monoterpenoid precursors by
condensation with ammonia (either on workup or, perhaps,
in the plant itself). Others are derived from loganin (2), seco-
loganin, or other precursors by largely unknown reactions
(Mann, 1987). Several monoterpene alkaloids are thought
to be artifacts of isolation. For example, gentianine (3), bud-
damine (4), and cantleyine (5) often are not found in the
original plant materials when these are carefully investigated
(Fig. 36.1). Gentiopicroside (6) probably is the usual precur-
sor of gentianine (Cordell, 1981; Fodor and Colasanti, 1985).
Aucubin (7) is likely the precursor of buddamine (Stermitz
and Harris, 1985).
The biosynthesis of simple monoterpenes has not been
studied extensively. Acetate, mevalonate, and geranylpyro-
phosphate are incorporated into actinidine. However, neither
loganin (2) nor actinidine (8) serves as a precursor for 13-
skytanthine (9) or its derivatives in Tecoma stans (Bigno-
niaceae) (Fig. 36.2). These compounds appear to be derived
from an intermediate preceding loganin in the biosynthetic
pathway.
Both loganin and loganic acid are incorporated into genti-
opicroside (6) (a monoterpenoid compound, but not an alka-
loid), the proposed precursor of gentianine.
8iological Activity
Flowers of Penstemon whippleanus (Scrophulariaceae)
serve as a host for the plume moth, Amblyptilia (Platyptilia)
mica. These flowers contain (+ )-boschniakine (10) and
other iridoid-monoterpene-derived alkaloids (McCoy and
Stermitz, 1983). Another host of this moth, Castilleja rhexi-
folia (Scrophulariaceae) contains rhexifoline (11), an iridoid
monoterpene alkaloid, as the major alkaloid of the seeds and
flowers. The moths and adults of the insect contain rhexifo-
line (Roby and Stermitz, 1984). Rhexifoline (11) also can
arise in some instances from the presence of ammonia in
workup from penstemonoside, but this possibility was spe-
cifically precluded in this study by use of bicarbonate in
place of ammonia in the workup.
Actinidine (8) is found in the defensive secretion of the
Australian cocktail ant, lridomyrmex nitidiceps (Fodor and
Colasanti, 1985). This compound is alleged to be attractive
to cats.
Medical Uses of Monoterpenoid AIkaloids
There has been much interest in gentianaceous plants be-
cause of their widespread use in folk medicine in Europe.

R
~ r-gIUCOSYI

- o~
. 0
NH,
,;? .&

N
o 0

gentianine (3)

a-
gentiopicroside (6)

W
OH
··,OCH'
f'
NH

"--0
\ i
HO
N

buddamine (4) cantleyine (5)

CH,O,C
o ':::H
~
H'···
:::,..
"'O~o~ OH
oHO~

secologanin (1)
HO
OH

'ow"' O-glucosyl

Joganin (2)

Fig. 36.1. Fonnation of simple monoterpenoid alkaloids.

670 Alkaloids of Terpenoid Origin

{]-- N
,>(11.<, N
I
'8- N
I
CH, CH,
actinidine (8) tecostidine hydroxyskytanthlne-n p-skytanthine (9)

~ ·X2:c
o -"H
OHC, ) : ' ) - - CH,O.C

'C.J N
I P'

""
H

w-·.· --
N

(+)-bosehniakine (10) rhexlfoline (11) gentionavine

H0Y'il
W
CHO
~
CHO HODJ"'N+
I
tr I an alkaloid of
Vakrlartllo!Ji<lrtIllls
(12)

"'"
NH
,

Fig. 36.2. Some representative monoterpene alkaloids.

At the beginning of the 1900s, at least 20 Gentiana spp. were
commonly used. Gentianine (3), a widely studied alkaloid, is
not particularly toxic and, in low doses, exhibits a central
nervous system stimulant action. Gentianine also exerts hy-
potensive, anti-inflammatory, and muscular relaxant actions.
The reputed tonic effects of gentian are probably due to the
hypotensive and muscle relaxant actions.
Valeriana officinalis is used widely in Europe as a seda-
tive. ill addition to iridoid monoterpenes, this plant contains
several monoterpenoid alkaloids, such as (12).
Sesquiterpenoid Alkaloids
Several classes of sesquiterpene alkaloids have been re-
ported; these do not appear to be closely related biosyntheti-
cally. Important among these alkaloids are those of Nuphar
and Dendrobium (Orchidaceae), and the Celastraceae and
Hippocrateaceae. About 130 sesquiterpene alkaloids are
known (Verpoorte et al., 1991).
Dendrobium Alkaloids
The genus Dendrobium (about 1200 species) is the largest
genus of the family Orchidaceae [the largest plant family,
with 20-25,000 species (Dressler, 1981»). Many of these
species contain alkaloids and some contain sesquiterpene
picrotoxins (see Chapter 21). A Chinese drug "Chin-Shih-
Hu," derived from the orchid Dendrobium nobile, is used
as a tonic (Cordell, 1981). The principal alkaloid of this
drug is dendrobine (13) (Fig. 36.3). This alkaloid is from a
cadalane skeleton, involving copaborneol (14), in a similar
manner to tutin and coriamyrtin (see Chapter 21). All three
parts of the molecule were labeled almost equally by mevalo-
nate.
Dendrobine (13) lowers blood pressure and has weak an-
tipyretic and analgesic action. This alkaloid modulates gly-
cine neurochemical activity (Wink, 1993).
lfupbar and Castor Alkaloids
The rhizomes of Nuphar japonicum and N. luteum
(Nymphaeaceae) contain sesquiterpene-derived alkaloids
that possess a quinolizidine nucleus (Howard and Michael,
1986). These compounds are based on a CIS skeleton of
which part has been elaborated into a 3-substituted furan
(Howard and Michael, 1986) (Fig. 36.4).
The original structure of ( - )-deoxynupharidine (IS) was
not correct and much of the earlier literature concerning
these alkaloids contains erroneous structures. The compound
has a IR,4R,7R,9aR configuration, as indicated in Fig. 36.4
(Howard and Michael, 1986). Similar alkaloids have been
isolated from the scent glands of the Canadian beaver, Cas-
tor fiber (Fig. 36.4). The oil of this gland or castoreum is
used as a fixative in the perfumery industry. (- )-Deoxynu-
pharidine (IS) is one of the components of the complex mix-
ture of compounds found in this oil. Although it is not clear,
 T
T -- ~ T
T

TT
TT
# --
T

T
pT T
Alkaloids of Terpenoid Origin

#
__
671

T
from 4- 14C_mevalonate
T from S.lHz-mevalonate

copaborneol (14)
dendrobine (13)

FIg. 36.3. Biogenesis of dendrobine (modified from Cordell, 1981; used with permission of the author).

the beaver probably obtains the alkaloids from food plants
of the genus Nuphar (Howard and Michael, 1986).
Alkaloids of the Celastraceae
and Hippocrateaceae
Although members of the Celastraceae have been known
to contain aIkaIoids for at least 40 years, these compounds
have not been extensively stndied until comparatively re-
cently. These alkaloids most commonly occur in the seeds
of Euonymus europaeus, Tripterygium wilfordii, and in
leaves of khat, Catha edulis (16-20) (Fig. 36.5).
A series of sesquiterpene evoninoate alkaloids have been
isolated from the liana Hippocratea excelsa (Hippo-
crateaceae) from Mexico (Mata, 1993; Mata et aI., 1990).
This plant, called "cancerina," is used medicinally to treat
skin ailments and for its pesticidal properties. The main alka-
loid, hippocrateine I (21), was cytotoxic in the 9 PS system
(EDso 1.85 X 10- 1 flog/mI) (Mata et aI., 1990). This plant
also contains small amounts of the antitnmor triterpene
tingenone (see Chapter 23).
The presence of complex sesquiterpenoid alkaloids in
both the Celastraceae and Hippocrateaceae confirms the
close relationship between these families.

Khat
(+)-nupbaridine (-)-deoxynupharidine (15) Sesquiterpenoid alkaloids similar to those of other celas-
"traceous plants occur in leaves of khat (Brenneisen and El-
Sohly, 1992; Crombie, 1980) but do not appear to be respon-
sible for the effect of chewing fresh khat (Szendrei, 1980).
The active compound is a simple amine, cathinone (see
Chapter 28). A series of complex sesquiterpenoid cathedulin
aIkaIoids has been characterized from khat (Crombie et aI.,
1990).

Jlliscellaneous Types of Sesquiterpenoid

Alkaloids
castoramine l-epideoxynupharidine
Other sesquiterpenoid aIkaIoids are found in Fabiana im-
Fig. 36.4. Alkaloids from Nuphar and Castor. bricata (Solanaceae) [fabianine (22)] and in Pogostemon pa-
672 Alkaloids of Terpenoid Origin

OAc 0

,.o~ oA
OAc 0

Ac.o~O\Acr
O~
~, N
rn,

0
HO
OH
o
OAc OAc 0\Jy~
I 0,.,
"
(:~c
..
maytoline (16)

(OAC
:'('" % :~Ok
/ hippocraleineI(21) ~)
A.,.o~O\AC!
lAC 0 HO 10H 0 OAc

:~ ~
~.

o 0 0
o
01.0 OAc
o 0 OH CH,OH ~O
evoninol (18) I "" H

N H OH
evonine (19)
evoninic acid (20) 0

Fig. 36.S. Sesquiterpene alkaloids from the Celastraceae.

tchouli (Lamiaceae) [epiguaipyridine (23)] (Fig. 36.6). Other DlTBKPEI'IOID ALKALOIDS

sesquiterpene alkaloids from Gaillardia pulchella (As-
teraceae) [pulchellidine (24), neopulchellidine (25), and pul- Several types of aIka10ids are based on diterpenoid struc-
chellin (26) (Fig. 36.6)] have anti-inflammatory activity tures. Chief among these are aIka10ids derived from kaurene,
(Strunz and Findlay, 1985). those ultimately derived from macrocycIic precursors, and

H9JJOH
, 0

~.",O 0
HO~H
OHO
• H °
!
OH
H

pulcheJlidine (24)

~
neopuIchellidine (25) u1cheJlin(26)

17,

~ ~I
"'-N

N 'H

OH

epigualpyridine (23) fabianine (22)

Fig. 36.6. Some miscellaneous types of sesquiterpene alkaloids and pulchellin.


diterpene 19-carboxylic acid derivatives (Benn, 1993).
About 640 diterpene alkaloids are known (Verpoorte et aI.,
1991).
Diterpenoid Alkaloids Derived
from Kaurene
Oiterpene alkaloids derived from kaurene are known
from several families. These compounds are found in the
Ranunculaceae (Aconitum and Delphinium), Garryaceae
(Garrya), Asteraceae (Inula royaleana), Escalloniaceae
(Anopterus), and Rosaceae (Spiraeajaponica) (Benn, 1993;
Pelletier, 1992). In contrast to many other types of alkaloids,
these diterpenoid alkaloids do not have a pronounced bitter
taste. Many (especially the aconitines) produce a tingling
sensation on the tongue, but in view of the extreme toxicity
of diterpene alkaloids, tasting these compounds is not recom-
mended. Two to five milligrams of several C l9 diterpene
esters is sufficient to be lethal in humans; aconitine (27)
and pseudoaconitine (28) are highly toxic to man (Cordell,
1981). Aconitine has an L0 50 i.v. in mouse of 0.17 mg/kg
(Wink, 1993). Plant material containing alkaloids from Del-
phinium, Aconitum (Ranunculaceae), and Spiraea (Rosa-
ceae) have been used in Chinese traditional medicine (Han
et aI., 1988). Aconitine (27) also inhibits growth of the radi-
cle in Lepidium seedlings (Wink, 1993).
Four basic skeletal types of kaurene-derived diterpene
alkaloids are known: the atisine, heteratisine, Iycoctonine,
and veatchine types.
Alkaloids from the Garryaceae
A number of species of the genus Garrya, the only genus
of the family Garryaceae, contain relatively simple diter-
(+kaurene (30) veatcbine (29)
aconitine (27)
Fig. 36.7.
Alkaloids of Terpenoid Origin 673
pene-derived alkaloids. The family of plants is found primar-
ily in the southwestern United States and Mexico. The veat-
chine (29) skeleton of Garrya alkaloids incorporates a
kaurene (30) skeleton without rearrangement (Fig. 36.7)
(Geissman and Crout, 1969). Two of the principal alkaloids
of these plants, garryine (31) and veatchine (29), are known
to be toxic. The LOso of veatchine hydrochloride in mice is
12.5 mg/kg.
Alkaloids of Delphinium and Aconitum
Plants of the genera Delphinium and Aconitum have long
been recognized as poisonous (Cutler, 1992). Extracts of the
roots and leaves of Aconitum species were used in ancient
times as poisons, but also for treatment of illnesses such as
neuralgia, hypertension, gout, and rheumatism. In the past,
preparations of Delpinium and Aconitum also have been used
medicinally as cardiotonics, febrifuges, sedatives, and ano-
dynes (Benn, 1993; Benn and Jacyno, 1983). Alkaloids of
both genera have been used in Chinese traditional medicine
(Han et al., 1988). Arrow poisons made from Aconitum spe-
cies formerly were used by the inhabitants of Hokkaido and,
possibly, still are used by other peoples of Siberia and
Alaska. The active ingredients of these arrow poisons are a
series of diterpene alkaloids (Bisset, 1976). Aconitum spe-
cies were used in Europe for trial by ordeal.
Two main structural types of diterpene alkaloids are
found in these genera. One group includes a series of com-
paratively simple and relatively nontoxic amino alcohols and
esters modeled on a Czo skeleton. These alkaloids are not
extensively oxygenated and contain, at most, one methoxyl
&9r o
garryine (31)
pseudaconitine (28)
Kaurene and veatchine.
674 Alkaloids ofTerpenoid Origin
group. Most of these alkaloids possess a veatchine (29) or
an atisine (32) skeleton (Fig. 36.8).
The second group is based on a C 19 , instead of a C20
skeleton. Compounds of this group are usually of an aconi-
tine (27) or Iycoctonine (33) structural type (Fig. 36.8).
These compounds are more heavily substituted than those of
the C20 series, and, usually, two of the alcohols are esterified,
typically one with acetic acid, and the other with an aromatic
acid, such as benzoic or veratric acid. Lycoctonine (33) has
an LOs. i.p. in mouse of 350 mglkg (Wink, 1993).
Of these C 19 esterified alkaloids, most attention has been
paid to aconitine (27), the best known compound, because
it is extremely poisonous. One must regard many early re-
ports with caution, however, as aconitine is extremely diffi-
cult to isolate and purify. Subcutaneous administration of
aconitine hydrobromide to cats produced bradycardia.
12
veatcbine skeleton
18
atisine (32)
OH
aconitine (27)
Fig.36.8. Veatchine and atisine skeletons; aconitine and lycoctonine.
Larger doses produced tachycardia and pronounced cardiac
irregularities, finally culminating in cardiac arrest. Respira-
tory failure appeared to precede heart failure (Benn and Ja-
cyno, 1983). Electrophysiological studies have shown that
aconitine prolongs depolarization after stimulation of a nerve
and that this depolarization is blocked by tetrodotoxin. Thus,
aconitine (27) appears to bind to the nerve-cell membrane
in such a way as to prevent nonnal closing of sodium chan-
nels (Benn and Jacyno, 1983). The LOs. of aconitine (27)
in rabbits is 0.04-0.5 mg/k:g.
A second alkaloid, mesaconitine (34), also is widely dis-
tributed in this group of plants, and predominates in some
Aconitum species. It has similar properties to aconitine. Mes-
aconitine (34) has an LOso s.c. in mouse of 0.2 mg/kg (Wink,
1993).
Removal of the 8-acetate group of aconitine produces a
12
17
18
atisine skeJeton
17
Iyeoctonine (33)

OH
aronine (36)
OH
mesaconine (37)
OH
HO
mesaconitine (34)
Fig. 36.9. Aconine, benzaconine, and mesacorune.
compound, benzaconine (35), about 300 times less active
than aconitine (27) (Fig. 36.9). Mesaconine (37) also belongs
to this series.
Complete saponification of aconitine produces an alkan-
olamine, aconine (36), that lacks the cardiac effects of aconi-
tine but has antiarrhythmic properties. The compound has
curare-like effects on neuromuscular transmission, often re-
sulting in death from respiratory paralysis (Benn and Jacyno,
1983).
Methyllycaconitine (38) occurs in numerous Delphinium
species. The hydroiodide of this alkaloid shows curare-like
properties greater than those of aconitine (27) or mesaconi-
tine (34). This compound is a potent, nondepolarizing neuro-
muscular poison, acting as a competitive inhibitor of acetyl-
choline at nicotinic receptors in the same way as
tobocurarine (Benn and Jacyno, 1983). Methyllycaconitine
(38) has an LDsoi.v. in mouseof5-18 mg/kg (Wink, 1993).
Alkaloids o/Terpenoid Origin 675
~,"_ _ ."OCH3
OCH3
,
, OH
~,-{5o methyllycaconitine (38)
OH
As observed above, two types of activity, sometimes
called aconitiform and curariform activity, are involved.
These compounds appear to exhibit neurotoxicity by inter-
acting with membranes in such a way as to hold sodium
channels open, following an action potential, so that pro-
longed depolarization results. This activity is similar to that
of other natorallipophilic neurotoxins such as batrachotoxin
(a steroidal alkaloid), veratrldine (a steroidal alkaloid), and
grayanotoxin I (a nonalkaloidal diterpene). All four seem to
act at the same receptor site. As grayanotoxin I is not an
alkaloid, it has been suggested that the nitrogen may not be
a necessary structural featore for this type of activity. Also,
as previously mentioned, the ester function of these com-
pounds is very important for activity. These ester groups
may play a role in the orientation of the molecules on the
receptor site (Benn and Jacyno, 1983).
Inspection of models indicates that methyllycaconitine
676 Alkaloids of Terpenoid Origin
(38) closely resembles ( + )-tubocurarine with regards to the
disposition of many nitrogen and oxygen atoms and would
fit the "curariform" template (Benn and Jacyno, 1983).
Erythropbleum Alkaloids
Species of the genus Erythrophleum (Fabaceae: Caesal-
pinioideae) are often highly toxic. As few as two leaves
of Erythrophleum chlorostachys, a plant native to northern
Australia, have been reported to be poisonous to a goat and
have produced poisoning of goats, sheep, horses, and cattle.
In Africa, Erythrophleum guineense has been used as a trial-
by-ordeal plant.
Many species of this genus contain N-alkylarninoethyl
esters of diterpene 19-carboxylic acids that possess cardiac
activity similar to digitalis glycosides [such as cassaine
(39)]. Many of these alkaloids display potent cytotoxic activ-
ity (Fig. 36.10) (Suffness and Cordell, 1985).
Erythrophleum alkaloids have cardiac activity (they in-
crease contractile strength) and a very strong local anesthetic
action. Although the latter action is more potent than co-
caine, it is accompanied by intense irtitation at the site of
admirtistration. Cassaine (39) inhibits (Na+, K+)-A TPase
(Wink, 1993). When the double bond is saturated, almost all
biological activity disappears. Erythrophleum bark is used as
a cancer remedy in Africa (Suffness and Cordell, 1985).
OCH,CH,N(CH,),
HO
~:-~'
~ rn,"/rn'd"" !: O~o
H ~o
o
HOP'
o i
HO OH
taxine B (41
~JtMo-~
'T ~O
cephalomannine (43)
Fig. 36.10. Cassaine. taxine I and n, and taxol.
Taxus Alkaloids
Yews (Taxus spp., Taxaceae) produce a series of alka-
loids such as spicataxine (40) and taxine-B (41) that are
highly toxic (Blechert and Guenard, 1990) (Fig. 36.10). Be-
cause of interest in taxol (42), the alkaloid chemistry of most
Taxus species and Austrotaxus spicata has now been investi-
gated (Blechert and Guenard, 1990).
Taxus alkaloids are derived from macrocyclic diterpenoid
precursors. These diterpenes are derived from macrocyclic
precursors (Blechert and Guenard, 1990) (see Chapter 22).
Four major structural types of Taxus diterpenes exist (Fig.
36.11).
Taxine I and II are extremely toxic. This activity may
arise because these alkaloids are effective calcium antago-
nists (Blechert and Guenard, 1990).
Taxol (42) is highly cytotoxic and has broad antitumor
activity. This alkaloid acts by a mechanism different than
any other antitumor drug. At concentrations completely in-
hibitory to cell division, taxol had no significant effects on
DNA, RNA, or protein synthesis, but BeLa cells were
blocked in late G 2 and/or M phase. In contrast to other anti-
mitotic agents such as colchicine, maytansine, vincristine,
or podophyllotoxin, taxol (42) was found to promote assem-
bly of calf-brain microtubules, and the microtubules so pro-
duced were resistant to depolymerization by cold or CaC!,.
ODO
spicataxine (40)
l,-o
H OCOCH,
»~
I I
OH OCOCH,
OCOC,Hs
~
taxol (42)
OCOCH,
OH
HO !
OCOC,Hs
OCOCH
3

~ OPP
Fig. 36.11. Four major structural types of Taxus diterpenes (Blechert and Guenard, 1990; modified and used with peImission of the copyright owner,
Academic Press, Orlando, FL).
This is a unique mode for mitotic inhibitors (Suffness and
Cordell, 1985). Two major problems are involved, however.
The compound has extremely low solubility and occurs in
very low yields in the plant (Suffness and Cordell, 1985).
Although the most common source of taxol is Taxus brev-
ifolia, this alkaloid, as well as related alkaloids, is encoun-
tered in the needles of several species of Taxus (Witherup
et al., 1990).
Another family of gymnospermous plants that often has
been considered closely related, the Cephalotaxaceae, do not
contain taxine alkaloids, but contain other structural types,
including homoerythrina alkaloids (see Chapter 33).
The alkaloid cephalomannine (43) has been isolated from
Taxus wallichiana (the compound name reflects the fact that
plant source was originally considered to be a Cephalotaxus
species) (Miller et aI., 1981; Powell et al., 1979). This alka-
loid has antitumor activity in KB cell lines.
smROID AND TKITEKPEI'IOID ALKALOIDS
At least 450 steroid and triterpenoid alkaloids have been
reported (Verpoorte et al., 1991). Most steroidal alkaloids
occur in a relatively small number of genera (Cestrum, Cy-
phomandra, Lycopersicon, Nicotiana, and Solanum) of the
family Solanaceae and of the family Liliaceae (Fritillaria,
Veratrum, and Zygadenus). Related alkaloids are known
from the Apocynaceae (Funtumia, Holarrhena, and Ma-
louetia) and Buxaceae. Alkaloids based on triterpenoid
structures are much less common. Probably the best known
ones are found in plants of the Buxaceae (especially Buxus,
Pachysandra, andSarcococca) (Gross et aI., 1985; Roddick,
1980, 1986).
Other steroidal alkaloids [such as samandarine (44) and
Alkaloids of Terpenoid Origin 677
batrachotoxin (45)] occur in animals (Fig. 36.12) (Daly et
al., 1993; Habermehl, 1967; Witkop and Gossinger, 1983).
Batrachotoxin occurs in the skins of the poison-dart frog
Phyllobates. The LD50 on subcutaneous injection in mice is
about 40 ng; the lethal dose in man is estimated to be 200
Ilg (Wink, 1993). The frog is so toxic that Indians only
scrape the dart across the frog's back. Batrachotoxin is an
important tool for the study of voltage-dependent sodium
channels (Daly et al., 1993).
SOLAlVlJ/fI ALKALOIDS
Steroidal alkaloids are widespread in the genus Solanum
(about 1400 species) and related genera of the Solanaceae
(0' Arcy, 1979, 1986; Gross et al., 1985; Prelog and Jeger,
1953, 1960; Sato, 1970; Schreiber, 1968). Many plants of
this group have economic importance; among them are to-
mato (Lycopersicon esculentum), potato (Solanum tubero-
sum), buffalo bur (Solanum rostratum), and eggplant (Sola-
num melongena). Steroidal alkaloids also occur in plants of
the genus Veratrum and related genera in the Liliaceae. All
told, steroidal alkaloids have been isolated from nearly 500
species of plants from these 2 families. Five major structural
types are known: the spirosolanes [solasodine (46)], solani-
danes [solanidine (49)], 22,26-epiminocholestanes [verazine
(47), and etioline (48)], a-epiminocyclohemiacetals [solano-
capsine (51)], and 3-aminospirostans [juribidine (50)]. An-
other large group of steroid-derived alkaloids have altered
C 27 skeleta based on cholestane. These are discussed in the
subsection "Veratrum alkaloids," below. Most of the alka-
loids occur as glycosides (Fig. 36.13) (Gross et aI., 1985;
Schreiber, 1979).
The co-occurrence of cuscohygrine (see Chapter 30) and
certain Solanum alkaloids has been reported for several spe-
678 Alkaloids o/Terpenoid Origin

~ NH

.amandarin. (44) batrachotoxin (45)

Fig. 36.12. Samandarine and batrachotoxin.

cies of Solanum and Cyphomandra (Ripperger and
Schreiber, 1981).
Techniques for the isolation and purification of steroid
alkaloids and the instrumental methods for characterization
(NMR and MS) have been reviewed (Atta-ur-Rahman and
Choudhary, 1993).
Biosynthesis
Glycoalkaloids appear to be synthesized in aereal por-
tions of Solanum species and not in roots, as in the case of
tropane alkaloids of many solanaceous species (Waller and
Nowacki, 1978).
The above-mentioned types of Solanum alkaloids are de-
rived from the same pathways as most other steroids in
plants. For more information on the formation of the various
precursors involved, see Chapters 23 and 24. The biosyn-
thesis and metabolism of the C27 sapogenins and alkaloids
are closely related (Ripperger and Schreiber, 1981; Gross et
ai., 1985). Acetate and mevalonate are incorporated into all
types of steroid alkaloids.
Cycloartenol and cholesterol serve as precursors for to-
matidine (52), solasodine (46), solanidine (49), soIanocap-
sine (51), and many other Solanum alkaloids. Cholest-4-en-
3-one (53) (Fig. 36.4) and 26-hydroxycholesterol were
shown to be the first products of metabolism. The (25R)
(54) and (25S) (55) stereoisomers of 26-hydroxycholesterol
are converted stereospecifically into soladulcidine (56) and
tomatidine (52), respectively (Gross et al., 1985).
Spirosolanes. The spirosolanes, such as tomatidine
(52) and solasodine (46), have the basic nitrogen incorpo-
rated into an oxaazaspirane unit that includes the original
steroidal side chain (Figs. 36.13 and 36.14). A biogenetic
scheme has been proposed (Fig. 36.15).
(25R)-Sapogenins can be formed from precursors such
as (25R)-26-hYdroxycholesterol (54) or (25R)-50l-furostan-
3(3,26-diol (58). 10 precursor 58, the tetrahydrofuran ring
involving oxygenation at C-16 has already been formed. The
biosynthesis of (25S)-sapogenins differs from that of (25R)-
sapogenins, because a different pro-chiral terminal group
(i.e., compound 54 versus compound 55) is involved, and
not because of stereochemical differences in reduction of an

~~HN~
H,N
HO
HO '"
solacongestidine (6S) solanacapsine (51) solasodin. (46)

HO
H,N

juribldine (50) solanidine (49) procevin. (90)

Fig. 36.13. Representatives of the major structural types of steroid alkaloids (modified from Gross et at., 1985).
 Alkaloids oj Terpenoid Origin 679

HO
tomatidine (52) tomatine (69)
H R =P-lycotetraosyl
H

HO
ligogenin (9) cholest-4-en-3-one (53)
H H

17

HO

HO

<al solanidine (49) solacongestidine (65)

Fig. 36.14 (8 & b). Some Solanum alkaloids and their precursors.
680 Alkaloids oj Terpenoid Origin

HO HO
(2SR)-26-hydroxycholesterol (54)
H
H

(2SS)-Sa-furoslan-3p,26-diol (59)
HO
(2SS)-5a-cholestan-3p.26-diol (55)
~NH, H

~
H
iH
~ I m-OH

HO
HO~ H

26-aminodihydrodiosgenin (63) 16P-hydroxy-5a-choleslanol (60)

o

HO

(b) 16p.26-dihydroxy-5cx-choleslanol (61) 16P-hydroxy-22-oxo-5cx-cholestanol (62)

Fig. 36.14_ (continued)

unsaturated A24 intermediate. Synthesis of tomatidine (52)
in Lycopersicon pimpinellifolium appears to utilize (25S)-
5a-cholestan-3f3.26-diol (55). but not (25S)-5a-furostan-
3f3.26-diol (59).
20-Hydroxycholesterol is converted into both tigogenin
(64) and solasodine (46). 16f3~Hydroxy-5a-cholestanol (60).
16f3.26-dihydroxy-5a-cholestanol (61). and 16f3-hydroxy-
22-oxo-5a-cholestanol (62) are convertible into spirostanes
[such as tigogenin (64)]. but not into spirosolanes (such as
52 and 46). The 16-hydroxy group appears to be introduced
after formation of the oxaazaspirane unit (ring F) (Fig.
36.15).
Introduction of the amino group occurs at an early stage.
This is supported by the incorporation of 26-aminodihydro-
diosgenin (63) into solasodine (46) in Digitalis lanata (Gross
et aI .• 1985).
The C-27 methyl group of (25R)-solasidine (46) is de-
rived from the C-2 group of mevalonate. whereas the C-27
methyl group of (25S)-tomatidine (52) is derived from the
C-3 group of mevalonate. This indicates that hydrogenation
of the A24 intermediate occurs by addition of hydrogen to
the 24 si.25 si face (Fig. 36.16).
Solanidine alkaloids. The second group of Solanum
alkaloids. the solanidine alkaloids. also occur as glycoaIka-
loids. An example of this type is solanidine (49).
A biogenetic scheme for solanidine (49) has been pro-
posed (Fig. 36.17) (Cordell, 1981; Gross et aI., 1985). The
amino acid arginine has been shown to be the source of
the nitrogen of solanidine (49) in Veratrum grandiflorum
(Ripperger and Schreiber, 1981).
The biosynthesis of solanidine (49) involves the intyrme-
diates verazine (47) and etioline (66), and loss of the 1613-
 Alkaloids oj Telpenoid Origin 681

cholesterol (99) 25 Rand 25S (54, 55) 25R 25R and 25S
/<"25S)~dOrmantNinone spirostanes H
/ / tigogenin (64)

,~~~,~~
1) --- ~o

w'.
22S 25S
22,26~epiminocholestanes 25 R and25S (22R, 25R)-solasodine (46)
(25R)-26-aminocholesterol (68) spirosolanes
solacongestidine (65)
verazine (47)

......
/
~ '.N:::::1" jjDO...
2S ' H

w·····
N N l
~ 25 ~ ~j): HN -+ N ..z.;".

o "'",OH
-OH

,
solanidine (49)

\
25R (25R)-solal1oridine (78) (25S)~teinemine solanidine type alkaloids

teo
(25S)-etioline (66)

-- ~O!~HNN1.
N
(25R)-solanacapsine (51)
(25R)~solacasine "~ ct-epiminocyclohemiacetals
~O~""""
.... '?'
"0 ----",
OCH3 OH

Fig. 36.15. Proposed biosynthetic scheme for the origin of steroid alkaloids with unaltered ~7 skeletons (modified from Gross et aL, 1985).

hydrogen atom (Gross et aI., 1985). Rubijervine (67) is de-

rived from verazine (47), but not etioline (66) in the rhizome
of Veratrum grandiflorum (Gross et aI., 1985).
22,26-Epiminocholestanes. Alkaloids with this struc-
ture are intennediates in the biosynthesis of spirosolane, so-
lanidine, a-epiminocyclohemiacetal, and 3-aminospirostane
alkaloids. (25R)-26-Aminocholesterol (68) is precursor to
the 22,26-epiminocholestanes. The biosynthesis of verazine
H (47), etioline (66), and solacongestidine (65) is discussed

. .
above.

~
N
I
," 3-Aminospirostane alkaloids. Alkaloids of this group,
such as jurubidine (50) (Fig. 36.13) are probably synthesized
analogously to the corresponding spirostanols (e.g., tigo-
(2SR)-spirosolane
(2SS)-spirosolane genin). The 3-amino group is most likely introduced by
• from C-3 of mevalonate
transamination late in the biosynthesis (Gross et aI., 1985) .
• from C-2 of mevalonate

Fig. 36.16. Stereospecific reduction of the .6,24 intennediate in the Biological Activity of Solanum Alkaloids
fonnation of spirosolanes (modified from Gross et al., 1985).
",-Tomatine (69) (Fig. 36.18) has a half-life of about 6
days in tomato plants. This alkaloid inhibits the growth of
several Gram-positive and Gram-negative bacteria and ani-
682 Alkaloids oj Terpenoid Origin
no
dormantinol
In :~n
~ ~
--
no '" - no '"
rubijervine (67)
(l2a-hydroxysolanidine)
N~I
no
solanidine (49)
- no
etioline (66)
Fig. 36.17. Proposed biogenesis of solanidine (modified from Cordell, 1981; used with permission of the author).
mal pathogenic fungi. a-Tomatine and demissine (70) have
antifeeding effects for the Leptinotarsa decimlineata (Colo-
rado potato beetle), the two-striped grasshopper, and the to-
mato fruit worm (Juvik and Stevens, 1982; Juvik et al., 1982;
Levinson, 1976; Roddick, 1986). Incorporation of either a-
tomatine (69) or demissine (70) into a diet of potato leaves
at 0.1-0.5% makes the diet unpalatable to Leptinotarsa de-
cemlineata larvae (0.3% for adults), whereas similar
amounts of solanine (71) do not. The adults normally feed
in the presence of up to 0.6% solanine (71) and a-chaconine
(72) (Levinson, 1976). The foliage of cultivated tomatoes
contains significantly lower levels of a-tomatine (69) than
the fruit and foliage of some wild Lycopersicon species
(Juvik and Stevens, 1982). Although a-tomatine (69) is cor-
related with mortality of Helicoverpa zea, this compound
does not occur at high enough levels to explain resistance
in many accessions of Lycopersicon species; other chemical
factors such as 2-tridecanone may be involved (Barbour and
Kennedy, 1991; Juvik et al., 1982).
a-Tomatine probably is toxic because it complexes with
3-J3-hydroxy steroids and alters membrane permeability.
Pure a-tomatine (69) has an LO so i. v. in rat of 18 mglkg
but is not very toxic orally (I glkg).
Solanine (71) is a mitotic poison (Cordell, 1981) with an
LOso i.p. in mouse of 42 mg/kg (Wink, 1993). However,
2.8 mglkg is toxic to humans (Roddick, 1986).
a-Chaconine (72) is a potent inhibitor of cholinesterase
dormantinone
.... OH ........
no.
~-r
""
-
"'on ......
no
verazine (47)
isozymes. This alkaloid has an LOso i.p. in rat of 84 mglkg
(Wink, 1993). a-Chaconine also disrupts biomembranes by
cholesterol binding. A 70: 30 mixtore of a-chaconine and
a-solanine exhibited maximal synergistic effects in destabi-
lization of cell membranes (Roddick et al., 1988). a-Chacon-
ine is a feeding deterrent to Clwristoneura (Lepidoptera)
(Wink, 1993).
The potato glycoalkaloids leptine I (73) and demissine
(70) are among the most active inhibitors of human plasma
cholinesterase (Beier and Nigg, 1992). a-Chaconine (72),
commersonine, solamargine (79), solanine (71), and solani-
dine (49) all possess this activity (Wink, 1993).
Many steroidal alkaloids are repellent or antifeedant to
insects. This may be attributable largely to the membrane
destabilizing effects of the alkaloids (Roddick et al., 1988).
Demissidine (76), solacauline (75), soladulcine (74), sola-
nine (71), and tomatidine (52) are phagorepellent to Leptino-
tarsa decimlineata (Colorado potato beetle). a-Chaconine
(72), solanidine (49), solanine (71), and tomatidine (52) are
feeding deterrents to Clwristoneura (Wink, 1993).
A variety of steroidal alkaloids have antifungal activity
(Clark and Hufford, 1992; Wink, 1993). In tomato and in
potato, glycosidic alkaloids play a role in inhibition of the
growth of fungi. Glycoalkaloids, such as a-tomatine (69)
and solanine (71), are hydrolyzed by J3-glucosidases and the
aglycones react with membrane sterols and cause damage
to the cell membrane of the fungos (Nahrstedt, 1979). A
 Alkaloids of Terpenoid Origin 683

highly active alkaloid, solacongestidine (65) exhibited mini-
mal inhibitory concentration (MIC) values of 0.4-0.8 ",g/ml
and verazine (47) at 3.1 ",g/ml for Candida albicans and
Trichophyton rubrum. Solacongestidine was active against
several other fungal species, but essentially inactive against
Aspergillus species tested (Clark and Bufford, 1992). Sola-
casine (77), soladulcidine (56), solafloridine (78), solamar-
gine (79), solanidine (49), solanine (71), solanocapsine (51),
solasodine (46), solasonine, tomatidenol, and tomatilladine
all exhibit varying degrees of antifungal activity (Wink,
1993).
Although the larvae of many ithomiine butterflies feed
on solanaceous plants and must be adapted to the presence
of steroid alkaloids, the distasteful properties of adults are
not derived from steroid alkaloids. The adults do not appear
to be able to sequester these compounds, and their toxicity
is due to the presence of pyrrolizidine alkaloids (Drummond,
1986).
As mentioned above, demissine and several other steroid
alkaloids are repellent or toxic to the Colorado potato beetle.
Races of this insect are adapted to several Solanum species,
including S. eleagnifolium, S. rostratum, and S. tuberosum,
and the insect has a recognized ability to adapt to new combi-
nations of steroid alkaloids (Barbome, 1986).
Solanum alkaloids, especially those of the 22,26-epimino-
cholestane types have been converted to pregnane deriva-
tives and used as sources of contraceptive and anti-inflam-
matoty drugs (Bradley et al., 1979; Schreiber, 1979).

ORO_glucose

°HOH~~O'~O OH-:'....
OHOO~
RO D.xyl... ~O HO OR
",·tomatine (69) HOHO OH
R = p-.ycotet....y.
D-Rluoose OB Iycotetraose
H

OH

HO""""\ _0 0 OH
';o~L< _0
D-gluc~e ~~~O
D-gaJadose
o n-solanine (71)
L.~OH
'O~OH
L-rhamnose 0 OB

D.xyl.., ~OHD':""
OHO OOH
HO~O HO'L< ~O 0

O~O~A ?~
HOHO~ 0-..1 . -

D-glucose OH

OH

O~O :::,..

HO --r---...OJ O~ D-gI",."
",-chaconlne (72)

~ OH
L-rhamnose on o. OB
OB L-rhamnose
(a)

Fig. 36.18 (8 & b). Biologically active steroid alkaloids.

684 Alkaloids of Terpenoid Origin
H vated in western Bolivia because they are especially drought
R = O-rha(1-2)-O-rha(1-4)-glc
a-solamargine (79)
HO
demissidine (76)
solacasine (77)
(b) (X--soladulcine (74) (L-rham., D-xyl, D-glu, D-gal)
Fig. 36.18. (continued)
Solanum Alkaloids in Potatoes
It has long been known that "greened" potatoes (those
that have been exposed to the sun), or potatoes exposed to
certain fungi, produce Solanum alkaloids and are somewhat
toxic. Both people and livestock have died from eating po-
tato vines, sprouts, peels, or green and cull potatoes. Potato
breeders in the United States attempt to keep the a-solanine
(71) content of potato cultivars below 200 floglg fresh weight
(Beier and Nigg, 1992). Fried potato peels contain as much
as 1400 flog/g a-solanine and a-chaconine (72), whereas the
recommended upper safety limit is 200 flog/g (Beier and
Nigg, 1992).
Certain species of potatoes that are cultivated in Andean
regions of South America are also known to contain larger
amounts of these alkaloids than are found in the usual Sola-
num tuberosum cultivars. Plants of S. X ajanhuiri are culti-
and frost tolerant. The Aymara Indians that cultivate them
are relatively tolerant of the bitter taste present. Further,
these people consume clay along with the potatoes that ab-
sorbs much of the mixture of Solanum alkaloids. Geophagy
probably was an essential technique for solving the original
impasse these secondary compounds posed to the domestica-
tion process (Johns, 1985, 1990).
Teratogenic Properties
Many plants that contain Solanum alkaloids are responsi-
ble for the poisoning of livestock and humans. Potatoes in-
fected by the fungus Phytophthora infestans have been re-
ported to be responsible for an abnormal incidence of
congenital defects in humans and other animals. These re-
ports have prompted many studies into the nature of these
problems. Of the alkaloids tested, demissine (70), 22-isode-
missine, and a-tomatine (69) have been shown to be inactive.
Solasodine (46) had weak teratogenic activity, but
5a,22j3H,25j3H-solanidan-3j3-01 (81) or 22j3H,25aH-so-
lanid-5-en-3j3-01 (82) possessed strong teratogenic activity
(Cordell, 1981; Keeler, 1986).
VERATRlIM ALKALOIDS
The alkaloids of Veratrum spp. (LiJiaceae) have long been
recognized as useful in medicine. In addition to the steroid
alkaloids found in this genus, structurally modified com-
pounds of two basic types are encountered: the jerveratrum
alkaloids and the ceveratrum alkaloids. Examples of the for-
mer class are jervine (83) and veratrarnine (84) (Fig. 36.19)
(Cordell, 1981; Jeger and Prelog, 1960a; Tomko and Vot-
icky, 1973); examples of the latter are protoveratrine A and
B (85 and 86) (Greenhill and Grayshan, 1992).
A simpler group of compounds with the cevane skeleton
occurs in the genus Fritillaria (Liliaceae). Medicinally, the
most important alkaloids of Veratrum are the polyesters of
protoverine (87) that have hypotensive properties.
Biosynthesis
12-Hydroxysolanidine (epirubijervine) (88) may serve as
a precursor for a C-nor-D-homo-steroid derivative (91). Pos-
sibly 12j3-hydroxyteinemine (92) may serve as a precursor
for veratramine (84). Reductive cleavage of the C(16)-N
bond yields the skeleton of the jerveratrum alkaloids (Fig.
36.20) (Gross et al., 1985). Isorubijervine (89) (Fig. 36.21),
a solanidine alkaloid with a leaving group at C-1B, can form
a C(18)-N bond. Reduction of the resulting quaternary salt
by cleavage of the C(16)-N bond yields the heterocyclic
skeleton of the ceveratrum alkaloids. The alkaloid procevine
(90) has been isolated from Veratrum grandiflorum (Gross
et al., 1985). As the configuration at C-22 is opposite that of
most naturally occurting ceveratrum alkaloids, anrakorinine
 Alkaloids o/Terpenoid Origin 68S

HO
27
veratramine (84)

J+1lo OH
HO

protoveratrine A, R=H (85) protoverine (87)

protoveratrine B, R=OH (86)

CH3-O ~I o
:::::,..
OCH3
OH
H

veralridine (94) H

HO
cyclopamine (96) cyclopsine (97)

Fig. 36.19. Veratrum alkaloids.

(93) may serve as a more likely precursor for these alkaloids
(Gross et al., 1985).
Biological Activity
Veratrum alkaloids cause repetitive discharges of nerve
cells, apparently by delaying repolarization (possibly by ac-
tion on lipid components and an ATPase in the cell mem-
brane) (Levinson, 1976). Veratridine (94) binds to the so-
dium channel and keeps it permanently open and active
(Greenbill and Grayshan, 1992). Protoveratrines A and B
inbibit inactivation of Na+ channels. Cevadine (95) and pro-
toveratrines A and B (85, 86) depolarize membranes (Wink,
1993).
Alkaloids of Veratrum are highly toxic to livestock. Con-
sumption of these compounds results in teratological effects,
especially in sheep (Keeler, 1986). One of the most bizarre
effects is the production of lambs with one eye or "cyclop-
ism." Under some circumstances, this deformity may affect
as many as 25% of the lambs produced (Keeler, 1986). The
three most active alkaloids are jervine (83), cyclopamine
(96), and cyclopsine (97) (Keeler, 1986). Jervine has an LDso
i.v. in mouse of 9.3 mg/kg and veratradine (94) of 1.4 mg/kg;
rubijervine (67) in rat of 70 mg/kg; and protoveratrine a
lethal dose in rabbit of 0.1 mg/kg (Wink, 1993).
Many of this group of alkaloids possess antifungal prop-
erties. Among the active compounds are cevadine (95), iso-
686 Alkaloids ojTerpenoid Origin

HO HO

(91)
I (not known to
epirubijervlne (88) .. occur naturally)
(12.hydroxysolanidine)

&n ~
;
~ H 7' •....•",QHN
f ~
7' !
H 0

HO ~
H
1 ! ~ HO ~ (not known to
occur naturally)

HO
~
U~.,~th
~
H H

jervine (83)
HO

/ veratramine (84)
/'

HO
Fig. 36.20. Proposed biogenesis of jerveratrum alkaloids (modified from Cordell. 1981; used with permission of the author).

rubijervine (89), jervine (83), protoveratrine A and B
(85,86), pseudojervine, rubijervine (67), veratramine (84),
veratridine (94), and verazine (47) (Wink, 1993).
These alkaloids are widely used today in the treatment
of hypertension. Medicinally, the most important alkaloids
of Veratrum are the polyesters of protoverine (87) that have
hypotensive properties, Plants from Veratrum and Fritillaria
have been used in Chinese traditional medicine (Han et ai.,
1988),
Veratrum plant material has also been used as an insecti-
cide (Greenhill and Grayshan, 1992). Protoveratrine B (86)
is a feeding deterrent to Syntomis larvae; veratrine (94) is a
feeding deterrent for Sehistoeerca (Wink, 1993).
STEROIDAL ALKALOIDS IN THE
APOCYNACEAE
In addition to the indole alkaloids of the Apocynaceae, a
number of genera possess alkaloids based on a steroidal
structure (Alta-ur-Rahman and Muzaffar, 1988; Cerny and
Sorrn, 1967, Jeger & Prelog, 1960). Most important among
these are Funtumia, Holarrhena, and Maluoetia. Similar al-
kaloids occur in the family Buxaceae (Pachysandra and Sar-
cocca). Alkaloids such as holaphylline (98) are based on
the 5a-pregnane skeleton and appear to be derived from
cholesterol (99) and pregnenolone (100) (Fig, 36,22) (Gross
et ai., 1985). A series ofbiosynthetic routes leading to major
subgroups of these alkaloids has been proposed (Gross et
ai., 1985),
Holarrhena antidysenteriea (Apocynaceae), an Indian
plant, is used for treatment of dysentery. The steroidal alka-
loid conessine (101) was the main antiamebic constituent
(Borris and Schaeffer, 1992), The same compound occurs
in Wrightia tomentosa, Another Indian plant, Chonemorpho
fragrans (Apocynaceae), afforded the alkaloid chonemor-
phine (102) which had an MIC of 25 fLg/ml in vitro (Borris
and Schaeffer, 1992).
Conessine (101) is active against Candida albieons at
a concentration of 100 fLg/ml (Clark and Hufford, 1992),
 Alkaloids of Terpenoid Origin 687

HO
skioooomenioe

Fig. 36.21. Proposed biogenesis of ceveratrum alkaloids (modified from Gross et aI., 1985).

HO

cholesterol (99) holophyllamine conessine (101)

chonemorphine (102) pregnenolone (100) bolaphylline (98)

Fig. 36.22. Alkaloids with a ~I-carbon skeleton and possible precursors.

688 Alkaloids oj Terpenoid Origin

~"'''''N#HCH3 NHCH,
..."H.

l
...."OH
"
H
.~ D
·""OH .... "OH

CH,-NH CH,-NH \~. CH,-NH

cyclovirobuxine (l05) buxamine-G (104)

cycIobuxine·D (103)
o carbon from C-2 of mevalonic acid (buxenine-G)
• 4-pro-R H of mevalonic acid

Fig. 36.23. Buxus alkaloids (modified from Gross et aI., 1985).

CH'02C~~
~
HO
N
. . . j" '" ......"..,,',--,..' /
i OCOCH,
OCOCH 3
.,
yuzunmme

Fig. 36.24. Proposed biogenesis of daphniphylline (modified from Cordell, 1981; used with pennission of the author) and some representative
Daphniphyllum alkaloids.

Conessine (101) is phagorepellent to Pieris, Bombyx, Ly-
rnantria, and Dysdercus (Wink, 1993).
BUXUS ALKALOIDS
The genera Buxus and Pachysandra of the family Buxaceae
contain a series of steroidal alkaIoids similar to those of
HolarrhelUl (Apocynaceae) (Atta-ur-Rahman and Muzaffar,
1988; Brown, 1970; Cerny and Sorn 1967; Tomko and Vot-
icky, 1973); in addition, these plants contain a series of tri-
terpenoid alkaloids commonly known as the Buxus alka-
loids. These are typified by cyclobuxine-D (103), based on
a cycloartenol skeleton (Fig. 36.23). The six terminal carbon
atoms have been removed and nitrogen functions are at-
tached at C-3 and C-20. Buxenine-G (104) probably results
from cleavage of the cyclopropyl ring to generate a seven
membered Bring.
Incorporation of [2_ 14C,(4R)-4-3HIl mevalonic acid
(MVA) into cyclovirobuxine (105) and cyclobuxine-D (103)
in shoots of Buxus sempervirens (Buxaceae) gave 3H: I'C
ratios of -3.4 and 3.3, consistent with the labeling pattern
shown and the involvement of ketone groups at C-3 and C-
20 in the biosynthetic pathway. Oxidative removal of the
4a-methyl group of cyclobuxine-D (103) also is evident
from these ratios (Fig. 36.23) (Gross et aI., 1985).
DAPlI1YlPlIl'LWM ALKALOIDS
The genus Daphniphyllum (Daphniphyllaceae) is the source
of complex triterpenoid alkaloids. Daphniphyllum rnacropo-
dum, a tall tree from Japan, has been particularly studied
(Yamamura, 1986; YamamUTa and Hirata, 1975). At least
19 alkaloids have been isolated from the bark, leaves, and
fruit of this plant. DaphniphyIIine (106) and codaphniphyl-
line (107) are the two major alkaloids of the bark (Fig.
36.24).
Labeled squalene was incorporated into both alkaloids
and degradation studies indicated derivation from six meva-
lonate units. A possible biosynthetic scheme has been pro-
posed (Fig. 36.24) (Cordell, 1981; Yamamura, 1986).
Plants of this genus have long been known to produce
mortality in livestock in Japan (Yamamura, 1986). D. ma-
cropodum has been used as a vermicide and asthma remedy
(Cordell, 1981).
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37
Miscellaneous Types of Alkaloids

Introduction Both the 'H- and 13C-NMR (nuclear magnetic resonance)

Hemiterpene Alkaloids spectra for several of the alkaloid groups below have been
Imidazole Alkaloids reviewed (Crabb, 1982). The results of feeding stodies lead-
Biosynthesis ing to the synthesis of several alkaloids of this group have
Other Sources of Imidazole Alkaloids been tabulated (Leete, 1983).
Lythraceae alkaloids
Maytansinoids
Antitumor Activity HEMITERPENE ALKALOIDS
Other Biological Activity
Muscarine Alkaloids Many groups of alkaloids possess five-carbon mevalonate-
Naphthylisoquinoline Alkaloids derived units as a part of the overall structure of the com-
Peptide Alkaloids pounds. In one previously discussed group, the ergot alka-
Purine or Xanthine Alkaloids loids, this mevalonate unit is attached to a tryptophan-de-
Biosynthesis rived portion and cyciized to form tricyclic and tetracyclic
Physiological Activity of Xanthine Derivatives alkaloids.
Pyrazine Alkaloids Another series of hemiterpene alkaloids is found in the
Securinega Alkaloids genus Alchornea (Euphorbiaceae). In these alkaloids (1-4)
Sesbania Alkaloids the hemiterpene uuit constitutes a major portion of the struc-
Betalains tore (Fig. 37.1) (Hart et al., 1970).
Biosynthesis
Chemosystematic Value
Betalains in Foods and Beverages IMIDAZOLE ALKALOIDS
Miscellaneous Alkaloids
Trigonelline and an Unusual Pyrrole Several alkaloids derived from histidine occur in plants.
Histronionicotoxins Probably the best known of these is pilocarpine (5), found
Huperzine A in species of Pilocarpus (Rutaceae) (Fig. 37.2). This com-
References pound is a peripheral stimulant of the parasympathetic sys-
tem and is used topically as a myotic to counteract the mydri-
atic effects of atropine and other parasympatholytic drugs.
Il'ITRODUCTION Pilocarpine is used for the treatment of glaucoma (as a
0.5-10% solution).
A number of miscellaneous types of alkaloids not easily Positively inotropic histamine-derived compounds have
assignable to other alkaloid classes, but that are of interest been isolated from members of the Cactaceae. N' ,N'-Dimeth-
because of their medical, drug, systematic, biosynthetic, or ylhistamine (6) from Echinocereus blanckii and dolicothe-
other properties, are surveyed in this chapter. Many of these line (7) from Dolichothele sphaerica have been studied. Dol-
are of limited distribution, whereas others, such as caffeine ichotheline has an EDso of 1.6 X 10-7 mollL (Figure 37.3)
(a xanthine base), are widely and sporadically distributed. (Wagner, 1988).

692
 Miscellaneous Types of Alkaloids 693

alchorneine (1) alchorneinone (2)

)(N'l
yTJ"""''\
N /
N~N\.,,"'"
~ V~I-H
r"'·····\.-N-/
OCH,
I
<
o

alchornine (4) isoalchorneine (3)

Fig. 37.1. Hemiterpene alkaloids from the genus Alchornea.

Biosynthesis baceae), Cynometra (Fabaceae), Cypholophus (Urticaceae),

Dendrobium (Orchidaceae), Dolichothele (Cactaceae),
Pilocarpine has been suggested to arise from condensa-
Glochidion (Euphorbiaceae), and Macrorungia (Acantha-
tion of an alcohol involved in the biosynthesis of histidine
ceae) (Maat and Beyerman, 1983). These include many
(as the phosphate) and acetoacetate (Fig. 37.2). A second
structural variants and may be of quite distinct origins.
path has also been suggested. There is little experimental
evidence to establish either pathway (Maat and Beyerman,
1983).
LYTHKACBAE ALKALOIDS
other Sources of Imidazole Alkaloids
About 45 alkaloids from the above-ground parts of members
Other imidazole alkaloids are known from Alchornea of the Lythraceae have been studied (Golebiewski and Wro-
(Euphorbiaceae), Casimiroa (Rutaceae), Cassia absus (Fa- bel, 1981). Several of these alkaloids contain quinolizidine

-+

pilocarpine (5)

Fig. 37.2.Proposed pathways for the biogenesis of pilocarpine (Maat and Beyennan. 1983, modified and used with pennission of the copyright owner,
Academic Press, Orlando, FL).
694 Miscellaneous Types of Alkaloids

serves as a precursor for much of the rest of the molecul.

N,N·dimetbylbistamine (6) dolicotheJine (7)
Fig. 37.3. Dolichotheline and cryogenine.
ring systems. Some of the best known alkaloids have been
isolated from the hallucinogenic plant Heimia salicifolia and
from crepe myrtle Lagerstroemia subcostata (Howard and
Michael, 1986).
The biosynthesis of Lythraceae alkaloids is not well
understood. Lysine serves as a precursor for part of the mole-
cule; all carbons except the carboxyl group of lysine are
incorporated. Further, the lysine-derived portion enters the
molecule via a symmetrical intermediate. Phenylalanine
[3- 14C]Phenylaianine is incorporated specifically into cry,
genine (8) (Fig. 37.3), and is the precursor for both of th
aromatic rings. Feeding experiments with other labeled ph.
nylalanine precursors established that two intact C6 -C3 unit
are incorporated into lactonic Lythraceae alkaloids, such a
vertine (9) and verticillatine (10) (Fig. 37.4) (Golebiewsk
and Wrobel, 1981).
The American Indians used plants of the genus Heimi.
to prepare intoxicating and stimulating beverages that pro
duce a mild psychosomirnetic effect. Plants of this genu:
were commonly used medicinally (Golebiewski and Wrobel
1981).
JllAYTANSINOmS
A series of novel ansa-macrolides has been isolated from
plants of several genera of the Celastraceae, as well as othel
families. The macrolide alkaloid, maytansine (11), was first

O~

.o~ ~~~:~ ~~
CO,H 0 H
o _~~

OCH, OCH, OCH,

HO~i ~ '! O~l!

.~.
HO
l! H N
H
N
H
N

?' ?' 1
I"'"
.0 OCOCH, HO ""- I HO ""-
OCI;I, OCOCH, OCH, OCH,

(-)-Iasublne I demethyllasubine I

10-epidemethoxy· abresoline
(al abresoline

Fig. 37A (8 & b). Some representative Lythraceae alkaloids and a proposed biogenetic scheme for their fonnation (Golebiewski and Wf, 981;
modified and used with pennission of the copyright owner, Academic Press, Orlando. FL).

OCH,
Iythrine
0 0
12
L3
15
I'
OCH,
OH
(b)
vertine (9)
Fig. 37.4. (continued)
obtained from the fruits of May tenus ovatus (Fig. 37.5). Sim-
ilar alkaloids have been obtained frum the stem bark of
Maytenus buchanan;; andM. serrata and lither plant sources.
Another celastraceous plant, Putterlickia verrucosa (Celas-
traceae), proved to be rich in maytansine (11); the plant
contained as much as 12 mg/kg of maytansine. Maytansi-
noids also have been isolated from Trewia nudiflora (Eu-
phorbiaceae) and Colubrina texensis (Rbamnaceae) (Reider
and Roland, 1984; Smith and Powell, 1984).
Techniques for the isolation and purification and both 1H-
and 13C_NMR and mass spectrometry of these alkaloids have
been reviewed (Smith and Powell, 1984).
Of the compounds found in these plants, maytansine (11),
maytanprine (12), maytanvaline, and maytanbutacine
showed antitomor activity, but most of an accompanying
series of structurally· related compounds did not (Fig. 37.5)
(Smith and Powell, 1984). The LDso s.c. in mouse of may-
tansine is 0.48 mg/kg (Wink, 1993).
A complex series of maytansinoids has been isolated from
Miscellaneous Types of Alkaloids 695
H H
-+-Iysine
OH OCH,
OH OCH, OH
cryogenin. (8)
OH OCH,
verticillatin. (10)
Trewia nudiflora (Powell et al., 1981, 1983). Several include
an ususual second macrocyclic ring attached to the macrocy-
dic ring found in inost maytansinoids (Powell et aI., 1981,
1982).
The biosynthesis of these alkaloids has been little stodied.
The origin of the various parts of the molecule has been
suggested (Fig. 37.5). In general, the biosynthesis of ansa-
mycin antibiotics of microbial origin and maytansanoids
from higher plants are related (Smith and Powell, 1984).
Antitumor Activity
Maytansine (11) has been stodied as an antitomor agent.
Average ED,o values for these materials are in the range
10-4 _10- 6 ltg/mi. Maytansine (11) is highly active in a
variety of murine tomor systems including BI6 melanoma,
colon 26, Ll210 leukemia, Lewis lung carcinoma, and P-
388 leukemia (Smith and Powell, 1984). Several members
of the maytansinoid family of alkaloids have antileukemic,
696 Miscellaneous Types of Alkaloids
CR,·O
maytanslne (11)
CI o CI
OCR,
maysenine
(aJ
Fig. 37.5 (a & b). Maytansinoids (modified in part from Suffness and Cordell, 1985; used with pennission of the copyright owner, Academic Press,
Orlando. Fl.).
cytotoxic. antitubulin, and antintitotic properties (Cordell.
1978; Suffness and Cordell, 1985). The antitumor activity
is mainly produced by the prevention of microtubule protein
polymerization because of tubulin binding. Maytansine (11)
and vincristine have been shown to compete for the same
binding sites but utilize different binding mechanisms (Re-
ider and Roland. 1984). At 6 X 10-8 M, maytansine irrevers-
ibly inhibits cell division in the eggs of sea urchins and clams
and also irreversibly inhibits the in vitro polymerization of
tubulin. This compound is 100 times more effective than
vincristine as an inhibitor of marine eggs. Maytansine inhib-
its DNA synthesis. but not RNA or protein synthesis.
Although maytansine has been studied in an extensive
series of clinical trials, there does not appear to be sufficient
antitumor activity and the future of maytansine as an antican-
cer drug appears doubtful (Reider and Roland, 1984).
The maytansinoid compounds trewiasine (13). dehydro-
maytanvaline (12)
o
N-methylmaysenine
actomycin
trewiasine (14), and demethyltrewiasine (15) were excep-
tionally active in the PS, B1. and KB tumor lines (Powell
et al., 1981).
Other Biological Activity
Maytenus ilicifolia from southern South America has
been used as a menses inducer by indigenous people of Para-
guay (Ahmed et al., 1981).
Extracts of Trewia nudiflora (Euphorbiaceae) that contain
maytansanoids have been shown tu have insect antifeedant
activity and produce several other effects in insects that may
limit herbivory (powell et al .• 1982, 1983; Reider and Ro-
land, 1984; Smith and Powell, 1984). Several maytansinoids
were antifeedant to larvae of Ostrinia nubilalis, the Euro-
pean com borer. whereas others significantly retarded devel-
opment of the larvae (Madrigal et al., 1985).

CH,-O
CI
CH,-O
OCH,
Irewiasine (13)
(b) demethyltrewiasine (15)
Fig. 37.S.
Trewiasine (13), from the seeds of Trewia nudiflora (Eu-
phorbiaceae), gives greater than 50% inhibition of radicle
elongation with velvetleaf (Abutilon theophrasti) (Malva-
ceae) (Powell and Spencer, 1988).
!llVSCARll'lE ALKALOIDS
The alkaloid muscarine (16) is found in a number of fungi
of the genera Amanita, Clitocybe, and Inocybe (Fig. 37.6).
The amount of muscarine (16) present usually is quite low
(about 0.0003%). Fungi of the genera Clitocybe and Inocybe
usually are responsible for' 'muscarine" poisoning. The best
known species of muscarine-containing alkaloids is un-
doubtedly Amanita muscaria; however, much of the activity
of this species is attributable to ibotenic acid (17) and musci-
mol (18) (Antkowiak and Antkowiak, 1991; Kendrick,
1985). This attractive mushroom grows in most temperate
climate areas of the world and occasionally is responsible for
human poisonings, although these are relatively uncommon
(Wang and Joullie, 1984). Symptoms of poisoning include
headaches, nausea, vomiting, salivation, lacrymation, diar-
Miscellaneous Types of Alkaloids 697
CI
dehydrotrewiasine (14)
(continued)
rhea, bronchoconstriction, hypotension, and vasodilation.
Amanita muscaria has been used by several indigenous
groups for religious rites and as a hallucinogen.
Muscarine (16) is derived from glutamic acid and pyruvic
acid (Fig. 37.6) (Wang and Joullie, 1984). The carbons of
pyruvate are incorporated at positions 2 and 3 of the ring
and the methyl group at C-2. The carbons at position 2,3,
and 4 of glutamate were incorporated into positions 4 and
5 of the ring of muscarine and at the methylene at C-5. The
carbons at positions 1 and 5 of glutamate are lost during
biosynthesis (Wang and Joullie, 1984).
The action of muscarine (16) and acetylcholine on smooth
muscle is very similar; muscarine is a potent parasympatho-
mimetic drug (Antkowiak and Antkowiak, 1991). The term
"muscarinic activity" is used to describe the direct periph-
eral action on cholinergic receptors in smooth muscles of
the gastrointestinal tract, eye, exocrine glands, and heart
(Wang and Joul!ie, 1984). Much early experimental work
with muscarine is unreliable, as many of the materials used
were impure.
The mushroom Amanita muscaria has a reputation for its
insecticidal properties. Pure muscarine, however, is devoid
698 Miscellaneous Types of Alkaloids

4~).CO.- H OH
HO,C 3 __1'\ _
H NH3+ HO.C~CO,- --+
H NH3+

(+)-(2S,3R,SS)-muscarine (16) musclmol (18) ibotenic acid (17)

J:J-
HO

"
J:) N+
,CH3 HO
N+
,CH3

--""'-"CH
o CH3 3 o I 'CH3
CH3

(+)-(2S,3R,SR)-allomuscarine (+)-(2S,3S,SR)-epimuscarlne

Fig. 37.6. Muscarine and related alkaloids (modified from Wang and Joullie, 1984; used with pennission of the copyright owner, Academic Press,
Orlando, FL).

of such properties. Compounds such as ibotenic acid (17)
and muscimol (18) appear to be responsible for much of this
activity, as well as the potent effect on the central nervous
system in mammals (Wang and Joullie, 1984). Both ibotenic
acid and muscimol bind to 'Y-aminobutyric acid and gluta-
mate receptors (Antkowiak and Antkowiak, 1991). Ibotenic
acid is converted to muscimol upon drying (Kendrick, 1985).
The oral LDs. ofmuscimol in rat is 45 mgikg (Wink, 1993).
Muscimol (18) induces food aversion in Opossum (Wink,
1993).
posed (Fig. 37.7) (Bringmann, 1986). Feeding studies with
acetate suggest that these alkaloids are derived by a type of
polyketide pathway.
Ancistrociadus abbreviatus is widely used in folk medi-
cine (Bringmann et al., 1990). Leaves of the Ancistrociadus
tectorius are used in Thailand to treat dysentery and malaria
(Tantisewie and Ruchirawat, 1992).
Michellamine B (19), from Ancistrocladus korupensis
(formerly considered to be A. abbreviatus) has been shown
to possess potent activity against mv-1 and mV-2
(Manfredi et al., 1991; Thomas and Gereau, 1993).

l'IAFHTIfYLlSOQUIi'IOLIl'IE ALKALOIDS PEPTIDE ALKALOIDS

An unusual group of perhaps 20 alkaloids is found in the
families Ancistrocladaceae and Dioncophyllaceae. The
monotypic genus Ancistrociadus, Ancistrocladaceae, occurs
in Africa and Asia (Bringmann, 1986). The genera Dionco-
phyllum and Triphyophyllum are members of the Dionco-
phyllaceae, the only other plant family known to produce
this type of alkaloid. These plants are native to the Old World
tropics (Bringmann, 1986). The co-occurrence of certain al-
kaloids suggests a relationship between the two families
(Bringmann et al., 1990).
A biogenetic scheme for these alkaloids has been pro-
A series of over 100 alkaloids with a peptide structure have
been isolated and characterized. In these compounds, a 10-
or 12-membered (sometimes 13 or 14) ring spans the 1,3 or
1,4 positions of a benzene ring. These alkaloids are primarily
composed of simple amino acids. The basic properties are
caused by an N-methyl or an NoN-dimethyl amine group of
an N-terminal amino acid (Jouillie and Nut!, 1985;
Tschesche and Kaussman, 1975).
Peptide alkaloids were first studied because of their thera-
peutic, antibiotic properties. There is some evidence that
peptide alkaloids may serve as ionophores in the plant and
 Miscellaneous Types of Alkaloids 699

from Ancistrocladus species from Triphyophyllum species

OCH,
(a) triphyophyttine isotriphyophyttine

OCH,

(b) michellamine B (19)

Fig. 37.7 (a & b). Proposed biogenetic scheme for naphthylisoquinoline alkaloids and michellamine B (Bringmann, 1986; modified and used with
pennission of the copyright owner, Academic Press, New York).
700 Miscellaneous Types of Alkaloids
are important in the absorption of nutrients from the soil
(Joullie and Nutt, 1985).
The bark of Scutia buxifolia (Rharnnaceae) contains scut-
ianine A, B (20), C, D, F (21), and G (22). Similar com-
pounds have been isolated from the roots of Melochia tomen-
tosa (23 and 24). A number of 14-membered-ring peptide
alkaloids have been isolated from members of the genus
Zizyphus (Rbarnnaceae) (Fig. 37.8). An aIkaIoid from this
family, ziziphin (25), blocks activity of the sugar (but not
the salt) receptors of flies (Stiidler, 1984).
These compounds are particularly common in the Rbam-
naceae but also occur in the families Celastraceae, Euphor-
biaceae, Hymenocardiaceae, Menispermaceae (Cocculus),
Pandaceae, Rubiaceae (Canthium, Oldenlant/ia), Stereulia-
ceae (Melochia, Waltheria), and Urticaceae (Lagarias et al.,
1979; Schmidt et al., 1985). Several structural types have
been recognized (Fig. 37.8) (Schmidt et al., 1985).
Stems, leaves, and flowers of Bouvardia ternifolia (Rubi-
aceae) from Mexico were shown to contain cytotoxic and
antitumor compounds. Fractionation revealed two cyclic
hexapeptides, bouvardin (26) and deoxybouvardin (27) (Fig.
37.8) (Suffness and Cordell, 1985). The antitumor effects
of these compounds were attributed to the ability of these
compounds to inhibit protein synthesis because of an effect
on the 80-S ribosome. Similar compounds have been found
to be the antitumor principles of Rubia akane and R. cordi-
folia (Suffness and Cordell, 1985).
Certain linear peptide aIkaIoids are known from marine
sponges (Schmidt et al., 1985).
PURINE OK XAN11IIl'IE ALKALOIDS
Both purine and pyrimidine bases occur as constituent parts
of nucleic acids and plant products. In addition, a number
of free purine and pyrimidine bases have been isolated from
plants (Atta-or-Rahman and Choudhary, 1990; Brown,
1991; Wang, 1973). The pyrimidine glucoside vicine (28)
was ftrst isolated. from seeds of Vicia species in 1870. How-
ever, purine bases appear to be much more common that
pyrimidine bases in nature. The most important purine alka-
loids are derived from the xanthine nucleus. Xanthine itself
has not been found naturally, but several of its N-aIkyl deriv-
atives are of considerable importance. The most important
of these are 1,3,7-trimethylxanthine (caffeine) (29), 1,3-di-
methylxanthine (theophylline) (30), and 3,7-dimethylxan-
thine (theobromine) (31) (Fig. 37.9). These alkaloids are
major constituents of plants used as stimulating beverages
by people throughout the world.
Coffee, Coffea arabica and Coffea canephora (Rubia-
ceae), is native to East Africa but widely cultivated in many
tropical countries. The seeds contain 1-2% caffeine com-
plexed with chlorogenic acid. All parts of the coffee plant
contain caffeine, although the greatest concentration is in
the frnits (Waller and Nowacki, 1978). Caffeine also occurs
in Genipa and Oldenlandia (both Rubiaceae) (Hemingway
and Phillipson, 1980). Cola (or kola) is derived from Stereu
iaceae trees of the genus Cola (Stereuliaceae) which at
widely cultivated in West Africa, but also in other tropic,
areas of the world. The cotyledons of the seed are the soorc
of cola flavoring. The caffeine content may be as high a
3.5%. A dried paste made from the seeds of Paullinia cupan,
(guararui) is the base of several beverages prepared in Brazil
The beverage often contains 2.5-5% caffeine (29). Yerb.
mare, flex paraguariensis, is widely used as a tea in southen
South America. The dried leaves of this plant often contail
about 2% caffeine. The leaves of another species flex guay
usa, which contain 1.5-3.5% caffeine, are used daily bJ
Jivaro Indians (Lewis, 1992).
Tea is derived from the leaves of Camellia sinensi,
(Theaceae), a plant native to eastern Asia. Different grade,
and types of teas are prepared by various processes of bruis-
ing, aging, and drying tea leaves. Significant chemical
changes occor during these procedures. Dried tea often con-
tains 1-4% caffeine (29) along with smaller amounts of
theob.romine (31) and theophylline (31) (Cordell, 1981).
Cacao, from Theobroma cacao (and related species of
the Sterculiaceae), is derived from the seed, which is fer-
mented and roasted. These seeds contain 0.9-3% theobro-
mine (31) and the husks 0.2-3%. The genus Theobroma is
native to the New World but is extensively cultivated in
several tropical areas, especially West Africa.
Other purine and pyrimidine derivatives with side chains
have been found in plant extracts. Many of these are physio-
logically active in plants as cytokinins and are related struc-
turally and metabolically to zeatin (Horgan and Scott, 1991).
Other purine aIkaIoids occor in Banisteriopsis inebrians
(Malpighiaceae), Holarrhena mitis (Apocynaceae) [triacan-
thine (32)], Leontinus edodes (Tricholomataceae) [deoxyeri-
tadenine (33)], trans-zeatin (34) in Zea mays (Poaceae), and
Lupinus angustifolius (Fabaceae) [lupinic acid (35)] (Atta-
or-Rahman and Choudhary, 1990). The uracil-derived amin'o
acid willardiine (36) has been isolated from the seeds of
Acacia willardiana and other species of this genus (Brown,
1991). The seeds of Lathyrus tingitanus contain another
amino acid, lathyrine (37), that is similar in structure (see
Chapter 13) (Brown, 1991). The pyrimidine glucoside vicine
(28) is the causative agent of favism, a genetic defect in
individuals that result in acute hemolytic anemia that can
prove fatal. This problem is most common in those of Medi-
terranean descent (Brown, 1991).
The fruits of Zizyphus jujuba (Rbarnnaceae) are con-
sumed directly and also used as a folk medicine in several
countries. This material, zizyphiJructus, contains the highest
levels of cyclic AMP (1100-500 nmoVg) known from either
plant or animal sourees (Hikino, 1985). This uriental plant
drug also contains high levels of cyclic GMP (30-60
nmoVg). Cyclic AMP may be responsible for the antiallergic
activity of this material (Hikino, 1985).
Biosynthesis
Cell-free enzyme systems capable of synthesizing caf-
feine (29) and related xanthines have been prepared from
 Miscellaneous Types of Alkaloids 701

(b) deoxybouvardin (27)

Fig. 37.8 (a & b). Peptide alkaloids.

702 Miscellaneous Types of Alkaloids

o CH, o

CH31~)
o '-NJ--N
'"llO
o N
I
N

CH,
I
CH,
xanthine skeleton caffeine (29) theophylline (30) theobromine (3I)

Y NH,

(x);
NH, ( N:):NH
I);
N?' N
~N NH OH

N N ~CO'H
(aJ
triacanthine (32) deoxyeritadenine (33) trans-zeatin (34) lupinic acid (35)

o
1~ N NH,

~CO'H
willardiine (36) lathyrine (37) vicine (28)
o o 0yNH,

HO_N~
Ayo.gIUCOSYI
o
J-.... NH,
O~N)
HN , ...
OJ-.HN

convicine
HO~
HO OH
3·hydroxyuridine (39) saxitoxin (40)
(bJ

Fig. 37.9 (a & b). Xanthine and related alkaloids.

Camellia (Thea) sinensis (tea) and Coffea arabica (coffee)
plants. Caffeine was fonned rapidly by extracts of green
coffee berries, but little by more mature ones, and not at
all by seedlings. Biosynthesis of caffein proceeds from 7·
methylxanthosine in the presence of an active purine nucleo-
side phosphorylase or 7.methyl·,y"·nucleoside hydrolase.
Methionine and S-adenosylmethionine serve as precursors
for the methyl groups of purine alkaloids. These act in the
presence of methyltransferases on 7·methylxanthine (38)
and theobromine (31) to produce caffeine. A pathway for
the origin of these compounds in coffee and tea plants has
been proposed (Suzuki et aI., 1992; Waller and Denner,
1981) (Fig. 37.10).
Physiological Activity of Xanthine
Derivatives
Xanthine derivatives have a number of phannacological
properties in common. Five major actions are observed: (I)
central nervous system and respiratory stimulation, (2) skele·
tal muscle stimulation, (3) diuresis, (4) cardiac stimulation,
and (5) smooth·muscle relaxation. Caffeine (29) increases
central nervous system activity and its main effect is on the
cerebral cortex, where it acts to produce clear thought and
reduce drowsiness and fatigue. The nonnal dose is 100-200
mg (Cordell, 1981). The oral LDso in mouse is 127-137
mg/kg; the oral LD50 in rat for theobromine (31) is 950

HO-P-O~
I
?
OH
&>--i6:f).- i:\) -iYy) OANH
HO OH 7-methylxanthosine
adenosine monophosphate (AMP)
-),j::> -'l)=5
o
1,3-dimethylxanthine (30) I-methylxanthine
(theophylline)
Fig. 37.10. Biogenesis of xanthine alkaloids (modified from Suzuki et aI., 1992; modified and used with permission of the copyright owner, Elsevier
Science Ltd., The Boulevard, Langford Lane, Kidlington OXS 1GB, UK).
mg/kg (Wink, 1993). Both caffeine and theophylline (30)
inhibit cyclic AMP phosphodiesterase (Wink, 1993).
Incorporation of I % caffeine (29) or theobromine (31)
into artificial diets was totally lethal to the bruchid Calloso-
bruchus maculatus (Janzen et al., 1977). Caffeine has anti-
feedant properties toward Phormia, polyphagous Syntomis
larvae (Lepidoptera), bees, Agelaius, Bombyx, and Ly-
mantria (Wink, 1993).
Caffeine is autotoxic to Coffea seedlings. Caffeine, the-
ophylline and theobromine inhibit growth of lettuce seed-
lings and certain other species of plants (Wink, 1993).
3-Hydroxyuridine (39), from plant material of Baillonella
toxisperma (Sapotaceae), inbibits growth of seedlings of sev-
eral plants and is responsible for the allelopathic effects ob-
served. However, the compound did not inbibit growth of
Zea mays (Ohigashi et al., 1989).
An unusual purine base, saxitoxin (40), has been isolated
from several marine dinoflagellates (Atta-ur-Rahman and
Choudhary, 1990). Saxitoxin inhibits Na+ channels. This
compound is considered to be the most toxin nonprotein
compound known; it has an LD50 i.p. in mouse of 10 J.Lg/kg
(Wink, 1993).
PYKAZIl'IE ALKALOIDS
Pyrazine alkaloids (Fig. 37.11) are known to occur in both
,Iants and insects. These alkaloids serve as warning and
!larm substances from lridomyrmex humilis ("driisena-
neisen") and Ondontomachus species ("Stachelameisen")
Miscellaneous Types of Alkaloids 703
NH
I
ribosyl
OANH N
oANJ-N
I
CH3
7-methyl,anthine (38) 3,7-dimethylxanthine
(31) (theobromine)
1,7-dimethylxanthine
caffeine (29)
(paraxanthine)
(Nahrstedt, 1982). Monarch butterflies sequester pyrazines
that have a quinoline-like odor from their host plant, Asclep-
ias curas.avica. It is thought that these compounds serve as
warning odors. In a sense, they may be aposematic odors,
as the insects are well protected with cardiac glycosides and
pyrrolizidine alkaloids. Other lepidoptera such as Zygaena
lonicerae and an Australia Amata species also contain these
compounds. One can smell the compounds from the last two
insects simply by disturbing them (Harborne, 1987, 1989;
Rothschild et al., 1984). The compounds are thought to arise
from the host plants.
3-Isobutyl-2-methoxypyrazine (41) is a major odor com-
ponent of Capsicum annuum. Pyrazines that lack the 2-me-
thoxyl substituent are partially responsible for the odor of
fermented and roasted coffee and cacao (Nahrstedt, 1982;
Rothschild et al., 1984).
SEClJIlIl'lEGA ALKALOIDS
Securinine (42) is the major alkaloid of Securinega suffruti-
cosa and related species. These alkaloids only occur in the
Euphorbiaceae. Eight of the 13 carbon atoms are derived
from tyrosine; lysine serves to label other parts of the mole-
cule (Fig. 37.12).
Securinine nitrate is a central nervous system stimulant
similar to but less toxic than strychnine. This compound
raises blood pressure, stimulates respiration, and increases
cardiac output (Cordell, 1981).
704 Miscellaneous Types of Alkaloids

3·propyl-2-mdhoxypyrazoline 3-butyl-2.methoxypyrazoline (41)

Capsicum annuum (Solanaceae)

Fig. 37.11. Pyrazine alkaloids.

G o
w
OH

CO,H
c8."~09~ CO,H HO CO,H

--+

~~- OP
securinine (42)

Fig. 37.12. Biogenesis of securinine (Leete, 1980; modified and used with permission of the copyright owner, Springer-Verlag, Berlin).

;600
~1u HN
o
HN
~
o o
o
sesbanine (43) sesbanimide A (44) sesbanimide B (45)
o
HN
o o
sesbanimide C (46) cycloheximide (47)
(actidione)
Fig. 37.13. Alkaloids from Sesbania.
SESBA1'IlA ALKALOIDS
A number of unusual alkaloids have been isolated from the
seeds of Sesbania drummondii (Fabaceae, coffee bean, rattle
bush, or rattle box), a plant of the southeastern United States
(Fig. 37.13) (Powell and Smith, 1981; Powell et ai., 1976,
1984; Suffness and Cordell, 1985). Other species of this
genus also appear to contain alkaloids. The seeds are poison-
ous to cattle, goats, and sheep. Although the alkaloid sesban-
ine (43) occurred in small amounts and was isolated as a
part of antitumor screens, the actual activity resided with
an even more minor compound, sesbanimide (44), that was
finally isolated in 5 X 10-'% yield. Sesbanimide is the
major cytotoxic and antileukemic compound in the plant.
Two additional antitumor compounds have been isolated,
sesbanimide B (45) and C (46) (Powell et al., 1984).
The structure of sesbanimide is similar to that of the anti-
biotics cycloheximide (47), streptimidone (48), and strepto-
vitacin A (49), but, so far, all evidence suggests that these
alkaloids are plant products and not fungal metabolites (Suff-
ness and Cordell, 1985).
8ETALAINS
Betalains are a group of alkaloidal pigments restricted to
about 10 families in the order Caryophyllales (formerly the
Centrospermae). These pigments occur in all plant parts,
vary in color from yellow to red-violet, exist as zwitterions,
are water soluble, and are accumulated in the vacuole. Two
main structural types and about 50 compounds have been
reported from plants (Strack et ai., 1993). The red color of
beets (Beta vulgaris) is due to the presence of the betalain
Miscellaneous Types of Alkaloids 705
0,/'-..0
"
H
OH
H
OHl
0
0
~
HN OH
'"
0
streptimidone (48)
OH
streptovatacin (49)
glucoside, betanin (50), a representative of the most common
type. In addition to these betalain pigments, the betaxanthins,
in which proline appears to replace the cyclodopa-derived
portion, are encountered in many plants of this group. This
second type is usually yellow in color (Steglich and Strack,
1990).
Betalain pigments in plants often were confused with an-
thocyanins until a number of investigators in the late 19th
century recognized that betacyanins contain nitrogen. How-
ever, purification of these pigments was difficult and, despite
study by many well-known chemists, betalains were not
fully characterized until 1963 (Wyler et ai., 1963). The be-
taxanthin, indicaxanthin (51), was characterized a year later
(Fig. 37.14) (Piatelli et ai., 1964).
Recently, a number of betalain pigments, as well as re-
lated metabolites, have been reported from fungi such as
Amanita muscaria (Dopp and Musso, 1974). Muscaflavin
(52), muscaaurin I (53), muscaaurin II (54), and similar com-
pounds now are known to occur in this species and several
other fungi, especially those of the genera Amanita, Hygro-
cybe, and Hygrophorus (Antkowiak and Antkowiak, 1991;
Steglich and Strack, 1990).
Techniques for the isolation and purification and instru-
mental methods for analysis of betacyanins have been re-
viewed (Strack et al., 1993).
8iosynthesis
Labeling studies indicate that tyrosine gives rise to both
parts of the molecule. However, little is known of the spe-
cific enzymology (Steglich and Strack, 1990). The formation
of cyclodopa (56) from DOPA has been difficult to establish.
Possibly, this occurs via a monohydroxylated precursor (Fig.
37.15) (Geissman and Crout, 1969).
706 Miscellaneous Types of Alkaloids

glucosyl-O
H

HO
, 10
CO"

11

I.

19 H .. ,.
CO,H
CO,H

£=<
betanin (SO) indicaxanthin (51)

00 """ o
HO"]N ,
"'"-
H - H

6 :5
HN+ CO,, CO,H
HN+ CO"
CHO

~~-
H H I
H H

HO,C"'- HN I CO,H
Ho,O"""" HN I CO,H
H
H
muscaaurin n (54) muscsaurin I (53) muscsflavin (52)
Fig. 37.14. Betalains, betaxanthins. and related pigments.

The presence of a series of structurally modified com-
pounds derived from DOPA in both higher plants and fungi
has been established (Fig, 37.17). Betalamic acid (57) has
been isolated from a number of betalain-synthesizing species
and a biogenetic pathway has been proposed (Fig. 37.16)
(Geissman and Crout, 1969; Fischer and Dreiding, 1972).
Stizolobic acid (55) occurs in Mucuna (Fabaceae); and mus-
caflavin has been found in several fungi (Fig. 37.17) (Mabry,
1977).
Most betalains and indicaxanthin (51) have a 2S configu'

H0:():J
HO
I :::,...
H,N CO,H
--+
~'<::::
u+
0
"".Q4"
H,N
--
CO,H
O~

HO~NH~CO'H -
DOPA

H0:(Q
I
HO:::"" NH CO,H
--
~
I
HO:::"" NH CO,H
4-

cyclodopa (56)

Fig. 37.15. Biogenesis of cyc1odopa (modified from Geissman and Crout, 1969).
 H0'fln
HO~
H.
H,W/A....CO,H
-
e· H'

,;7:1
"'"
OH

OH
Miscellaneous Types of Alkaloids

--
707

DOPA HOzCI>""" NHz

H

betanidin betanin (SO)

Fig. 37.16. Biogenesis of betanin (modified from Fischer and Dreiding. 1972; used with pennission of the copyright owner, Swiss Society of
Chemistry, Basel).

Hofu'~
: I
HO .."" H,N eO,H

/
b
DOPA

° ° HO

HO'cH~
O~NJe~
~
---' HO,e

HO ~ I
H,N eO,H
HO'~ :;=
H~H,N"~eO'H
/0
C

H'N-\'H

D
° ° eO,H

muscaflavin (52) stizolobic acid (55) betalamic acid (57)

Fig. 37.17. Cleavage of DOPA to produce muscaflavin, stizolobic acid, and betalamic acid (Mabry, 1977; modified and used with permission of the
copyright owner, Dr. T. J. Mabry),
708 Miscellaneou.f Types of Alkaloids
ration. Differences at C-15 have been encountered; both an
R and S series at that center are naturally occurring.
In the presence of a weak base, betacyanin and betaxan-
thin pigments undergo exchange reactions in which the dihy-
dropyridine portion of the pigment is transferred from one
amino acid to another. For example, in the presence of am-
monium hydroxide and proline, betanin (50) yields indicax-
anthin (51). Similar in vivo conversions may occur in plants.
Betalains are synthesized by hairy root cultures of Beta
vulgaris. The alkaloids are not excreted into the medium
(Flores et al., 1987).
Chemosystematic: Value
The distribution of betalains and anthocyanins in plants
is completely mutually exclusive. Betalains are found in the
families Aizoaceae, Amaranthaceae, Basellaceae, Cacta-
ceae, Chenopodiaceae, Didieriaceae, Nyctaginaceae, Phyto-
laccaceae, Portolacaceae, and Steguosperrnaceae. These
families, along with the families Caryophyllaceae and Mol-
luginaceae, are placed in the order Caryophyllales or, for-
merly, Centrospennae. Anthocyanins are known from the
last two families, but not from others in this order. Betalain
pigments from plants of the Caryophyllales have been tabu-
lated (Steglich and Strack, 1990).
A number of small genera from several families of the
Caryophyllales have been segregated and some are consid-
ered as families. However, the presence of these pigments
within the genera Agdestis, Dysphania, Gisekia, Halophy-
tum, Heetorella, and Petiveria suggest that these plants
should be maintained in the order Caryophyllales. Nonethe-
less, these data alone do not answer questions concerning
the rank at which they should be accepted.
Some have suggested that the small families Batidaceae,
Gyrostemonaceae, and Theligonaceae should be included in
the Caryophyllales. The absence of betalains and special
sieve-tube plastids containing protein inclusions from all
three families has been reported (Behnke and Turner, 1971;
Goldblatt et al., 1976; Mabry and Turner, 1964; Mabry et
al., 1975). These rmdings suggest that these families are
not close relatives of the other betalain-containing families.
Although the Batidaceae lack anthocyanins, these com-
pounds are present in the Theligonaceae and Gyrostemona-
ceae.
It has also been suggested that the betalain- and anthocya-
nin-producing families of this order developed from a com-
mon ancestor before the widespread occurrence of floral pig-
ments in angiospenns (Mabry, 1976). All families of the
Caryophyllales contain sieve-tube cells with proteinaceous
inclusions which are not encountered in other plant families.
However, because anthocyanins are known from most other
groups of plants including gymnospenns and ferns, it seems
likely that the ancestors of the Caryophyllales also possessed
anthocyanins.
Certain results of cladistic analyses suggest that the Mol-
luginaceae and CaryophylJaceae are not closely related, but
are relatively advanced and derived from betalain-containing
members of the order (Rodman et al., 1984). If so, the ability
to synthesize anthocyanins has been lost in most members
of the order but has been regained in these two families.
Two other families frequently allied with the order Caryo-
phyllales, the Polygonaceae and the Plumbaginaceae, are
shown to be more distantly related (Rodman et al., 1984).
To date, no plants are known that contain both types of
pigments.
Betalalns In Foods and Beverages
Adulteration of wines with juices of beets and of the froits
of Phytolaeea species has been known since at least 1860.
The similarity of spectral properties of anthocyanins and
betalain pigments makes this somewhat difficult to detect.
However, the pigments can readily be separated by electro-
phoresis and routine screening of many wines is conducted
(Strack et al., 1993).
Betanin from beets is used as a colorant in ice cream,
jam, and froit conserves (Strack et al., 1993).
JIIISCELLAl'IEOUS ALKALOIDS
Trigonelline and an Unusual Pyrrole
Trigonelline (59), N-methyloicotinic acid (Fig. 37.18), is
capable of promoting specific G2 cellular arrest but this ac-
tivity is dependent on the age of the organism. An unusually
substituted pyrrole (58), produced by older seedlings of
Pisurn sativum (Fabaceae), functions as an endogenous regu-
lator of trigonelline-induced G2 arrest. The ED50 of exoge-
nously added (58) in the inhibition of trigonelline-induced
cellular arrest in G2 is 5 X 10-7 M. This compound occurs
in sufficient quantities to account for the inability of trigonel-
line to induce G2 arrest in older roots (Lynn et aI., 1987).
HistronlonlC:otoxins
A series of potent alkaloids were first isolated from den-
drobatid frogs of western Colombia and northwestern Ecua-
dor, but are now known to be more widespread in distribu-
tion. These alkaloids affect at least three classes of channels
in nerve and muscle. The first two are receptor-regulated
channels, in particular the nicotinic acetylcholine receptor
channel. The histrionicotoxins are noncompetitive blockers
of this receptor-channel complex (Daly et al., 1993). The
second class of channels are the voltage-dependent sodium
channels. Histrionicotoxins reduce conductances in a man-
ner reminiscent of local anesthetics (Daly et al., 1993). De-
spite these effects, these alkaloids have relatively low toxic-
ity (Daly et al., 1993).
HuperzineA
The club moss Huperezia serrata has long been used in
Chinese traditional medicine. An alkaloid from this plant,
huperzine A (60) is one of the few drugs that appears to

~C02-
HOJJ---CHO
~N)
N
Cr"
I
CH3
(58) trigonelline (59)
Fig. 37.18.
have activity for treating Alzheimer's disease (Borman,
1993; Zhou et al., 1993). Clinical trials in China suggest that
the alkaloid improves memory and learning in aged individu-
als with memory impairment and also improves function in
patients with myasthenia gravis. Huperzine A exhibits strong
anticholinesterase activity (Zhou et al., 1993).
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Index

Abies 337, 338 acetic acid, 59, 514, 532, 674 actinomycin D, 568
Abies balsamea, 338, 383 acetoacetate, 19, 532, 539, 693 actinomycins, 568
Abies iasiocarpa, 338 acetoacetyl-CoA.313 Acu/eiferum, 287
abietanes. 405, 406. 412 acetoacetyl-CoA thiolase (AAeT), 313 acyl-ACP, 3, 21
abietic acid, 312, 412, 415 acetogenin, 56, 67, 74, 139 acyl-ACP thioesterase, 21
abiotic stress, 8 acetone, 206, 276, 535 acyl-ACP:glycerol-3-phosphate acyltransferase,
abortifacient, 404. 420 acetosyringone, 123 23
abortion, 227, 404 6-acetoxytoonacilin, 480. 484, acyl-ACP-l :lysophosphatidic acid
abrin. 231, 244 N-acetylanthranilic acid, 568, 570 acyltransferase, 23
Abrus fruticulosus, 463, 471 acetyl-ACP, 19 acylation, 23
Abrus precatorius, 244, 245, 463, 470 acetylcholine, 510, 511, 526, 528, 600, 609, acyl carrier protein (ACP), 3, 16, 19, 21, 23,
abrusosides A-D, 463, 470 664, 675, 697 40,41
abscisic acid, 3, 6, 33, 132, 145,367,500,501, acetylcholine receptors, 526, 528, 643 acyl-CoA, 3, 21, 57, 67
504,505 acetylcholinesterase, 599, 600 acyl-CoA alcohol transacylase, 5 j
( + )-(S)-abscisic acid. 500 acetyl-CoA, 6, 19-21,24,25,57,58, 121, acyl-CoA:lyso-phosphotidylcholine
abscission,leaf,415 313,531,532,539 acyltransferase, 26
absinthe, 346 acetyl-eoA carboxylase, 19 l-acyl-glycerol-3-phosphate,23
absinthin. 389 acetylenic carotenoids, see carotenoids, 3-0-acylingenol, 402
Abuta, 442, 588 acetylenic acyltransferases, 21, 23
Abuti/on theophra,., 84, 99, 309-311, 390, acetylenic compounds, 16, 42-50, 113. 136, Acyrthyosiphon, 559
697,711 222,324,381,387,420,514 Acyrthosiphon nipponicus, 363
Acacia, 53, 79, 193, 194, 218, 227, 233, 273, N-acetylglucosamine, 261 Acyrthosiphon pisU, 559
284,287,289,299 N-acetyl-D-glucosamine, 253 Acyrthyosiphon spartii, 559
Acacia berlandieri, 517 ,B-N-acetylglucosaminidase, 561 addictive properties, 523, 526, 588
Acacia catechu, 204, 260, 528 P.N-acetylhexosaminidase, 562 additives, food, 171,245
Acacia chiapensis, 289 3-acetyl-6-metboxybenzaldehyde, 125 Adenia, 285, 296
Acacia collinsii, 53 2'-acetylneriifolin, 468, 472 adenosine 5'-(a-D-glucopyranosyl
Acacia cornigera. 289 N-acetylphenylalanine, 238 pyrophosphate),249
Acacia jarnesiana. 289 O-acetyIserine, 219. 220 Adenostomafasiculatum, 125, 126
Acacia globulifera, 289
O-acetyl-L-serine, 219. 220 Adenostyles leucophylla, 552
Acacia hindsii, 289
N-acetyltryptamine, 660 S-adenosyhnethionine (SAM), 27, 45, 69, 186,
Acacia /caroo. 193 Achariaceae. 285, 287, 296 230, 238, 436, 508, 518, 531, 587, 598, 663,
Acacia mearnsii, 204, 206
Achillea millefolium, 88 664,702
Acacia melanoxylon, 79, 200
achiote, 499 S-adenosyl-L-methionine:3'-hydroxy-N-methyl-
Acacia senegal, 260
Achlya 444 (S)-coclaurine-4'-O-methyltransferase, 587
Acacia sieberiana. 284 S-adenosylmethionine:bergaptoIO-
Achlya ambisexualis, 444
Acacia sutherlandii, 284
Achlya heterosexuaIis, 444 methyltransferase, 133
Acacia willardiana. 700
Achras sapota, 318 , 321 S-adenosyl-L-methionine:(S)-scoulerine 0-9-
acacipetalin. 284
Acalypha indica, 286, 528, 529
Achryanthes, 442 methyltransferase, 598
acalyphin, 274, 286, 528 L-acofriose, 250, 251, 252 S-adenosylmethionine:xanthot9xol 0-
Acalyphoideae, 286 Acokanthera schimperi, 468 methyltransferase, 133
Acanthaceae, 101, 173, 361, 364, 365, 370, aconine, 675 adenovirus, 648
387,432,522,533,569,570,660,693 aconitiform activity, 675 adenylate cyclase, 420, 424
Acanthomyops cJaviger, 341 aconitine, 673-675 adenyltransferase inhibitor, 339
Acanthus mollis, WI, 105 Aconitum, 269, 673, 674 Adhatoda, 569, 570, 660
accumulation, vii, 1-9, 11, 13, 15, 19.25,29, Acorus calamus, 111, 129 Adhatoda vasica, 570
30,32,33-35,43,48,77,80,82,84-86, L-acovenose, 251, 252 adhesives, 12, 413
88, 92, 95, 115, 124, 132, 138, 143, 145, ACP transacyiase, 19 Adiantum, 174
151-153, 155, 156, 158, 166, 173-175, 184, ACP-track, 52 Adonis, 269
186, 195,200,217,229,249,253,256,257, Acraea, 289, 297 Adoxaceae, 360
261, 262, 264, 265, 270, 275, 294, 303, 326, Acraea horta, 289 ADP/ATP carrier protein, 420
337,339,368,377,502,535,557,558,565, Acremonium, 659 ADP-glucose, 162,249
566, 634, 664 Acrididae, 208, 316 adrenal gland, 439
Acer, 195, 197, 223, 232, 523 actidone alkaloids, 8, 12, 568, 570, 573-576, adrenaline, 591, 640
Acer pseudoplatanus, 242 610 adrenergic blocking agents, 659
Aceraceae, 195, 197,217,222,223,231,458, Acro/epiopsis assectella, 227, 459, 468, 470 a-adrenergic blocking agents, 640
523 Acronychia, 574 adrenergic drugs, 511, 522
Aceratium, 563 acronycine, 574 adrenolytic activity, 591
acetate, 19, 26, 31, 42, 45, 52, 56, 58, 59, 63, Actaea, 269 adults, 41, 99,109,111,113,124,221,223,
64,67,68,72-74,80,85, 113, 114, 118, actin filaments, 237 227,228,253,285,294,308,317,362,364,
139, 142, 152, 174, 182, 187,203,206,222, Actinidia po/ygama, 362, 366 366,384,418,441,447,550,551,552,669,
269,303,313,316,377,384,442,447,463, Actinidiaceae, 361, 362 682,683
465,466,471,507,543,669,678 actinidine, 362, 669 Aegilops, 101, 128
acetate-malonate pathway, 56, 65, 76, 80, actinidiolide, 362 Aegi/ops ovala, 118
85-87, 104, 121, 122, 148,531-534,539, Actinomycetes, 65, 244 aesculetin, 130
543, 561, 570, 571, 573 actinomycin A, 568 Aesculus californicus, 222

713
714 Index

Aesculus hippocas/anum, (horse chestnut), 231 alcohol. 16.30,31,37.38.44,51-55.58. 108. isopavine. isoquinoline, jervatrum. lupine.
Aesculus parviflora, 218, 222 109. ll5. 122, 315 mesembrine. Mesembryanthemaceae,
Afghanistan. 553 alcohol dehydrogenase, 599 monoterpene, monoterpene-iridoid.
aflatoxin, 5, 65, 66, 70 alcohols,long chain, 51 monopterpene-derived indole alkaloids,
aflatoxin Bit 420 aldehyde. 2. 3. 13. 16.30.31.44.51.58.63. morphinandienone, morphine, muscarine,
Africa. 29. 48, 77. 85.177.209.210.213.222. 109. 113. 122. 288. 324. 328. 339. 376. 507. naphthylisoquinoline, Nuphar, oxaporphine,
228. 245. 288. 361. 365. 379. 390. 395.402. 508.509.513.531.548.549.578-581.586, pavine, peptide, phenanthroindolizidine.
4ll. 425, 460. 468. 477. 478, 480. 481. 484. 587.600.610.630.631.656.663 phenanthroquinolizidine,
514. 522. 551. 553. 558. 588. 623. 640. 641. alder. European black. 83 phthalldeisoquinoline, Picralima, piperidine,
647.676. 698.700, 7ll alder, green, 451 polyamine, polyhydroxypiperidine,
(+ )-afzelechin-7-0-,B-D-apioside. 463 aldol condensation, 57. 63. 64. 142. 155.507. proaporphine, protoherine, protopine, purine,
Agalinis.78 531 pyranoquinoline, pyrazine, pyridine,
AgaUnis purpurea, 78, 452 aldol reductase, 588 pyrrolidine, pyrrolizidine,
agar, 260 aldopentoses, 248 pyrroloquinazoline, quinazoline,
Agaricales,46 aldose reductase. 588, 591. 599, 600 quinazolinocarboiine, quinoline, 4-quinolone,
Agatha. 413 aldoses, 247. 248. 249.262 quinolizidine, quinolone, rhoeadane,
agathic acid, 420 aldoxime. 275. 276. 303 rutacridones. sarpagine, Sceletium,
Aga/his australis, 405 Alectra, 392 secophthalideisoquinoline, Securinega,
Agauria salicifolia, 411 aleprolic acid, 26, 28 taxane, Taxus, tetrahydrobenzylisoquinoline,
Agavaceae. 231. 257. 457 Aleurites, 402, 403 tetrahydroprotoberberine,
Agave wightii, 457 Aleurites ford;;, 35, 244 tetrahydroisoquinoline, tropane,
Agdes/is, 708 Alexa, 253, 561 tropoloisoquinoline, Veratrum, and xanthine
Agelaius. 523. 528. 619. 640. 650. 651. 703 alfalfa. 31. 39. 53. 83. 167. 179. 181. 183. alkaloids, and C-alkaloid E. C-alkaloid G,
Agera/um houstonianum, 317. 384 189-192.261,270.393,457.459.460 glycoalkaloids, glycosidic alkaloids,
agglutination, 244 algarobilla, 195 protoalkaloids. pseudoalkaloids, saponic
aggregation pheromones. 35-37, 41. 111,324. algae. 4. 9. 26. 29, 32. 39. 46. 48. 56. 70. 96. alkaloids
342. 344, 383 114.130.142.172.242.246.254,265.266, alkaloid N-oxides. 507. 546, 547. 550, 552.
aginoside, 459 324. 340, 380. 381. 396. 419. 420. 425. 433. 553. 565. 662
Aglaia cordata, 480 435.486.488.492,495.497,510.515 alkamides. 514. 528
Aglaia adorata, 533 algae. blue-green, 4. 234. 239, 240. 246 aikaues. 30. 53. 54
aglycone. 5, 85. 124. 136. 151. 152. 158. 159. algae. brown. 32. 210. 260, 265. 420. 495. 497 alkenes. 30. 53
165-167. 170. 171. 173. 174. 177. 178.201. algae. green. 172,234.239.240.246,257. alkylation. 316. 549. 553. 656
N-alkylation, 316
267.273.274.287.288.296.302.303.361. 260.265.340.381.396.419.420.494.495,
497 O-alkylation.316
366. 441. 456. 459. 682
Allamanda cathartlca, 364, 365
agmatine, 531 algae. red, 29. 40. 260, 265. 340. 381. 442.
Agrimonia. 209 495.513.515 allamandin. 364. 365
allelochemics. 9
agrimony. 209 algal blooms. 239
allelopatbie compuunds. 26. 32. 70. 78. 79. 83.
Agrobac/erium tumefaciens. 47, 110, 123, 129, algicidal. 78. 145
85.99. 122. 125-127. 174, 310. 311,
520 alginate. 260
agrobactine, 521 alginic acid, 260 344-346.350.367.389.390.394.395,424.
451. 510. 523. 703. 7ll
agroclavine, 655-658 alimentary toxic aleukia, 378
allelopathy. vii. 38. 41, 78. 83. 85. 92, 106.
Agros/is/achys hookeri, 420, 423 alizarin, 65, 87. 89
109. 122, 125-127.300.309.324.344.345,
AIDS. 562 alkaline phosphatase, 208
350. 367. 376, 395. 396, 453. 454
Ailanthus, 660 alkaline picric acid, 273 allenic acids, 49
Ailanthus aitissima, 662 alkaloid biosynthesis, 2, 8, 16 aIlenic group, 49
Aizoaceae, 623, 708 alkaloid enzymology, 2 allenic linkage, 45
ajma1acine. 2. 10. 506. 628-632. 640. 645. 654 alkaloids derived from both phenylalanine and allergenic effects. 67. 78. 267. 269. 389
19-epi-ajmalicioe, 630 tyrosine, 617 alligator weed. 168
ajmalidine, 640 alkaloids. 2. 3, 6, 8-15.93.97. 102. 106. 107, alliin. 227
ajmaline, 640 138. 171. 188. 209. 240. 254. 270. 289. 309. meso-allitol. 264
A}uga. 418. 442 321.324.351.360.361.365.366.369.385. Allium. 226, 227. 459. 468. 588, 597
Ajuga remota, 418 398.412.428,441.472,477.506.507. Allium cepa, 34, 38
ajugarins, 418 509-513. 517, 520-523. 525. 528-533, 538. Allium porrum, 51
akee.222 539.542-571.573-588.591-601.603-617, allocryptopine, 600, 601
akoammicine, 632. 634 619-632.634-643.645-659.661-678. allomatatabiol, 362
akuanunidine, 641 680-686. 689-695. 697, 698. 700. 703. 705. D-allomethylose, 250
akuammine. 641 708-711; see also acridone, Ammyllidaceae, allomones.9. 10. 83. 110. 168. 300. 307. 324.
Alangiaceae. 360. 579, 581. 598. 612. 639 3-aminospirostane. aporpbine. 339-341.352.367.379.380,382,383,390.
alangiside, 611 Aspidosperma, Aspidosperma- Hunteria, 447.486,511
Alangium lamarckii. 611-613 azafluoranthene, benzophenanthridine, Allomyces arbuscula, 376
alanine. 220. 300. 302. 513 benzylisoquinoline, berberine, Allomyces javanicus, 376
alanine aminotransferase, 601 bisbenzyHsoquinoline, bisindole, Buxus, Allomyces macrogynus, 376, 396
L-alanine:aldehyde aminotransferase, 1 Calycanthus, carbazole, p-carboline. Allophylus cobbe. 285. 289
DL-alanine-DL-aspartine (DL-ala-DL-asp), 240 Ca/haranthus, Cephalotaxus. ceveratrum, allose. 247. 249
DL-alanine-DL-Ieucine (DL-ala-DL-leu), 240 clavine, Corynanthe. Cryp/ostyline, cularine, alloxanthin. 498
DL-alanine-DL-metbiooine (DL-ala-DL-met). dehydropyrrolizidine, dibenzopyrrocoline, allyl isothiocyanate, 266, 308, 309
240 dihydrofuroquinolone, diterpene, S-allylcysteine, 227
alantolactone, 390, 392 ebumamine-vincamine, 22,26- S-allylcysteine sulfoxide, 227
Alaska,673 epiminocholestane, ergot, peptide, Erythrina, allylglucosinolate. 303. 307. 308. 309
Alberta. 338 Erythrophleum, Eupomatia, evoninoate, allylic oxidation, 42, 43, 387
Albizia, 227, 228 furoquiooline. harman, hasubanan, allylic pyrophosphate. 315. 326. 370. 371, 393
Aiblzia amara, 521, 529 hemiterpene, homoerythrina, Hun/eria, S-allylmercaptocysteine, 227
albiziine, 227, 228 hydroxyindolizidine, iboga, ibogan, almond. 287. 290. 294. 415. 561
Alces alces, 207 imidazole, indole, indolizidine, Alnus, 363
Alchornea, 640, 692, 693 iodoJoquinazoline, ipecac, ipecacuanha, Alnus crispa, 451
 Index 715

Alnus glutinosa, 83 2-aminoadipic acid, 218, 226 /l-aroyrin, 432, 447, 452, 458
Aloe, 85-87, 91, 543 L-2-aminoadipic acid, 234 p.amyrin cyclase, 447
Aloe saponaria, 85 6-(L-aminoadipyl)-L-cysteinyl-D-valine, 234 anabasine, 507, 508, 510, 526, 528, 538, 539
aloesaponarin. 85, 86 L-2-amino-6-(amidino)hexanoic acid, 227 Anabasis aphylla, 557
alpinigenine. 603 p-aminobenzoate synthase, 97 Anacardiaceae, 67, 68, 88, 173, 195, 197,206,
Alstonia. 637, 640, 660 p-aminobenzoic acid, 97, 105 269,337,412,447
Alstonia angustifolia, 640 4-aminobutanal, 549 anacardic acid. 68, 74
alstonine, 640 y-aminobutyric acid (GABA), 221, 517, 588, Anacridium melanorhodon, 208, 212
Aistroemeria, 269 698 Anadenanthera peregrina, 514
Alstroemeriaceae, 269 2-aminobutyric acid, 513 anaferine, 539
Alternanthera philexeroides, 168 4-aminobutyric acid, 221 Anagallis, 444
Alternaria, 238 4-arylcoumarins, 187 anagyrine, 552, 558, 559
Alternaria alternata, 67 S-(3-amino-3-carboxypropy1)-8-methyl anabygrine, 539
Alternaria kikuchiana, 238 sulfoxime, 231 anal glands, 343
Alternaria mali, 238 l-aminocyclopropane-l-carboxylic acid (ACC), analgesia, 122,346,596,597,623,646,650,
Alternaria solani, 377, 397 230,231,233,238,297,289 670
altholactone, 139 l-aminocyclopropane-l-carboxylic acid anamafana, 36
L-altromethylose, 250 synthase (ACC-synthase), 230 Anamirta, 385
altrose, 249 2-amino-2-deoxy-D-glucose, 250 Anartia. 363, 637
aluminum, 171 26-aminodibydrodiosgenin, 680 Anastrepha suspensa, 340
Alyssum, 309 L-2-amino-6-guanidinohexanoic acid, 223 anatabine, 526, 538
Alzheimer's disease, 710 cis-l-amino-3-hYdroxymethYlcyclobutane-l- Ancistrocladaceae, 698, 710, 711
Amanita, 235, 237, 246, 697, 705 carboxylic acid, 222 Ancislrocladus, 698
Amanita muscaria, 35, 697, 705 2-amino-4-methylhexanoic acid, 222 Ancistrocladus abbreviatus, 698, 710, 711
Amanita pantherina, 235 2-amino4-methylenehex-4-enoic acid, 222 Ancistrocladus korupensis, 698, 711
Amanita phalloides, 235, 237 2-amino4-methylhex-4-enoic acid, 222 Ancistrocladus tectorius, 698
Amanita verna, 235 2-amino-4-methyl-6-hydroxyhex-4-enoic acid, andirobin, 476
Amanita virosa, 235 222 Andrachne, 610
Amanitaceae, 35 2-amino-5-methyl-6-hYdroxyhex-4-enoic acid, Andrena, 344, 381
a-amanitin, 237 222 androcymbine, 617
amanullin,237 L-2-aminooxy-3-phenylpropionic acid (AOPP), Androcymbium, 617
Amaranthaceae, 79, 168, 179,387,390,442, 195 Andrographis paniculata, 370, 375
458, 662, 708 a-amino-,8-propionic acid, 294 andromedane, 411
3-aminopropionitrile, 223, 226 Andropogon gerardii. 125
Amaranthus palmeri, 79, 376
,8-aminopropionifrile, 226 Andropogon nardus, 346
Amarathus retrojlexus, 390
( - )-a-aminopropiophenone, 522 anemia. acute hemolytic, 700
Amaryllidaceae, 231, 457, 510, 560, 617, 619,
aminopropyltransferases, 517 Anemia mexicana, 414. 424
620, 622-624, 627
3-aminospirostane alkaloids, 677, 681 Anemone, 269
Amaryllidaceae alka1oids, 617, 619, 620
Ammi majus, 133, 135, 138 Anemonel/a, 269
Amato, 703
Ammi visnaga, 137 anemonin. 269
amatoxins, 237
(R)-anunirin, 135 Anemonopsis, 269
Amazon, 588, 607
ammodendrine, 538 anesthesia. 36
arober,413 Ammodendron conolly;;, 538 anesthetic compounds, 136. 525, 535, 537,
Amblyptilia mica, 669 ararnonia, 220, 221, 253, 290, 669 607,641,650,676
Ambrosia, 47, 376, 387, 388, 392, 395 ammonium hydroxide, 708 anethole, 344
Ambrosia artemisiifolia, 376 amebiasis. 599 E-anethole, 113
Ambrosia chamissonis, 388 amoorastatin, 481 Anethum graveolens, 241
Ambrosia confertiflora, 388 Amorpha, 158, 186 angelic acid, 321, 322
Ambrosia cumanensis, 388 Amorpha fruticosa. 158 Angelica, 136
Ambrosia psilostachya, 387, 388 AMP phosphodiesterase, 267 angelicin, 135, 136
ambrosiol, 388 cAMP phosphodiesterase, 120 angina pectoris, 588
amebicidal, 559, 652 amphetamine, 522, 529 angiospenn, 12, 13, 19,50,92, 115, 142, 172,
amenorrhea, 570 amphibians, 510, 552, 560, 561 173, 176, 194,212,265,280,286,310,324,
amentoflavone, 173 amphipods, 340, 381, 420 365, 387, 401, 405, 442, 454, 510, 533, 544,
Ames assay (mutagenesis), 165 Amphypterygium adstringens, 67, 74 545,708
aroides, 36, 508, 513, 514, 517, 518, 528, 529, Ampithoe /ongimana, 420 angustifoline, 554, 555, 556, 558
576, 617, 655, 659 Amsonia. 640 (+ )-angustifoline, 554
amine oxidases, 509, 510, 531 AM-toxin I, 238 Angylocalyx, 253
aroines, 10,37, 105, 123,507,508,513-517, aroygdalin, 254, 277, 279, 280, 287-289, 297, anbaladine, 581
529, 530, 575, 579, 610, 666 299 anbalarnine, 579, 580, 581
amines, primary, 507, 509 (R)-aroygdalin, 277, 287, 297, 299 anhalanine, 581
amines, secondary, 507 amygdalin hydrolaae, 280 anhalonidine. 581
amines, simple, 507, 513-515, 521 aroygdalin 6"(4-hydroxybenzoate), 277 anhalonine, 581
amino acid metabolism, 508 amygdalin 6"[4-hydroxy-(E)-cinnarnate], 277 (3,6-anhydro-L-xylo-hexulono-l,4-lactone
amino acids, vii, 3,5, 6, 8, 13, 19, 28, 46, 94, Amygdaloideae, 264, 287 - hydxate, 265
97, 101, 102, 104, 105,207,209,216-232, a-amylases, 259 1,5-anbydro-D-mannitol, 262
234,237,241,244,274,277,290,294,300, /l-aroylases, 259 3',4'-anbydrovinblastine,- 645, 652
302,303,314,462,506,508,513,568,619, amyloglucosidase, 561 Aniba, 139
657,680,698,700,708,710 amyloidosis, 619 Aniba colo, 139
a-amino acids, 508 aroylopectin, 257, 259, 260 Aniba duckei, 528
D-amino acids, 234 aroylose, 257-260 Aniba pseudocoto, 139
L-amino acids, 215, 216, 234, 302 amylo-(l,4-> 1,6)-transglucosylase, 259 anibine, 528
amino acids, a-hydroxy1501 amyotrophic lateral sclerosis (ALS), 226. 294. animals, 3, 9, 10, 12, 13, 16, 17, 19, 24, 30,
amino acids, primary, 215 299 32,33,35,47,59,70,71,76,78, 80,91,
amino acids, sulfur-containing, 226. 227 a-aroyrin, 432, 447 94, 102, 106, 137, 165, 167, 176, 177, 179,
716 Index
187, 193,206-208,210,222,223,226,234,
235,239,241,242,244,245,252-254,261,
264,274,286,288-290,294,296,306,307,
317,324,329,338,339,341,349,361,365,
378,390,420,427,433,435,437,439,442,
445, 452, 456, 460, 462, 466, 479, 486, 498,
503,506,508,510,511,513,515,517,518,
520, 533, 537, 538, 542, 546, 549, 552, 553,
559, 561, 568, 581, 588, 597, 615, 618, 640,
645, 658, 659, 677, 681, 682, 684
animals, polyphagous, 380, 390, 437, 445, 591,
597,603,613,618,619,640,641,662,664,
703
anisaldehyde, 122
anise. 122
Anisomorpha buprestiodes, 341
Anisotes, 569, 570
annatto,499
Annona cherimolia. 67. 73
Annona muricata. 67
Annona reticulata. 585
Annona squamosa, 67
Annonaceae, 46, 59, 67, 74, 104, 105, 139,
290, 392, 581, 585, 588, 598, 609, 610, 614,
639
AnnonaIes, 337
Annoniflorae. 337
anodynes, 673
Anopterus. 673
anolexia, 364
anrakorinine, 684
ansamycin. 695
ant, see also ants
ant, Australian cocktail, 669
ant, thief, 533, 542, 552
antagonisms, 4; see also calcium antagonists.
serotonin antagonists
antenna pigments, 496
antennae, 552
antenna! receptors, 309
anthelminthic compuods, 28, 69, 346, 479,
539,599
Anthemideae, 36, 46, 387
Anthemis altissima. 277
Anthemis cairica. 277, 297
Anthem;! glycoside A. 277
Anthemi! glycoside B, 277
antheraxanthin, 496, 504
antheridia. 444
antheridiogens, 414
antheridiol, 444
antheridium, 414, 424, 444
anthochlors. 174
anthocyanidin, 151, 152, 162, 163, 167,
170-172,177, 191, 193, 200, 204, 206, 213
anthocyanin biosynthesis. 162. 163
anthocyanins, 8, 151, 152, 156, 158, 159, 162,
163, 170, 171, 175, 177, 189, 190, 193,498,
653, 70S, 708, 709
Anthonomis grandis. 35, 342, 542
anthothecol, 480
anthranilate synthase, 98
anthranilic acid, 11, 94, 98, 99, 459, 507,
568-571, 575, 576
anthraquinone glycosides, 76, 89, 91
anthraquinones, 8, 9, 56, 64, 65, 76, 80, 82,
85-89,91,92,94, 104, 177
anthrone dimers, 76, 91
anthrones, 76, 85, 88, 91
Anthyl/is l'uineraria, 184
antiamebic activity, 559, 599, 612, 686
D-antiarose, 250
antiarrhythmic effects, 600, 640, 675
antiarthritic compounds, 392
antibacterial activity. 48, 85, 267, 339, 392,
510,525,601
antibiotics, 4, 6, 35, 48, 56, 64, 65, 71, 77, ants, 35, 53, 54, 88, 124, 176,273,289,291,
192, 209, 234, 235, 249, 253, 262, 309, 310, 340,341,343,344,361,362,380,382,419,
389, 395, 415, 458, 481, 601, 695, 698, 705 447,452,514,538,540,542,552,563; see
antibiotics, macrolides, 65 also ant, Driisenameisen. fire ants,
antibiotics, macrocyclic. 65 Stachelameisen
antibiotics, ansa-macrolide, 694 anls, leaf cutter, 340, 380,452, 514
antibiotics, polypeptide, 601 ants, Pharaoh, 563
anticancer properties, 379, 423, 452, 453, Aphanamixis, 477
481-483,564,576,619,627,645,652,696 Aphanamixis grandi/olia, 481
anti-carcinogenic properties, 210 aphanostatin. 481
anticholinergic drug, 537 Aphelandra squarrosa, 522
anti-cholinesterase activity, 709 Aphelenchoides besseyi. 419
anticoagulants, 132,261 aphids, 41, 53, 99, \05,262,269,270,308,
anticonvulsants, 136, 591 340, 343, 349, 362, 363, 365, 366, 383, 468,
antidepressant, 148 525, 550, 552, 559, 562, 567
antidiarrheal compounds, 599, 600 aphid, black hean, 363
antidotes, 179 aphid, cabbage, 308
antiexudative, 460 aphid, damson-hop, 363
antifeedants, 49, 113, \18, 136, 138, 213, 267, aphid-host plant compatibility, 262
288, 316, 361, 365, 379, 380, 390, 395, 396, aphid. melon, 67
398, 412, 415-418, 423-425, 472, 473, aphid, pea, 363
478-481,483,484,570,573,591,623,682, aphid, peach-potato, 363
696,703 aphid, turnip, 383, 393
antifertility compounds, 553. 566 aphid, vetch, 363
antifungal activity, 26, 35, 40, 47, 48, 64, 85, Aphis cylisorum, 559, 567
\18, 145, 146, 148, 179, 183, 269, 309, 3\0, Aphis fahoe, 363
339,392,414,447,458,459,510,515,517, Aphis nerii, 468
525, 558, 591, 599, 601, 603, 682, 683, 685 Aphis po/ygama, 362, 363
antigenic effects. 244 aphmdisiac, 36, 382, 537, 550, 552, 640
antihepatotoxic compounds. 168 Apiaceae, 3, 26, 39, 42, 45-48, 73, 109, \11,
antiherbivore compounds, 447 122, 130, 134, 136, 137, 153,208,251,252,
anti-mY activity, 209 328, 332, 337, 341, 346, 360, 387, 395,460,
anti-HSV-I activity, 423 537, 542, 543, 6\0
antiinflammatory compounds, 85, 122,261, Apieae, 134
392,420,460,564,601,606,670,672,683 apiforol,l64
anti-itching effects. 346 apigeuin, 152, 158-160, 162, 164-166
antijuvenile honnone activity, 49, 317, 384 apiin.252
antileishmaniacal activity, 847 2R-,B-D-apio-D-furanosy1-(1-6)-,B-D-
antileukemic activity, 364, 365, 482, 484, 533, glucopyranosyloxyphenylacetonitrile. 277
615, 645, 694, 695, 705 apiose, 251, 252
antimalarial compounds, 69, 392, 395, 482 D-apiose, 252
antimalarial effects, 569, 648, 649, 650, 651, Apis mellifera, 445
652,666 Apium, 146
antimicrobial effects, 40. 50, 59. 67, 118, 137, apocarotenoids, 499
346, 458, 574, 591, 599, 600, 601, 603, 606, Apocynaceae, 98, 319, 361, 364, 466, 468,
640 469,506,510,511,521,549,615,629,
antimitotic effects, 120, 510, 645, 676, 696 635-641,645,647,648,652,653,660,668,
antimutagenic effects, 165 677, 686, 689, 690, 700
antimycotic effects, 140 apoplastic space, 288
antineoplastic effects, 120 aporphine alkaloid biosynthesis, 588
anti-nutritional effects, 208 aporpbine alkaloids, 578, 588, 590-592, 594,
antioxidant properties, 120, 164, 166,207,499 605,627
antiplaque properties, 603 aposematic labelling, 364. 366. 466. 468, 470.
antiprotozoan effects, 392 498, 551, 564, 567, 703; see also warning
antipyretic properties, 122, 136,641,670 coloration
antirheumatic effects, 122 apparency, 209, 212
antirrhinoside. 358, 364 apple pomace, 260
Antirrhinum majus. 158, 189. 358 apples, 174, 2\0, 215, 238, 277, 290, 346, 381,
antismoking properties, 538, 540 397
antispasmodic effects, 137. 346, 646 apricots, 277, 290, 346
anti-termite properties, 460 Aquifoliaceae. 290. 625
Antitoxicum, 563 Aquilegia, 269
antitubulin, 696 Arabidopsis Ihaliana. 4, 41, 303. 310, 314
antitumor compounds, 67, 104, 120, 145, 149, arabin,310
209, 234, 235, 254, 261, 378, 393,402, 404, D-arabinitol, 264
420, 445, 452, 460, 468, 473, 481, 482, 511, L-arabinitol, 262, 264
546,553,559,564,568,574,576,581,591, O-a-L-arabinopyranosyl-(1-6)-/3-D-glucose,
599, 601, 605, 606, 613, 623-625, 627, 645, 266
648, 653, 654, 671, 676, 677, 695, 696, 700, arabinose, 172,248,249,456
705,711 L-arabinose. 248. 260, 456
antitussive effects. 460, 591, 596, 597, 603 Araceae, 111, 123, 287, 515, 6\0
antiulcer effects, 167, 460 arachidic acid, 17
antiviral properties, 48, 120, 128, 192,209, arachidonic acid, 34. 209
2\0,261,468,482,510 Arachis hypogaea, 65. 145. 226
antiyeast effects, 603 Arachnoides standish;;, 253
 Index 717

Araliaceae, 42, 45, 46, 48, 134,337,360,459, Artemisia annua, 348. 392 Atalantia, 573
460, 569, 570, 610, 612 Artemisia californica. 345 Atelia herbert-smith;;, 222, 231
Aralidiaceae, 360 artemisia ketone. 348 Athalia rosae, 418
Araliiflorae, 337 Artemisia maritima, 392 atisine, 673, 674
Araliopsis, 570, 573 artemisinin. 392. 607 Atkinsonella. 659
Araucariaceae, 405. 412, 413 artemisyl skeleton, 346 ATP, 6, 9, 14, 19,21,23,81,97, 155, 166,
Arbacia. 420 arteriosclerosis, 640 226,315,588,603,631,656
Arbacia punctulata. 420 Arthrobacter globiformis, 483 ATPase, 601, 603, 660, 676, 685
arborine, 568, 569 arthropods, 13, 79, 324, 340, 349, 439, 479 atractylenolide I, 392
arbusculin-A, 389, 390 artichokes, 520 Atractylodis macrocephala, 392
arbutin, 77, 78. 104 Arum maculatum, 515 Atractylodis rhizoma, 392
Arbutus. 78 Arum nigrum, 515 atrioventricular conduction disturbances, 623
Arbutus unedo. 78 Arundo, 101 Atropa belladonna, 3, 534, 535, 537, 558
Archaebacteria, 401 aryl hydroxylation, 136 Atrophaneura aleinaus. 591
Arcthosiphon pisum, 363 aryl-sulfatase, 160, 188 atropine, 511, 535, 537, 664, 692
Arctiidae, 551 ,B-asarone, III Alta cephalotes, 340, 380, 452
Arctostaphylos, 78, 125, 126 E-asarone, 113, 136 AUa sexdens, 514
Arctostaphylos giandulosa, 125 ascaricide, 392 attack, 319, 326, 339, 340, 342, 370, 372, 377,
Arctostaphylos uva-urai. 209 Ascaris, 392 380,391,401,414,415,447,468,478
Arctoteae-Calenduleae, 387 Asclepiadaceae, 361,466,515,563,571,573, Attacus atlas, 650
Areca, 513, 528 655,666 attIactants, 339, 342-344, 350, 362, 363, 366,
Areca catechu. 528 Asclepias, 466 381,382,397,445
Arecaceae, 25, 458, 569 Asclepias curassavica, 466, 468, 471. 703 aubergenol, 377
arecoline, 511, 528 Asclepias labri/ormis, 466 aubergenone, 377
Argemone, 603, 605 Asclepias syriaca, 468 Aucubaceae, 360
Argemone mexicana. 603 Ascobolus furfuraceus, 71 aucubin, 358, 363, 669
Argemone platyceras, 587 ascochitine, 63 aucuparin, 148
argemonine. 605 Ascochyta/abae, 63 Aurantioideae, 571, 573, 575
argentilactone, 269 Ascochyta rabiei, 186 aureomycin, 65
Argenlina, 244, 380, 563 Ascomycetes, 659 auricular fibrillation, 651
arginase, 220, 221 ascorbic acid, 158, 159, 162,202,207,209, aurones, 151, 156, 173, 174, 177, 188
arginine, 215, 220, 221, 223, 226, 517, 521, 210,247,265,266,271,300,587,623 auroxanthin, 499
531,534,546,547,680 L-ascorbic acid, 247, 265, 271 AQstralia, 29, 79, 177,226,229,287,294,
L-arginine, 220, 239 Asia, 525, 574, 624, 640, 666, 698, 700 380, 389, 551, 561, 563, 574, 605, 615, 617,
arginine decarboxylase, 517. 531, 547, 548 asimicin, 67 664, 666, 669, 676, 703
arginyl-tRNA synthetase, 220 Asimina triloba. 67, 74 Austrobaileyaceae,610
Argyreia. 658 asirinin, 118 Austrotaxus spicata, 676
aril, 222, 223 asparagine, 215, 226, 230, 231, 290, 291 autonomic nervous system (ANS). 510
Arion rufus. 559 asparagus, 227 autumnaline, 617
aristolactams, 591 Asparagus adescendens, 459 auxin, 3, 53, 146, 165, 166, 190,306,389,483
(- )-aristolochene, 371, 372 Asparagus ojficinalis, 227 Avena coleoptile assay, 33, 146, 389, 510
5-epi-aristolochene cyclase, 372 asparanin B, 459 Avena sativa, 98, 230, 459
Aristolochia, 591, 613 Aspartame, 245, 246 avenacin, 459
Aristolochia argentina, 269 aspartate aminotransferases, 601 avenalumin I, 98
Aristolochia clematitis. 591 aspartic acid, 215-217, 220, 230, 290, 293, avenalumin n. 98
Aristolochia indica, 372 294,570 avenalumin m, 98
Aristolocbiaceae, 36, 269, 372, 387, 591, 609 aspartic ,B-semialdehyde, 518 avenalumins, 568
aristolochic acids, 591, 615, 616 3-aspartylsemialdebyde, 217 avenic acid, 230
Aristotelia, 563, 564 Aspergillus, 59, 63-65, 212, 234, 658, 683 avocado, 419
Arizona, 553, 582, 690 Aspergillus niger, 212, 414, 591 axivalin, 390
Armoracia lapathifolia, 303, 306 Asperula, 85 ayabuasca, 660
Armoraeia rusticana, 168 Aspbodelaceae, 87 8-azabicyclo[3.2.1]octane system, 533
anny wonn, 361, 379 asphyxia, 642 Azadirachta, 473, 476, 484
anny wonn, African, 361, 379, 380,415 Aspidiaceae, 544 Azadirachta indica, 473, 478, 479, 484
anny wonn, bertha, 308 Aspidosperma, 560, 632, 634-636, 640, 645, azadirachrin, 379, 479, 480, 483-485
anny wonn, fall, 145, 390, 479, 481, 658 652, 660, 666 azafluoranthene alkaloids, 588
anny wonn, southern, 228, 289, 390 Aspidosperma alkaloids, 632, 645 azetidine-2-carboxylic acid, 3, 222
anny wonn, yellow-striped, 390 Aspidosperma-Hunteria alkaloids, 634 azidirone, 479
Arnica, 392 aspidospennatan, 636
arogenate dehydratase, 101, 106 Aspilia, 48 baccharinoids, 379
arogenate dehydrogenase, 106 aspirin, 122, 123 Baccharis, 378. 395
arogenic acid, 101, 102 Asteraceae, 26, 36,42, 43, 45, 46, 48-50, 77, Baccharis cordifolia, 378
aroma, 324 88, 108, 109, 117, 125, 134, 158, 159, 168, Baccharis gaudichaudiana, 420
aromatic alkaloids, simple, 513 173-175, 177, 179,257,279,280,282,286, Baccharis megapolamica, 378, 395
aromatic compounds, 45, 94, 96, 508, 529 287,316,317,319,320,322,326,328,337, bacilli, Gram-positive, 600
aromatic ring, 45, 56, 57, 76, 80, 99, 106, 115, 345, 346, 374, 378, 380, 384, 386, 387, 390, Bacillus, 234, 253
151,187 392,393,395,396,405-407,412,413,415, Bacillus acidocaldarius, 26, 39
aromatization, 525 418,420,439,458,510,514,549,550,552, Bacillus brevis. 234
arrow poisons, 12, 187, 456, 463, 469, 470, 553, 559, 673 Bacillus polymyxa, 234
511,588,607,652,673 Astereae, 387 Baeillus subtilis, 69
Artabotrys uncinatus, 392 Asteridae, 277 backcrosses, 338
Artemia salina, 145 asthma, 137, 564, 576, 689 bacteria, viti, 2-4, 8, 9, 19, 22, 23, 27, 32, 49,
Artemisia absinthum, 333, 346. 389 Astragalus, 229, 253, 290, 299, 561 56,65,72,77,80,83,94,97-99, 101, 102,
artemisia alcohol, 348 Astragalus lentiginosus, 561 104, 106, 121, 122, 125, 134, 167, 193,210,
Artemisia, 332, 345, 346, 389, 552, 559 astringency, 206, 207, 209, 210, 346 218,234,235,237,239,240,244-246,249,
718 Index

252.253.259,270.273,286.290,306.312, bean, mung, 102, 108, 166. 222, 260 Berberidaceae, 1I8, 280, 282, 557, 598, 603,
313,324.339,401,402,460,481,483,484, bean, precatory, 244 609,610
486,488,490,494-496,498,510,517,520, bean, tonka, 130 Berberidales, 337
559,561,573,601,613,650,681 bean, winged, 290 Berberidopsis beckleri, 282, 296
bacteria, anaerobic, 22 bearberry, 209 berberine, 506. 511, 586, 598-600
bacteria, Gram negative, 603, 640, 681 beaver, 670 berberine alkaloids, 586, 597
bacteria, Gram positive, 69, 558, 603, 681 beaver, Canadian, 670 berberine bridge, 598
baikiain, 218 bebeerine, 606 "berberine-bridge" enzyme, 598
Bailfonella toxisperma, 703, 711 bee flowers, 176, 177 Berberis, 586, 587, 598
Baja California, 441 beech. 115 Berberis aggregata, 599
Balanites aegyptica, 460 beer, 70, 165,316,378; also see kaffir beer, Berberis canadensis, 587
Balansia, 659 root beer Berberis slolonifera, 241, 587
Balansia cyperi, 660 bees, 151, 176, 177,257,344,362,385,445, Berberis wilsoniae, 598, 613
Balansiae, 659 640,641,703; also see bee flowers, bumble bergamotene, 376
Balansiopsis, 659 bees, carpenter bees. euglossine bees, (+ )-(E)-endo-p-bergamoten-12-oic acid, 381,
Balfourodendron, 573 honeybees, solitary bees 394
Baliospermum, 403 bees, solitary, 381 bergamotin, 335, 336
Balsaminaceae, 82 beetle, Agasicles, 168 bergapten, 113, 133, 135-137
Balsamodendron pubescens, 475 beetle, blister, 382 bergaptol, 133
bamboo, 115, 607 beetle, bombardier, 79 Bergera, 663
bamboo shoots, 290 beetle, Colorado potato. 31, 39, 231, 682, 683, berry, see bearberry, blueberry, chinaberry,
bananas, 215, 228, 517 689 mulberry, raspberry ketone, raspberry,
Banisteriopsis argentea, 514 beetle. confused flour, 35 serendipity berries, strawberries
Banisteriopsis caapi, 660 beetle, cucumber, 445 Besseya alpina, 363
Banisteriopsis inebrians, 700 beetle, driedfruit, 36 Besseya plantaginea, 363
Banyambo tribe, 652 beetle, flour, 562 Beta vulgaris, 3. 222, 705. 708
I/I-baptigenin, 181 beetle, hide, 35 betacyanins, 423, 705
Baptisia, 188-190,229,558 beetle, Khapra, 35 betalnin, 171, 177, 506, 692, 705, 706, 708,
Baptisia australis, 554 beetle, ladybird, 363, 366, 542, 552 710.711
Baptisia leucophaea, 8, 558 beetle, Mexican bean, 67. 480 betalain glucoside, 705
Baptisia spherocarpa, 8 beetle, Mexican water, 439 betalamic acid, 706, 708
bark beetle, European elm, 83, 169 beetle, mustard, 309 betanin, 705, 708
bark beetle, hickory, 84 beetle, red flour, 35 betaxanthins, 705, 708
bark beetle, pine 343 beetle. rust-red flour, 460 betel,210
b",k beetles, 37, 72, 168,339 340,342,343 beetle, sawtoothed grain, 37 betel nut, 528
b",k, 30, 40, 67, 85, 86. 88,110.117,139, beetle, scarabaeid, 53 Betula alba. 447
174,193-195,206,209,244,252,319,342, beetle, soldier, 49, 50, 542 Betula pendula, 120, 129
343,353,403,405,413,447,480,528,561, beetle, striped cucumber, 67 Betula platyphyl/a, 121
608.640,645.649,663,676,689,691,695, beetle, western pine, 343 Betula resinijera, 451
700 beetles, see also bark beetles, bruchid beetles, Betulaceae, 197, 242
bark, willow, 122 chrysomelid beetles. diabrotid beetles, dung betulin, 447
bark, yohimbe, 640 beetles, flea beetles, beetle-pollinated beverages, 110, 136, 140, 364, 692, 694, 700,
b",ley. 15,59,70, 129,240,517,518,522, flowers, water beetles 708
523 beetles, dung, 515 beverages, intoxicating, 694
bartenders, 137 beetles, leaf, 444, 445, 447 beverages, stimulating, 694
base, see purine base, pyrimidine base, beets, 423, 705, 708 Beyeria, 407
tetrabase, Schiff-base, xanthine base Begonia, 444 d-beyerene, 408
Basellaceae, 708 Begoniaceae, 444 ent-beyerene, 407, 408
basidiomycetes, 45, 46, 48, 107 Belgium, 378 bhang, 336
Bataceae, 304 belladonna, 534, 535, 537 Bhesa, 664
batatasin I, 147 Bellardia trixago, 500 bibenzyl compounds, 136, 147, 148
batatasin III, 147 Beltian bodies, 289 bibenzyl synthase, 147, 149
batatasin IV, 147 Bentazon, 99 BMens, 47
Batidaceae, 708, 711 benzaconine, 675 BMens pilosa, 47
batrachotoxin, 675, 677 benzaldehyde, 581 biflavonoids, 151, 173
bats, 176, 177,344 benzoate hydroxylase, 104 big blue stem, 125
Battus philenor, 591 benzofurans, 312, 316, 317, 322 biglandulic acid, 269
Battus poiydamas, 591 benzoic acid, 121, 148,674 Bignoniaceae. 82, 86, 88, 114,337,361,362,
bay leaf, 340, 352 benzoic acid 2-hydroylase. 121 568,669
Bayer Company, 122 benzophenanthridine alkaloids, 578, 586, 600, bilharzia, 459
bean, viii, 26, 32, 437, 559 601,610.614,616 Billia, 223
bean, black, 167, 561 benzophenones, 136, 139, 148 binding, see cholesterol binding, HIV -1 cell
bean, broad, 48, 244, 414, 623 benzopyrans, 312, 316 binding, hormone binding sites
bean, calabar, 663 benzoquinone, 76, 77, 78, 80, 104, 124 bioassay, brine shrimp, 67, 145, 149
bean, castor, 22-24, 26, 244, 261, 369, 399, p-benzoquinone, 76, 77, 124 biochanin A, 186
407,414 benzoxazinone, 99 biogenetic isoprene rule, 312, 427
bean. coffee. 705 N-benzoylantbranilic acid, 568 Biomphalaria glabrata, 209
bean, dry, 261 benzyl acetone, 113,344 biosynthesis, see alkaloid, anthocyanin,
bean, dwarf, 414 benzyl benzoates, 140 aporphine, carotenoid, fatty acid, flavon-3,4-
bean, fava, viii benzyl isothiocyanate, 309 diol, flavonoid, iridoid monoterpene, lupine
bean, French, 156, 186 benzylglucosinolate, 287, 303, 310 alkaloid, monoterpene, polyamine,
beans, jack, 222, 244 benzyIisoquinoline alkaloids (BIQ), 2, 3, 12, polyketide, proanthocyanidin, protein,
bean, kidney, 241, 244 136,337,560,561,575,578,579,583-588, quinolizidine alkaloid, rubber, sesquiterpene,
bean, lima, viii, 287, 290, 295, 299. 341 591,594,597,598,605,607-610,613,614, squalene, stilbene, terpenoid, tetraterpene,
bean, mescal. 560 616, 652, 660, 664, 668 and triterpene biosynthesis
 Index 719

biosynthesis, channeled,S, 153,275,277,556 Bombyx, 341, 641, 689, 703 Brucea javanica, 482, 662, 667
biosynthesis, rubber, 319 Bombyx mori, 35, 36, 118, 341, 419 bruceantin, 482
biosynthetic pathways, vii, 2, 3, 6, 11, 12, 56, Bonajusia, 637 bruceoside A, 482
85,95, 179, 182,217,226 bone, 223. 437 bruchid beetles, 40, 132, 138,217,220,221,
birch, 8, 129 Boraginaceae, 3, 18,77,82,85, 108, 177,257, 223, 232, 245, 296, 523, 529, 544, 562, 565,
birch, Alaska paper, 451 285,290,294,336,337,452,510,547,549, 615,627,653,703,708
birch, Japanese 121 551-553 Bruchophagus roddi, 31
birch, Scandinavian, 120 borneol, 331, 345, 346, 451 bmcine, 641, 642
birch, white, 447 ( + )-boroeol, 335 Brugia pahangi, 479
birds, 175, 176, 179, 344, 361, 466, 486, 498, D-bomesitol, 264 Brugmansia, 537
511,517; see also bird-pollinated flowers, D-( - )-bornesitol, 264 BrUtifeisia, 537
hummingbird flowers, hummingbirds, L-bomesitol, 264 Brussel's sprouts, 306
ladybird beetles, red-winged blackbirds L-( +)-bornesitol, 264 Bryonia, 34, 35
bisabolenes, 374 bornyl acetate, 343, 344 bryophyllin B, 468
P.bisabolene, 376 ( - )-boroyl pyrophosphate, 331 Bryophyl/um, 468
y-bisabolene, 375 (+ )-bornyl pyrophosphate, 330, 333 Bryophyllum pinnatum, 468
a-( - )-bisabolol, 383, 384 ( - )-bomyl pyrophosphate cyclase, 330 bryophytes, 9, 114, 164, 324, 369, 500, 510
bisbenzylisoquinoline alkaloids, 605-607 d-bomyl pyrophosphate cyclase, 330 Bryum capillare. 179
bisindole alkaloids, 628, 645, 652-654, 666 I-hornyl pyrophosphate cyclase, 330 Buchenroedera, 549, 566
bisnaphthoquinones, 85 (+)-boroyl pyrophosphate syuthase, 330 buckwheat, 76, 162
bitter principles, 386, 389 Borrer;a, 611, 612, 638, 665 bud, see dormancy, bud
bitter taste, 171, 175,253,269,272,316,322, Borreria verticillata, 662 buddamine, 669
361,361,364,386,389,390,417,444,452, borrerine, 662 Buddleja davidii, 390, 397
460, 463, 466, 478, 482, 483, 511, 552, 641, borreverine, 662 Buddlejaceae, 361, 390
649, 673, 684 boschnaloside, 358 buddlejin A, 390
bitterbrush, 208 Boschniakia rossica, 361 buddlejin B, 390
bittersweet taste, 525 ( + )-boschniakine, 669 buddlejin C, 390
Bua orellana, 372, 499 boschnialactone, 361 buds, 7, 136, 335, 436
Bixaceae, 372 Bothriospora, 611, 612, 638 budwonn, cotton, 30, 481
bixin, 499 Bothrops atrox, 179 budwonn, tobacco, 169, 171, 220, 380, 415
black locust, 244 Botrytis, 48, 594, 601 bufadienolides, 466, 468
black rot disease, 72 Botrytis cinerea, 145 buffalo bur, 677
black spot disease, 67. 238 Botrytis tulipae, 269 Bufo marinus, 594
blackbirds, red-winged, 523, 619 Bouvardia ternifolia, 700 bufonid toad, 594
blackbrush, 208 bouvardin, 700 bufotenin, 514
blackcurrant, 346 Bowdichia nitida, 79 bugs, 285, 468; see also greenbugs, ladybugs,
blackwood, 79 Brachynus, 79 lygaeid bugs, mealybugs, milkweed bugs
B1akeslea, 501 bradycardia, 623, 647, 674 bulbocapnine, 590, 591
B1attela germanica, 136 brain, 597, 640, 659, 676 Bulbocodium, 617
bleomycin A2, 235 brain, mouse, 640 bulbs, 457, 472, 623
Blighia, 222, 223 Brassica, 306, 309, 310, 345, 363 a-bulnesene, 373, 376
Blighia sapida, 222 Brassica campestris, 306, 309 bumble bees, 362, 420
Blighia unijuga, 222 Brassicajuncea, 306, 309, 310 Bupleurum falcatum, 460
blindness, 603 Brassica napus, 30, 39, 306, 307, 311, 437 Burseraceae, 30, 337, 387, 412, 473, 475, 576
blisttning, 267 Brassica nigra, 309, 311 bush rats, 29
blocking agents, see a-adrenergic blocking Brassica oleracea, 51, 52, 190.306,309,310 Bushmeo of Namaqualand, 623
agents, adrenergic blocking agents, Brassica rapa, 306 Busse massaiensis, 222
cholinergic blOCking agents. ganglionic Brassicaceae, 4, 51, 52, 108, 168, 179,267, Z,E-l,3-butadiene hydroperoxide, 24
blocking agents, neuromuscular blocking 300,302,303-305,308,310,311,345,418, 2-butanone, 276
agents 437,444,466, 468, 521, 537 E-Ll2-butenoyl-S-ACP, 20
blood, 174,209,244,384,447,452,456,479 brassinolates, 444 butterflies, 10, 13, 123, 136-138, 177, 191,
blood brain barrier, 229, 597 brassinolide, 437, 454 192,265,297,307,309,310,341,344,350,
blood pressure, 517, 522, 528, 606, 640, 643, Brazil, 378, 390, 395, 588, 595, 610, 645, 700 361,466,470,535,550-552,559,564,566,
670,703 bread, 30, 658 591,711
blood sugar, 223 brefeldin A, 420 butterflies, danaid, 550, 551
bloodroo~ 601 Bretschneideraceae, 304, 310 butterflies, ithomiine, 535, 683
blossoms, see flowers brevicomin, 37, 343 butterflies, swallowtail, 591
blowfly, 67 exo-brevicomin, 343 butterfly, black swallowtail 136, 138,307
blue jays, 466 Brevicoryne brassicae, 308 butterfly, blue lycaenid, 559
blue mahoe, 77 brevilagin 1, 196 butterfly, buckeye, 364, 365
blueberries, 171 brevilagin 2. 196 butterfly, cabbage, 307, 309
bluegrass, 52, 54 British Columbia, 338 butterfly, checkerspot, 363
Boehmeria, 563 Briza spicata, 30,41 butterfly flowers. 177
D-boivinose, 250 broccoli, 306, 311 butterfly, hairstreak, 294
boldine, 591 bromohydroquinone, 340 butterfly, monarch, 383, 466, 471, 472, 551,
Bolivia, 114, 535, 684, 690 Bromus rigidus, 126 591,703
boll weevil, 35, 342, 380, 542 bronchial dilator, 137 butterfly, queen, 551
bollwonn, 49, 50, 169, 380 bronchoconstriction. 643, 697 butterfly, yellow, 623
bollworm, cotton, 415 bronchodilating effects, 522 butylated hydroxyanisole (BHA), 166
bollwonn, pink, 49, 50, 415 Brosimum, 134 butyrate, 152
Bomarea, 269 Broussonetia, 571 butyrospennol, 473, 476
Bombacaceae, 28, 77, 387 Broussonetia papyri/era, 145 butyrylcholinesterase, 600
Bombax,77 broussonin A, 145 butyryl-S-ACP, 19, 20
Bombus terrestris, 419 broussonin B, 145 Buxaceae, 677, 686, 689
bombykol, 36 Brucea antidysenterica, 482 buxenine-G, 689
720 Index

Buxus, 677, 689 caUinecdysone-B, 237 canthine derivatives, 660

Buxus alkaloids, 689 Callistephus chinensis, 158, 439 Canthium, 700
Buxus sempervirens, 689 Callitricaceae, 361 cantleyine, 669
callose, 247, 259 Capirona, 611
C 4 starter unit, 69 Callosobruchus chinensis, 460 CapparaIes, 304
Cs units, 326, 370 Callosobruchus maculatus, 5, 40, 132, 138, Capparidaceae, 302, 303, 308, 521
C6 -C, compounds, 106, 121, 122, 139, 148, 293,296,217,223,232,315,522,523,529, Capparis, 302
195,530,622 537,544,558,562,565,609,615,627,640, Capparis decidua, 521
C6 -C2 compounds, 106 642, 653, 703, 708 capric acids, 25
C6 -C3 compounds, 106, 109, 115, 121, 139, Callosobruchus phasecoli, 340 Caprifoliaceae, 173,355,361
148, 193, 195,613,694 Ca/oncoba echinata, 28 capsaicin, 110,517
C7 non-protein amino acids, 222 calophyUolide, 187 capsaicinoids, 517
C-17 side-chain cleavage, 439 Calophyllum inophyllum, 187 capsanthin, 486, 494, 504
C,racetylenes, 45 Calospilos miranda, 417 Capsella bursa-pastoris, 309
C 17-tenninal olefms, 44, 45 calotropin, 466, 468 Capsicum, 110,377,488,499,504,513,517,
C 20 isoprenyl ethers of glycerol, 401 Caltha, 269, 549 530
Cn-sterols, 437 Calvin cycle, 248 Capsicum annuum, 377, 494, 703
C 29 alkane, 52 Calycanthaceae, 610, 655, 664, 665 capsidiol, 373, 377, 517
C 29-sterols, 439 calycanthine, 664, 665 capsorubrin, 494
cabbage, 51, 52,171,306-309,520 Calycanthus alkaloids, 655 capsules, 593, 596
cabbage, Chinese, 132, 135 Calycanthus florida, 665 Capuronetta, 637
cabbage looper, 390 Calyceraceae, 361 Caragana, 215
cabbage, red. 171 CaJypogeia granulara, 368 Carapa procera, 480
Cacalia,77 Calypogeia tosana, 143 caraway, 47
cacao, 219, 700, 703 Camellia sinensis, 171, 195, 700, 702 carbamate group, 663
Cactaceae, 515, 522, 523, 578, 581, 692, 693, camels, 525 carbamoylputrescine, 531
708 Cameroons, 640 carbazole alkaloids, 575, 576, 655, 662, 663,
cacti, 148,441,453,523,581-583,615; see cammelinin, 310 666
cactophilic yeasts, coccus cacti Camoensia, 558 carbinolamines, 508
cactus, agria, 441, 582 Campanulaceae, 45, 46, 257, 458, 540 carbocation, 329, 374. 432
cactus, cina, 582 campesterol, 427, 435, 582 carbohydrate, 194,207,208.217,247-250,
cactus, organ pipe, 441, 582 camphene, 331, 345 252,254,260,261,265,324
cactus, peyote, 148, 151,522,523,581 ( - )-camphene, 331 carbohydrates, structural, 259
cactus, saguaro, 441, 582, 615 ( + )-camphene, 331 ,B-carboline alkaloid, 10, 514, 649, 655, 660
cactus. senita, 441, 582 d-camphene,331 2·carbomethoxy~4,4*bis(3-methyl*2-
cadalane skeleton, 670 I-camphene, 331 butenyloxy)chalcone, 168
cadaverine, 8,510,517,518,537.540,545, campho" 330, 331, 345, 346, 451 carbon dioxide, 6, 19,20,21,24,94,230,231,
554-556 ( - )-camphor, 345 261,290,313,328,329,336,435,488
cadinenes, 346, 375 ( + )-camphm, 335, 345 cis-2-(carboxycyclopropyl)glycine, 218
y-cadinene, 375, 381 Camptotheca acuminata, 648, 654 2-carboxy-4-hydroxy-l-tetralone, 82, 86
cadinol, 346 camptothecine, 628, 630, 648 trans-2-(2-carboxymethylcyclopropyl)glycine,
Caenocoris nerii, 468 camptothecine, 20(RS)-9-amino-derivative, 648 222
Caenorabditis elegans, 67 Canada, 322, 338 2-carboxy-4-oxotetraIone (COT). 81, 82, 86,
Caesaipinia, 194 canadine, 598, 600 87
Caesalpiniodeae, 86,105.179,197,221,228, ( - )-canadine, 598 3(3-carboxyphenyl)aIanine. 215
412, 543, 558, 676 canaline, 220, 221, 232 S·(2-carboxypropyl)cysteine, 226
caffeic acid, 108, 193, 518 Canavalia ensiformis, 220, 221, 244 carcinogenesis, 306
Z-caffeic acid, 113 canavanine, 220, 221, 231 carcinogenic compounds, 59, 65, 70, 110. 165,
E-caffeic acid, 113 L-canavanine, 215, 220, 221, 232 294,306,311,510,529,553,574,591,640
caffeine, 511, 692, 700. 702, 703 cancer, see also anticancer, antitumor, carcinoma, nasopharyngial, 606
caffeoyl acid, 104 carcinoma, leukemia, tumor carcinoma, squamous cell, 235
caffeoylputrescine, 518 cancer cell growth, 645 Cardamine cordi/olia, 309
3-caffeoylquinic acid, 171 cancer, esophageal, 210 cardenolides, 9, 309, 456, 462, 463, 465, 466,
Cakile, 305, 311 cancer, gastric, 601, 648 468-472
Cakile edentula, 305 cancer, human colon, 64& cardiac activity, 676
Cakile lanceolata, 305 cancer, liver, 553, 648 cardiac arrest, 674
Cakile maritima, 305 cancer metastasis, 562 cardiac effects, 675
Calabar Coast, 663 cancer remedy, 676 cardiac glycosides, 249, 250, 267, 433, 456,
calabash, 643 cancer, stomach, 606 463, 465, 466, 468-470, 552, 703
caiactin, 466 cancer, throat, 193,210 cardiac irregularities, 674
Calamintha ashei, 346, 451 cancerina, 671 cardiac muscle, 468
calcium, 260, 264, 402, 418, 437, 640 Candida albicans, 432, 588, 591. 683, 686 cardiac stimulation, 522, 640, 702
calcium antagonists, 676 candy, 462 cardiomuscular calcium transport, 418
calcium chloride, 676 Canellaceae, 379, 387 (S)-cardiospennin, 282, 285, 287, 289
Calendulae, 287 Cannabaceae, 316, 336, 522 (S)-cardiospermin p-hydroxybenzoate, 282,
California, 125, 128, 338, 345, 349, 389, 483, cannabidiol, 336 284,287
559 cannabidiolic acid, 336 (S)·cardiospennin p-hydroxycinnamate, 282.
California bay laurel, 340 canniabinol, 336 287
caliminthone, 346 cannabinolic acid, 336 (S)-cardiospermin sulfate, 282
Calindrinia ciliata, 126 Cannabis sativa, 336, 522 cardiotonic, 114, 392, 445, 462, 673
C-alkaloid E, 643 canteloupe, 468 cardiovascular effects, 650
C-alkaloid G. 643 Cantharellus cibarius, 496 cardon. 441, 582
C-alkylation, 316 cantharidin, 382 3-carene, 343
Callianthemum, 269 canthaxanthin, 498 caribou, 207
Callicarpa, 417 canthin·6-one, 655, 662, 667 Carica papaya, 287, 309
 Index 721

Caricaceae, 286, 287, 304 Castor jiber, 670 cell culture, colon 8, 517, 695
Carisseae, 637 castor oil, 35 cell culture, L-121O (lymphoid leukemia), 420,
canninic acid. 89 castoreum, 670 601,695
carnation, 156,231 .232 casuarictin, 197 cell culture, LE, 482
carnauba see wax, camauba, 52 Casuarina, 173 cell culture, LL, Lewis lung carcinoma, 482,
camegeine, 581, 582 Casuarinaceae, 173, 197,242,244 695
Carnegiea g;gantea. 441, 582 catabolism, 4, 5, 297 cell culture, murine P-3381ymphocytic
carob gum, 260 catalase, 79 leukemia, 482
carotene, 401 Catalpa, 361, 362 cell culture, murine tumor systems including
a-carotene, 486, 491, 492. 495 Catalpa oVata, 82 B16 melanoma, 695
p-carotene, 486, 491, 492, 494-497, 499, 504 Catalpa speciosa, 362 cell culture, plant, 1,2,8,39, 156, 179, 181
£-carotene. 486 catalpalactone, 82 cell culture, 9 PS system, 671
{-carotene, 490 catalpal,361-364 cell culture, Walker 256 carcinosarcoma, 640
(6'R)-p, ..carotene, 486 catalpanol, 82 cell cultures, parsley, 4, 156
(15Z)-{-carotene, 491 catalposide, 361-363 cell cultures, PS, B 1 and KB tumor lines, 696
,8-carotene dioxygenase. 497 catechin, 159, 171,200-204,206 cell cycle, 231
(3R,3'R)-p,p-carotene-3,3'-diol, 494 (+ )-catechin, 171, 193,202-204,206 cell cycle, 0, phase, 231, 520, 528
(3R,3'R,6'R)-,B,E-carotene-3,3'-diol.486 (+ )-(ZR,3S)-catechin, 201 cell cycle, G2 and/or M phase, 676
carotenoids, acetylenic. 495 (- )-(2S,3R)-catechin, 201 cell cycle, G2 cellular arrest, 708
carotenes, alicyclic, 492 ent-catechin, 201 cell cycle, G2 Factor, 231
carotenoid biosynthesis, 488. 496 catechin xyloside, 169 cell cytosol, 19
carotenoid pigments, 498 catechol, 67, 124 cell division, 520, 619, 623, 676, 696
carotenoids, 10, 171, 173, 177, 314, 322, 348, catechol structure, 67 cell free enzyme systems, see enzyme systems
367, 384, 486-488, 490-492, 494, 496-504 catecholamine, 517, 640 cell recognition, 261
carotenoids, acyclic, 491, 492 caterpillar, saddleback, 390 cell suspension cultures, 2, 13, 92, 93, 128,
carpenter bees, 177, 362 caterpillars, 29, 32, 137, 138,316,437,455; 138, 155, 158, 178, 179, 184,553,554,587,
Carpophilus hemipterus, 37 see also lepidopteran caterpillars, noctuid 600,601,631,652,653,654,667
carrageenan, 260 caterpillars cell wall fractions, 135
carrot, 26, 48, 72, 73, 113, 128, 129, 136, 328, Catha, 452 cell walls, 184,226,253,259-262,271,561,
399,486,490,492 Catha edulis, 210, 522, 671 613
Carthamus tinctorius, 48 catharanthine, 630, 632, 634, 635, 645, 647, cell walls, plant, 3, 8, 259-262, 270
Carum carvi, 47 652 cell-cell communication, 261
(-)-trans-carveol, 335 (+ )-catharanthine, 635 cellobiose, 254
carvone, 339, 340, 341, 346, 451 Catharanthus, 629, 637, 640
cells, 1-3, 8, 9, 13, 14, 18, 22, 32, 35, 51, 53,
d-carvone. 344 Catharanthus alkaloids, 628, 645
59,71,72,85,96, 110, 120, 128, 131, 138;
Catharanthus longijolius, 645
carvone oxide, 344 see also cancer
Catharanthus ovalis, 645
Carya, 82, 84 cells, cell free enzyme systems, chemosensory
Cotharanthus roseus, 2, 110, 241, 354, 355,
Carya illinoensis, 84 cells, epidermal cells, epithelial cells,
366, 506, 511, 629-632, 634, 635, 640, 645,
Caryedes brasiliensis, 220 extracellular enzymes, mv-1 cell binding,
652-654
Caryophyllaceae, 88, 156, 171, 458, 514, 568, leukemic cells, mesophyll cells, nerve-cell
Catharanthus trichophyllus, 645
662, 708, 709
cathartic, 35, 91, 364, 365, 402, 479 membrane, oil cells, cell culture, cell walls,
Caryophyllales, 197,705,708,709
caihenamine, 631 red blood cells, nelVe cells, secretory cells,
caryophyllanes, 375 cathenamine reductase, 631 sex cells, squamous cell carcinoma
caryophyllene, 342, 346, 371, 375, 379 cathinone, 522, 671 cells, chemosensory, 588, 651
p.caryophyllene, 371, 375 (S)-cathinone, 522 cells, HeLa, 676
caryopbyllene cyclase, 375 cats, 361, 362, 591, 643, 669, 674; see also cells, leukemic, 145
caryopbyllene epoxide. 379 civet cat cells, mouse lymphoma, tk locus, 645
caryophyllene oxide, 346, 380 cattle, 71, 91, 290, 317, 420, 437, 460, 540, cells, nerve, repetitive discharges, 685
Caryophyllidae, 171 553, 658, 676, 705 cellulose, 254, 257, 259, 260, 270, 272
Caryopteris.417 Caulanthus, 305 cembrene, 398, 401, 402, 413, 419
casbene, 401, 408, 414 Cauierpa, 380, 396, 419 Centaurea, 47
casbene synthase, 401, 402 Caulerpa ashmeadii, 380, 396 Centaureo solstidalis, 317, 322
cascara sagrada, 91 cauliflower, 306, 309, 311 Central America, 229, 298, 525, 640
Casimiroa, 693 Caulophyllum thalictroide, 557 central nervous system, 229, 510, 514, 522,
casimiroine, 571 Cavariella aegopogii, 340 596,640,642,647,670,698,702
cassaine, 406 , 412, 676 CD, see circular dichroism Centrospennae, 171,705,708,711
cassava, viii, 274, 276, 290, 294, 297 cedar leaf oil, 346 cephaeline, 610, 611, 652
Cassia, 85, 88, 91, 543 cedar, western red, 340 Cephaelis, 610-612, 638
Cassia absus, 693 Cedrela toona, 399 Cephaelis ipecacuanha, 610, 612
Cassia fistulosa, III cedrelone, 475, 479, 480 cepbalomannine, 677
Castanea sativa, 252 Celastraceae, 210, 240, 269, 270, 321, 452, cephalosporin C, 235
castanospennine, 254, 270, 560-562, 566 466, 470, 522, 525, 528, 549, 575, 664, 668, cephalosporins, 234
Castanospermum australe, 254, 561 670, 671, 694, 695, 700 Cephalosporium, 234, 235
castelanone, 482 celery, 48, 137, 556 Cephalotaxaceae, 617, 624, 626, 677
Cassia, 85, 88, 91, 543 celery root, 48 cephalotaxine, 625, 627
Castilla elastica, 319 cell culture, 3, 4, 8, 9, 67, 82, 86, 87, 117, Cephalotaxus, 617, 624-627, 677
Castilleja hispida, 552 132, 133, 143, 153, 156, 181, 182, 184, 186, Cephalotaxus alkaloids, 617, 624-627
Castilleja integra, 363 188, ZOO, 202, 209, 290, 506, 533, 554, 557, Cephalotaxus harringtonii, 625, 627
Castilleja lineoriijolia, 552, 559 558, 567, 586, 598, 601, 614, 616, 629, 631, Cephalotaxus wilsoniana, 625, 627
Castilleja miniata, 557 636, 640, 645, 646, 649, 653 Ceratiola ericoides, 125, 175,451
Castilleja occidentalis, 552 cell culture, Bl6 murine melanoma tissue ceratiolin, 175,451
Castilleja rhexi/olia, 552, 669 culture, 482 Ceratitis capitala, 31, 40, 381
Castilleja sulphurea, 552 cell culture, carcinoma of the nasophamyx Ceratocystis, 342
Castor, 668, 670 (KB), 380, 420, 444, 445, 452, 468, 479, Ceratocystis fimbriatum, 27, 40, 72, 135, 377
castor bean, see bean, castor 481, 606, 663 Ceratocystis u1mi, 72, 73, 237
722 Index

Ceratonia siliqua, 260 cherry laurel, 274 chromatography, centrifugal thin layer (C1LC),
Ceratophalus, 269 chestnut, 194, 252 457
CercidiphylIaceae, 197 chestnut, Moreton Bay, 561 chromatography, countercurrent, 1
Cercospora rosicola, 501 chestnut, Spanish, 195 chromatography, droplet countercurrent
cereal grains, 78, 98, 99, 256, 378, 518, 520, chewing gum, 321, 462 (DCCC),457
658 chicken, 35 chromatography, gas liqnid (OC or OLC), 54,
cerebral cortex, 346, 702 chickpea, 184, 186, 188 142,217,302,305,326,351
cerebral vasodilation, 640 chicle, 312, 318, 321 chromatography, gas liquid (FID), 457
cerin,447 childbirth, 660 chromatography, gas capillary, 326
Cervus eZaphus, 207 Chile, 388, 563 chromatography, gel permeation, 318
Cestreae, 537 chimonanthine, 665 chromatography, high performance (HPLC), I,
Cestrum, 677 chimpanzee, 48 105, 132, 138, 142, 187, 188, 191,212,217,
cevadine, 685 China, 210, 244, 306, 522, 606, 646, 648, 709 232,295,302,353,365,398,457,465,471,
cevane skeleton, 684 china aster, 158 487,514,655
ceveratrum alkaloids, 684 chinabeny, 479 chromatography, ion exchange, 302
a-chaconine, 682, 684 chio-shih-hu, 670 chromatography, liqnid (LC), I, 38, 132, 295
Chaenorrhinum, 522 Chisocheton paniculatus, 475 chromatography, paper (PC), I, 212, 217, 223,
Chaetocnema con/inis, 7 chitin, 247, 253, 260, 261, 270-272, 414 294,302,305,309
Chagas' disease, 479, 645 chitinase, 414 chromatography, thin layer (1LC), 1,38, 142,
chalcid,31 chives, 226 212,217,294,302,353,362,398,465,466,
chalcone 2,3-epoxide, 159 chloramphenicol, 234 514
chalcone glycosides, 178 Chiorelia fusca, 242 chromenes, 312, 316, 322
chalcone isomerase, 156, 158, 173 chlorofonn, 507 chromium ion «(Yi+), 209
chalcone reductase, 179 chlorogenic acid, 104, 108, 128, 171, 193,700 chromones, 477, 576
chalcone synthase, 142, 156, 179, 184 Chlorophyceae, 260 chromoplast stroma, 488
chalcones, 151, 156, 158, 159, 173, 174, 177, chlorophyll, 8, 171, 177, 207, 314, 398, 399, chromoplasts, 177,488,492,499,504
179, 181, 188, 190 414, 486, 488, 496, 498, 499 cluomoproteins, 496
Chamaecyparis, 337 chlorophyll a, 496 chromosomal cleavage, 645
Chamaecytisus hirsutus, 559 chlorophyll synthesis, 230 chromosomes, 4, 5
chamigrane, 381 chlorophyUide a, 399 chrysanthemic acid, 348, 430, 431
chamise, 125, 128 Chlorophyta, 396, 419, 425, 495 Chrysanthemum, 348, 436
Chamorros, 226, 294 Chiorophytum, 280 Chrysanthemum coronarium, 49
channa, 623 chloroplast membranes, 17, 18 chrysanthemyl alcohol, 348
channel, see nicotine acetylcholine receptor chloroplasts, 8, 9, 14, 17-19, 22, 23, 26, 82, chrysanthemyl skeleton, 346
channel, sodium channels, voltage-dependent 94,99, 105, 130, 166,241,313,314,488, chrysazin, 88
sodium channels, channeled biosynthesis, 492,494-499,518,520,554,556,557, chrysmanthemic acid, 348
ion channels chloroquine, 606, 607, 614, 625, 649, 650, 666 trans-cbrysanthemic acid, 348
chanoclavine cyclase, 3 chloroquine phosphate, 606 Chrysolina, 92
chanoclavine I, 656, 658, 659 chloroquine-resistant, 606, 607, 625, 651 Chrysolina brunsvicensis, 92
chanoclavine-I cyclase, 656 chloroquine-sensitive, 606, 607 Chrysolina quatirigemina, 92
chaparral, 78, 125, 126, 128, 345 chlorosis, 237, 238, 423 Chrysomela, 124
chaparrinone, 482 chocolate, 346, 462 chrysomelid beetles, 14, 84, 88, 124, 128, 363,
Chauliognathus, 542 Choisya (ernata, 573 468,552
Chauliognathus iecontei, 49 cholera, 77 chrysomelid, elm leaf, 88
chaulmoogric acid, 29, 36 (25S)-a-cholestau-3,B,26-diol, 680 Chrysomelidae, 289, 447, 453, 454, 472
chavicine, 539 5,B-cholestan-3,24-mone, 437 Ciuysomelina, 124, 363
chavicol, 113 cholestane, 677 Chrysopa septempunctata, 362
chayote, 31,40 7-cholestenol,582 Chrysopa siossonae, 53
chebulagic acid, 196 cholest-7-en-3,8-01-5,6-epoxide,442 chrysophsnol, 85, 88
cheese, 517 cholest-4-en-3-one, 678 Chrysopidae, 362, 366
cheilanthatriol, 422 cholesterol, 312, 313,427,428,433,435,437, Chusquea, 101
Cheilanthes farinosa, 422 439, 440, 442, 458-460, 462, 468, 470, 582, chymotrypsin, 245
Cheiranthus, 468 678,686 Cker, 181, 186
Cheiranthus X allion;;, 468 cholesterol binding, 682 Cker arietinum, 181
chelerythrine, 601, 603 chollc acid, 208, 213 Cichorieae, 387
chelidonine, 601, 603 choline, 208, 300, 510 Cichorium intybus, 439
chelidonine sulfate, 601 choline phosphotransferase, 23 Cicindelinae, 289
Chelidonium majus, 557, 600, 601 chOlinergic blocking agents, 510 Cicuta virosa, 47
chelilutine, 601 cholinergic drugs, 510, 511, 623, 664, 697 cider, 210
chelirubrine, 601 cholinesterase, 510, 549, 623, 647, 664, 682 cigarettes, 462, 526
Chelone giabra, 361 cholinesterase inhibitors, 537, 664 Cimifuga, 269
chemical ecology, 189 213, 231, 232, 271, chondriol, 48 cimiphytine, 641
296, 510, 529, 565, 709 chondrocoIe A, 340 Cinchona, 85,628, 648-652
chemical messages, 12, 338 chondrodendrine, 606 Cinchona ledgeriana, 649
chemosystematic studies, viii, 324, 337, 338, Chondrodendron, 511 Cinchona succirubra, 649
352,367,387,398,413,473,477,486,494 Chondrodendron tomentosum, 607 cinchonamine, 649
chemotaxis, 367, 376, 391, 392, 444 Chonemorpha fragrans, 686 Cinchoneae, 612, 638
Chenopodiaceae, 3, 88, 179. 222, 390, 458, chonemorphine, 686 Cinchonideae. 638
557, 581, 708 chorismate mutase, 101, 102, 104, 106 cinchonidine, 649-651
Chenopodium, 390, 442 chorismate synthetase, 97 cinchonidinone, 649
Chenopodium quinoa, 460 chorismic acid, 65, 80, 93-98, 101, 102, 106, cinchonine, 649-651
Chenopodium rubrum, 3, 557 122 Cinchonoideae, 612, 637
Chenopodium strictum, 390 Choristoneura, 682 cinchophylline, 628, 652
cherries, 37, 277, 290 Chortoicetes, 228 cineole, 331, 340
cheny, black, 277, 288, 298 chromatography, 367 1,4-cineole, 345
 Illdex 723

1,8-cineole, 331, 342, 344~346 CNS, see central nervous system colorin, 559
cinnamaldehyde, 110 CoA esters, 23, 109 Colubrina lexensis, 695
cinnamic acid, 3, 106~11O, 118, 121, 122, 126, CoA ligases, 109 columbamine, 598-600
128, 130-132, 138, 139, 147, 148, 152, 155, coadaptation, vii, 10,84, 177,208.209,307, columbianetin, 134
156, 165, 193, 196,203,509,515,529,533, 441,447,466,511,525 cotyledons, 700
564, 620, 624 coal, 53 Colymbetinae, 439
E-cinnamic acid, 106~ 109, 130 coca, 535 Combretaceae, 88, 147, 195, 197,533,610
cinnamic acid o-hydroxylase, 130 cocaine, 511, 531, 534, 535, 537. 544, 641. comfrey, 553
Cinnamomum camphora, 585 676 Commelilla, 146
Cinnamomum zeylanicum, 419, 424 cocarcinogenic diterpenes, see diterpenes. Commelilla communis, 171
cinnamon, 110 cocarcinogenic commersonine, 682
cinnamoyl-CoA oxidoreductase, 109 Coccinellidae, 542 Commiphora rostrata, 30, 40
cinnamyl acetate, 110 coccinellines, 542 communication, interplant, 33
cinnamyl alcohol dehydrogenase, 109, 115 cocculidine. 609 community succession, 209
cinnamyl alcohol, 109, 113 cocculine, 609 compartmentation, 9
cinnzeylanine, 418, 424 cocculolidine, 609 complexation, 170, 177, 207~209, 213
cinnzeylanol, 418, 424 Cocculus, 385, 608, 609, 700 concanavalin A, 244
circular dichroism (CD), 230 Cocculus carolinus, 609 condensation, 19, 21. 56-58, 65, 94, 96, 97.
Cirsium japonicum, 49 Cocculus trilobus, 609 117,315,326,327,348,351,359,369,396,
Cistaceae, 197 coccus cacti, 89 398,405,428,430,431,432,444,465,473,
citral, 340~343, 346 cochineal, 89 488; see also aldol condensation, Claisen
(E)-citra!, 343 Cochlearia, 537 condensation, Claisen-type condensation,
citric acid cycle, 3 Cochliobolus, 423 imino-aldol type~condensation, Mannich
citrinin, 63, 70 cocklebur, 389 condensation
citronella!, 342, 344, 346 cockroaches, 340, 640 condensed tannins, 8, 12, 156, 164, 193, 194,
citronellol, 342~344, 346 cockroaches, American, 343, 383 198,200,204,206,207-209,212
(S)-( - )-citronellol, 358 coclaurine, 586 condensed tannins, acid butanol assay, 212
Citrullus vulgaris, 499 (R,S)-coclaurine, 595 conessine, 686
Citrus, 158, 175,337,340,370,476,482-484, (S)~coclaurine, 586 confertiflorin, 388, 390, 392
499,573 cocoa, 165 Congo Republic, 640
Citrus aurantium, 34 coconut, 346 y-coniceine. 543, 544
Citrus paradisii, 175 coconut oil, 25 8-coniceine, 561
citrus waste, 260 codaphniphylline, 689 coniferin, 115, 117
civet cat, 37 codeine, 511, 593~597 Coniferopsida, 337
civetone,37 Codium.260 conifers, 198,324,337,338,342,343,352,
Cladophora, 260 codonocarpine. 521 398,510
Cladosporium, 415 Codonocarpus australis, 521 coniferyl alcohol, 115, 117, 123
Claisen condensation, 57, 64, 148, 155 Coelospermum, 85 coniine, 8, 531, 537, 543, 561
Claisen-type condensation, 57, 142 coenzyme Q, 76, 104, 125 Conium, 542, 543
clams, 696 coevolution, vii, 10, 12~14, 137,511 Conium maculatum, 3, 8, 543, 557
clastogenic effects, 645 coevolved, 10 Connaraceae, 231
Clausena, 660, 663 cofactor, 156, 158, 159. 162, 179.207,276, Conopharyngia, 637, 647
Claviceps, 3. 26, 315, 655, 658, 659 371,488,491,508,535,587 Conospermum, 82
Claviceps paspa/i, 655, 660 Coffea, 702, 703 Conradina canescens, 346, 352, 451
Clavicipitaceae, 659 Coffea arabica, 700, 702 Consolida, 269
clavine alkaloids, 655 Coffea canephora, 700 contraceptives, 376, 462, 683
clay, 684 coffee, 104, 165,219,346,700,702,703 Convallaria majus, 222
Cleistopholis patens, 588 coffee bean, see bean, coffee convergence, 12, 54
Clematis, 267 Coit, 101 Convolvulaceae, 41. 72, 251, 377, 533, 537,
C!ematopsis, 267 cola, 165 549, 559, 565, 655, 658
clerodanes, 406, 417, 418 Cola, 700 Convolvulus, 658
neo-clerodane, 417 colchicine, 507, 511, 617~619, 676 convulsions, 591, 607, 642, 658
ent-clerodanes, 418 (7S)-( - )-colchicine, 617 cooking, 36, 137, 245
clerodendrin A, 417 Colchicum, 617 copabomanes, 375
clerodendrin B, 417 Colchicum autumnale, 617, 619 copabomeol, 386, 670
Clerodendron, 417, 418 Coleogyne ramosissima, 208 (+ )-a-copaene, 381
Clerodendron infortunatum, 417 Coleoptera, 179,297,352,393,447,453,454, COPalfera, 226, 232, 413
CJerodendron trichotomum, 418, 666 472,650 copalic acid, 420
clinal variation, 8, 338 coieoptile, 33, 146,280 copalyl pyrophosphate, 408, 414
Clitocybe, 697 Coleus barbatus, 420, 426 copalyl pyrophosphate synthetase, 408
clones, 8, 288 Coleus forskohlii, 420 copigmentation, 171, 177
Clostridium perjringens, 261 coliolic acid, 26 co~pigments, 152
clove, 59, 110 collagen, 200, 206. 220 copper ethylacetoacetate, 294
clover, 35, 179, 179, 296 collards, 306 Coprosma, 85
clover, red, 72, 179, 186, 561 Colletes, 37, 344 Coptis, 269, 598
club moss, 540, 708 Col/etia, 610 Coplis japonica, 598, 600
Clusiaceae, 69, 88, 91, 148, 149, 173, 187, colletotrichin,415 Cordia, 77
197,209,412 Colletotrichum, 415 Cordia alliodora, 336, 337, 452
Cneoraceae, 134, 473, 475~477, 485, 575, 576 Colletotrichum coffeanum, 186 Coreopsis, 45
Cneorum tricoccum, 477 Colletotrichumfalcatum, 145 Coreopsis lanceolata, 49
Cnestis glabra, 231, 232 Colletotrichum lindemuthianum, 148, 184 coriamyrtin, 670
cnicin, 389 Collosobruchus maculatus, 619 coriander, 26
Cnicus benedictus, 389 CoIocasia alltiquorum, 26, 40 Coriandrum sativum, 26
Cnidosco!us texanus, 517, 529 Colombia, 607, 708 Coriaria arborea, 384
Cnidoscolus urens, 517 coloration, warning, 542 Coriariaceae, 197,244,384,610
724 Index

coriariin A, 210 cowpeas, 392 cultures, callus, 47, 326, 413, 473, 535, 586,
corilagin, 194, 209 Coxsackie, 210 587,601,610,625,627,645,653
( - )-coronaridine, 635 crambe, 306, 307 cultures, hairy root, 47, 353, 526, 528, 534,
( + )-coronaridine, 635 Crambe abyssinica. 306, 307 708
cork, 53, 447 Crassulaceae, 282, 290, 539 cultures, suspension, 2, 3, 9, 13, 93, 128, 135,
com (Zea mays), 53, 65, 105, 173, 192,290, crayfish,44O 326,353,366,368,452,457,473,553,554,
435, 648; also see maize Creatonos, 552 557,587,594,598,601,610,614,616,631,
com borer, 417 Creatonotos transiens, 552 654
com borer, Asiatic, 480 creosote bush, 120 Cunoniaceae, 197
com borer, European, 696, 711 crepe myrtle, 694 Cupressaceae, 46, 179,338
Comaceae, 197, 359-361 crepenynic acid, 42. 43 Cupressus macnabiana, 338
Cornales, 360 Crepis, 45 Cupressus sargentii, 338, 351
Comanae, 360 o-cresol, 124 cupric ion (CU2 +), 209
Comiflorae, 337, 360 p-cresol, 124 Curacao, 210
comin,355 Crithidia fasciculata, 645, 660 curare, 511, 607, 628, 643, 645
coronaridine, 632 crocein, 499 curare-like effects, 675
coronary artel}' flow, 588 crocin,254 curares, calabash, 643
coronary dilation, 640 Crocus sativus, 499 curares, tube, 605, 607
coronatine, 238 crops, 53, 219, 227, 300, 306-308, 317, 336, curarizing agent, 643
Coronilla, 290 366, 378, 389, 457, 482 curarizing effects, 650
Coronilla varia, 291 Crotalaria, 548, 549, 551-553 curcin,244
coronopilin, 388, 389 Crotalaria retusa, 551 curine, 606
corpora allata, 318, 384 Crotalarieae, 550, 566 Curtisiaceae, 360 ,
cortex, 320, 439 crotepoxide, 104 cuscohygrine, 531, 532-534, 539, 677
cortexone, 440 Croton, 403, 405, 420, 591, 610 Cuscuta, 658
corticosteroids, 439 Croton macrostachys, 104 Cuscuta platyloba, 559
cortisone, 462 croton oil, 402, 403, 425 Cuscuta refiem, 559
Corydalis, 605 Croton salutaris, 595 Cuscutaceae, 559
cOl}'nantheal, 649 Croton tiglium, 402 cutch,204
CorynantM alkaloids, 630-632, 634, 640, 645, Crotonoideae, 286 cuticle, 53, 53
crown gall, 110, 128 cutin, 51, 53, 54, 111
649
corynantheal, 649 crown rust, 98, 105 cutworm, variegated, 316, 479
corynanthean, 612, 636, 638 crownvetch, 291, 295 Cyamopsis tetragonolobus, 260
Corynocarpaceae, 290, 610 Cruciferae, see Brassicaceae cyanide determinations, 294; see also Feigl-
Corynocarpus, 290 crustaceans, 260, 437, 440 Anger method, Guignard test. picrate
cost, see metabolic cost method, sodium picrate paper
crustacyanin, 498
cyanide oxygenase, 290
Costa Rica, 220, 295 cryogenine, 694
cyanide-resistant respiration, 6
Costelytra zealandica, 179, 291 cryptaustoline. 605
cyanidin, 152, 167, 170, 172, 177, 190, 191,
costunolide, 391 cryptic marking, 550
193,200, 210
COT, see 2-carboxy-4-oxotetralone cryptocapsin, 494
cyanidin 3-0-g111coside, 171
cotinine, 526 Cryptocarya, 563, 565
{J-cyanoa1auine, 226, 289, 290
Cotoneaster, 499 Cryptocarya bowie;, 605 3-cyanoalanine, 223, 226, 231
cotlon, 3D, 34-36, 39, 78, 171,228,342,378, Cryptocarya massoia, 269
3-cyano-L-alanine, 215
380, 391, 395 cryptolepine, 666 ,B-cyanoa1auine synthase, 232, 287, 289
cotton boll weevil, 342 Cryptolepis sanguinolenta, 666 cyanobacteria, 17, 495
Cotton effect, 230 cryptopine, 594 cyanoformic acid, 231
cottonseed, 256 cryptopleurine, 564 cyanogenesis, 273, 274, 280, 287-289
cottonseed meal, 380 cryptostyline alkaloids, 581 cyanogenic glycosides, vii, 5, 6, 8, 9, 14, 273,
cottonseed oil, 35, 36 Cryptostylis.581 274, 276, 277, 280, 282, 285-290, 294, 295,
cotyledoos, 52, 128, 164, 174, 190,220,231, cryptotanshinone, 413 297,298,300,302,303,310,517,528; see
244,261,276,288,308,447,634 cryptowolline, 605 also pseudocyanogenic glycosides
cotylenins, 415 Ctenuchidae,551 cyanogenic glycosides, meta-substituted, 280
p-coomarate, 107, 108, 152 cubebanes, 375 cyanogens, cyclopentenoid, 289
p-coumarate:CoA ligase. 155 cubenol,381 cyanoginosin-LR, 239, 245
4-coumarate:CoA ligase, 109, 133 cucumber, 53, 346, 444, 472 cyanohydrin, 273, 274, 276, 280, 282, 290,
p-coumarate-3-hydroxylase, 108 Cucumis sativus, 444 295-297, 299
o-coumaric acid, 122, 126, 130, 132 cucurbic acid, 33, 79 cyanolipids, vii. 6, 273, 285, 287, 289. 294,
p-coomaric acid, 54,102,106-109,118,121, Cucurbita. 452. 488 297, 298, 321
122, 131, 132, 142, 147, 155, 156, 193, 195, Cucurbita maxima, 444, 452 cyanophoric compounds, 282
269, 509, 518, 624 Cucurbita pepo, 33, 39, 370 Cyathea spinulosa, 173
coumarin, 11, 113, 130-138, 179, 190,262, Cocorbitaceae, 31, 33, 229-232, 411, 444, Cybister tripunctatus, 440
387, 478, 575, 576 445, 447, 454, 463, 472 Cycadaceae, 226
coumarins, 8-prenylated, 663 cucurbitacin B, 444 cycads, 173, 226, 290, 294
Z-o-coumarinic acid, 130 cucurbitacin C, 444 Cycas, 226, 294
p-coumaroyltryptamine, 518 cucurbitacin E, 444 Cycas circinalis, 226
Coumarouna, 130 cucurbitacin E glucoside, 445 cycasin, 294, 296
p-coumaryl-CoA, 156 cllcurbitacin F, 444, 445 cyclamates. 462
coumaryl glycosides, 9 cucurbitacin I, 445 cyclase ll, 331
coumestan glycoside, 179 cucurbitacins, 309,427,444,445,447, cyclic AMP, 700
coumestans, lSI, 179 452-455 cyclic AMP phosphodiesterase, 703
coumestrol, 179, 191 lOa-cucurbita-5,24-dien-3p-ol, 444, 452 cyclic GMP, 700
couplings, see NMR couplings, oxidative cucurtiitine, 229 cyclilols, 247, 264, 271
coupling, radical coupling cularine alkaloids, 563, 605, 606, 610 cycloalliin, 227
courtship, 383, 551, 552 Culex pipiens, 402 cyc1oartenol, 427, 432, 433, 435, 436, 444,
cows, 35 cultures, see also cell cultures 463, 678, 689
 Index 725

cycloartenol cyclase, 432 Dalechampia spathulata, 344 dehydrochloroprepacifenol.381

cyc10buxine D, 689 damage, 7, 8, 31, 32, 91, 136 4,21-dehydrocorynantheine aldehyde, 631
cyclodopa, 705 damascenine. 568 dehydrocrepenynic acid, 42, 43
cycloeucalenol, 435, 436 ,B-damascenone, 500 dehydrodiconiferyl alcohol ,B-D-glycosides,
cycloeucalenol:obtusifoliol isomerase, 436 dambonitol, 265 llO
cyclohexene oxides, 104 danaidal, 551 dehydmgenation, !l7, !l8, 158, 508, 553
cyc1ohexylcarboxylic acid, CoA derivative, 26 danaidone, 551 7,8-dehydroiridotrial glucosides, 358
cyclooxygenase, 167 Danainae, 550, 551 dehydmiridodiol, 362
cyclopamine, 685 Da""us, 383, 466, 551 dehydromatricaria ester, 43, 49
cyclopentenoid rings, 273, 274, 285, 287 Danaus chrysippus, 552, 564 dehydropyrrolizidine alkaloids, 550
"cyclopism," 685 Danaus gilippus, 551 3-debydroquinate dehydratase, 97
(2-cyclopentenyl)g!ycine, 274, 276, 277, 285 Danaus plexippus, 383, 466, 471, 472, 551, 3-dehydroquinate synthase, 97
cyc1opentenylcarboxylic acid, 28 7ll 3-dehydroquinic acid, 96, 97
cyclopsine, 685 daphnanea, 402, 403 debYdrosanguinarine, 601
cyc1osativene, 381 Daphne genkwa, 404 dehydrosecodine, 634
cyclosporin A, 235 Daphne mezereum, 404 debydroshikimic acid. 95, 193
cyclovirobuxine, 689 Daphne odora, 419 3-dehydmshikimate, 97
D-cymarose, 250, 251, 465 daphnetoxin, 403 3-dehydroshikimate reductase, 97
p-<:ymene, 345, 346 Daphniphyllaceae, 361, 689 12,13-dehydrosparteine, 559
cymopol, 340 daphniphylline, 689 dehydrotestosterone, 440
Cymopolia barbata, 340 Daphniphyllum, 668, 689, 691 dehydrotrewiasine, 696, 711
Cymopterus watsoni, 136 Daphniphy/lum macropodum, 689 deidaclin, 285, 286
Cymmchum. 563 Datiscaceae. 244 Delia antiqua, 227
Cynarese, 387 Datura, 269, 532, 537, 545 Delia brassicae, 309
Cynometra, 693 Datura !erox, 534, 535 delirium, 537, 658
Cyperaceae, 337, 659 Datura innoxia, 534 delirium tremens, 537
Cyperus, 660 Datura stramonium, 534. 535, 537. 573 Delonix regia, 222
Cyperus iria, 384 Datureae, 537 delpbinidin, 152, 167, 170, 177
Cypholaphus, 693 Daucus carata, 3, 26, 48, 72, 73, 128, 136, delpbinidin 3-glucoside, 171
Cyphomandra, 677 328,557 Delphinium, 269, 673, 675
Cyphomandra betacea, 534 Davallia, 280 demethylation, also see oxidative
cysteine, 45, 217, 226, 232, 241, 290, 321, 513 Davallia trichomanoides, 287 demethylation
L-cysteine, 234, 303 Davidiaceae, 361 N-demethylation. 595
cysteine sulfoxides. S-substituted 226 DCCC, see chromatography, droplet demethylcoclaurine, 591
cysteine synthase, 220 countercurrent 3-demethylfamesyl pyrophosphate, 430
cystine, 215. 226 de novo origin, 9, 18 demethylpapaverine, 588
Cystoseiraceae, 210 de novo synthesis, 21 demethylsuberosin, 133, 137
cytisine, 556, 558, 559 dealkylation, 437 demethyltrewiasine. 696, 711
Cytisus praecox, 559 delmyol, 377 demethylvestitol, 184
Cytisus scoparius, 559 decanoic acid. 25 demissidine, 682
cytochalasin, 72 2-decanone, 30 demissine, 682-684
cytochalasin B, 72 decanortriterpenes, 476 denbrobine, 385, 375, 670
cytochrome bs, 22 decarboxylation, 45, 52, 53, 58, 77, 81, 87, 98, Denbrobium, 385
cytochrome oxidase, 288 142,222,223,226,229,253,315,360,435, Dendrobates, 560
cytochrome c oxidase, 645 507,508,513,514,517,531,537,580; also Dendrabiurn, 385, 560, 668, 670, 693
cytochrome P-450 dependent monooxygenases, see oxidative decarboxylation Dendrobium nobile, 670
133, 158, 159, 179, 182, 202, 276, 296, 303, I-decene-l,IO-dicarboxylic acid, 32 Dendroctonus, 37, 340, 342, 343
317,335,355,441,600; see also Decussocarpus gracilior, 173 Dendroctonus brevicomis, 343
monooxygenases de-epoxidation, 497 Dendroctonus frontalis, 343
cytokinins, llO, 700 deet,340 Dendrodoris limbata, 380
cytomegalovirus, 561 deer, white-tailed, 207, 390 dendmlssin, 382
cytoplasm, 8, 19, 107, ll5, 152, 153,261,313, defense, 6, 7, 8, 12-14, 30, 39, 50, 78, 79, dendroprimine, 560
314,318,319,483,488 124, 128, 129, 134, 137, 179, 183, 193, Dendrosius, 382
cytosol, 18, 19, 26, 106, 319, 368, 414, 430, 207-209,213,231,232,261,269,270,273, Dennettia tripetala, 290. 297
629 288-290, 296, 310 deodorization, 35
cytotoxic activity, 59, 67, 69, 74, 120. 149, defense, plant, 6, 7, 213, 288 I-deoxocucurbitacin, 444
209,267,316,338,380,389,393,415,420, defensive compounds. vii, 6, 7, 8, 33,41.79. 2-deoxy sugars, 250
444, 445, 452, 455, 468, 471, 472, 479, 481, 122, 124, 125, 209, 231, 269, 273, 288, 290, 6-deoxy-D-allose, 250
482,484,510,591,601,606,640,648,652, 291,293,310,322,339-343,353,362,367, 6-deoxy-L-altrose, 250
663, 666, 671, 676, 696, 700, 705 372,376,380,382,439,442,447,455,458; 3-deoxyanthocyanins, 164
see digestibility reducing substances deoxybouvardin, 700
Dactylis glomeratus, 659 defensive compounds, qUalitative, 7, 209 deoxychalcone. 158
Dacus dorsalis, 111, 128 defensive compounds, quantitative, 7, 209 deoxyeritadenine, 700
Daemonorops, 569 defensive secretion, 49, 500 6-deoxy-D-galactose, 250
daffodils, 430, 452, 510, 620, 622 defensive substances, digestibility-reducing, 6-deoxy-L-galactose, 251
daffodils, King Alfred, 620 207 6-deoxy-D-glucose, 251
daga, 336 deficiency, see fatty acid deficiency, human 6-deoxy-D-gulose, 250
Dahlia, 200 immunodeficiency virus (HN) deoxyhaningtonine. 625, 626
DAHP, see 3-deoxy-D-arabino-heptulosonic Degenariaceae, 610 3-deoxY-D-arabino-beptulosonic acid
acid 7-phospbate dehydration, 20, 44, 97, 315 7-phosphate (DAHP), 97
daidzein, 178, 181, 184, 191 dehydroabietic acid, 415, 420 2-deoxybexoses, 247, 250
Dalbergia, 78, 187 20,2I-dehydmajmalicine, 631 6-deoxybexoses, 247, 250
Dalbergia refusa, 78 dehydroaporphines, 588 deoxyloganic acid, 354, 355
dalbergiones, 187 dehydroascorbic acid, 265 epi-deoxyloganic acid, 354
dalbergiquinols, 187 dehydrochelerythrine, 601 8-epi-deoxyloganic acid, 358
726 Index
epi-deoxyloganin, 353, 358
6-deoxy-L-mannose, 250, 251
6-deoxy-3-0-methyl-D-galactose, 251
6-deoxy-4-0-methyl-D-glucose, 251
6-deoxy-3-0-methyl-L-mannose, 250, 251
6-deoxy-3-0-methyl-L-talose, 250, 251
( - )-deoxynupharidine, 670
2-deoxy-D-erythro-pentose, 250
4-deoxyphorbol, 402
12-deoxyphorbol, 403
deoxypodophyllotoxin, 120
5-deoxyproanthocyanidins, 201, 206
2-deoxy-D-ribose, 250
6-deoxy-L-talose, 251
dephosphorylation, 23
depolymerization, 676
depressants, central nervous system, 539
Depressaria pastinacella, 136, 138
depression, 514, 517, 607, 643
depression, bone marrow, 235
depression, smooth muscle, 603
depside,70
dermatitis, 336, 389, 394, 403, 424
Dermestes maculata, 35
Dermocype austroverwta, 91
Derris, 186, 253
Derris elliptica, 543
desacetoxyvindoline, 634, 652
desacetylconfertiflorin, 388, 390, 392
desacetylipecoside, 611
desacetylisoipecoside, 611
desacetylvindoline, 634
desaturase, 3, 21, 22, 26, 34, 43
desaturation, 3, 21-23, 34, 35; also see fatty
acid desaturation
desert, 52, 120, 125, 128
Des/onfainia, 444
Desfontainiaceae, 444
desmethoxyyangonin, 140
desoxymannojirimycin, 253
desoxynorjirimycin (ON]), 253, 254
desoxyvasicine, 570
desoxyvasicinone, 570
desulfobenzylglucosinolate, 303
detergent, 208, 428, 430, 432, 459, 490
deterrency, 603
deterrent, 173, 179,288,291,295,309,316,
339,340,350,361,380,382,390,395,
415-418,441, 451v 452, 468, 472, 479,511,
523,528,537,538,540,543,550,558,559,
562,582,588,591,597,600,603,613,618,
640,641,650,658,660,664,682,686
detoxication, 5, 10, 136, 138, 186, 209, 288,
290
detritus, 207
Deutzia crenata, 355
deutzioside, 355
development. 1,3,6,7,9, 10, 12, 14,40,46,
71,78,92,98,111,122,135,171,196,207,
234,235,238,239,259,275,287,288,297,
298
dextrins, 259
DHAP. see dihydroxyacetone phosphate
DHNA, see 1,4-dihydroxy-2-naphthoic acid
dhurrin, 5, 276, 280, 282, 287, 288, 290, 296,
299
(S)-dhurrin, 277, 282
diabetes, 174
dhurrin j3-g1ucosidase, 282
Diabrotica barberi, 113
Diabrotica undecimpunctata IlOwardii, 113,
128
Diabrotica virgifera virgifera, 113. 128
Diabroticina, 447
diabrotid beetles, 447
1,4-diacetoxy-l.3-diene, 380,419
Diacl'isia virginica, 390
diacylglycerol, 19,23.24,40
diacylglycerol acyltransferase, 24
Diadema, 340
Diadema antillarum, 420
Diadromus pulchellus, 227
diamides, 518
diamine oxidases, 509, 510, 554, 599
diamines, 509, 510, 513, 515, 517, 518, 531,
540
2,4-diaminobutyric acid, 223, 226
a, y-diaminobutyric acid, 234
L-2,4-diaminobutyric acid, 226
L-a, y-diaminobutyric acid, 226
2,6-diaminopimelic acid, 217
2,3-rliaminopropionic acid. 223, 226
a,,B-diaminopropionic acid, 226
dianthalexin, 568
dianthrone, 85, 88
Dianthus, 568
Dianthus caryophyllus, 156
diaphoresis, 528
6,6'-diapocarotenoic acid. methyl ester. 499
diarrhea, 452, 599, 612, 697
Diarthron vesiculosum, 404, 425
dibenzopyrrocoline, 605
dibenzopyrrocoline alkaloids, 605
S-(1,2-dicarboxyethyl)cysteine, 227
Dicentra, 605
Dichapetalaceae, 29
Dichapetalum, 29, 30
Dichapetalum toxicarium, 29
1-(3 ,5-dichloro-2,6~dihydrox y-4-
methoxyphenyl)-l-hexanone, 71
2,5-dichlorophenol, 125
Dichroa, 569
dicotyledonous plants. 19,69,88, 108, 115,
164, 172, 189, 194,242,286,324,458,510,
5l7,562
dicoumarol, 132, 137
Dicranum. 173
dictamnine, 571, 573
Dictylomatoideae, 574
dictyol-E, 420
dictyopterene A, 32
dictyopterene B, 32
Dictyopteris deticulata, 32. 39
Dictyostelium, 71, 74
Dictyotales, 420
1,2-didehydrosparteinium ion, 556
2,6-dideoxy-D-ribo-hexose, 250, 251
2,6-dideoxy-D-_l}'lo-hexose, 250, 251
2,6-dideoxy-3-0-methyl-O-lyxo-hexose, 250,
251
2,6-dideoxy-3-0-methyl-D-ribo-hexose, 250,
251
2,6-dideoxy-3-0-methyl-D-xylo-hexose, 250,
251
2,6-dideoxy-3-0-methyl-L-arabino-hexose, 251
Didieriaceae, 708
Diels Alder reactions, 573
(3S,5R,6S,3'S,5'R,6'S)-5,6,5',6'-diepoxy-
5,6,5',6'-tetrahydro-,6,j3-carotene-3,3'-diol,
486
diet, 16, 17,34,35,92,99,113,136,167, 176,
191,193,207,208,212,217,220,223,228,
245,254,261,289,291,306-308,310
digalactosyl diglycerides, 17
1,6-digalloylglucose, 196
D-diginose, 250, 251, 465
digitalis glycosides, 676
Digitalis, 85, 465, 468
Digitalis lanata, 468, 680
D-digitalose, 251, 465
digitonin, 468, 470
D-digitoxose, 250, 251, 465
diglycerides, 287, 437
diglycerides, monogalactosyl, 17
digoxin, 468
dihydroactinidiolide, 362
dihydrobenzophenantbridine oxidase, 600, 616
dihydrobenzophenanthridines, 600, 60 I
dihydrobiochanin A, 186
dihydrochalcone, 156, 174-176
dihydrocinnamic acid, 109, 125, 147,451
dihydro-m-coumaric acid, 147
dihydro-p-coumaric acid, 624
24,25-dihydro-9a,11a-epoxyparkeol, 444
dihydroflavonoI4-reductase, 162, 163,200
dihydroflavonols, 151, 156, 158, 159, 162,
163,175,188,190,201
dihydrofuroquinolone alkaloids, 573
dihydrokaempferol, 159, 162, 163
(2R,3R)-dibydrokaempferol, 162
dihydrokawain, 140
8-Z-dihydromatricaria acid, 49
dihydromethysticin, 140
dihydromyricetin, 163
( + )-dihydromyricetin, 200
dihydromyricetin reductase, 202
dihydronepetalactone, 358. 362
dihydroparthenolide, 390, 392
dihydrophenanthrenes, 139, 140, 146, 147, 149
9,10-dihydrophenanthrenes, 147
3,4-dibydroxypyridine, 220
dihydroquercetin, 159, 163, 175
(+ )-dihydroquercetin, 175, 200
(2R,3R)-dihydroquercetin, 159. 162
dihydroquercetin 3-acetate, 175, 176
dihydroquercetin reductase, 200
dihydroquercetin 3-0-rhamnoside, 175
dibydrosanguinarine, 600, 601, 616
16,17-dihydrosecodin-17-ol, 635
rlihydrostilbenes, 140
dihydroxyacetone phosphate (DHAP), 19
3,4-dihydroxybenza1dehyde, 620, 621, 622
2,4-dihydroxy-I,4(2H)-benzoxazin-3-one
(DIBOA), 98, 99
2,4~dibydroxy-1 ,4(2H)-benzoxazin-3 -one
(DIBOA) glucoside, 99, 101
(3R,3'S,5'R)-3.3'-dihydroxy-,8,K-caroten-6'-
one, 494
16,8,26-dihydroxy-5a-cholestanol, 680
20,22-dihydroxycholesterol, 439
3,4-dihydroxycinnamic acid, 118
ent-Ia,10j3-dihydroxy-9a,ISa-cyclo-20-
norgibberell-16-ene-7,9-dioic acid 10,19-
lactone, 414
7,2'-dihYdroxy-3,4' ~dimethoxyisoflavan, 184
2,7-dihydroxy-3,4-dimethoxyphenanthrene, 148
2,7-dihydroxy-4,8-dimethoxyphenanthrene, 148
2,3-dihydrodipicolinic acid, 217
(22S,25R,26R)-3/3,26-dihydroxy-22,26-epoxy-
6-oxo-Sa-cholest-7-ene, 463
6a,7-dihydroxymaackiain, 186
6a,7-dihydroxymedicarpin, 186
2,4-dibydroxy-7-methoxy-l,4(2H)-benzoaxazin-
3-one (DIMBOA), 94, 98, 99, 101, 104, 568
2,4-dihydroxy-7-methoxy-l,4(2H)-benzoaxazin-
3-one (DIMBOA) glucoside, 99
3,3'-dihydroxy-5-methoxybibenzyl, 148
7,4'-dihYdroxy-2'-methoxyisoflavan, 184
2-(3,4-dihydroxy-S-methoxyphenyl)ethyIamine,
592,593
2R,5R-dihydroxymethyl-3R,4R-
dihydroxypyrrolidine (DMDP), 253, 254
erythro-9,10-dihydroxy-l-octadecanyl acetate,
35
1,4-dihydroxy-2-naphthoate, 87

1,4-dibydroxy-2-naphthoic acid (DHNA), 81,
82,86,87
l,4-dihYdroxy-2-naphthoic acid synthetase, 81
12,13-dihydroxyoleic acid, 26
lO,16-dihydroxypalmitic acid, 53
3,4-dihydroxyphenethylamine (dopamine), 523,
579, 580, 628
3,4-dihydroxY-P.phenethyl-O-P.D-
glucopyranosyl-(I->3)-4-0-caffeoyl-P.D-
glucopyranoside, 108
3',4'-diliydroxyphenols.208
3,4-dihydroxyphenylacetaldehyde, 2, 3, 584,
587
3,4-dihydroxyphenylacetonitrile, 277
3,4-dihydroxy-L-phenylalanine (L-dopa), 229,
587
3,4-dihydroxyphenylpyruvic acid, 3, 587
5,7-dihydroxyproanthocyanidins, 201
5,8-dihydroxypsoralen, 133
2,7-dihydroxy-3,4,6-trimethoxy-9,10-
dihydrophenanthrene, 148
2,3-dihydroxy4,7,8-trimethoxyphenantltrene,
148
2,7-dihydroxy-3,4,6-trimethoxyphenanthrene,
148
3,4-dihydroxytyrarnine, 578, 579
3',4'-dihydroxyusambarensine, 652
la,25-dihydroxy-vitamin D, glycoside, 437
3,4-di-O-isobutyryl-6-0-caprylsucrose, 269
Dilleniaceae, 197
DIMBOA, see 2,4-dihydroxy-7-methoxy-
1,4(2H)-benzoaxazin-3-one
dimeric aporpbines, 588
2,6-dimethoxybenzoquinone, 78, 79
2,6-dimethoxy-p-benzoquinone, 78
3,5-dimethoxy-4-hydroxycinnamic acid, 300
3,5-dimethoxy4-hydroxycinnamoylcholine,
302
1O,l1-dimethoxystrychnine, 641
di-O-methyl tubocurarine, 607
dimethylallyl pyrophosphate (DMAPP), 312,
315,316,326-329,335,348,369,370,430,
431,488,656
dimethylallyl transferase, 3, 133,488
4-dimethylallyltryptophan, 656
4-()', ~imethylallyltryptophan), 656
1,4-dimethylazulene, 368
N' ,N"-dimethylhistamine, 692
ID-di-O-methyl-chiro-inositol, Z64
1,3-di-O-methyl-myo-inositol, 265
I-D-l,4-di-O-methyl-myo-inositol, 265
E-4,8-dimethyl-l,3,7-nonatriene, 341
N,N-dimethyltryptamine, 511, 514
1,3-dimethylxanthine,7oo
3,7-dimethylxanthine, 700
a-dimorphecolic acid, 26
dinoflagellates, 703
dinosaurs, 511
Dioclea megacarpa, 220
2,3-lrans-3,4-trans-diol (2R,3S,4R)-( +)-
3,4,5,7,3',4'-hexahydroxyflavan, 200
Dioncophyllaceae, 698, 708
Dioncophyllum, 698
Dioseorea, 33,457,462,510,513,528
Dioscorea balalas, 147
Djoscorea composita, 241
Dioscorea delloidea, 457
Dioscorea rotundata, 148
Dioscoreaceae, 147, 148,457,462,510,528,
537
Dioscoreophyllum cumminsii, 245
dioscorine, 528
diosgenin, 457, 458, 462
diosindigo A, 82, 85
Diosmeae, 575, 576
Index 727
Diospyros, 85 Z-13-docosenoic acid, 35
Diospyros diepenhorstii, 209, 212 2-doclecanone. 30
dioxygenases, 158, 159, 186, 202 dogs, 609
dipeptides. 657 Dolichoderus scabridus. 362
diphosphomevalonate decarboxylase, 315 dolichodial, 358
Diphysa robinioides, 145 dolicholactone. 358
Diploclisia, 442 dolichoprenols, 321
Dip/odea pinea, 340 Dolicholhele, 693
Dip/adus, 420 Dolichothele sphaerica, 692
Diplodus holbrooki, 420 dolichotheline, 692
diploids, 4, 337 dopa, 587, 591, 705, 706
dipropyl sulfinate, 227 L-dopa (dihydroxyphenylalanine), 229
Dipsacaceae, 360, 361 dopa decarboxylyase, 515
Dipsacales, 360, 361 dopamine, 2, 229, 510, 523, 535, 578-582,
Dipterocarpaceae, 197,412 585-587. 591, 595, 610, 640
Dipteryx odorala, 130 dopamine receptors, 591
disaccharide esters, 108 dopaminergic, 510
disaccharides, 247, 253, 254. 266, 270, 287 donnancy, bud, 500
Discaria, 610 dormancy, seed, 500, 501
disease, see Alzheimer's, blackrot, black spot, Dorslenia, 134
Chagas', Dutch elm, Hodgkin's, Lou Draba cuneifolium, 305
Gehrig's, Parkinson's, rust, veno-occlusive. Draba platycarpa, 305
and yellow rice diseases Dragendorff's reagent (alkaloids), 547, 560,
Dislium, 228 648
dispersal, vii, 9, 35, 40, 149, 151, 152. 171 drimane, 379
dispersal, seed, vii Drosera, 63, 80
dissemination, 30 Droseraceae, 63, 80, 82, 197,297
distasteful properties, 550 , 683 Drosophila, 441, 453, 454, 549. 582, 583, 615
distillation, 324 Drosophila melanogasler, 441
diterpene acids, 342 Drosophila mettleri, 441, 582
diterpene alkaloids, 408, 626, 668, 672, 673, Drosophila mojavensis, 441. 582, 583
689,690 Drosophila nigrospiracula, 441, 582
diterpene 19-carboxylic derivatives, 673 Drosophila pachea, 441, 582
diterpenes, 77, 312, 337, 339, 341, 369, 370, drugs, see adrenergiC drugs, anticholinergic
380,381,398,399,401-408,411-416. drugs, cholinergic drugs, drugs of abuse,
418-420,423-427,431,488,500,626 parasympatholytic drugs,
seco-diterpenes, 413 parasympathomimetic drugs, soporific drugs
diterpenes, acyclic, 399 drugs of abuse, 12,511,535,593
diterpenoids, B-secokaurene, 420 drununondin A, 69
diterpenes, bicyclic, 404, 405 drummondin B, 69
diterpene 19-carboxylic acids, N- drmmuondin C, 69
a1kylaminoethyl esters, 674 DrUsenameisen. 703; also see ants
diterpenes, cocarcinogenic, 244, 402, 403, 413. Dryopleris, 68
420,424 Drypetes, 304
diterpenes, 5a,lOJ3-configuration, 398, 404, Duboisia, 528, 535, 537
405,412 Duboisia leichhardlii, 532, 534
diterpenes, 5,B,lOa-configuration, 398, duckein, 528
404-407,411,412 duckweed, 145
diterpenes, grayanoid, 411, 412 Dufour's glands, 37, 563
diterpenes, macrocyclic, 414 dulse, 260
diterpenes, monocyclic, 401, 402 dung, 14,71
diterpenes. tetracyclic, 401, 407 dunnione, 87
diterpenes, tricyclic, 398, 405-407 dust, 535, 552
diterpenoid precursors, macrocyclic, 676 Dutch eJm disease, 72
diuretic, 136, 392, 702 Dutch Indies, 649
diurnal rhythm, 7, 510, 543, 553 duvatrienediol, 401, 414
diversity. 3, viii, 6, 7, 10, 13 4.8,13-duvatrien-l,3-diol,414
divi-divi, 195 a-4,8,13-duvatrien-I,3-diol,414
djenkolic acid, 227 Dyera.652
Djibouti, 210 dyestuff, 85, 89, 267
DMAT synthetase, see tryptophan Dysdercus, 689
dimethylallyltransferase synthetase Dysdercus koenigii, 111
DNA,3-5, 14.26, 135, 137, 156, 237, 246, dysentery, 564, 570, 612, 640, 662, 686, 698
314,393,529,549,553,568,573,623,648. dysentery, amebic, 564, 612
653,660 Dysoxylum, 607
eDNA, 156,280.295,314.629 dyspepsia, 364
T-DNA,123 Dysphania, 708
DNA intercalation, 573, 599, 601, 645, 651 Dytiscinae, 439
DNA polymerase, 521, 601, 623
DNA recombinant methods, 3, 10 earwonn, com, 99, 173, 192
DNA, synthesis, 520, 613, 645, 648, 676, 696 earwonn, European com, 99
DNA-dependent RNA polymerase, 645 Ebenaceae, 82, 85, 197
ONJ, see desoxynojirimycin ebumamine-vincamine alkaloids, 640, 653
dock, 76, 91 ebuman, 636
l-docosanol, 53 Ecballium. 230
728 Index

Ecballium e/aterium, 437 Encelia ventorum, 316 epiJucumin 4"-p-(,B-D-glucopyranosyloxy)-(E)-

ecdysis, 419, 479, 484, endophytic fungi, 655, 658, 659 cinnamate, 277
ecdysone, 440-442, 454 endoplasmic reticulum, 18,21,23,26,51,313, epilucumin 4"-p-(,B-primeverosyloxy)-(E)-
a-ecdysone, 444 318,326, 368, 526, 528, 598 cinnamate, 277
,B-ecdysone, 440 endopolygalacturonase, 261 epilucumin, 279
ecdysteroid, 427, 440, 442, 452, 453, 455 a-l,4-D-endopo!ygalacturonic acid lyase, 262 epimastigotes, 660
echinacein, 36 endosperm, 22-24, 26, 39, 287, 288, 399 22,26-epiminocholestane type alkaloids, 677,
Echinocereus blanckii, 692 energy storage, 16, 17,32,591,497 681,683
Eclipta alba, 179 England, 190,210,363 a-epiminocyclohemiacetals, 677, 681
ecology, 3, 10, 12, \3,41, 128, 135, 177, 189, enkephalins, 597 epinephrine, 511, 522
311,510,544,550; see also chemical enrnein, 408, 419, 420 Epipactis palustris, 147
ecology enniatins, 238 epipassicoriacin, 285
Ecuador, 708 5-enolpyruvylshlkimate, 97 epiphytic, 659
edema, 378. 460 5-enolpyruvylshikimate-3-phosphate (EPSP), epiproacacipetalin, 282
edible oils, 16 97 (R)-epiproacacipetalin, 282
eggplant, 677 5-enolpyruvylshlkimate-3-phosphate synthase epirubijervine, 684
eggs, 37, 88, 124, 128, 179,220,291,340, (EPSP synthase), 97 epitetraphyllin B, 285, 296, 298
342,363,393,437,444,447,498,551,696 enoyl-ACP reductase, 20 epithelial cells, 324
Ehrlich's reagent, 547 Entamoeba histolytica, 392, 564, 612, 640, 652 epivolkenin, 285, 286, 296
eicosatetra-5,8,1l,14-enoic acid, 34 (S)-epilotaustralin, 282 epoxidation,431
Ekebergia, 663 (S)-epilucumin, 277, 279 epoxide, 282
Elaeocarpaceae. 444, 537, 543, 546, 563 Enterobacter aerogenes, 97, 105 epoxydon, 72
elaeocarpine, 563 enzyme-linked immunosorbent assay (ELISA), (8R,9R,10S)-9,10-epoxyheptadec-16-ene-4,6-
Elaeocarpus, 444. 543, 563, 565 1 diyne-8-ol. 49
Elaeocarpus dolichostylus, 444, 453 enzyme, nitrogenase, 290 24-ethoxyhopane, 431
elaidate,35 enzyme systems, cell free, 326, 328, 329, 331, Z-12,13-epoxyoleic acid, 27
elaiosome, 35, 40 373,407,488,587,592,629,645,655,700 Z-9,lO-epoxystearate,27
Eleagnaceae, 244, 660 enzymes, 1-10, 13, 19,21-24,42,58,78,94, (3S,5R,6R,3'S,5'R,6'Sj-5',6'-epoxy-5,6,5',6'-
eleagnine, 660 95,97,98,101,102,107-109,115,117, tetrahydro-,B,,B-carotene-3,5,3'-triol,486
Eleagnus, 660 120, 132, 135, 138, 153, 155, 156, 158, 159, 14,15-epoxyprieurianin, 481
Eleagnus angustifolia, 660 162-165,173,178,179,181,182,184,187, EPSP, see 5-enolpyruvylskikimate
electroantennogram, 31, 113 188, 190, 195, 196,200,203,207-209,212, EPSP synthase, see 5-enolpyruvylskikimate
electron carriers, 22, 76 220,221,227,230,231,241,252,257, synthase
electron microscopy, 318 260-262, 266, 269, 270, 273, 275, 276, 280, Equisetaceae, 521
electron transport chain, 166 287,288,290,294-296,300,302,303,311, Equisetum paiustre, 521
electrophoresis, 217, 708 313-315,319,321,322,326,327,329, equol, 179
electrophoretic separation, 587 331-333,335,348,351,369-373,375,371, Erantis, 269
elemanes, 374 389,396,401,408,414,424,425,428,430, eremanthine, 391
elemicin,111 432,436,444,447,452,453,455,459,471, Eremanthus, 390
Eleocharis microcarpa, 32 473,488,490,492,497,503,504,508-510, eremophilanes, 371, 374
a-eleostearic acid, 35 513,516,520,528,531,532,535,556,561, ergine, 655
elephantin, 393 586,587,594,598,599,600,614,616, ergocornine, 658, 660
Eleutherococcus senticosus, 462, 470 629-631, 648, 654, 656-658; see also ergocryptine, 658, 660
elicitors, 33, 39,133,134,138,142,178,179, "berberine·bridge" enzyme, enzyme-linked ergolines, 656
184, 186,261,262,270,271,372,377, 402, immunosorbent assay, rubber transferase ergometrine, 658, 660
414,600,601,6\3 enzyme ergonovine, 658, 659
elimination reaction, 107,327,329,349,370, enzymes, anabolic, 4 ergosterol, 442
431,621,656 enzymes, branching, 259 ergol, 26, 316, 568, 575, 655, 658-660, 666
Z-elimination, 22, 97 enzymes, catabolic,S, 7 ergot alkaloids, 511, 655-660, 666-668, 692
ELISA, see enzyme linked immunosorbent enzymes, debranching, 259 ergot alkaloids, peptide containing, 657
assay enzymes, extracellular, 209 ergotamine, 511, 656-658, 660
elk,207 enzymes, hydrolytic, 194, 319 ergotism, 655, 658
ellagic acid, 194,208,210 enzymes, peroxidase, 117 Ericaceae, 71, 78, 82, 88, 122, 195, 197, 361,
ellagitannins, 193-197,206,209,210,212, Epacridaceae, 361 408,411,413,554
213 Ephedra sinica, 522 Ericales, 361
ellipticine, 628, 645 Ephedraceae, 522 Ericanae, 360, 361
elm, 237 ephedrine, 511, 513, 522, 530 Eriobotrya japonica, 148
elongation, 3, 21, 23, 51, 52 epicatechin, 165,201 eriodictyol, 158, 162-164, 167, 175
elymoclavine, 656, 657, 658 ( - )-epicatechin, 202-204, 206 (2Sj-eriodictyol, 162, 164
Elymus, 101 ( + )-epicatechin, 172 erucic acid, 35
embelin,77 ( - )-(2R ,3R)-epicalechin, 201 Ervatamia, 637, 647
embryo, 288, 361, 411 (+ H2S,3S)-epicatechin, 201 Ervatamia heyneana, 648
emetic, 361, 466, 468, 479, 601 ent-epicatechin, 201 Erwinia carotovora, 262
emeline, 361, 511, 564, 579, 610, 612, 613, Epichloe, 659 erychroside, 468
638,652 epidermal cells, 9, 51, 52, 137, 155, 156, 166, erysimoside, 468
emodin, 64, 65, 85, 87, 91 191, 193, 282, 299, 510, 557 Erysimum, 468
emodin anthrone, 91 epievodone, 346,451 Erysimum cheiranthoides, 309,468
emodin 1-0-methyltransferase, 85 epigallocatechin, 172, 203 Erysiphe graminis, 288, 558
Empetraceae, 125, 175,451 ( - )-epigallocatechin, 172 erysodiene, 608
emulsin, 280. 287 ( + )-epigallocatechin, 172 erysodienone, 608
emulsin, almond, 561 epiguaipyridine, 672 (- )-(5S)-erysodienone, 608
enamine, 507, 553 epiheterodendrin, 282, 284, 288 erysopine, 608
encecaiin, 316, 317, 322 (R)-epiheterodendrin, 282 erythraline, 608
Encelia, 316, 322 Epilachna borealis, 445 Erythrina, 290, 294, 299, 560, 598, 608-610,
Encefia farinosa, 125 Epilachna varivestis, 288, 297 614,627
 Index 729

Erythrina alkaloids, 608. 609 Eumaeus ataia, 294 fagopyrin, 91

Erythrina christa-galli, 608 Euodia, 570, 573 Fagopyrum, 76
Erythrina flabelliformis, 609 Euonymus, 452 Fagopyrum esculentum, 162, 190,543
meso-erythritol, 262 Euonymus europaeus, 269, 270, 671 Fagus grandifolia, 117
erythrocytes, 459 eupahyssopin, 392 falcarindiol, 50, 113, 136
a-erythroidine, 608 Eupatorieae, 387, 510, 549, 550 falcarinol,48
,B-erythroidine, 608 eupatoriochromene, 317 falcarinone, 45
erythromycin, 65 Eupatorium jhanii, 500 familial Mediterranean fever, 619
erythromycin A, 65, 67 Eupatorium rugosum, 317, 321 a-farnesene, 381
Erythronium, 269 euphol, 447, 473 (E)-,B-farnesene, 383
Erythrophleum, 412, 676 apo-euphol, 473, 475, 480 (E,E)-a-famesene, 383
Erythrophleum alkaloids, 668, 676 LJ1-euphol, 473, 476 (Z,E)-a-famesene, 383
Erythrophleum chlorostachys, 676 Euphorbia, 197,319,337,344,385,398,402, farnesol, 344, 370, 380-383, 396
Erythrophleum guineense, 676 403 E-farnesol, 370, 501
erythrose, 249 Euphorbia iagascae, 26, 27 (E,E)-farnesol, 381, 382
erythrose-4-phosphate, 94, 96, 97 Euphorbia lathyrus, 229 Z,E-farnesol, 370
Erythroxylaceae, 412, 533-535, 537 Euphorbia tirucalli, 402 2-E-6-E-farnesol, 370
Erythroxy!um, 412, 532, 533, 534 Euphorbiaceae, 26, 35, 45, 46, 50, 69, 88, 173, 2-Z-6-E-farnesol, 370
Erythroxylum coca, 532, 533, 535 197,229,240,244,245,253,269,276,282, famesyl acetate, 381
Escalloniaceae, 359, 361, 673 286,288,299,304,319,321,337,344,385, farnesyl diphosphate, see famesyl
Escherichia coli, 81,96,97, 101. 104, 106, 398,401-407,412-414,420,423,424,426, pyrophosphate
156,245,517,629 444,466,510,513,517,537,542,549,554, farnesyl diphosphate synthase, 319
Eschscholtzia, 605 575,581,592,595,610,639,640,692-697, farnesyl octanoate, 381
Eschscholtzia californica, 33, 290, 296, 600, 700, 703, 709 farnesyl pyrophosphate (FPP), 315, 319, 321,
601,616 Euphoria longan, 222 322,326,327,335,351,367,369,370-373,
Eschscholtzia tenuifolia, 2. 587, 616 euphoric effect, 597 394,396,428,430,431,455,488
( - )-eschscholtzine, 605 Euphydryas, 361, 363, 366 2-cis-6-trans-farnesyl pyrophosphate, 370
esculetin, 130, 132 Euphydryas anicia, 363 E,E-farnesyl pyrophosphate, 321, 367, 369,
essence d'iris, 452 Euphydryas chalcedona, 363 370,375,377,387
essence, 324 Euphydryas cynthia, 363 E,E-farnesyl pyrophosphate synthetase, 369
essential oil, 30-32, 42, 45, 47, 52, 59, 109, Euphydryas phaeton, 361 famesyl pyrophosphate synthetase. 326, 327.
lll, 122, 130,324, 326, 332, 337-344, 346, Eupomatia, 591 351,368-370,396,399,488
349,351,367,368,370,381,384,388,398, Eupomatia alkaloids, 591, 616 2-E-6-E-famesyl pyrophosphate, 370, 374, 375
452,499,516,568,575 Eupomatiaceae, 591, 609 2-trans~6-trans-farnesyl pyrophosphate, 370
estradiol, 439, 440 Euproctis subfiava, 417 2-Z-6-E-famesyl pyrophosphate, 367, 370
17,B-estradiol, 439 Eurema, 623 famesyl transferase, 414, 488
estragole, 113, 128 Eurema hecabe mandarino, 265, 623 fatigue, 647, 702
estrogen, 179 Europe, 37, 83, 91, 92, 138, 169, 184,210, Fatoua, 134
estrogenic effect, 70, 439 233,235,237,244,246,297,340,349,351, fatty acid biosynthesis, 19,21.40.56
estrone, 436, 439, 440 363,364,383,393,417,426,452,471,537, fatty acid deficiency, 35
ethanol, 206, 217 563,610,641,645,658,669,673 fatty acid, desaturation, 54
ether, 535 Eurycoma longifofia, 662 fatty acid elongation, 4
Ethiopia, 459 eusiderin, 121 fatty acid metabolism, 339, 343
ethylamine, 513 Euxylophora, 569, 570, 573 fatty acid synthase, 56, 156
ethylene, 3, 6, 73, 231-233, 238, 289, 297, Evodia, see Euodia fatty acids, vii, 3, 16-19,21-29,31,32.
520 evodiamine, 570 34-43,45,51-53,55,56,58,67,68,109,
ethylene glycol, 262 evolution, vii, 1, 5-7. 9-14, 32, 160. 135, 190, 113,223,324,339,340,343,383,402,441,
ethylmalonate, 57 246,304 499,515,582; see also fluorofatty acids,
5-ethyl-2-methoxyphenol. 124 evoninoate alkaloids, 671, 690 fatty acid deficiency
etiolated, 275, 277, 282 Excoecaria, 403 anteiso-fatty acids, 25
etioline, 680, 681 excretion, 5, 7, 70,165,208.245,288,413 E-fatty acids, 35
eucalyptol, 346 expectorant, 460, 601 iso-fatty acids, 25
Eucalyptus, 69, 140, 204 expression, 3, 9, 14, 33 trans-fatty acids, 35
eucalyptus, 194,212 exudate, 30, 40, 125 fatty acids, acetylenic, 35, 42, 43
Eucalyptus camaidulensis, 345 eye-spot, 495 fatty acids, conjugated unsaturated, 18, 26
Eucalyptus citriodora, 345 fatty acids, cycIopentenoid, 26-29, 36
Eucalyptus robusta, 69 F.b.ce.e, 29, 31, 46, 79, 85, 86, 88, 91, HI, fatty acids, essential, 35
Eucalyptus sideroxylon, 142 123, 130, 134, 140, 142, 145, 149, 158, 159, fatty acids. hydroxy, 16.24,26,27,35,51, 53
Euclea, 85 168,173-175,178,179,183-188,190,197, fatty acids, 3-acetoxy, 35
Eucommiaceae, 321. 361 206,215,218-223,226-229,231,244,246, fatty acids, cycIopropanoid, 16,27,35
Eucommiales, 360 253,254,257,260,261,267,280,282,286, fatty acids, cyclopropenoid, 16, 17.27,35
eudesmane, 372. 374. 377 287,290,298,405,412,413,456,458,460, fatty acids, dihydroxy, 26, 27
eudesmanolides, 387, 388, 392 462,463,466,510,514,515,517,521,528, fatty acids, epoxy, 16, 27
(+ )-eudesma-4(14)-7(ll)-dien-8-one, 392 538,543,549,552-554,557-559,561,562, fatty acids, long chain, 51-53
eugeniin, 197 564,566,569,570,581,598,608,610,660, fatty acids, odd carbon numbers, 24
eugenol. 110, 113, 344 663, 664, 676, 693, 700, 705, 706, 708, 709 fatty acids, primary, 17, 18,25
eugenone, 58, 59 Fabiana imbricata, 671 fatty acids, saturated, 16, 41
Euglena, 495 fabianine, 671 fatty acids, unsaturated, 16, 18,21,22,24,34,
Euglenophyceae, 495 FAD, 432, 508 35,36,40,41,402
Eug/ossa, 344 Fagaceae, 195, 197,252,264 fatty acids, ..:19-unsaturated C 18• 4
euglossine bees, 344, 352 Fagara, 569, 570, 573-575, 610 fatty acids, unusual, 16, 25, 26
eukaryotic organisms, 4, 8, 22, 23, 234, 244, y-fagarine, 573 fatty acyl-CoA reductase, 51
433,623 fagaronine, 601, 615 fatty alcohols, 51
eukaryotic pathway, 16, 18, 19,23 Fagaropsis, 575, 577, 610, 667 fatty aldehydes, 51
Euiaema, 344 Fagaropsis angolensis, 576 favin,244
730 Index

favism, 700 flavone synthase n, 158 forb,207

feathers, 486, 498 flavone synthases, 158 formamide, 290
febrifuge, 569, 673 flavones,4, 151, 152, 156, 158-160, 162, fonnic acid, 99, 294, 343, 570
febrifugine, 569 164-166,171,174,177,178,189,191 Formica, 343
fecal pellets, 460 flavonoid biosynthesis, 151, 153, 173, 186 fonnononetin, 178, 179, 181, 186
Fedia cornucopiae, 353 flavonoid sulfates, 159 2~formylantbraquinones, 88
feeding activity, 35 flavonoids, 4, 5, 8, 9, 11, 14, 56, 102, 108, 4-formyl-8-hydroxyquinoline, 571
feeding stimulants, 35, 168, 174, 265, 308, 136, 139, 142, 149, 151-153, 155, 156, N-formylloline, 659
310,350,363,418 158-160, 162, 164-169, 172, 173, 175, 177, forskolin, 420, 426
Feigl Anger method, 273, 286, 290, 294 179,184,187-191,193,194,198,200,210, Forsythia intermedia, 117, 129
Felidae, 362 212, 213, 261, 387, 420, 498, 499, 533, 558, Forsythia suspensa, 117
( - )~endo~fenchol cyclase, 332 575 founder effect, 389
fenchone, 345 flavonoids, A-ring, 151, 179 Fouquieraceae, 197, 360, 361, 365, 458
fennel,332 f1avonoids, B-ring, 151, 152, 174, 178, 202 fragrances, 12
fenugreek, 528 flavonoids, C-ring, 151 frsgrances, floral, 326, 352, 709
Ferdinandusa, 611 flavonol glycosides, 4, lSI, 167, 168 France, 210, 658
fermented products, 700, 703 flavonol sulfate, 159 Frankia, 83
fern allies, 164,442 f1avonols,4, 151-153, 156, 158-160, frsss, 136, 343, 361, 552
femane, 431 164-167, 175, 177, 189, 190 free radical, 580
ferns, 9, 40, 68, 164, 172-174, 194,253,254, flavoprotein, 280, 431 French Congo, 640
279,286,318,324,376,3%,414,422,424, flavoring agents, viii, 12, 109, 324, 346, 349, friedelin,447
431,442,462,497,510,533,543 506,700 Frilillaria, 677, 684, 686
fern, bracken, 376, 396, 414, 442, 454 flavoxanthin, 499 frogs, 466, 560, 564, 664, 666, 677
ferric ions (Fe+ + +),209,543 flavylium cation, 171 frogs, dendrobatid, 560, 708
ferrous ion (Fe++), 158, 159, 162, 166. 202, flax, 274, 276, 282, 288, 290 frontalin, 37, 343
266,598 flea beetle, 168,308,445 fructans, 247, 257
ferruginol,413 flea beetle, sweet potato, 7 {3-D-fructofuranosyl O-a-D-galactopyranosyl-
ferulate, 152 fleas, 641 (1-6)-a-D-glucopyranoside, 256
ferulic acid, 54, 107, 108, 113, 115, 118, 122, flexilin, 380, 419 fructosans, 257
126,131,132,517 flies, 177, 289, 344, 441, 515, 582, 641, 700; fructose, 247-250, 253, 256
feruloylputrescine, 517 also see blowfly, fruit fly, houseflies, sawfly, D-fructose, 247, 248, 250, 256
Festuca arundinacea, 659 Spanish fly; see fly below D-fructose 6-phosphate, 248
fever, 619, 662 Flindersia /ournieri, 662 fructose-l,6-bis(phosphate),252
fiber, 336 flindersine, 571, 573 fructose-I,6-bis(phosphat)ase, 520
Ficus, 134, 563 Flindersioideae, 571, 573, 575, 576 frui~ 7-9, 30, 31, 35,47,59,77,94, 110, 121,
Ficus carica, 137 Florida, 191, 245, 270, 294, 346, 349, 350, 127, 128, 152, 171, 175, 177, 194,203,206,
fig, 137 352, 365, 394, 3%, 423, 453, 504 210,220,223,229,231,237,238,244,256,
filamentous fungi, 517 flour, 30, 41 265,269,272,277,279,280,285,287-290,
Filipendula ulmaria, 209 Flourensia dentala, 317 297,305,320,324,337,346,362,381,397,
filixic acid, 69 Flourensia ilicifolia, 317 402, 403, 420, 445, 457,459, 460, 463, 472,
fire, 126, 127, 345 flowers, 7, 8, 26, 30, 111, 136, 152, 153, 156, 473, 476, 480, 482, 483, 486, 490, 492, 494,
rife ant, 35, 383, 397, 533, 542, 543 159, 162-164, 170, 171, 173-177, 188-190, 498,499,504,517,535,537,558,567,570,
fir, Douglas, 202, 257, 338 207,231,232,256,269,299,306,320,324, 611, 659, 666, 689, 695, 700; see also dried
fir, balsam, 338, 383 328,335,344,348,362,381,382,385,386, fruit beetle, fruit flies, grapefruit, miracle
fir, alpine, 338 392,396,411,412,439,457,459,471,472, fruit, oriental fruit moth, passion fruit, pome
firs,338 486,494,498,499,511,515,516,552,558, fruits, tomato fruit worm
Fischer projections, 246 608,669,700; see also bee flowers, fruit conserves, 708
fisetin,166 cauliflower, sunflower moth, flowering fruit flies, 582
fisetinidol-4a-ol, 206 plants, safflower, sun flower, wall flower fruit fly, Caribbean, 340
fish, 12, 32, 39, 79, 85, 340, 348, 380, 381, flowers. beetle-pollinated, 177 fruit fly, European cherry, 37
390, 393, 419, 420, 439, 456, 460, 486, 498 flowers, bird-pollinated, 176, 177 fruit fly, Mediterranean, 31, 340, 381
fish poisons, 12, 460 flowers, hummingbird, 177 fruit fly, oriental, 111
fitness, increase, 6 fluoroacetic acid, 29 fruit juices, 165
fixative, 670 fluorofatty acids, 29 fruits, pome, 381
Flacourtiaceae, 28, 282, 285, 287, 296, 298, tv-fluorofatty acids, 29 Frullania, 389
418,522 tv-fluorooctadec-Z-9-enoic acid, 29 fucose, 247, 250, 260
flagellate, 645 lrJ-fluorooleic acid. 29 D-fucose, 249, 250, 465
flatus, 261 lrJ-fluoropalmitic acids, 29 L-fucose, 247, 250
flavan-3,4-diol biosynthesis, 200 fluridone, 501 a-fucosidase, 561
flavan-3,4-diols, 162, 163, 193, 200-204, 206 fly, see flies above a-L-fucosidase, 562
flavan-3-ols, 159, 193,200-204,206,210,212 fly, cabbage root, 309 fucosidases, 544
2,3-cis-flavan-3-ols, 203 fly, carrot rust, 113 fucosterol, 444
2S-flavan-3-ols, 202 fly, onion, 227 fucoxanthin, 495
flavan-4-01s, 200 foam, 316, 456, 468 Fucus, 495
flavanone, 151, 156, 158, 164, 173, 175, 179, Foeniculum vulgare, 332 fuels, 12
188,201 foliage, 682 Fumaria capreolata, 9, 588
flavanone 3-hydroxylase, 59, 162 folic acid. 97 Fumaria parvijlora, 241
(2S)-flavanone 3-hydroxylase, 162 folicanthine, 665 Fumariaceae, 303, 581, 598, 600, 601, 603,
flavanonols, 156 Folin-Denis assay (phenols, tannins), 210 605,610
flavin mononucleotide, 303 food additives, see additives, food fumonisin, 70
flavone C-glycosides, 160, 162 foods, 319, 321, 346, 349, 376, 377, 393, 394, fumonisin B I , 70
flavone glycosides, 4, 151-153, 167, 168, 172, 447,456,460,466,499,517,564,663,689, fungal endopolygalacturonase, 402
173, 178, 188 692,708 fungal metabolites, 3, 8, 35, 64, 65, 70-72, 84,
flavone sulfate, 159 forage, 179,219,227,274,290,437,456,460, 85,99, 133-135, 138, 142, 148, 183, 184,
flavone synthase I, 158 470 186, 193,210,238,245,253,254,260-262,
 Index 731

270,273,288,319,339,342,343,367,368, galanthine, 620 geophagy, 684

372,374,376,378,397,402,408,411,414, Galbulimina, 542, 543 Geraniaceae, 68. 195, 197, 337
415,420,447,486,501,502 Galega, 569, 570 geraniaI, 341-344, 346
fungal mycelia, 561 Galerina, 237 geranicardic acid, 68
fungal parasites, 659 Galeruca tanace/i, 88, 92 geranii herba, 209
fungi, vii. viii, 2, 3, 8, 9, 12, 17,26.32,42, Galerucinae, 447 geraniin, 197,208-210
45,47-49,53,56,63-65,70-74,76-78, Galium, 85, 86 geraniol, 326-328, 333, 340, 342-344, 346,
80,84-87,91,97, 104, 106, 107, 117, 121, Galium molJugo, 87, 241 349, 353, 354, 383, 396, 611
122, 125, 134, 135, 137, 145, 148, 164, 167, gallic acid, 193-196, 198,208,209,212,213 geranium, 68, 74
173, 174, 183, 184, 186, 188,217,218,234, gallic acid glycosides, 123 Geranium, 195, 197, 208
235,237,240,242,249,252-254,261,262, ( - )-gallocatecbin, 172 Geranium maculatum, 209
269, 273, 286, 288, 290, 295, 306, 309, 312, ( + )-gallocatecbin, 202 Geranium pyrenaicURl. 195
315,318,319,324,329,342,343,367,368, gal1otannins, 193, 194, 196, 210, 212, 213 geranyl diphosphate, see geranyl
374,376-378,380,390,395-397,408,411, galloyl D-glucose, 207, 210 pyrophosphate
414, 415, 427, 433, 442, 444, 459, 486, 488, O-galloylation, 206 geranyl phosphate, 328
495,497,501,502,514,517,520,543,558, galls, 194,514; see also crown gall, crown-gall geranyl pyrophosphate (GPP), 82, 315, 324,
559, 561, 562, 566, 573, 574, 591, 594, 601, tumors 326-333, 335, 336, 342, 368-370, 431, 488,
616,655,658-660,666,682,684,697,705, gambier, 204 669
706; see also endophytic fungi, filamentous gametes, 376, 396, 444 geranyl pyrophosphate synthetase, 326, 399,
fungi, fungi imperfecti. mycorrhizal gametophytic compounds, 368 401,488
fungal, rust fungi ganglionic blocking agents, 511 geranyl transferase. 488
fungi imperfecti. 235 gangrenous condition, 658 geranylcitronellol. 419. 423
fungi, rust, 110 Gardenia jasmino/des, 353, 358 geranylfamesyl pyrophosphate, 422
fungicidal compounds, 35, 145,377,459 Gardenieae, 612, 638 gemnylgeranial, 419
fungistatic compounds, 175 gardenoside, 358 gemnylgeraniol, 399,420, 750
fungitoxic compounds, 173, 175, 179, 184, 186 Gardneria, 638 geranylgemnyl pyrophosphate (OOPP), 370,
fungus, black-rot, 377 garlic, 226 399,401,402,407,414,415,425,486,488
fungus, blue stain, 342 Garrya, 673 geranylgeranyl pyrophosphate-geranyl
fungus, brown rot, 183 Garryaceae, 321, 360, 361, 408, 668, 673 transferase, 488
fimgus, red rot. 145 garryine, 673 gemnylgemnyl pyrophosphate synthase, 399,
fungus, snow mold, 273 gas chromatography, see chromatography, gas 401, 402, 488
fungus, take-all, 459 Gascardia madagascariensis, 422 gemnylhydroquinone, 336, 337
Funtumia. 677. 689 gascardic acid, 422 geranyUinalyl pyrophosphate, 399, 405, 412
furanocoumarins, 7, 113, 130, 132-135, 137, gastroenteritis, 460, 561 Gerbera jameson;;, 287
138,316,484,571,575 gastrointestinal tract, 237 gennacrane A epoxide, 374
furanocoumarins. angular, 132-134, 136 gastrointestinal tract, tone and peristalsis, 664 gennacranes. 374
furanocoumarins, linear, 133, 134-137 Gastrolina depressa, 84 gennacranolide lactones, 386
furanoses, 247. 248 Gastrolobium, 29, 660 gennacranolides, 386-388
furoquinoline alkaloids, 568, 570, 571, 573, gaudichaudioside, 420 gennacrene A, 372, 383, 387
575, 576, 610 Gaultheria procumbens, 122 gennacrene D. 383
(25R)-5a-furostan-3p,26-diol, 678 gas chromatography/mass spectrometry (GC/ Gennany, 168, 553, 641
fusaric acid. 237. 543 MS), 30, 38, 40 gennination, vii, 6, 24, 31, 32, 54, 78, 83, 84,
Fusarium, 70, 74, 186,237,238,269,378 GDP-glucose, 259 92,93,99, 105, 109, lIO, 118, 125-128,
Fusarium amygdali. 415 gedunin, 476, 477 132, 135, 167, 175, 183,220,231,240,265,
Fusarium javanicum, 186 Geigera. 390, 573 287,288,309,311,317,340,344-346,350,
Fusarium moniliforme. 70, 414 geissoschizine, 2, 632, 634, 635, 642 376, 378, 379, 389-392, 394, 396, 414, 415,
Fusarium oxysporum, 237. 543 gel,26O 435,459
Fusarium sambucinum. 135 gelsemicine, 646 gennination, seed, 317, 390, 395, 415
Fusarium solani, 145, 186. 442 Gelsemieae, 638 Gesneriaeeae, 87, 88, 164, 173, 174, 361
Fusicladium effusum, 84 gelsemine. 646 Giardia intestinalis, 652
fusicoccin, 415, 750 Gelsemium, 640, 646 Gibberella fujikuroi, 408
Gelsemium eiegans. 646 Gibberella pulicaris, 135
GABA. see ,),-aminobutyric acid, Gelsemium sempervirens, 646 gibberellic acid, 3, 408, 411
Gabon, 647 generalist feeder, 10, 92, 124, 135, 136, 361 gibberellins, 6, 10, 132, 361, 378, 398,407,
Gabunia, 637 genes, 3, 4, 8, 16,41, 153, 189-191,239,245 408, 411, 414, 423, 425, 426
Gagea, 269 genes. ras, 321 ginger, 114
Gaillardia pulchella, 672 Genipa, 700 gingerol, 114
D-galactan, 259 geniposide, 361 Ginkgo biloba, 173,200,202,413,420
galactans, 260 geniposidic acid, 360, 361 Ginkgoaceae, 68
meso-galactitol, 262, 264 Genista canariensis, 560 ginkgolides, 413, 420
galactoglycerols, 30 Genisteae. 549, 557 ginseng, 48, 460
O-a-D-galactopyranosyl-(l-6)-O-a-D- genistein, 167, 178, 179, 184, 191 girinimbin,663
galactopymnosyl-(1-6)-O-a-D- genistein,7-0-glycoside, 167 Gisekia, 708
glucopyranosyl-(1-2)-/3-D-fructofuranoside, ginseng, Siberian, 462 glabrine, 231
254,256 gentian, 359-361, 364 glands, see adrenal, anal, Dufour's, mammary,
4-0-/3-D-galactopyranosyl-D-glucopyranose, Gentiana, 670 mandibular. Nasonov, oil, scent and thyroid
254 Gentiana lutea, 364 glands, glandular swelling, and glandular
galactose, 172, 244, 248, 249, 260, 456 Gentianaceae, 149, 359, 361, 364, 366 trichomes
D-galactose, 248, 259, 260, 456 Gentianales, 88, 360 glandular swelling, 662
a-galactosidase, 561 Gentiananae. 360 glaucarubalone, 482
/3-galactosidase, 561, 562 gentianine, 669, 670 glaucine, 588, 591
galactosides, 266 gentiobiose, 254, 266 glaucolide-A, 390
galacturonic acid, 248, 260, 261 gentiopicrin, 364 glaucoma, 603, 664, 692
D-galacturonic acid, 248, 260, 456 gentiopicroside, 359, 699 Gleditisia triacanthos, 215, 226
galanthamine, 622, 623 gentisic acid, 82, 106. 113 Globulariaceae, 358, 361
732 Index

Glochidion, 693 7-0-glucosyltransferase, 132 Giycyrrhiza echinata. 182

glomerin, 569 N[15(,8-glucosyl}oxy-8-hydroxypalmitoyl]- Glycyrrhiza giabra, 184, 460, 462, 463
GIomeris margilUlta, 569 taurine, 37 glycyrrhizae radix, 460
Glomus etunicatum, 167 p-glucosyloxymandelonitrile, 280 glycyrrhizic acid, 460, 462, 463
Glomus macrocarpum, 167 p-glucosyloxymandelonitrile, 4'-caffeoyl ester, glycyrrhizin. 460. 462, 463
Gloriosa, 617 280 glyoxylic acid. 222. 273. 274. 579
D-glucans, 254, 260 glucotropaeolin, 303, 304 glyoxysomes, 24
glucobarbarin, 303 D-glucuronic acid. 248. 252. 253. 260. 264. Glyphosate. 97. 195
glucobrassicin, 306, 309 456 Glyptopetaium, 452
glucocapparin, 308 ,B-glucuronidase. 294. 561- Gnetales, 173
,B-glucogallin, 197 glutamate receptors, 698 gnetins, 140
,B-O-glucogallin, 196 glutamic acid. 80. 215. 217. 218. 220, 226. Gnetum, 140, 149
glucoiberin, 308 697 Gnidia giaucus, 404
gloconasturtiin, 303, 304 y-glutamic acid-(cysteine)n-g1ycine, 241 Gnidia iatifolia, 404
D--d-gluconolactone, 629 glutamine. 98. 220. 226, 228. 253 gnidiglaucin, 404
6-D-glucopyranosyl esters, 30 ,B-glutamylaminopropionitriIe. 226 gnidilatidin, 404
3'·O-,8-D-glucopyranoside of 4-(3',4'- y-glutamylcysteine,241 Gnophaela ialipennis, 552, 565
dihydroxyphenyl)butan-2-one, 110 )"glutamyl-cy.teine-glycine ()"glu-<:ys-gly). goat•• 390, 411. 676. 705
[4'-O-(,8-D-glucopyranosyl-3'-O-(,B-D- 241 goitrigenic derivatives, 300, 307
galuctopyranosyl)-,B-D-glucopyranosyl]olean- )"glutamyl-3-cyuooalunine.231 goitrin,307
12-ene-28-oic acid, 460 ()"glutamylcysteine).-,B-alunine, 241 goldenseal, 603
3-0-,B-D-glucopyranosyl-D-glucopyranose, 254 y-glutamyl-S-methyl-L-cysteine.241 Golgi bodies, 338
4-0-a-D-glucopyranosyl-D-glucopyranose, 254 4-glutamyIsemialdehyde. 226 gouada, 111
4-0-,8-D-glucopyranosyl-D-glucopyranose, 254 glutathione. 234. 240. 241 goniothalamin, 139
6-0-{J-D-glucopyruoosyl-D-glucopyranose, 254 glutathione reductase, 240 Goniothalamus giganteus, 67, 139
a.D-glucopyranosyl-a-D-glucopyranoside, 254 glyceollin. 182. 184. 261 goniothalenone, 139
O-,B-D-glucupyranosyl-(l-6)-,B-glucose, 266 glyceollin I. 182. 184 Goodeniaceae, 257, 361
4-,B-glucopyrano.yloxy-3- glyceollin II. 182. 184 Goodeniales, 360, 361
hydroxymethylbutyronitril-2-ene, 285 glyceollinm. 182. 184 gorlic acid. 29
4'-O-,B-D-glucopyranoside of 4-(4'- glyceraldehyde. 247. 249 Gossypium. 13.35.77.78.369,378
hydroxyphenyl)butan-2-one, 110 glyceridea. vii. 16. 25. 26. 30. 32. 35. 38-40 Gossypium hirsulum, 35, 369
O-<>-D-glucopyranosyl-(l-3)-,B-D- glycerokinase, 23 gossypol. 8. 376. 378. 380
fructofuranosyl a.D-glucopyranoside, 257 glycerol. 16. 18, 19. 23. 35, 40 (- )-gossypol. 376
3,B-D-glucopyruoosyloxy-4-methyl-2-(5H)- glycerol glucosides, 267 gout. 619, 673
furanone, 285 glycerol-3-phosphate. 23 goyazensolide, 391
D-glucosamine, 248, 250 sn-glyceroI3-phosphate. 21. 23. 24 grain, see cereal grain
glucose, 3, 13. 19. 52. 132. 162. 172. 174. glycerophospholipids, 17 gramicidin S. 234, 236
194-196. 249. 253, 256, 257, 260. 264. 269, glycine. 273. 591 gramiue. 513. 514. 523. 525
290. 291, 328,456, 588 Glycine max. 158. 182. 184. 221. 238. 241. Gramineae, see Poaceae
D-glucose. 207, 210. 247. 248. 256, 265. 267. 261.293 grandifoliolenone.473
456.465 glycine neurochemical activity, 646, 670 grape. 142. 145. 171
glucose mimic, 254 glycine receptor, 642 grapefrui4 175. 340
a-glucosidase, 561 glycinol, 182 grass. 30. 78. 101. 107. 115. 179. 230. 238.
a-glucosidase inhibitors, 254, 561, 562 glycoalkaloida, 678. 680. 682, 690 284. 290, 294. 346, 352, 391, 514, 564, 659.
,8-glucosidase inhibitors 207, 254 glycogeo, 254. 259. 270 666,667; see also bluegrass, ryegrass
a.glucosidases, 253, 254 glycolipids. 16. 17, 30 grass. "drunk." 659
{J-glucosidases. 78. 85. 115, 117. 131. 132. glycolysis. 3. 248 grass, orchard. 659
138.207.254.280.287-290.294-296.298. glycolytic pathway, 19 gras•• pereunial rye. 179.659
300, 561. 562. 629. 630. 682 glycoproteins. 72. 206. 237. 244. 259. 561. 562 gras•• rye. 376
D-glocose 6-phosphate. 252 ,B-glycosidase, 273, 280, 286-289, 294, 296 grass, "sleepy," 659
7-0-glucoside-3-0-rutinoside,8 glycosidase inhibitors, 535 grasshopper. 124, 125.317.384.468.522
glucosides, 266; see also betalain glucoside, glycosidases, 561 grasshopper, migratory. 316, 479
cucurbitacin E glucoside, cyanidin 3-0- glycoside sulfates, 458 grasshopper. striped. 559
glucoside, 7,8- glycosides. 151-153. 158-160. 162. 166. 167, grasshopper, two-striped, 682
dehydroiridotrial glucoside, delpbinidin 171-174. 177, 178. 189. 190. 192, 201. 244. grassluod. 125
3-glucoside.2.4-dihydroxy-1,4(2H)- 247.249.250.252-254.256.266.267.269. Gratiola, 444
benzoxazin-3-one (DmOA) glucoside, 2.4- 273. 274. 280. 282, 285, 286, 288-290. 296, Gratiola officinalis, 444, 445
dihydroxy-7-methoxy-I.4(2H)-benzoaxazin- 300.312.441; see also uothroquinone. gravid females, 309, 468
3-one (DIMBOA) glucoside, 7-0-glucoside- cardiac, chalcone, coumaryl, cyanogenic, grayuoin. 277
3-0-rutinoside, glycerol dehydrodiconiferyl alcohol, digitalis. flavone grayanotoxin I. 675
glucosides, o-hydroxybenzyl-,8-D-glucoside, C~, flavone, flavonol, gallic acid, iridoid, grayuootoxins. 398. 408. 411-413
3-hydroxyindole ,8-D-glucoside, hypolaetin kaempferol,lactone-fonning, monoterpene, grazing. 8. 126. 179. 296
8-0-glucoside, iridodial glucoside, iridotrial nitrile, phenylethyl alcohol, phenolic, Greeks. 658
glucoside, isoxazolinone glucosides, prinasin phenylpropanoid, pseudocyanogenic, green leaf volatile complex, 31, 309
2'-glucoside, quercetin 3-g1ucoside, quercetin, secoiridoid, sesquiterpene, steroid, greeobugs. 363, 365. 562
secoiridoid glucoside, .13-isoxazolin-5-one stilbene, strophanthidin, and triterpene greenbugs. biotype B. 113
glucoside glycosides Griffonia simplicifolia, 228
glucosinolates. 6. 8. 209. 266. 287, 290. 295. C-glycosidea. 152. 160. 162. 192 Griselinaceae, 361
300.302-308.310.311,468 glycosidic alkaloids, 249 griseofulvin, 64
D-glucosone, 265 Glycosmis, 568, 574, 663 griseophenone B. 64
6-0-glucosylaucubin, 363 Glycosmis arborea, 568 Qros.ulariaceae. 359
6-C-glucosylchrysin, 162 C-glycosyl flavones, 151, 162, 172, 173 groundsel. 550
8-C-glucosylchrysin. 162 glycosyl transferase, 321 growth inhibiting compounds, 33, 118, 510
,B-glucosyltransferases, 276 glyco.ylation, 151. 160. 162. 170, 190.206. growth regulators. 164. 367.437.445.486.
C-glucosyltransferase, 162, 190 276 500. 501, 510
 Index 733

guaiacol, 124 hardwood, 115 hemagglutinins, 234, 240, 242, 244

guaianes, 374 hares, snowshoe, 208, 451 hemiacetals, 247, 630
a-guaiene, 373, 376 harmalan. 660 hemicellulose, 259, 262
guaianolides, 387, 394 harmaline, 660 hemigossypol, 378
Guam, 226, 294 harmalol, 660 hemiparasite, 78, 364, 552, 559
L-guanidinohomoarginine, 226 harman, 568, 570, 655, 660 Hemiptera, 289, 658
guangdougen. 168 harman alkaloids, 8, 568, 576, 655, 660 hemiterpene alkaloids, 692
guanosine diphosphate-D-glucose, 259 harmine, 10, 570, 576, 660 hemiterpenes, 312, 315~318, 335, 655, 692
guar gum, 260 harmoI,660 hemoglobin, 234, 242, 246
guarana, 700 Harmonia axyridis, 363 hemolymph, 460
Guarea, 477 harringtonine, 625, 626, 627 hemolysis, 459
Guarea guidona, 481 Harrisonia, 475, 477 hemolytic, 458, 459
guayule. 109, 127,312,319,320 Harrisonia abyssinica, 481 Hemsleya carnosiflora, 444
Guettarda heterosepala, 649 harrisonin, 481 Hepatica, 267
guettardine, 649 hashish, 336 Hepaticae, 412
Guettardoideae, 612, 637 hasubanan alkaloids, 592, 615 hepatitis. 460
Guignard test (HCN), 273, 294, 296 hasubanonine, 592, 613 hepatotoxic compounds, 168, 209, 227, 232,
guinea pig, 543, 564, 600 haustorium, 78, 92,452, 659 378, 552, 553
gulose, 249 Haworth perspective fonnulas, 246 heptaketide, 64
gum, 260; also see carob gum, chewing gum, hay, 40, 132, 137 heptanal, 113
guar gum, gum acacia, gum arabic, gum Hazunta, 637, 647 n-heptane, 52, 337
mastic headache, 570, 640 Heracleum, 136
gum acacia, 260 headspace trapping, 326 Heracleum sphondylium, 515
gum arabic, 260, 271 heart, 35, 244, 462, 581, 697 he,bicide, 93, 97, 99, 105, 127,352,496
gum mastic, 447 heart conditions, 651 herbivores, vii, 7, 9~11, 13, 15, 32, 34, 121,
Gunneraceae, 197,337 heart failure, 674 128, 135-138, 207-209, 212, 213, 289, 290,
gut, 207, 208, 213, 245, 253, 340, 343, 460 heartwood, 78, 85, 88, 121, 136, 145, 148, 310,339,340,365,510,511,515,546,558,
gutta, 320, 321 149, 187,324 566,659
gutta percha, 312, 318, 320, 321 Hebenstretia dentata, 358 he,bivO'y, 9,10,14,30,53,135-137,209,
Guttiferae, see Clusiaceae Hectorella, 708 288,289,339,340,345,380,420,441,452,
Gymnema sylvestre, 463 Hedeoma drummondii, 338 696
gymnemagenin, 463 Hedeoma reverchonii, 338 he,bs, 36, 47, 110, 125, 126, 130,346
gymnemic acids, 462 Hedera, 610 Hemandiaceae, 581, 609
gymnomitr-8(12)-en-9a-ol, 368 Hedera helix, 459, 612 hemanduIcin, 385
gymnomitr-8(12)-en-9-one, 368 hederagenin, 459 heroin, 511, 597
gymnosperms, 37, 115, 140, 164, 173, 191, hederasaponin C, 458 herpes simplex virus, see virus, herpes simplex
194,226,264,286,290,324,337,338,382, a-hederin, 458 hesperetin, 175. 176
401,402,405,412,413,420,442,510,538, Hedyotideae, 612, 638 heteratisine, 673
543,624,626,677,709 Heimia, 694 heterodendrin, 284
gynocardin, 285, 289, 298 Heimia salicifolia, 694 (S)-heterodendrin, 282
Gyrinops, 444 helenalin, 390, 392 Heterodera g/ycines, 125, 128
Gyrostemonaceae, 304, 708, 709 Helenieae, 387 Heterophyllum, 287
He/enium amarum, 390 Heteroptera, 285
habitat, 4, 7, 31,125,136 He/enium microcephaium, 390 Heteropteris, 290
Hackelia cali/ornica, 552, 565 heliangin, 389 Heterotheca subaxillaris, 125
Haemadoraceae, 257 Heliantheae, 36, 46, 387 heteroyohimbine types, 631
haemanthamine, 621 ~623 Helianthemum scoparium, 126 Hewa brasiliensis, 5, 287, 288, 296, 297, 312,
haemanthidine, 621 Helianthus, 389, 390, 415 318-320,322,327
hair loss, 220 Helianthus annuus, 47, 415 hexadecanal, 30
hairpencils. 383, 552 Helianthus occidentalis, 415 (7Z)-hexadecenal,,31
hairy root cultures, see cultures, hairy root Helianthus tuberosus, 257, 389, 520 (9Z)-hexadecenal, 31
Haiti,537 Helichrysum, 45 (11Z)-hexadecenal,31
Halictus, 37 Heliconius, 289, 297 (E)-3-hexadecenoic acid, 17, 26
Halimeda, 419 Helicoverpa zea, 1,30,92,169,175,265,316, hexadecanol, 52
halimedatrial,419 381,390,437,682 hexadecatrienoic acid. 17
hallucinations, 523, 658 Heiicteres, 444 hexahydroxydiphenic acid, 194, 213
hallucinogens, 12, 111, 148,361,514,523, Heliothis, 316, 380 hexahydroxydiphenoyl group, 207, 212
525,535,546,559,581,647,655,658-660, Heliothis virescens, 169,220,231,415,481 hexaketide, 63, 64
694, 559, 697 Heliothis zea, see Helicoverpa zea hexanal, 113
halogenated secondary metabolites, 340 heliotrine, 549, 553 hexanoic acid, 86
Ha[ophytum, 708 Heliotropium, 547, 552 I-hexanol, 31
Haloragaceae, 197 Heliotropillm indicum, 551, 553 (2E)-hexenal, 31
Haloragidaceae, 337 Heliotropillm popovii, 553 (3E)-hexenal, 31
HamameIidaceae, 195, 197,252,361 Helix pomatia, 559 E-2-hexenal, 113
Hamamelis virginiana, 252 Heileborus, 267 E-2-hexenol, 31, 32
hamamelitol, 264 Helleborus joetidus, 515 E-3-hexadecenoate, 26
D-hamamelitol, 252 helminthosporal, 378 hexapeptides, 700
hamamelose, 251, 252, 264 helminthosporin, 64, 65, 85 hexen-I-ol, 31, 32
D-hamamelose, 252 He/minrhosporium, 378, 396, 423 (3Z)-hexenol, 31, 32
Hamelieae, 612, 638 Helminthosporium carbonum, 179, 184, 186 Z-3-hexen-l-01, 31, 32
Hannoa klaineana, 662, 667 Helminthosporium gramineum, 64 hexenyl acetate, 309
Hannoa undulata, 482 He/minthosporium maydis, 72 (3Z)-hexenyl acetate, 30
Haplopappus heterophyllus, 317 Helminthosporium sacchari, 378, 396 Z-hex-3-enyl acetate, 309
Hap!ophyton cimicidum, 641 Helminthosporium sativum, 378 2-hexuloses, 248
Haplophyton crooksii, 641, 653 Helopeltis, 650 D-arabino-hexulose, 250
734 Index

D-arabino-3-hexulose.250 honey, 177,256,257,343,385,402,553 hydrogen peroxide, 79, 117, 118, 592

Hibiscus, 77 honey locust, 215, 226 hydrogen sulfide, 227
Hibiscus eiatus, 77 honeybee, 35, 78, 177, 343, 445 hydrogenation, 507
Hibiscus sabdariffa, 171 honeydew, 99, 105,257,385,468,550,559, hydrolase, 162, 188,229,231,261
hide-powder method (tannins), 210 561 hydrolysis, 23, 24, 52, 83, 87, 89, 130, 136,
hides, 193,210 hops, 316, 363 193, 194,206,208,212,213,221,226,227,
higenamine.591 hordenine, 513, 514, 522, 523 253,256,259,267,269,288,290,294,300,
Hillia, 611, 612 Hordeum distichum, 522 302,305-307,309
Hillioideae, 612, 637 Hordeum vulgare, 288, 298, 522, 523 hydrolyzable tannins, 12, 193-195, 197,
Himantandraceae, 543, 610 honnona! activity, 408, 414, 500, 501 207-210, 212
Hintonia, 444 honnone, 3, 6, 12, 32, 33, 165,231,297,317, 13{S)-hydroperoxylinolenic acid, 32
Hippocastanaceae, 217, 218, 222, 223, 231, 318,322,367,383,384,393,395,396,398, Hydrophyllaceae, 177, 337
273,458 419,425,437,439,444,452-455,484,514, hydroquinone terpenoids, 336, 351
Hippocratea excelsa, 671, 690 516,518,520,659; see also antijuvenile hydroquinones, 76-79, 83, 94,104,124-126
Hippocrateaceae, 668, 670, 671 honnones, ecdysones, honnone binding sites, w-hydroxy acids, 54
hippocrateine I, 671 juvenile honnones, juvenile honnone hydroxamic acid, 98, 99, 105
Hippomane, 403 mimics, molting or moulting honnones, a-hydroxyacetosyringone, 123
Hippuridaceae, 337, 361 phytohonnones, plant honnones 3-hydroxyacyl-ACP dehydratase, 20
Hippuridales, 360, 361 honnone binding sites, 520 12-hydroxyamoorastatin, 481, 482
Hiptage, 290 hormones, plant, 6, 12 3-hydroxyanthranilic acid, 568
hiptagin, 291 homwonn, tobacco, 30, 49, 221, 526 y-hydroxy-L-arginine, 223
hhcinol, 146, 148 horse chestnut, see Aesculus hippocastanum, 4-hydroxy-L-argbrine, 223
hirsutin,310 232 m-hydroxybenzoic acid, 148
histamine, 168,517,692 horseradish, 168, 300, 303, 306 p-hydroxybenzoic acid, 77, 82, 104, 125, 126,
histidine, 168, 215, 575, 692, 693 horseradish peroxidase, 117, 645 165,277
histidine decarboxylase, 168 horses, 70, 676 hydroxybenzoic acids, 104, 106, 108, 121, 122,
histtionicotoxins, 708 Hortia, 569, 570 128,148
HIV, 209, 210, 213 host plants, vii, 70, 98, 363, 364, 366, 441, o-hydroxybenzyl-~D-glucoside, 122
HIV-I, 91, 254, 521, 562, 616, 698, 711 468 8-hydroxybergapten, 133, 134
HIV-I cell binding, 462 hosts, vii, 9, 10, 13,37,39,41,53,54,67,71, (2R,3R)-3-hydroxy-2-'H-butenoate, 21
lHV-l reverse transcriptase, 521, 600, 601. 613 74,78,84,92,93,98, !lO, 128, 177. 183, 2-hydroxy-3-butenylglucosinolate, 305
HIV-2,698 209,210,217,221,235,237,238,244,261, (2R)-hydroxy-3-butenylglucosinolate, 307, 308
HMO-CoA, see (3R)-3-hydroxy-3- 270,285,288,289,294,297,308,309,311, D-3-hydroxybutytyl-S-ACP, 20
methylglutaryl coenzyme A 545, 552, 559, 564, 565, 566, 574, 582, 591, IO-hydroxycamptothecine,648
HMG-CoA reductase, see 659, 669, 689, 690, 703 9-hydroxycanthin-6-one, 662
hydroxymethylglutaryl-CoA reductase Hottentots, 623 lO-hydroxycanthin-6-one, 662
HMO-CoA reductase, see ~hydroxy-~ houseflies, 35 {N-[3-(3-hydroxy-3-carboxypropylantino)-2-
methylglutaryl coenzyme A reductase human immunodeficiency virus, see virus, hydroxy-3-carboxypropyll-acetidine-2-
HMO-CoA synthase, see 3-hydroxy-3- human immunodeficiency (1llV), 210 carboxylic acid}, 230
methylg1utaryl-CoA synthetase humans, 31, 35, 36,47,67,99, 110, 123, 132, 16~hydroxy-5a-cholestanol, 680
Hodgkin's disease, 645 137, 138, 165, 167, 168, 174, 177, 191,213, 2O-hydroxycholesterol, 680
hodgkinsine, 665 226, 227, 244, 245, 253, 265, 267, 290, 294, 22~hydroxycholesterol, 439
Hodgkinsoniafrutescens, 665 299,306,313,317,321,324,346,361,378, (25R)-26-hydroxycholesterol, 678
HODMAT, see 4-dimethylallyltryptophane, 380,382,389,402,403,417,462,466,478 26-hydroxycholesterol, 678
hydroxy derivative hummingbirds, 177 4-hydroxycinnamic acid, 155
Hokkaido, 673 humulanes, 375 hydroxycitronellol, 353-355
holaphylline, 686 humulene, 371, 375, 393 IO-hydroxycitronellol, 353, 354, 358
Holarrhena, 677, 686, 689 humulene cyclase, 375 (S)-( - )-IO-hydroxycitronellol, 358
Holarrhena antidysenterica, 686 humulone, 316 7-hydroxycoumarin, 132
Holarrhena mitis, 700 Humulus lupulus, 316, 363 hydroxydanaidal, 550, 551, 552
holocalin, 287 humus, 207 ( - )-(R)-hydroxydanaidal, 550
(R)-holocalin, 280 Hunteria alkaloids, 634, 635, 637 ( + )-(S)-hydroxydanaidal, 550
HolocaJyx balansae, 280, 297 Huperezia serrata, 708 D-3-hydroxydecanoic acid, 35
holoparasite, 78 huperzine A, 708, 709, 711 7 a-hydroxy-3-desoxyzaluzanin C, 390
holothurins, 458 Hura, 403 8-hydroxydihydrobiochanin A, 186
Holygarna lactone, 269 Hyadaphis, 383 a-hydroxydihydrochalcone, 174, 189
Homaliaceae. 522 Hyalophora cecropia, 384, 444 2-hydroxy-2,3-dihydrogenistein, 179
Homalium pronyense, 521 hybrids, 8, 164, 177, 188,287,337,338,344, 7-hydroxydihydromatatadiether, 362
Homeosoma electellum, 415 351,376,437,535,552,558,559 4-hydroxy-3,5-dimethoxyphenylethylamine,
homoarginine, 223, 517 hydnocarpic acid, 36 523
homocysteine, 513 Hydnocarpus anthelminthica, 28 5-hydroxy-3,4-dimethoxyphenylethylamine,
homoerytbrina alkaloids, 617, 624-626, 677 Hydrangea, 142, 569 523
Homoesoma electellum, 390 Hydrangea macrophylla, 171 20-hydroxyecdysone, 440, 442, 444, 454
homeostasis, 460 Hydrangeaceae, 142, 143, 359, 361, 569 (3S,5R,6S)-3-hydroxy-5,6-epoxy-5,6-dihydro-~
homogentisic acid, 82, 106 ( - )-~hydrastine, 603 ionol,5oo
homohaningtonine, 625, 626 Hydrastis, 269, 603 18-hydroxy-9,10-epoxystearic acid, 53
homology, 9, 142 Hydrastis canadensis, 598, 603 3-hydroxyflavanone reductases, 200
homolycorine, 620 1,3-hydride shifts, 370 2-hydroxyflavanones, 162
homomethionine, 304 hydrocarbons, 16,44,51-54,324,332,339, 3-hydroxyflavanones, 175,201,202
homomonoterpene, 341, 342 367, 407, 425 3-hydroxyflavones, 200
Homoptera, 89 hydrocinnamic acid, 175 9-hydroxygeraniol, 354
homoserine. 217, 220, 222 Hydrocotyloideae, 134 IO-hydroxygenutiol, 354, 355, 358
homosesquiterpene, 341, 383 hydrogen cyanide, 231, 273, 274, 287-290, 5-hydroxy-6-C-glycosylflavones, 173
homospennidine, 548, 549 294, 296, 345 3-hydroxyheterodendrin, 282, 295
sym.-homospennidine, 520 hydrogen ion concentration, 28 E-4-hydroxyhex-2-ena!, 553
 Index 735

y-hydroxyhomoarginine, 223 15-hydroxyprostaglandin dehydrogenases, 167 Icacinaceae, 360, 361, 639, 648
erythro-4-hydroxyhomoarginine, 223 6-hydroxyprotopine, 600 ice cream, 708
4-hydroxyhomoarginine, 223 p-hydroxypyruvic acid, 106 ichneumonid parasitoids, 31
I-hYdroxy-2-(hydroxymethyl)anthraquinone,87 4-hydroxy-2-quinoline, 571 Ichneumonidae, 227
6,B-hydroxyhyoscyamine epoxidase, 535 14-hydroxy-4,14-retro-retinol, 498, 503 ichthyotoxic compounds, 85
3-hydroxyindole {3-D-glllcoside, 267 hydroxyrutacridone epoxide, 574 idose, 249
hydroxyindolizidine alkaloids, 561 12-hydroxysolanidine, 684 /lex guayusa, 700
a-hydroxyisopropyldihydrofuranocoumarins, 16-hydroxytabersonine, 634 /lex paraguariensis, 700
133 12,B-hydroxyteinemine, 684 llliciaceae, 387
15a-hydroxy-( - )-kallr-16-en-19-oic acid, 418 22-hydroxytingenone, 452 Illicium religiosum, 94
17-hydroxy-( - )-kaur-15-en-19-oic acid, 418 6-hydroxy-2,4,7-trimethoxyphenanthrene, 148 illudane, 376
hydroxylase, 26, 102 5-hydroxytryptophan, 228, 229 Ilybius, 440
6a-hydroxylase, 182 5-hydroxytryptamine, 514, 640 imagos,591
hydroxylation, 87, 107, 121, 142, 151, 152, 5-hydroxy-L-tryptophan, 215 imidazole alkaloids, 575, 610, 692, 693, 709
158,159,173,201,206,220,226,514,571, N-hydroxytyrosine, 275 imino-aldol type condensations, 507
573,587,615,620-622,624,656-658 3-hydroxyuridine, 703, 711 immune response, 6, 261, 562
13-hydroxylupanine, 559 hydroxywilfordic acid, 528 Impatiens balsamina, 81
13a-hydroxylupanine, 554, 555 5-hydroxyxanthoxin, 133, 134 imperatorin, 135. 136
(+ )-13a-hydroxylllpanine, 554 Hyenanche, 385 import, 19
17-hydroxylupanine, 559 Hyenanche globosa, 385 inandenine A, 521
8-hydroxylysergic acid, 659 hygrine, 531, 532, 539 inandenine B, 521
6a-hydroxymaackiain, 186 (R)-hygrine, 532, 534 incense, 413
( + )-6a-hydroxymaackiain, 182 Hygrocybe, 705 indenobenzazene, 610
p-hydroxy-(R,s)-mandelonitrile, 276, 277 Hygrophorus, 705 India, 265, 288, 389, 424, 478, 539, 553, 599,
5-hydroxymatatabiether, 362 Hylotrupes baju/us, 340 603, 609, 613, 640, 663, 686
6a-hydroxymedicarpin, 186 Hy/urgops, 340 Indian tobacco, 540
N-(4-hydroxy-3-methoxybenzyl)alkyl amides, Hymenaea,413 Indians, 523, 535, 559, 610, 658, 660, 677
517 Hymenocardiaceae, 700 Indians. American, 290, 523, 649, 694
N-(4-hydroxy-3-methoxybenzyl) amides, 517 Hymenoptera, 289, 340, 397, 426 Indians, Andean, 535
2-hydroxy-5-methoxy-3-[(8'Z,II'Z)-8',II', 14'- hymenovin, 390 Indians, Aymara, 684
pentadecatriene]-p-hydroquinone, 78 Hymenoxys odorata, 390 Indians, Aztec, 385
l-hydroxy-2-methylanthraquinone,87 hyoscyamine, 511, 535, 537 Indians, Hoti, 645
2-hydroxymethylanthraquinones, 88 (R)-hyoscyamine, 537 Indians, Jivaro, 591, 660, 700
3'-hydroxy-N-methy1coclaurine, 587 (S)-hyoscyamine, 535, 537 Indians, Juris, 588
3-hydroxymethyl-2(5H)-fllranone, 269 Hyoscyamus, 532, 535, 537 Indians, Tarahumara, 148
Hyoscyamus albus, 532, 535 indican, 267
(2S,4S)-4-hydroxy-4-methylglutamic acid, 226
Hyocyamus niger, 535 indicaxanthin, 705, 708, 711
(3R)-3-hydroxy-3-methylglutaryl coenzyme A
hyperglycemia, 591 indicine N-oxide, 553
(HMG-CoA),313
indigo, 267
,B-hydroxy-,B-methylglutaric acid, 580 Hypericaceae, see Clusiaceae
Indigo/era, 227, 232, 267, 290
3-hydroxy-3-methylglutaryl-CoA,313 hypericin, 76, 91, 92
Indigo/era spicata. 227, 232
{3-hydroxy-,B-methylglutaryl coenzyme A, 313 Hypericum androsaemum, 92
indole, 3, 6, 98, 113, 344, 514, 516
hydroxymethylglutaryl-CoA reductase (HMO- Hypericum drummondii, 69, 74
indole 3-acetaldehyde, 98
CoA reductase), 313, 314, 319, 326 Hypericum perforatum, 91, 93
indole acetaldehyde oxidase, 98
,B-hydroxy-,B-methylglutaryl coenzyme A hypersensitive response, 342
indole acetic acid, 3, 6, 98, 105, 165,514,516
reductase (HMOR), 313, 314 hypertension, 517, 640, 673, 686
indole 3-acetic acid, 94, 98, 165,437,514
,B-hydroxy-,B-methylglutaryl-CoA synthase hypertensive effects, 640
indole alkaloids, 353, 354, 358, 359, 365, 366,
(HMG-CoA synthase), 313 hypervitaminosis D, 437
560,563,575,610,615,628-632,634,636,
3-hydroxy-3-methylglutaryl-CoA synthetase, hyphae, 444
637,639,640,645,649,652-655,663,664,
313 hyphal elongation, 167
666-668, 686
2-hydroxynaringenin, 162 Hyphantria, 591, 603
indole, alkaloids, class 1, 630, 632, 634-636,
lO-hydroxynerol, 354 hypnotic, 537
641,645
hydroxynitrile lyase, 273, 282, 287, 289, 297, hypocotyl, 186,229,310,317,346
indole alkaloids, class 2, 632, 634
299 hypoglycemia, 222, 261, 647 indole alkaloids, class 3, 632, 634, 635, 645
a-hydroxynitriles, 273, 275, 285, 297 hypoglycin A, 222 indole alkaloids, class 5, 632, 634, 635, 645
18-hydroxyoleic acid, 53 hypoglycin B, 222 indole pyruvate decarboxylase, 98
16,B-hydroxy-22-oxo-5a-cholestanol, 680 hypolaetio 8-0-gl11coside, 167 indole 3-pyruvic acid, 98
16-hydroxypalmitic acid, 53 hypotension, 647, 697 indole-3-acetic acid, see indole 3-acetic acid
(IS,2S,3S)-3-hydroxy-2-(2'-cis-pentenyl) hypotensive effects, 591, 600, 606, 609, 640, indoleacetamide, 98
cyclopentane-l-acetic acid, 33 660, 670, 684, 686 indoleacetamide hydrolase, 98
I-hydroxyphaseollone, 186 Hyptis pectinata, 269 3-indoleacetonitrile, 306
4-hydroxyphenylacetaldehyde, 578, 586 hyptolide, 269 indoleamines, 517
(E)-p-hydroxyphenylacetaldehyde oxime, 275, hyrax, 468 indoleglycerol 3-phosphate, 98
276 indolizidine alkaloids, 533, 535, 543, 546,
1-(4'-hydroxyphenyl)-2-nitroethane, 290, 296 IAA, see indole 3-acetic acid 560-563, 565
m-hydroxyphenylpropionyl-CoA, 147 IAA oxidase, 132, 165 indolizidine system, 531, 533, 543, 546, 560,
p-hydroxyphenylpyruvic acid, 101, 102, 106 Iberis, 444 565,571
trans-4-hydroxypipecolic acid, 218 Iberis amara, 444, 445 indoloquinazoline alkaloids, 575, 610
trans-5-hydroxypipecolic acid, 218 iboga, 35, 634, 647, 648 indolyl glucosinolates, 302
trans-4-hydroxypipecolic acid-4-sulfate, 218 iboga alkaloids, 632, 634-637, 645, 647 3-indolylmethyl glucosinolate, 306, 309
12-hydroxy-4,6-pregnadien-3,20-dione, 440 ibogaine, 647 indospicine, 215, 227, 232
3-,B-hydroxy-5a-pregnane-20-one, 465 ibogaline, 647 inflammation, 392, 402, 517, 603
3-,B-hydroxypregn-5-en-20-one, 465 (- )-ibogamine, 635, 636 inflexin,415
4-hydroxyproline, 226 (+ )-ibogamine, 635, 636 inflorescence, 135, 136, 546, 659
trans-4-hydroxyproline, 226 ibogan alkaloids, 636, 637 infrared spectrophotometry (IR), 1; see also
trans-4-hydroxy-L-proline, 215 ibotenic acid, 697, 698 light
736 Index

ingenane, 402. 403, 424 invertase, 256 isobutyiamides, 36, 39

ingenol esters, 403 invertase inhibitor, 253 isobutylamine.513
inhibition, 26, 59, 78, 83, 95, 99, 123, 145, iodine, 307 3-isobutyl-2-methoxypyrazine, 703
146, 166, 188,209,311,510,517,520,521, iodoplatinate, 547 isochiorogenic acid, 104
523,526,535,537,540,544,549,550,558, ion channels, 651 isochondrodendrine. 606, 607
559,561,562,574,588,591,597,599-601, ion pair, 327, 329, 331, 351, 369-371, 396 isochorismate synthase, 97
603,606,607,612,613,616,619,623,625, ionization, 327, 329. 330, 369-371 isochorismic acid, 65, 80. 81, 88, 93, 97, 104,
627,640,641,645,647,648,650,651,654, ionones, 452 105, 122
656, 659, 660, 664, 673, 675, 676, 681, 682, a-ionone. 492 isocodonocarpine, 521
685, 696, 697, 700, 703, 708, 711 ,8-ionone, 384, 492 Isocoma wrightii, 317
inhibitors, 9, 13, 31, 33, 39, 40, 83, 88, 89, 93, ionophores, 65, 698 22-isodemissine, 684
99, 104, 105, 109, 110, 118, 125, 126, 128, ipecac alkaloids, 610, 611. 652 isodihydronepetalactone, 362
132, 135, 145-147, 164, 166, 187, 191, 195, ipecac root, 610 isodomedin, 415
231,234,242,246, see also ipecacuanha alkaloids, 610, 628 Isodan, 408, 415, 419
adenyltransferase inhibitors, cholinesterase ipecoside, 610, 611 Isodon inflexus, 415
inhibitors, a-glucosidase inhibitors, f3- Iphigenia.617 /sodon japonicus, 447
glucosidase inhibitors, glycosidase inhibitors, ipolamiide, 358 Isodon kameba, 415
invertase inhibitors, mixed function oxidase ipomeamarone, 378 Isodon shikokianus, 415
inhibitors, monoamine oxidase inhibitors. Ipomoea, 658 isodonal, 419
proteinase inhibitors, trypsin inhibitors Ipomoea halalas, 72, 377 isoelaeocarpine, 563
inhibitors of ,B-glucosidases, 254 Ipomoea purpurea. 7 ( + )-isoepoxydon, 71
inhibitors of glycosidase activity, 544 Ipomoea violacea, 655, 658 isoeugenol, 113
injury, 8, 30, 31, 122, 131,591,613 Ipomopsis, 444 isoflavanone, 179, 181, 186
Inocybe.697 Ipomopsis aggregala, 444, 452 isoflavans, 151, 179, 184
inositol,591 Ips, 340, 342 isoflavone,O-methyltransferase, 179
chiro-inositol. 264 Ips confusus, 343 isoflavone synthase, 178
D-chiro-inositol, 264 Ips paraconfusus, 343 isoflavones, 151, 178, 179, 181, 182, 184,
myo-inositol. 253, 264, 271 Ips pini, 343 186-188, 190,261,439
myo-inositol, hexakis-o-phosphate, 264 ipsdieno1, 343, 344, 352 isoqavonoids, 174, 178, 179. 186, 192. 316
scyllo-inositol,264 (+ )-ipsdieno1, 343 isogramine, 525
inotropic effects, 581, 591, 603, 692 ipseno1, 343 isohaningtonine, 625, 626
insect-host plant relationships, 441 lridaceae, 82, 87, 179,257,452,499 isoiridomynnecin, 362
insecticidal effects, 36, 40, 49. 111, 114. 186. iridal, 452 isoleucine, 217, 222, 232, 273, 274, 276, 282,
187,221,316,318,322,348,351,361,393, iridodial, 353-355, 361, 363, 366 286,287,300,302,513,547,549
398, 412, 418, 419, 424, 472, 478, 480, 483, epi~iridodial, 354
(2S)-isoleucine, 549
484,514,528,533,538,545,550,609,619, 8-epi-iridodial, 358 isoliquiritigenin, 158, 181, 182
isolysergic acid amide, 659
623, 642, 697 iridodial glucoside, 355
E-Z isomerization, 132
insecticides, viii. 36, 41, Ill, 118, 128, 186. iridodiol, 362
isoneomatatabiol, 362
348, 363, 412, 418, 419, 423, 478, 510, 525, iridoid glycosides, 353, 355, 358, 359,
526, 662, 686 isopavine alkaloids, 605
361-366
isopelletierine, 540
insecticides, carbamate, 110 iridoid monoterpene biosynthesis, 353
insecticides, organophosphate, 537 isopentenyl diphosphate, see isopentenyl
iridoid monoterpenes, 46, 87, 88, 124,324,
pyrophosphate
insectivorous, 52, 240 337, 353-355, 358-364, 366, 552, 579, 610,
isopentenyl diphosphate A-isomerase, 315
insects, viii, 8-10, 13, 14,35-37,39-42,49, 611, 648, 668-670; see also monoterpene isopenteny1 pyrophosphate, 312, 315, 319, 321,
50,52-54,83,84,89,92,93,99,111,118, iridoid alkaloids, monoterpene derived 326-329, 335, 348, 368-370, 401, 488, 494
122, 124, 127, 129, 130, 132, 135-138, 169, indole alkaloids isopentenyl pyrophosphate isomerase, 488
173, 174, 176, 177, 179, 184, 187, 189, 191, iridomynnecin, 353, 361. 362 isopentenyl pyrophosphate A3-A 2-isomerase,
207-209,212,213,217,220,221,227,228, Iridomyrmex, 353, 361, 362 315
231, 232, 244, 254, 260, 262, 269, 273, 285, Iridomyrmex humilis, 362, 703 isopentenyl pyrophosphate:dimethylallyl
288-290,293-295,297,298,300,305, Iridomyrmex nitidiceps, 669 pyrophosphate isomerase, 315
307-311,313,317,318,322,324,329,338, Iridomyrmex nilidis, 362 isophorone, 124
340-343,346,348,353,361,363,365-367, iridotrial,354 isophyllocladene, 412
379, 380, 382-384, 390, 395, 396, 398, epi-iridotrial, 354, 358 isopimaric acid, 415
416-419, 422, 437, 439, 440-442, 444, 445, 8-epi-iridotrial, 358 isopimpinellin, 133-136
447,452,454-456,460,466,468,472,478, iridotrial glucoside, 355 isopiperitenone, 333
479,486, 498, 504, 510, 511, 514, 515, 526, iris, 452 ( - )-trans-isopiperitenol. 333, 335
528, 537, 538, 540, 543, 545, 550, 559, 563, Iris germanica, 452 ( - )-isopiperetinone, 333
567, 570, 582, 583, 588, 591, 600, 603, 615, Iris pallida, 452 isoprene, 312, 315, 319, 321, 322, 326, 346
641, 652, 653, 682, 690, 696, 703; see also Iris pseudacorus, 452 isoprene rule, 312, 346, 371; also see
insect vision iris, yellow flag, 452 biogenetic isoprene rule
insects, scale, 89 iron, 171,230,510,521,545 isoprene units. 312, 369
insects, social, 343 irone, 452 isoprenoid compounds, 313, 425
interactions, vii,S, 9, 10, 14, 15,32,37,71, irritant effect, 346, 378, 382, 402, 403, 423, isopropyldihydrofuroquinoJines, 571
76, 78, 79, 121, 122, 125; see also plant- 424,460 (+ )-cis-isopulegone, 333
animal, pIant~funga1, plant-herbivore, plant~ Isalis, 267 /sopyrum, 269
insect, plant~microbe, and plant~plant Isalis linctoria, 267 isoquinoline alkaloids, 441, 578-582, 584,
interactions iso-a-acids,316 612, 638, 652, 668
intennediates, Schiff~base, 508 isoalantolactone. 392, 396 isorubijervine, 684
intennediates, synunetrical, 526, 531, 532, 534, isoamyl acetate, 343 isosafro1e. 110
537, 540, 548, 554, 608, 694 isoasarone, 113 isosalipurposide, 158, 173
intennediates, unsymmetrical. 535, 548 isobalfourodine, 573 isosiphonodin. 269
introgression, 337, 338 isobergapten, 135 isotabtoxin, 238
Inula royaleana, 673 isobicyclogennacrenal, 376 isothebaine. 591, 592, 594
Inuleae, 387 isoboldine. 590, 591 isothlocysnates, 266, 302, 305, 306, 308-311,
inulin, 257 isobruceine A, 482 383

[( - )·I·isothiocyanoato·(4R)·
(methylsulfmyl)]butane, 306
( - )M3M isothujone, 340
isotopicallY-labelled precursors, 326
isotrlglochinin, 280
isovaleric acid diamide, 533
isovestitol, 184
isovincoside, 359, 628, 629, 654
isovitexin, 162, 166
isoxazolinone glucosides, 293
LJ3M isoxazolin-5--one, 293, 298
LJ3M isoxazolin-5M one glucoside 1,2,293
,B--(isoxazolin-5-on-2-yl)-~alanine,
isozymes, 5, 97, 102,300
Ithomiinae, 550, 551
Iva axillaris, 390, 396
ivy, 459
jacarubin, 148
Jacquinia pungens, 452
jacquinonic acid, 452
jam, 708
Jamaica, 222
Japan, 362, 383, 460, 472,600,649,689
japonicin A, 69
Jasminum, 32
Jasminum officinale, 326
jasmonate·induced proteins, 33
jasmonic acid, 16, 32-34, 39
jasmonic acid methyl ester, 32, 33, 39
Jatropha curcas, 244, 402, 424
Jatropha gosSYPifo/ia, 402
Jatropha multifida, 244
jatronilizine, 598-600
Java, 227, 649
jays, see blue jays
Jerusalem artichoke, 257
jerveratrum alkaloids, 684
jervine, 684-686
jhanic acid, 500
jojoba, 51, 52, 55; see also wax, jojoba
Juglandaceae, 82-84, 197, 337, 598
Jug/ans, 81, 82, 84, 363
Juglans nigra, 83
Juglans regia, 81, 83, 265
jugione, 81, 83-85, 92
Julianaceae, 67
julisporine, 562
Jungermannia, 412
Jungermannia subulata, 143
Juniperus, 179,337
Juniperus ashei, 338
Juniperus pinchotii, 338
Juniperus scopulorum, 338
Juniperus virginiana, 338
Junonia coenia, 364, 365
juribidine, 677, 681
Justicia hayatai, 120
justicidin A, 120
justicidin B, 120
juvabione, 383
juvenile honnone, 317, 318, 367, 383, 384,
395,398,419,440,442,444,479
juvenile honnone ill, 384
juvenile honnone mimics, 367, 383, 384
kaempferol, 152, 158, 166, 188
kaempferol glycosides, 172
kaempferoJ 3-0-xylosyIgaIactoside, 168
kaffir beer, 210
kairomones,9, 10, 1I0, 168,300,307,324,
339,341,352,363,367,380,381,447,454,
498,511
kale, 306
Kalmia, 411
Index 737
kamebanin, 415 lacrymation, 226, 227, 561, 697
kangaroos, rat, 29 p..lactam ring, 234
KAS I, see ketoacyl-ACP synthase (KAS I) lactation, 317, 659
KAS II, see ketoacyl-ACP synthase (KAS II) lactic acid bacteria, 520
KAS ill, see ketoacyl-ACP synthase (KAS ill) lactobacillic acid, 27
katemfe, 245 lactone forming glycosides, 247, 267, 269
(- )-kauran-16a-ol, 418 lactones, 37, 59, 117, 130
kaurene, 673 lactose, 254
ent-kaurene, 398, 407, 408, 411, 420 Lactuca, 537, 599, 650
I-kaurene, 408 lactucarium, 389
kaurenoic acid, 415 Iactucin, 389
kaur-l6--en-19-oic acid, 418, 420 Ladenbergia, 640
290 kava, 139, 140 ladybugs, 542
kavakava, 139 Laetisaria arvalis, 26
kavalactones, 140 laetisaric acid (9Z,12Z,8-
kawa, 74, 139 hydroxyoctadecadienoic acid), 26, 27
kawain, 140 Lagerstroemia subcostata, 694
kawakawa, 139 Lagodon, 420
K.edde's reagent, 267 Lagodon rhomboides, 420
kerosene, 535 lambs,685
,B-ketoacyl-acyl carrier protein, 156 Lamiaceae, 49, 50, 77, 108, 168, 257, 269,
3-ketoacyl-ACP reductase, 19,20 280, 326, 328, 330-332, 337, 338, 346, 358,
3-ketoacyl-ACP synthase (KAS I), 19, 21 361,371,387,405,406,408,412,413,415,
3-ketoacyl-ACP synthase (KAS II), 19-22 416, 418-420, 426, 442, 447, 451, 459, 672
3-ketoacyl-ACP synthase (KAS ill), 19-22 Lamiales, 88, 360, 361
ketocarotenoids, 498 Lamianae, 360, 361
l1-ketocycloartenol, 444 Lamiananae, 360
a-keto acids, 508 Iamiide, 358
,B--keto esters, 58 laminarabiose, 254
a-ketoglutararic acid, 65, 80, 81, 158, 159 laminarin, 260
ketones, 48, 51, 52, 76, 288, 317, 339, 507, lantadene B, 451
579,689 Lando/phia, 319
ketoses, 247, 248, 250, 253, 262 lanosterol, 431, 433, 436
khat, 210, 213, 522, 530, 668, 671 lantadene A, 447, 451
Khaya nyasica, 480 Lantana camara, 447
Khaya senegalensis, 480 !apachol,85
khellin, 137 a-lapachone, 82
khivorin, 476 larch,257
kidneys, 174, 380 Lardizabalaceae, 610
kievitone, 182, 186 Larix iaricina, 415
Kiggelaria africana, 289 Larrea divaricata, 120, 210
kinase C, 402 larvae, 9, 10, 35, 40, 53, 67, 84, 88, 92, 93,
kinetin, 3, 6 111, 123, 124, 128, 132, 135, 136, 138, 175,
ldaineanone, 482 179, 184, 190,208,217,220,221,227,228,
Klamath weed, 91, 92 232, 245, 253, 265, 269, 285, 288, 289, 294,
knockdown effect, 348 296,297,307,308,310,311,316,317,
Know/tonia, 269 340-342, 363-366, 380, 381, 390, 394, 402,
Koenoline, 663, 666 412,415,416,418,424,437,441,444,445,
kohlrabi,306 447,459,460,466,468,470,471,479,480,
kokusagin, 136 522, 526, 529, 535, 537, 544, 550-552, 558,
kola, 700 559,562,565,591,597,603,609,613,615,
kolavenol, 380 619, 627, 640-642, 650, 653, 658, 660, 664,
kolavenyl pyrophosphate, 408 682, 683, 686, 696, 703, 709
Korea, 460 lasalocid A, 67
K-PLMF I, 123 Lasiantlulea fruticosa, 380
Krameria, 35, 210 lasidiol angelate, 380
Kramericeae, 35 Lasiocampidae, 437
Krebs cycle, 3, 6, 226 lasiokaurin, 420
Kreysigia, 617 Lasius carniolicus, 419
Laspeyresia pomone/la, 381, 468
laballenic acid, 49 latex, 318-322, 402-404, 466, 587, 593, 596,
labdadienols, bicyclic, 405 597
labdadienyl pyrophosphate, 407 lathyrine, 700
9,,BH-labdadienyl pyrophosphate, 414 L-Iathyrine, 215, 223, 226
labda-8(17),13-dien-15-yl (copalyl) lathyrism, 226
pyrophosphate, 407 Lathyrus, 174, 189,215,223,226
labda-8(l7),13-dien-15-yl pyrophosphate, 406, Lathyrus cicera, 223
407 Lathyrus clymenum, 223
ent-/-Iabda-8(17),13-dien-15-yl pyrophosphate, Lathyrus hirsutus, 223
408 Lathyrus iatifo/ius, 223
labdane, 404-406, 420 Lathyrus odoratus, 174, 189, 223, 293
Labiatae, see Lamiaceae Lathyrus pusillus, 223
Laburnum anagyroides, 142 Lathyrus sativus, 223, 226, 290, 518
laccase, 140 Lathyrus sylvestris, 223
lacewings, 362, 363 Lathyrus tingitanus, 226, 700
738 Index

Iaticifers, 318, 319, 320, 465 (- )-lepidozenaI, 376 limonin D-ring lactone hydrolase. 483
Latin America, 319, 499 Lepidozia vitrea, 376 Limonium, 571
Latlfa, 537 Lepioto, 237 limonoate dehydrogenase, 483
laudanosine, 587, 588, 591 Lepipolys, 364 limonoate D-ring hydrolase, 483
laudanosoline, 605 leprosy, 36, 85 limonoic acid A-ring lactone, 483
Lauraceae,46, 1l0, 121, 139,340,380,387, leptioe I, 682 limonoids, 11,473, 475-485, 576
419, 510, 528, 563, 585, 592, 598, 605, 610, Leptinotarsa, 537, 597, 619, 650 B-seco-limonoids, 480
614,660 Leptinotarsa decemlineata, 31, 231. 412. 682 C-seco-limonoids. 476, 480
Iaurate, 35 Leptochloa dubia, 125 D-seco-limonoids, 476, 477
laureline, 591, 592 Leptocoris isolata, 285. 289, 294 Linaceae, 282, 549
Laurencia, 381 Leptopyrum. 269 linalool, 31, 337, 339-341, 344, 346
Laurencia pinnata, 442 Leptosphaeria macuians, 309 linaIyl acetate, 341
lauric acid, 17, 25, 35 Lepus americanus, 208,451 linalyl alcohol, 346
Laurus nobilis, 340 Lespedeza sericea, 78, 452 linalyl diphosphate, see linaIyl pyrophosphate
Lavandula officinalis, 130 lethal dose, 526, 677, 685 linaIyl pyrophosphate, 328, 329, 331, 332
lavender, 130 lethal substance, 522, 526, 537, 558, 562, 582, (3R)-linalyl pyrophosphate, 332
lawsone, 81, 87 609,619,640,642,673,677,685,703 (3S)-linaIyl pyrophosphate, 332
laxative, 35, 91, 517 lettuce, 83, 118, 346, 389, 459, 558, 703 linamarin, 9, 276, 277, 282, 287-290, 295,
leachate, IS, 83, 109, 126 Leucaena leucocephala, 219, 220 297, 299, 517
leaf hopper, 385 Leucathoe grayana, 411 Linaria, 569, 570
leather, 193, 204, 210 leucine, 226, 282, 285, 300, 302, 513, 578, 580 Lindero, 380
leaves, 7, 14, 16, 17, 18,22,24,29,30,31, D-Ieucine, 234 liniment, 122,346
35, 39, 40, 41, 51, 54, 55, 72, 78, 83, 84, L-leucine, 215, 217, 274, 625 linoleic acid, 17, 18,22,24,26,27,30,32,34,
88,91,92,99, 105, lll, 123-132, 135-138, (2S)-leucine, 549 35, 42, 43, 53
142, 148, 152, 171-174, 184, 193, 194, 196, leucoantbocyanidins, 162. 163, 200. 206 9Z,l2Z-linoleic acid, 26
197,206-210,212,220,226,227,238,240, leucoanthocyanins, 201 linolenic acid, 17, 18, 22, 24, 26, 30, 32, 34,
242,256,269,277,280,282,287-290,294, leucoapigeninidin, 164 35
296, 298, 300, 303, 307, 308, 320, 326, 330, leucoblasts, 326 a-linolenic acids. 17
338, 340, 341, 345, 351, 362, 371, 373, 381, leucocyanidin, 163 2-linoleoyl-I,3-dipahnitio,35
384,386,411-414,420,423,437,454, leucocytes, 591 a-linoleyl phosphatidylcholine, 22
457-459, 463, 466, 468, 470, 473, 476, 480, leucodelpbinidin, 163 linseed oil, 308
486,496,497,499,514,517,518,521,522, Leucojum aestivum, 623 Linum, 537
528,535,537,552-554,556,557,561, leucoluteolinidin, 164 Linumflavum.117
566-568,608, 611, 617, 647, 652, 658, 659, leucoplasts, 326 Linum usitatissimum. 274, 288
671, 673, 676, 689, 698, 700; see also hay leukemia, 145, 511, 627, 645, 648, 654 linustatin, 282, 287, 288, 299
leaf, cedar leaf oil, elm leaf chrysomelid, liana, 33, 671 Lipophis erysimi, 383
green leaf volatile complex, leaf beetles, leaf Libocedrus vateensis. 118 lipase, 24, 39
abscission, leaf cutter ants, leafhoppers, leaf lice,641 lipid, vii, 4, 6, 8, 14, 16-19,22-25,30,32,
lipids, leaf movement, South American leaf lichen, 56, 70, 77, 85-87 35, 39-41, 45, 49-55, 74, 92, 93, 135, 138,
blight, velvetleaf licorice, 462 152, 166, 191, 207, 208, 298; see also
lecanoric acid, 70 licorice, European, 184 cyanolipids. glycerophospholipids,
Lecithydaceae, 197 Liebennann-Burchard test. 456 glycoJipids, phospholipids
lectins, 234, 240, 242, 244, 245, 246, 261, 271, light, vii, 3, 4, 7, 8, 13, 26, 30, 40, 42, 50, 78, lipid metabolism, 4
272 91,92, lll, 120, 126, 128, 129, 131-138, lipid peroxidation, 209
Lecythis ollaria, 229 145, 153, 163, 164, 177, 206, 209, 237, 289, lipids, leaf, 17, 18
leek, 51, 226 320,328,414,477,486,491,494-497,554, lipids. seed. 32
legumes, 3, 6, 78, 145, 179, 181,218,220, 634 lipoquinones, 9
221, 226, 228, 229, 232, 241, 242, 244-246, light gap specialists, 7 lipoxygenase, 24, 26
256, 261, 280, 290, 391, 398,460, 514, 543, light screens, 165 5-lipoxygenase, 209. 267
549, 552, 554, 558, 559, 566, 567 light-harvesting complexes, 496 Lippia dulcis, 385
Leguminosae, see Fabaceae lignanolides, 117 Lippia rehmanni, 447. 451
Leishmania, 606 lignans, ll, 54, 102, 106, 117, 118, 120, Liquidambar formosana, 196
Leishmania mexicana amazonensis. 660 127-129, 190 liquidambin, 196
leishmaniasis, 599, 612 lignification. 11,259 liquids. supercritical, 326
leishmanicidal, 599 lignin, 3, 11,54, 102, 106, 108, 114, 115, 117, liquiritigenin, 158.201
Lemaireocereus thurberi, 582 123, 127, 128,208,213,259,288 (2S)-liquiritigenin, 178
lemmatoxin, 460 Ligusticum, 136 Liriodendron tulipi/era. 591, 613
Lemna, 29, 40, 537, 540, 543, 591, 613, 640, Liliaceae, 3, 35, 51, 85-87, 173,222,226, liriodenine,591
641,650 231,257,267,269,280,444,457,459,466, D-(-)-liriodennitol,264
Lemna minor. 145, 439 468,510,543,617,619,625,677,684 lirioferine.591
Lemna paucicostata. 289 Lilium longifIorum, 267. 271 liriotulipiferine. 591
Lemnaceae, 439 Lilium pardarinum, 458, 472 Litchi chinensis, 223
lemon. 346 limes, 137,257,528,535 lithiumsalts,16
Lens culinaris, 48 Limnanthaceae, 52, 304, 308 Lithospermum, 196
Lentibulariaceae, 361 Limnanthes douglasH, 52, 55 Lithospermum erythrorhizon. 85
lentil,48 limonene, 331, 332, 337, 339, 340, 342, 343, little bluestem, 125, 346
Leonotis nepetaejolia, 49 345, 346, 351 livOI, 65, 168,209,237,313,380,552,553
I..eontice, 558 (- )-limonene, 331, 335, 340, 351 liver, cirrhosis, 460. 619
Leontinus edodes, 700 (+)-limonene, 331, 340 liver, rat, 361, 431
Lepidium, 526, 537, 540, 558, 599, 601, 641, (- )-(4S)-limonene, 335 liverwort, 130, 136, 142, 145, 174,368,369,
650,673 d-limonene. 331 376, 386, 389, 412
Lepidoptera, 136, 365, 366, 390,437, 551, I-limonene, 331, 333, 335 livestock, viii, 29, 70, 91, 132, 136, 290, 306,
564,566,591,623,640,641,650,658,660, limonene cyclase, 331 307,317,378,380,383,390,402,403,447,
682, 703, 711 E-limonene oxide, 344 466, 517, 546, 552, 559, 561, 659, 684, 685,
lepidopteran caterpillars. 591 Z-limonene oxide, 344 689
 Index 739

Loasaceae, 361 (- )-lupinine, 554, 555 maize (Zea mays), 70, 98, 105,415,436,501,
Loasales, 360, 361 Lupinus, 179,229,510,553,554,558,559 517
Loasanae, 360 Lupinus angustifolius. 554, 700 Malacosoma americana, 288, 437
Lobelia, 531, 540 Lupinus argenteus, 552, 559 Malacosoma neustria, 437, 455
Lobelia berlandieri, 540 Lupinus fulcratus, 559 malaria, 392, 395, 482, 569, 599, 612, 640,
Lobelia inflata, 540 Lupinus luteus, 554, 556, 557 648, 649, 654, 662, 698
lobeline, 538, 540 Lupinus poiyphyllus, 3, 8, 9, 554, 557 malaria, tertian, 662
lobsters, 498 lutein. 486, 494-496, 505 malaria, vivax, 651
locoweed, 561 luteoforol, 164 male scent organ, 552
locust, 353, 379, 444, 460, 484; see also black luteolin, 152, 160, 164, 189, 191 Malesherbiaceae, 285, 287
locust, honey locust luteone, 179 malic acid, 160
locust, desert, 444, 478-480 lutoid particles, 318 Mallotus japonicus, 69
locust, migratory, 221 lyase, 158, 261 Maloideae, 264, 287
Locusta, 221, 228, 460, 618, 650 lycoctonine, 674 malonamide starter, 65, 67
Locusta migratoria, 53, 253, 288 lycomarasmin, 237 malonamido-CoA, 65
Locusta migratoria migratorioides, 221 lycopene, 486, 490-492, 499 malonate, 152, 155, 156, 463, 465, 471
Loganiaceae, 149,361,510,511,615,636, E-lycopene, 492 malonic acid, 148
638,640,641,646,652,653,660 lycopersene, 490 malonyl-ACP, 19, 20
loganic acid, 354, 359, 669 Lycopersicon, 30, 39-41, 146,230,269,381, malonyl-CoA, 19, 21, 23, 51, 58, 139, 142,
loganin, 353-355, 358, 365, 610, 611, 501,677,682 147, 155, 156, 531, 535, 539
628-630, 649, 669 Lycopersicon esculentum, 30, 230, 677 Malouetia, 677
Lolium perenne, 271, 659 Lycopersicon hirsutum, 30, 39-41, 381 Maipighia glabra, 265
Lotium tementulum, 659 Lycopersicon pimpinellifolium, 680 Malpighiaceae, 265, 290, 361, 514, 660, 700
Lomalia, 82 Iycopodine, 540 maltose, 254
Lonchocarpus, 186, 253 Lycopodium, 510, 531, 540, 544. 545 Maluoetia, 686
Lonchocarpus costaricensis, 226, 543 lycorenine, 620, 621 Malva sylvestris, 241
Lonchocarpus sericeus, 543 lycoricidine, 510, 623 Malvaceae, 18,28,35,77,309,378,569,570,
long chain alcohol, see alcohols, long chain lycoricidinoi, 510, 623 662,697
longicyclene, 375 lycorine, 620, 622, 623 malvidin, 167
longifoiene, 375 Lycoris radiata, 510. 623 Mamestra configurata, 308
Lonicera japonica, 459 lygaeid bugs, 468 mammalian eyes, 171
Lonicera morrowii, 355 Lymantria, 591, 603, 689, 703 mammalian systems, 19,35,37,65,72
lophenol, 582 Lymantria dispar, 361, 380, 411 mammals, 8, 9, 35-37, 101, 104, 106, 125,
lophocereine. 581, 582, 662 lymphoma, non-Hodgkin's, 235 130, 132, 136, 137, 207, 208, 228, 253, 288,
Lophocereus, 580 lysergic acid amide, 655, 658, 659 290,306,307,312,313,340,361, 378,402,
Lophocereus schottii, 441, 580, 582 lysergic acid. 316, 511, 655-657, 659, 660 411,444,468,478,498,507,511,517,553,
Lophoco/ea heterophylla, 143 Lysergsaurediethylamid (LSD), 659 559,581,591,594,698
Lophopetalum toxicum, 470 lysergic acid, diethylamide (LSD), 316, 511, mammary gland, 659
Lophophora williamsii, 523, 580, 581 525,659 Mammea siamensis, 209, 212
lophophorine, 581 lysergylalanine, 657 Mancinella, 403
loquat, 148 lysergyltripeptide, 658 (R)-mandelonitrile, 289
Loranthaceae, 45, 197,244,246,466 Lysichiton,610 (R)-( + )-mandelonitrile lyase, 280, 295
lotaustralin, 9, 276, 277, 287, 288-290, 296, lysine, 215, 217-219, 507, 517, 531, 537-540, mandibular glands, 343
297,299 542, 543, 554, 561, 694, 703 Mandragora, 537
(R)-lotaustralin, 282 D-lysine, 217, 218, 538 Mandragora oificinarum, 537
Lotoideae. 220 L-lysine, 217, 218, 239 mandrake, 537
Lotononis, 549 lysine decarboxylase, 554 Manduca sexta, 30, 40, 208, 221, 245, 526
Lotus, 179 Lythraceae, 88, 149, 197, 554, 692-694, 709 Manettia, 612, 638
Lotus corniculatus, 184, 289 Iyxose, 249 manganese ion (Mn 2 +>, 315, 319, 428, 488
Lotus pedunculatus, 179, 291 Mangifera indica, 67
Lotus scoparius, 126 rna huang, 522 mangiferin, 148
Lotus uliginosus, 184 maackiain. 179, 181, 182, 186 mango,67
Lou Gehrig's disease, 226, 294 (- )-maaackiain, 179, 182 mangostin, 148
LPP, see linalyl pyrophosphate ( + )-maackiain, 182 mangrove, 204
LSD, see lysergic acid, diethyl amide macarpine, 601 Manihot esculenta, 276, 290, 297
lubimin, 377 Machaerium, 187 Manihot glaziovii, 319
lubricant, 16, 35, 52 Machaerocereus gummosus, 582 Manilkara sapota, 321
(R)-lucumin, 277, 279 Mackin/aya, 570 manna, 257
lunacrine, 571 Madura, 140 D-marman, 259
Lunaria biennis, 521 Maclura pomijera, 145 mannans, 259, 260
lunarine, 521 macIurin,148 Mannich condensation, 507, 531
Lunasia amara, 571 Macrorungia, 693 mannitol, 260, 262. 264
lunasine, 571 Macrosiphon a/bifrons, 559 D-mannitol, 262, 264
lung edema, 378 Macrotermes subhyalinus, 419 mannose, 248, 249, 253
Lunularia, 146 madder, 85, 87. 89 D-mannose, 248, 249, 259, 260
lunularic acid, 142, 143, 145, 146 Maesa lanceolala, 77 mannosidase, 544
lupanine, 9, 510, 554-556, 558, 559, 567 maesanin,77 ,B-D-mannosidase, 294
( + )-lupanine, 554, 555 maesaquinone, 77 mannosides, 266
lupeol,447 magnesium ion (Mg 2 +), 81,155,171,264, mannosidosis, 561
Luperini,447 315,319,326,371,375,401,428,488,656 manooi, 405, 412
lupine alkaloid biosynthesis, 554 Magnolia kobus, 118, 128 mantid,468
lupine alkaloids, 9, 514 Magnoiiaceae, 118, 121, 123,387,591,610 maple. 223, 231, 523
lupines, 2 Magnoliales, 109,286,610 Mappia.648
lupinic acid, 700 Magnoliidae, 280, 575 Marah macrocarpus, 411
lupinine, 554, 559 maitenine, 452 Marantaceae, 245
740 Index

Marchantia polymorpha. 143 Melanchra persicariae, 550 Merrillia, 575

margarine. 35, 499 Melanophryniscus.560 mesaconine, 675
marigold. Mrican, 48 Melanoplus, 528 mesaconitine. 674, 675
marijuana, 324, 336 Melanoplus bivittatus, 559 mescaline, 511, 513, 522, 523, 579, 580, 581
marine animals, 223 MeJanoplus difjerenlialis, 460 mesembrenol, 624
marine borers, 78, 85, 88 Melanoplus sanguinipes, 316. 318, 384, 460, mesembrine. 624
marine compounds, viii, 14, 32, 48. 340, 380. 479 mesembrine alkaloids. 624
381, 394, 396, 398, 419, 420, 423, 425, 442, Melastomataceae, 197 Mesembryanthemaceae, 617, 623
495, 506, 696, 700, 703 Melia, 484 Mesembryanthemum, 617, 623, 624
marine organisms, viii Melia azadirachta, 479, 480 Mesembryanthemum alkaloids, 624
mannesin, 133 Melia toosendanan, 480 mesophyll cells, 9, 282, 299, 557
(S)-mannesin, 133, 135 Meliaceae, 337, 361, 399, 473, 475, 477-480, Mespillus germanica, 269
(+ )-(S)-mannesin, 133 483-485,533,571,573,575,576,601,608, messages. see chemical messages
Martyniaceae, 361 663 metabolic cost, vii, 1.6,7, 13,46, 193,208,
3-epi-maslinic acid, 447 meliacin A2, 480 209, 245, 510
mass spectrometry (MS), I, 54, 55, 132, 138, melianone, 473, 480 metabolism, see amino acid metabolism, fatty
142, 170, 179, 191,212,234,247,300,302, meliantriol. 480 acid metabolism, lipid metabolism. terpeDoid
326,353,367,379,396,427,455,457,470, meliatoxin AI> 480 metabolism
487,506,554,645,655,695 meliatoxin A2, 480 metabolism, primary, vii. 1,3-6, 10, 16,94,
mass spectrometry. chemical ionization (CI), meliatoxin B 2, 480 96, 104, 166, 214, 248
457 meliatoxin Bb 480 metabolites, primary, vii. 3-6, 16.25,247.510
mass spectrometry. fast atom bombardment meliatoxins Ah 480 metabolites, shunt, 6
(FAB), 170, 212, 223, 457 Melica, 659 metal, 169, 170, 177,208,209,237,240,260,
mass spectrometry. tandem, 655 Melicope, 574 276
massoia lactone. 269 Melilo/us alba, 130, 132, 137, 138 metals, heavy, 240, 241, 242
masticatory, 522, 528, 538 Melilotus, 130 metaphase, 120
Mastixiaceae. 361 Melioideae, 477 Metarrhizium. 253
( - )-matairesino1, 117, 118 melizitose, 257 methadone. 597
mare, see yerba mare mellitoxin, 385 exo-cis-3,4-methanoproline, 218
matricaria acid, 49 Melochia, 571, 700 methiooine, 27, 45, 63, 186,215,217,226,
matricaria ester, 43 Melochia tomentosa, 666, 700 230,232,238,513,568,570,580,598,700,
matrine, 556, 559 Melodinus, 637, 647 702
Matthiala. 159 Melodorumjruticosum, 59, 74 12-methoxyabietic acid, 415
Matthiola incana, 163 Meloidae, 382, 393 lO-methoxyajmalicine, 640
Maurandya antirrhiniflora, 364 Meloidogyne incognita, 459 4-methoxy-l-allylbenzene, 113
maytanbutacine, 695 Meloidogyne javanica, 479, 482 4-methoxybenzaldehyde, 124
maytanprine. 695 melosatin A, 666 6-methoxybenzoxazolinone (MBOA), 94, 99,
maytansine, 676, 694-696 melosatin B, 666 100, 101, 104
maytansinoids, 692, 694-696, 711 membrane, 3, 9, 14, 16-19,22,23,32,35,41, a-methoxy-A<>:-butenolide. 269
maytanvaline. 695 49, 65, 115, 135, 153, 166, 179, 182, 191, 9~methoxycanthin-6-one, 662
Maytenus. 452 208,231,237,261,270,314,319,321,326, 4-methoxycinnamaldehyde, 113
Maytenus buchananii, 695 331, 376,401, 415, 427, 428, 430, 433, 440, 4~methoxydalbergione, 78. 79
May tenus ilicifolia, 695, 696 444,452,459,468,490,492,497,517,518, 5~methoxy-N,N-dimethyltryptamine, 514
Maylenus ova/us, 695 520, 528, 550, 556, 574, 598, 603, 606, 660, 9-methoxyellipticine, 645
Maytenus serrata, 695 675, 682, 685; see also chloroplast lO-methoxycamptothecine, 648
MBOA, see 6-methoxybenzoxazolinone membrane, nerve-cell membrane, plasma I-methoxycanthin-6-one. 662
meadowfoam, 52, 55 membrane, thylakoid membrane, tonoplast IO-methoxycanthin-6-one, 662
meadowsweet, 209 membrane 2-methoxycarbonyl-3-prenyl-l,4-
meal, see cottonseed meal, oahneal membrane penneabilility, 35, 338, 520, 682 naphthoquinone. 87
mealybugs, 561 memory impainnent, 709 16-methoxy-2,3-dihydro-3-dihydroxy-N(I)-
measles. 120 menaquinone, 80, 81, 92 methyltahersonine. 634
mechanism, cationic, 327 Mendonciaceae. 361 a-methoxy-,..hydroxy-Ll<>:-butenolide, 269
meconic acid, 596 Menispennaceae, 179,245,290,385,387,442, 6-methoxY-7-hydroxycoumarin, 133
medicagenic acid. 459 510,511,581,588,592,598,606,608-610, I-methoxy-3-hydroxymethylcarbazole, 663
Medicago sativa, 179. 183, 261, 456 700 3-methoxy-4-hydroxyphenylethylamine, 523
medicarpin, 181, 183, 186 Menispermum dauricum, 606 lO-methoxyibogamme,647
(- )-medicarpin, 181, 183 Menispermum, 385 methoxylation, 580
medicinal uses, viii, 10,48. 69, 91, 92, 114, menses inducer, 696 methoxymedicarpin, 183
122, 123, 128, 139, 168, 188, 189, 192, 193, Mentha piperita. 328, 332, 333, 335, 351 6-methoxymellein, 73. 129
209,213,229,244,313,324,346,353,367, Mentha spicata, 335, 351 6-methoxY-N-methy1-1,2,3,4-tetrahydro-,8-
376, 392, 395, 397, 398, 420, 424, 426, 452, p-menthane-3,8-cis-diol, 346 carboline, 660
455,456,460,462,463,468,470,471-473, meotho1, 335, 346 4'-methoxynOIprotosinomenine, 608
481-483,507,530,535,544,546,553,559, I-menthol, 333 2'-methoxyphaseollin-flavan, 186
564,566,576,593,603,615-617,623,627, menthol esters, 333 5-methoxypodophyllotoxin, 117
628, 634, 640, 648, 649, 653, 655, 659, 662, menthone, 333 4-methoxy-l-propylbenzene, 113
667,671,673,684--686,692,694,710,708 ( - )-menthone, 335 ( - )-5'-methoxysativan, 179
medicine, 12,91,350,362,452,455,460, 1-3,4-menthone lactone, 335 16-methoxytabersonine.634
506,522,535,537,570,593,601,609,613, Menyanthaceae, 361 4-methoxy-l-vinyl-,B-carboline, 660
640, 642, 645, 648, 669, 670, 671, 673, mercaptoethanol, 107, 155 N-methylanthranilate, 568
684-686, 690, 698, 700, 708 Mercurialis perennis, 513 N-methy1ation, 513, 587
medicine. Ayurvedic, 539 Merendera, 617 methyl (2E,6E)-famesoate, 384
medicocarpin, 183 Merilliodendron megacarpum, 648 methy13,B-isobutyryloxy-l-oxomeliac-8(30)-
megastigrna-5,7(E).9-trien-4-one. 500 Meris alticola, 364 enate, 480
Megoura viciae, 363 Meris paradoxa, 364 methyl angolensate, 476
melacacidin. 200 merogedunin. 477 methyl azoxymethanol. 290, 294

methyl chavicol, 341
methyl cinnamate, 344
methyl ester of triglochinin, 280
methyl esterification, 260
2-methyl famesyl pyrophosphate. 430
N-methyl groups, 508, 531
methyl jasmonate, 16, 33, 34, 39
methyl salicylate, 122,344
methyl thujate, 340
methylamine, 513
NP-methylamino-L-alanine, 226
,8-N-methylamino-L-alanine, 294
4-N-methyIaminobutanal, 532
N'l-methyl-L-amino-2,3-diaminopropionic acid,
226
O-methylandrocymbine, 617, 618
O-methylanhalonidine, 581
methylation. 151. 152. 173.265.513.571.
573. 587. 588. 590. 595. 597. 623
C-methylation, 69
O-methylation, 206
C-methyl-branched inositols, 265
3-methylcarbazole, 663
24R-methylcholest-5,7-dien-3,8-ol, 441
24S-methylcholest-5.7-dien-3,B-ol. 441
4a-methyl-7-cholestenol,582
N-methylcoclaurine. 586. 591
N-methylconiine, 543
22-methyl-')'-cyc1oiridal, 452
N-methylcytisine, 558, 559
NI-methyl-L-2,3-diaminopropionic acid, 226
3,3'-rnethylenebis(4-hydroxycoumarin), 132
methylenebisphloroglucinol, 56, 69
24-methylenecycloartenol, 436
2-(methylenecyclopropyl)-3-methylalanine. 222
methylenedioxy bridge, 110, 118, 571, 598,
600.601
4-metbyleneglutamic acid, 217, 218, 226
a-methylene-,),-hydroxybutyric acid, 269
4-methyleneproline, 218
Z,z-methylene interrupted system, 24
4a-methylergosta-8.24(28)-dien-3,B-ol. 436
4a-methylergosta-8,24(28)-dien-3,8-01 to 24-
methylenelophenol (J8-..::F)-sterol
isomerase, 436
4a-methylergosta-8.14.24(28)-trien-3,B-ol. 436
methylethylketone, 276
methyleugenol, 111, 113
E-methyleugenol, 136
N-methylflindersine, 571, 573
4-methylglutamic acid. 215. 217. 218. 226
erythro-4-methylglutamic acid, 215
4-methyl-3-heptanol. 31
N-methyl-trans-4-hydroxy-L-proline, 226
D-I-O-methyl-muco-inositol, 264
ID-3-0-methyl-chiro-inositol, 264
ID-I-O-metbyl-muco-inositol,264
ID-I-0-methyl-myo-inositol, 264, 265
ID-4-0-methyl-myo-inositol, 264, 265
lL-I-O-metbyl-myo-inositol, 264, 265
IL-2-0-methyl-chiro-inositol, 264
lL-3-0-methyl-chiro-inositol, 264
O-methyl-scyllo-inositol,264
5-0-methyl-myo-inositol, 264
methylisoeugenol, 113
E-metbylisoeugenol, 113
2-methyljuglone, 80
7-metbyljuglone, 63, 80
metbyllycaconitine, 675
methylmalonate, 57
methybnalonyl-CoA. 65
2-methyl-6-methoxyfuranobenzoquinone, 79
N-methylnicotinic acid, 708
O-methylnorbelladine, 622, 623
6-0-methylnorlaudanosoHne, 587
Index 741
7-methyl-~-nucleoside hydrolase, 702 Microplitis croceipes, 32
methylodoratol, 174, 189 microsomal fractions, 22. 23. 26, 107, 128,
4-metbyl-2-oxopentanoic acid, 580 155. 158.209.275.276.277.290.302.335.
methylphloracetophenone, 58, 59 368. 428. 430-432. 436. 444. 447. 452
cis-3-metbyproline, 218 microtubule assembly, 618, 676
cis-4-methylproline, 218 microtubule protein polymerization, 696
metbylpseudolycorine, 620 Microtus montanus, 101, 104, 105
N-methylpseudopelletierine, 540 mildew, powdery, 309
N-methylputrescine, 532, 535 milk. 70. 210. 390. 553. 659. 667
O-methylpsychotrine, 613 milk sickness, 317
N-methyl-..1 1-pyrrolideine, 532 milk thistle, 168
N-methylpyrrolideine, 532, 533 milkweed bug. 49. 317. 468. 470. 479
N-methylpyrrolidine. 531. 532 Milletia, 186
N-methyl-..1 1-pyrrolinium cation, 532, 539 millipedes. 273. 289. 569
I-methyl-Al_pyrrolinium cation, 534 mimicry. 552. 564
N-methyl-..1 1-pyrrolinium salt, 533 Mimosa, 218, 227
I-methyl-A'-pyrrolioium chloride, 535 mimosa extract, 206
l-methyl-J2-pyrroline. 533 Mimosa pudica, 123, 218
6-methylsalicyIate synthetase, 56, 58 mimosine, 219, 220, 230, 232
6-methylsalicylic acid. 56. 58. 59. 121. 122 L-mimosine, 219
Se-methylselenocysteine, 229 L-mimosine synthase, 219, 220
14a-methylsterol 14a-demethylase, 436 mimosoid legumes, 227, 514
(S)-Z-N-methylstylopine. 600 Mimosoidae. 179.221.227.514.521.543
3-(metbylsulfinyl)propyl glucosinolate, 304 Mimusops balala, 321
E-3'-metbylsulfonylallyl E-cinnamate, 110 mint. 5. 49. 77. 257. 338
4-methylsulfmyl-3-butenyl isothiocyanate, 310 miracle fruit, 245
3-methyl-l,4-thiazane-S-carboxylic acid, Z27 miserotoxin, 290
methylthioethers, 45 mistletoe, 244, 246
methyltransferase. 85. 108. 133.531.587-599. mite, two spotted spider, 67, 68, 341
601.702 mites. 9. 34. 445. 478
4'-O-methyltransferase, 179 mitigative effect, 346
7-O-methyltransferase, 179 mitochondria. 8. 18. 19.41.99. 107. 166. 187.
N-methyltransferases, 587 191.209.313.318.338.361.419.420.601.
N-methyltynunine, 522, 624 645
7-methylxanthine,7fYl mitogenic, 244
methysticin, 140 mitosis, 618, 623
metronidazole, 392 mitotic poison, 682
mevalonate. 11. 65. 81. 82. 85. 86. 132. 133. mitragynine. 630
312.315.316.326.395.401.430.447.465. mixed function oxidases, 107, 118,333,348,
488.490.492. 655. 656. 669. 670. 678. 680. 656
689.692 mixed function oxidases, P450 dependent, 276,
mevalonate 5-diphophosphate, 315 333. 526. 600
mevalonate kinase, 315 mixed function oxidases (pSMO or
mevalonate pathways, II polysubsb'ate mixed function oxidases), 348
mevalonate 5-pyrophosphate decarboxylase, mixed function oxidase inhibitors (PSMO
315 inhibitors), 110
mevalonic acid. 8. 87. 312-315. 319. 321. 326. mogroside V, 463
328. 329. 348. 354. 355. 359. 368. 370. 383. (+ )-mollisacacidin. 206
384.401.442.447.486.490.573.581.656. 2,3-trans-3,4-( + )-mollisacacidin, 206
689 mollugin,87
(R)-mevalonic acid, 313 Molluginaceae, 171,708.709
mevalonic acid metabolism, 132 molluscicidal. 209. 390. 394. 459. 460. 470.
mevaloside. 269 471.559
mexicanolide,476 molluscs, 559
Mexico. 52. 91. 148. 219. 298. 320. 388. 466. molt. 317. 318. 384. 440. 444. 468
540. 559. 658. 671. 673. 700 molting hormones, 479; see also moulting
mezerein, 403 honnones
MFO, see mixed function oxidases momilactones, 414
minimum inhibitory concentration (MIC) monellin,245
values. 683. 686 Moniliniafructicola, 183, 377
mice. 230.403.460.560.564.599.627.645. Monimiaceae, 581, 592, 610
677 monkey, 226
mice, immunodeficient, 648 monoacylglycerols, 24
Michael addition, 389, 415 monoamine oxidase activity, 148
micha11amine B. 698 monoamine oxidase inhibitors, 514
Michigan. 362 monoamine oxidases. 509, 514, 517, 660
microbes. 4. 17. 191.207.253 monoamines, 509, 513-515, 517
Microcyclus ulei, 288, 296, 319 monocotyledonous plants, 19,87, lIS, 164,
Microcystis aeruginosa, 239, 245 172. 192. 206. 252. 280. 286. 324. 457. 510.
microfibrils, 259 517.562
microfilament assembly, 72 monocrotaline, 549, 551, 552, 553
Micromelum, 575, 663 monogalactosyldiacylglycerol, 19,23
microorganisms, 4, 42, 80. 88, 92, 94, 95, 106, monoIaurin, 35
126. 149. 234. 259. 296. 508. 515. 520. 568. Monolinia fruticola, 377
667.711 monomeric G-actin, 237
742 Index

monomorine I, 563 moth, silk, 36 mydesmone, 380

monomorine VI, 563 moth, sunflower, 390, 415 mydriatic activity, 537
Monomorium, 533, 542 moth, urania, 253 myocardial fibrosis, 35
Monomorium pharaonis, 563 moths, 177,269,270,288,289,344,361,364, myocarditis, 35
monooxygenases, 59, 98, 108, 121, 158, 159, 517,535,545,550-552,565-567,669,71l myopathy, 623
179,181,182,202,601; see also moths, arctiid, 551, 552, 565 Myoporaceae, 46, 361, 380
cytochrome P-450~dependent moths, sphingid, 535 Myoporum deserti, 380
monooxygenases, polysubstrate, 348 motion sickness, 537 Myosurus, 269
monooxygenases, tryptophan 2~monooxygenase moulting honnones, 440, 441, 454; see also myotic effects, 692
monosaccharides, 244. 247-250, 256, 264, molting hormones myrabolans, 195
270,272 mountain, Andes 535 myrcene, 331, 337, 342-344
monoterpene biosynthesis, 322, 326-329, 331, mouse, 528, 552, 559, 588, 591, 597, 600, 601, ,B-myrcene, 343
333, 350, 394 607,612,619,623,640,645,658,660,664, Myricaceae, 197, 244
monoterpene cyclases, 329, 342, 354 673-676, 682, 685, 695, 702, 703 myricetin, 152, 166, 195
monoterpene-derived indole alkaloids, 628, movement, leaf, 193 Myrioge1losporae, 659
630, 632, 634, 636, 638, 640, 655 mucilage, 582 myristic acid, 17,25,35, 101, 127, 129
monoterpene glycosides, 346 Mucor, 501, 502 Myristica jragrans, 25
monoterpene iridoid alkaloids, 364 Mucor muceda, 502 Myristicaceae, 179,514,610
monoterpene synthesis, 326, 326 Mucorales, 50 l, 502 myristicin, Ill, 128
monoterpenes, 5, 31, 47, 78,133,312,322, Mucuna, 228, 229, 232, 706 Myrithecium, 378
324,326-333,335,337-346,348-354, Mucuna pruriens, 228, 517 Myrmeca ruginodus, 88
367-370,381,383,412,430,451,452,455, mugineic acid, 230 Myrmecaphodius excavatacollis, 53
575; homomonoterpenes, iridoid mulberry, 35, 145,253 Myrmica rubra. 124
monoterpenes, monoterpene alkaloids, mulberry, paper, 145 myrosinases, 300, 302
monoterpene iridoid alkaloids, monoterpene mule deer, 207 Myrsinaceae, 68, 77
derived indole alkaloids MU1ldulea, 186 Mynaceae, 59, 69, 136, 140, 142, 197,337
monoterpenes, acyclic, 324, 329 ( - )-munitagine, 605 Myrtales, 197
monoterpenes, bicyclic, 329 muramine, 603 myrtan,204
monoterpenes, cyclic, 324, 329. 331 Murraya, 575, 660, 663 myrtenal,451
monoterpenes, irregular, 346 Murraya koenigii, 663 Myrtiflorae, 197
monoterpenes, methylcyc1opentanoid, 363 Musa, 514 Myzus persicae. 173, 363, 550
monoterpenes, monocyclic, 329 Musa sapentium, 517
monoterpenoid alkaloids, 525, 668-670 Musaceae, 581
NAD-dependent dehydrogenation, 335
Monotropaceae, 361 Musca domestica, 35
NADH, 19,20,22,26,51, 117, 166, 167,226,
muscaaurin I, 705
Montanoa tomentosa, 420 252
muscaaurin II, 705
Montiniaceae, 361 NADH dehydrogenase, 166, 191
muscaflavin, 705, 706
mood changes, 596 NADPH, 20-22, 51, 56, 58, 97,107,108, 1l7,
muscarine, 511, 537, 692, 697, 711
moose, 207 121,155,158,163,164,167,178,179,181,
muscarine alkaloids, 697
mopanols, 200 200, 202, 204, 275, 276, 277, 333, 335, 355,
muscarinergic acetyl choline receptors, 537
Moquinea, 390 430,431,490,491,600,630,631
muscarinic action, 528, 697
Moraceae, 134, 136, 137, 138, 142, 145. 149. NADPH-cytochrome c reductase, 431
muscimol, 697, 698
179,253,319,466,533,543,563,571 nagilactone C, 420
muscle, see cardiac muscle, skeletal muscle,
moracins, 145 nagilactone P, 420
smooth muscle, uterine muscle
morin, 166 Na1ldina domestica, 280, 297
muscle lactate dehydrogenase, 642
Morinda, 9, 82, 85, 229 muscle weakness, 612 nandinin, 280
Morinda amplexicaulis, 229 naphthoate synthase, 81
muscone,37
Morinda lucida, 9, 82, 86 muscular relaxant actions, 670 naphthoquinone, 56, 63, 64, 76. 80-87, 94,
Morinda reticulata, 229 104
mushrooms, 35, 235, 237, 246, 496, 517, 666,
Maringa aleifera, 306, 310 697,709 1,4-naphthoquinone, 81
Moringa stenopetala, 306, 310 musk deer, 37 naphthylisoquinoline alkaloids, 698, 709
Moringaceae, 303, 361 Mussatia, 114, 128 naphthylphthaIamic acid, 166
morphinandienone alkaloids, 586, 592 mussatioside I, 114 narciclasine, 510, 623, 623
morphinandienones, 592 mustard, 300, 308-311 narciprimine, 510
morphine, 51l, 585, 592-597, 613, 615, 623 mustard greens, 306 narcissidine, 620
morphine alkaloids, 585, 592-594, 605 mustard oils, 302 Narcissus poeticus, 620
morphogen, 71, 552 mutagenic, 137.510,549,615,645 Narcissus pseudonarcissus, 620
Marus. 253, 543 mutants, 4, 41, 94-96, 156, 230, 303, 313, narcotic compounds, 588, 596, 603
Morus alba, 142, 145,341 411,496 narcotine, 595-597, 603
Morus nigra. 341 mutations, 3-5, 7, 9, 10, 12 a-narcotine, 596, 603
mosquito repellent, 346 Mutisieae, 387 ( - )-a-narcotine, 603
mosquitoes, 67, 344, 641 mutualistic relationships, 30, 35 naringenin, 156, 158-160, 164, 167, 168, 175,
mosses, 40, 46,130,142,172,173,179,497; T-muurolol,381 176,201
see also club moss muzigadial, 380 (2S)-naringenin, 159, 162, 164, 178
moth, burnet, 9, 517 MV A, see mevalonic acid naringenin 7-rutinoside, 175
moth, catalpa sphinx, 361 myasthenia gravis, 623, 709 naringenin-chalcone synthase, 156
moth, cinnabar, 550 mycelium, 501, 502 naringin, 175, 176
moth, codling, 381, 397, 468, 472 Mycobacterium smegmatis, 69 Narthecium ossifragum, 269
moth, diamondback, 308, 309, 311, 468, 472 Mycobacterium tuberculosis, 262 nartheside, 269
moth, giant silkwonn, 384 mycology, 12 Nasonov glands, 343
moth, gypsy, 361, 380, 394, 41l, 424 mycomycin, 48 nasturtium, 303, 309
moth, leek, 227, 459, 471 mycorrhiza, vii, 9, 149 Nasturtium, 363
moth, magpie, 551 mycorrhizae. vesicular arbuscular (V AM), 167 Nasturtium ojJici1lalis, 304
moth, oriental fruit, 34 mycorrhizal fungi, vii, 261, 561 Nasutitermes,419
moth, oriental tussock, 417 mycotoxins, 5, 13, 15, 56, 70, 73, 74, 378, natural products, viii, 6, 13, 14, 15,40,56,65,
moth, plume, 552, 566, 669, 690 379, 395, 396, 655 92,93, 114

natural selection, vii, 4-6
Naucleeae, 638
nausea, 612, 697
naval stores, viii, 398, 412
Near East, 478
necic acid, 549, 551, 552
necrosis, 378, 423
Nectandra colo, 139
Nectandra megapotamica, 660
nectar, 176, 177, 362, 366, 550, 565
nectar guides, 177
nectar thieves, 176, 362, 366
nectaries. extrafloral, 362
nectaries. foliar, 289
Nectria, 253
neem tree, 478-480
Nelumbonaceae, 592, 610
Nelumbonales, 337
nematicidal, 49, 50, 398, 403. 419, 559
nematode, root-rot, 340, 479, 482
nematode, soybean cyst. 125
nematodes, 8, 9, 42, 49, 67, 184.340,403,
419,437,442,452,459,479,514
neoajmaline, 640
Neodiprion setifer, 340
neoflavonoids, 151, 187
neoherculin, 36
neohesperidin, 175, 176
neolignan, 54, 106, 121. 127, 129, 140
neolinustatin, 282, 299
neomatatabiol. 362
(+)-neomenthol, 335
d-neomenthol, 333
( + )-neomenthyl glycoside, 335
( + )-neomenthyl glucosyl transferase, 335
neonepetalactone, 362
neopulchellidine. 672
Neoterpes graefiaria, 364
neoxanthin, 486, 494, 496
9'-Z-neoxanthin, 501
Nepenthes, 52
Nepeta cataria, 358, 361
nepetalactol, 363
nepetalactone, 358. 361-363
Nephila clavipes. 551
neral, 341-343. 346
neriifolin, 468, 472
Nerium oleander. 98, 468, 470
nero1, 328, 349, 354, 365, 563
nerolidol. 370, 380
nerolidyl pyrophosphate, 371, 430
nerve transmission. 517
nerve-cell membrane, 674
nervous system. 510, 517, 623
neryl phosphate, 328
neryl pyrophosphate, 324, 326-332, 348
Netelia heroica, 32
neuralgia, 673
neurochemical activity, 591, 646
neurolathyrism, 223, 226
neuromuscular action, 607
neuromuscular blocking agents, 643
neuromuscular transmission. 675
neuron, 510
neuropteran. 53
Neurospora. 96
neurosporene, 490
neurotoxic syndrome, 70
neurotoxicity, 231, 296, 675
neurotoxin, 221. 223. 226. 299, 675
neurotransmitters, 510
New World, 447
New Zealand, 179, 385, 403, 563
Nicandra physaloides. 532
Nicandreae, 537
Index 743
Nicotiana, 230, 232, 269, 525, 526, 528, 532. (R,S)-norcoclaurine, 595
677 (S)-norcoclaurine, 586
Nicotiana debneyi. 377 (S)-norcoclaurine synthase. 586
Nicotiana glauca, 528 nordihydroguaiuretic acid (NDGA), 120,210
Nicotiana repanda. 526 norepinephrine, 640
Nicotiana rustica, 526, 528 norhannan, 660
Nicotiana sylvestris, 526 norlaudanosoline, 587, 595
Nicotiana tabacum, 526, 629 (S)-norlaudanosoline, 2, 3, 587
nicotinamide, 528 (S)-norlaudanosoline synthase, 2, 587
( - )-nicotianamine, 230 nomicotine, 526
( + )-nicotianamine, 230 nororientaline, 588
nicotine, 510, 511, 513, 525. 526, 528. 531, norpluviine, 620, 621
534, 538, 540 nonuspolinone, 533
(S)-nicotine. 525 nors doring, 402
nicotinic acetylcholine receptor channel. 708 North America, 337, 338, 352, 365, 388, 411,
nicotinic acid, 274, 277, 286, 507. 525, 526, 441,466,550.558,563
528,529,531,538,545,708 norvaline, 513
nicotinic receptors, 675 noscapine, 596, 597
Nigel/a, 269 Nothapodytes joetida, 648
Nigella damascena. 568 Notholaena, 174
Nigeria, 663 Notholaena standleyi, 423
NIH shift, 522 notholaenic acid, 423
nimbalide, 479 NPP, see neryl pyrophosphate
nimbin, 476, 479 nuclear magnetic resonance (NMR), 1, 14,58,
nimbolide, 473, 479, 482, 484 63,74,76,92,93,142,170,179,186-188,
nimbolidin A, 480 190,203,204,212,230,269,294,302,303,
nimbolidin B, 480 311,318,326,365,367,423,427,431,454,
ninhydrin, 217, 220, 226, 560 457,458,484-487,506,579,645
nitidine, 601 DC-nuclear magnetic resonance (NMR), 1, 58,
Nitidulidae. 37 117, 190,203,212,311,353,365,447,465,
nitric oxide, 293 487,531,535,546,568,579,584,615,617,
nitrile glycosides, 293 625, 628, 632, 655, 668, 692, 695
nitriles. 275, 302, 306 DC-I3C-nuclear magnetic resonance (NMR)
nitro acids. 290 couplings, 58
nitro compounds, 276, 290, 295. 298, 299. IH-nuclear magnetic resonance (NMR), 1,58,
303,591 63,76,92,203,212,311,365,423,435
a-nitrocarboxylic acid. 303 2H-nuclear magnetic rsonance (NMR), 548,
nitrogen. vii, 6-8, 208, 209, 219, 220, 229, 554
266,275,287,290,294,303,506-511,523, nuclear magnetic resonance, Fourier transform
531,544,546,554,565,567,580,581,584, methods, 1
617,621,622,649,668,669,675,676,678, nuclei, 318, 444, 502
680, 689, 705 nucleic acid synthesis, 648
nitrogen ftxation. 83. 219 nucleic acids, 3,167,207,249,520,615,700,
nitrogen fixing bacteria, 244, 261 709,710
nitrogen oxides, 293 5' -nucleotide phosphodiesterase, 208
l-nitro-2-(p-hydroxyphenyl)ethane, 276, 296 nucleotide sugars, see sugars, nucleotide
l-aci-nitro-2-(p-hydroxyphenyl)ethane, 275, nucleus. 337, 378, 442, 465. 475, 488
276 nudibranch, 380
2-nitro-3-(p-hydroxyphenyl)propionic acid, 275 nudiflorine, 528
aci-l-nitro-2-methylpropane.276 Nuphar, 525, 554, 668, 670
l-nitro-2-phenylethane, 303 Nuphar alkaloids, 525
2-nitrophenylglucosinolate, 303 Nuphar japonicum, 670
3-nitropropanol, 290 Nuphar [uteum, 670
3-nitropropionic acid, 290, 291, 294 nutmeg, 25, 111
nitrous oxide, 290 nutrition, 12, 126
Nocardia acidophilus, 48 nuts, 229; see also betel nut, chestnut, coconut,
noctuid caterpillars, 316 horse chestnut, nutmeg, peanut, tungnut,
nod factors, 261 walnut
nodosin, 419, 420 nuts, macadamia, 290
nomiiin, 476. 479, 481, 483, 484 Nyctaginaceae, 708
nona-2,6-dienal, 346 Nyctemera annuiata, 551, 564
non-apparency, 209 Nymania capensis, 477
nondepolarizing neuromuscular poison, 675 Nymphalidae. 364-366
(2E)-nonenal, 37 Nympheaceae, 197, 516, 581, 670
(2E,4E)-nonadienal, 37 NympheaIes, 337
non-protein amino acids, vii, 6, 28, 215, 217, nymphs, 317.444,479
218,220-223,226,228-232,234,240,241, Nyssaceae, 197, 360, 361, 648
274,277,285,289,294,303
noradrenaline, 510, 591, 640, 659 oak, 194, 195,208,209,213,264
noraporphines, 588 oak, cork, 447
norbelladine, 619-622, 624 oak, red, 252
O-norbelladine, 622 oatmeal, 451
(6S)-O-norbellidine, 622 oats, 37, 40, 70, 94, 98, 105, 230, 376, 459,
norcimiphytine, 641 517
norcoc1aurine, 586, 591, 605, 615 obacunone, 481
744 Index

obtusaquinone, 78, 79 olive, 98 Orobanche, 391, 392

obtusifoliol. 435, 436 olivetol, 336 Orobanche rapum-genistae, 557
Oceania, 226, 294 ololiuqui, 655, 658 orotate, 226
Ochnaceae, 173 Omphalea, 253 orris root oil, 452
Ochromonas ma/hamensis, 432 Onagraceae, 188, 197 orsellenic acid, 57, 58
Ochrosia, 645, 652 Oncidium ceboletta, 148 orthoacetate, 453, 468
Ochrosia elliptica, 645 oncinotine, 521 Orthoptera, 559
ochtodene, 340 Oncinotis inandensis, 521 oryzalexin A, 414
Ochtodes secundiramea. 340, 351 Oncinotis nitida, 521 oryzalexin B, 414
ocimene, 341, 344 oncogenes, 321 oryzalexin C, 414
,8-ocimene, 340 Oncopeltus, 658 oryzalexins, 414
(E)-p-ocimene, 341 Oncopeltusfasciatus, 49, 317, 468, 479 Orzyaephilus surinamensis, 37
Ocotea pseudocoto. 139 Ondontomachus, 703 OSB, see o·succinylbenzoic acid
Oeotea rodiaei, 605 one eye or "cyclopism," 685 osladin, 463
Oeateo veraguensis. 121, 127 onion, 34, 226, 227, 376 Osmanthus absolute, 500
ocoteine, 591 Onoclea neriifolia, 431 Osmunda japonica, 173
oeotine,605 D.( + )·ononitol, 264 osteolathyrism, 223, 226
oct-l-ene-3-o1, 31 Ontario, 338 osthol, 113, 136
octacosanol, 52 oogoniol I, 444 Ostrinia furnacalis, 480
octadecanol, 52, 54 oogoniol 2, 444 Ostrinia nubilalis, 99, 104,417,696,711
18-octadecanolide. 37 oogoniol, 444 Osyris alba, 557
octodene, 340 Oomycetes, 260 ouabain, 468
(9Z,11E,13E)-octadecatrienoic acid. 35 Operculina, 658 ovaries, 111,419
7,8,11,12,7',8',11',12'-octahydro-.p,.p.carotene, ophiobolanes, 415, 422 "over-production" of metabolites, 6
490 ophiobolin A, 422, 423 ovicidal,49
Odocoileus hemionus, 207 opbiobolin B, 422 oviposition, 13,37, 113, 129, 136, 173, 190,
Odocoileus virginianus, 207, 390 ophiobolins, 422 191,300,308-311,340,350,381,394,397,
odor, 324, 339, 340, 344, 346, 349, 351, 353, Ophiobolus graminis, 459 437,441,468,472,566,591
381,382,385,452 Ophiorrhiza mungos, 648 ovules. 596
odoracin. 403, 419 Ophrys, 344, 381, 382, 393, 395 oxalic acid, 160, 265
odoratol, 174 Ophrys bombyliflora, 381 Oxalidaceae. 173
odoratrin,419 Ophrys insectifera, 381 NJ-oxalyl-2,3-diaminopropionic acid, 223
( - )-odorinol, 533 Ophrys lutea, 344, 381 NJ-oxalyl-L-2,3·diaminopropionic acid, 226
Oecophoridae, 136 Ophrys sph. litigiosa, 381
oxazolidine-2·thiones, 305
Oenanthe crocata, 47 Ophrys tenthredinifera, 381
oxidation, 506, 509, 549, 580, 598, 600, 613,
oenothein B, 210 ophthahnology,664
622, 656, 663
Oenathera hooken', 173 opiate receptors, 597
a--oxidation, 24, 30, 44, 106
Oenothera microntho. 126 Opiliaceae, 45
P-oxidation, 24, 30, 43, 44, 121, 195
oestrone, see estrone opines, 239, 245, 246
ohchinolid A, 480 opium, 585, 593, 595-597 oxidation. Baeyer-Villiger type, 45
oxidative coupling, 173, 196, 197,210,588,
ohchinolid B, 480 opium poppy, 585, 593, 596
oil cells, 324 590-594
Opossum, 698
oil glands, 335, 353, 367, 368 opsin,497 oxidative decarboxylation, 77, 104
oil of citronella, 346 Opuntia ficus-indica, 582 oxidative demethylation, 663
oil seeds, 19, 336, 603 Oraesia, 591 oxidative desaturase, 22
oils, 16, 18, 19,25-28,35,42,43,45,55, orange, 313, 315, 340, 381, 473, 482-484, 496 oxidative pentose cycle, 248
109, 122, 137; also see castor oil, cedar leaf Orcbidaceae, 147, 148, 337, 343, 385, 393, oxidative phosphorylation, 187, 231,419,601,
oil, coconut oil, cottonseed oil, croton oil, 510, 537, 549, 560, 581, 670, 693 640
edible oils, essential oils, linseed oil, orcbids, 147, 149, 343, 344, 350, 352, 381, oxidoreductase, 109, 115
mustard oils, oil cells, oil glands, oil of 395,670 2,3.oxidosqualene:cycIoartenol cyclase, 433
citonella, oil seeds, orris root oil, rosewood orchinol, 147 2,3·oxidosqualene:lanosterol cyclase, 433
oil, seed oils, tung oil Orchis militaris, 147, 148 3-oxoactinidiol, 500
Olacaceae, 45 orcinol, 73, 147-149 oxoaporphine alkaloids, 588, 591
old house borer, 340 ordeal ceremonies, 463; see also trial by ordeal 10-oxogeranial, 354, 355
Oldenlandia, 700 Oreina cacaliae, 552 2-oxoglutarate, 158, 159, 162,202,226
Olea europaea, 98 organeUes, 19, 40 10-0xoneral, 355
Oleaceae, 32, 98, 361, 458 organic acids, 3 12-oxophytodienoic acid, 32, 39
OleaIes, 360, 361 organisms. see eukaryotic organisms, marine 100oxosparteine, 556
oleander, 98 organisms, microorganisms, parasitic 17 ·oxosparteine, 556, 559
oleandrin, 468 organisms, prokaryotic organisms, soil oxyanthin, 277
L-oleandrose, 251 organisms oxyanthin 5"-benzoate, 277
oleanolic acid, 447. 459, 460 Oricia, 573 oxygen, 13, 19, 21, 22, 24, 26, 27, 42, 44, 58,
olefin, 4, 20, 23, 35, 332, 333, 370, 373, 374, oridonin, 419, 420 63,67,74,94, 126, 152, 155, 156, 158, 159,
402, 435, 486 orientalidine, 594 162,206,226,231,266,276,290,294,315,
oleic acid, 17, 18,21-24,26,27,30,35, orientaline, 587 327,332,333,370,387,398,430,431,442,
42-44, 52, 53 ( - )·orientaline, 592 463,473,476,490,492,587,600,601,676
oleoresin, 338, 343, 398 orientalinone, 592 oxygen, molecular, 22, 26, 27, 42, 43, 107,
oleyl-ACP, 21, 23 ( + )·orientalinone, 592 108, 155, 158, 159, 178, 290, 303
oley1-CoA, 22, 23, 26 orienrin, 162 oxygen, singlet, 49, 640, 642
1·oleyl-2-palmitylphosphatidic acid, 23 Ormosia, 557 oxygenation, 46, 56, 131, 133
oligomeric proanthocyanidin, 201 ornithine, 220, 221, 226, 507, 517, 521, 525, Oxylobium, 29
oligophagous, 340, 380, 460 529,531,532,534,537,545-548,564,708 oxyresveratrol, 142, 145
oligosaccharides, 208, 244, 247, 249, 254, 256, ornithine carbamoyltransferase, 238 oxytocic, 600, 650
257,261,262,270,271 ornithine decarboxylase, 517, 531, 548 Oxytropis, 253, 561
olivacine, 628, 645 Orobanchaceae, 78, 361, 362, 391, 392, 557 (- )·ozic acid, 415
 Index 745

Pachlioptera aristolochiae, 591 parasympatholytic drngs, 510, 692 Peganum harmala, 570, 660
Pachycereus, 580 parasympathomimetic drugs, 697 pelargonidin, 152, 163, 177
Pachycereus pringlei, 441 parenchyma, ISS, 280, 526 Pelargonium, 68
pachydictyol A, 420 parisin.376 Pelargonium X hortorum, 68
Pachysandra, 677, 686 parkeol, 444 pellotine, 579-581, 660
Pacific islands, 139 Parkinsonia aculeata, 222 "'-peltatin, 117, 120
Paederia scandens, 363 Parkinson's disease. 229 ,B-peltatin, 117, 120
paederoside, 363 Paropsis atomaris, 289 peltogynols, 200
paeonia lactiflora, 209, 346 parsley, 4, 14,48, 134, 137, 138, 153, 156, Peltophorum africanum, 218, 222
Paeoniaceae, 195 158, 188,251,261,270 Peltophorum inerme, 222
Paeoniae radix, 346 parsnip, 128, 135-138 penicillin G, 234, 235
paeoniflorin, 346 parsnip root, 137 penicillins, 234, 235, 568
paeony, 209 parsnip, wild, 7, 136-138 Penicillium, 56, 58, 59, 64, 74, 234, 658
Pagiantha, 637, 648 Parsonia, 549 Penicillium atrovenetum, 290
paints, 16 parthenin, 388, 390, 392 Penicillium citrinum, 63
PAL, see phenylalanine ammonia lyase Porthenium, 109, 313, 319, 320, 390, 395 Penicillium digitatum. 520
Palaquium gutta, 321 Parthenium argentatum, 109,313,319,320, Penicillium griseofulvum. 56, 64
Palicourea, 664 517 Penicillium potulum, 56, 58, 59
Palicourea fendleri, 665 Parthenium hysterophorus, 389, 392 Penicillium urtieae, 59
palmatine, 600 parturition, 660 Penstemon, 177
palmitic acid, 17, 22, 23, 26, 30, 35, 53 passibiflorin. 285, 286 Penstemon barbatus, 364
palmitoleic acid, 17, 18, 67 passicapsin, 285, 286 Penstemon virgatus, 364
palmilOyl-ACP, 19, 21, 23 passicoriacin, 285, 298 Penstemon whippleanus. 669, 690
pabnitoyl-CoA,21 Passiflora edulis, 287, 500, 660 penstemonoside, 669
I-palmitoyl-2,3-diolein,35 Passiflora species, 10, 282, 285, 286, 289, 660 Pentaceras, 662
I-palmitoyl-2-linoleoyl-3-olein, 35 Passiflora warmingii, 282 1,2,3,4,6-pentagalloylglucose, 196, 197
palmityl-ACP, 23 Passifloraceae, 187,285-287,296-298,660 ,B-pentagalloylglucose, 193, 194, 196
patins, 25, 52, 115 passion fruit, 500 ,B-penta-O~galloyl-D-glucose, 196, 197,207,
palustrine, 521 passisuberosin, 285 210
Panama, 209, 344 passitrifasciatin, 285, 286 pentaketide, 59, 63
Panax ginseng, 460 Pastinaca sativa, 7, 136, 137 pentanortriterpenes, 473, 477
Panax quinquefolium, 48, 460 a-patchoulene, 373 peonidin, 177
Pandaca, 637, 647, 648 ,B-patchoulene, 373 pepper, 110,328,351,377,415,494
Pandaceae, 700 y-patchoulene, 373 pepper, ashanti. 538
Pangium edule, 285 patchouli, 373, 376, 384, 393 pepper, black, 110,517,538
Papaver, 593, 605 patchouli alcohol, 384 pepper, long, 539
Papaver bracteatum, 593, 597, 603 P-patchoulin, 376 pepper, red, 486, 494, 504
Papaver orientale, 592 patchoulol, 373, 374, 393 peppennint, 328, 332, 335, 351
Papaver rhoeas, 603 ( - )-patchoulol, 373 peppery taste, 290
Papaver somniferum, 585, 587, 588, 590, patchoulol synthase, 374 peptide a1ka1oids, 657, 692, 698, 700, 711
592-596, 601, 603 pathogen, 9, 15,26,27,48,67,71,72,84,98, peptide bonds, 215
Papaveraceae, 286, 303, 458, 510, 557, 576, 128, 137, 164, 186, 188, 209, 237, 238, 245, peptides, 215, 234, 235, 237-242, 244-246,
581,587,592,598,600,601,603,605,610 261,270-272,288,319,340,342,368,376, 261, 597; see also dipeptides, ergot
Papaverales, 576 377,408,414,415,442,458, SIS, 543, 558, alkaloids, hexapeptides, lysergyltripeptides,
papavetine, 588, 596 561,682 peptide alkaloids, peptide bonds, tripeptides
paper, American, 383 pathway, see acetate-malonate pathway, peptides, chloroplast transit, 19
paper manufacture, 136, 145 biosynthetic pathways, eukaryotic pathway, peptides, cyclic, 235, 237
Popi/io, 123, 124, 136, 173, 179, 190, 191, glycolytic pathway, mevalonate peptides, y-glutamyl, 241
207,208,220,221,231,307,341 pathways, phenylalanine-cinnamic acid Peregrinis maidis, 288
Papilio brevicauda, 136 pathways, prokaryotic pathway, skildmic perfumery, viti, 12, 32, 109, 122, 346, 385,
Papilio glaucus canadensis, 123 acid pathway patulin, 5, 59, 70, 72 500,670
Papilio glaucus glaucus, 123, 124 Paullinia cupana, 700 Pergularia, 563
Papilio glaucus, 208 pavine alkaloids, 586, 605, 606 Peridroma saucia, 316. 479
Papilio polyxenes, 136,207,208,307 pawpaw, see Asimina triloba perilla, 335, 351
PapUio xuthus, 173, 191 pea. ISS, 165, 181, 182,220,447 Perillafrutescens, 280, 294. 326, 335, 351,
Papilionoideae, 179,220,221,231,549,553, peach, 175,277,288,290,346,415 447
557,558 peanut, 65, 145, 226 ( - )-perillyl alcohol, 335
papyriferic acid, 451 pear, 30, 381 periplanone B, 383
Parabenzoin trilobum, 380 pear, Japanese, 238 Peritassa, 452
Parachartergus aztecus, 53 peas. 559 periwinkle, 511
paracoto, 139 paean, 84 perloline, 510
Paraguay, 420, 696 Pecten maximus, 498 Peronospora tabacina, 377. 414
paralysis, 607, 643 pectenoxanthin, 498 Persea, 419
paralytic effects, 645 pectinases, 261 Persian lilac, 479
Paramecium caudatum. 564 pectins, 170,247,259,260,262,270,402 perspiration, 664
parasites, 40, 53, 92, 183, 227, 391, 392, 394, Pedaliaceae, 118,361 Peru, 114, 535
424,452,533,545,551,559,564,566,614, Pedicularis, 552, 559 Peschiera, 637
650,652 Pedicularis bracteosa, 552, 559 pesticides, 12, 73, 111, 671
parasitic organisms, 10,41,67,73,78,92, Pedicularis crenulata, 552, 559 Petalostylis, 660
364,367,391-393,452,454,466,479,546, Pedicularis groenlandica, 552, 559 petals, 29, 91, 173, 177,231,328,494,498,
552, 554, 564, 566, 576, 652, 659, 660, 666, Pedicularis racemosa, 552, 559 499
689,690 Pedieularis semibarbata, 559, 566 Petasites, 553
parasilOids, 31, 32, 39, 41, 343; see also pedunculagin, 196, 197 petiole, 153, 276
ichneumonid parasitoids peduncularine, 563 Petiveria, 708
parasorboside, 269 Pegonum, 569, 570, 576, 660 petroleum, 16, 51, 53
746 Index

petroselenic acid, 26 L-phenylalanine, 178, 303, 274, 277, 304 photophosphorylation, 525
Petroselinum, 14, 133, 136 phenylalanine ammonia lyase, 4, 107, 130, photorespiration, 6, 7
Petroselinum crispum. 133, 155. 156, 261, 262 133, 155, 156, 184, 186, 195,509 5-phosphoribosyl-pyrophosphate transferase, 98
Petroselinum hortense, 14, 133, 153, 155,251 L-phenylalanine ammonia lyase, 107 photosensitizers, 49, 50
Petteria ramentaeea, 559 phenylalanine decarboxylyase, 515 photosynthesis, 3, 6, 8, 76, 96, 145. 166, 248,
Petunia, 159, 162, 163,202,269,437,453 phenylalanine hydroxylase, 102 266,338,414,486,488,496,497
Petunia hybrida, 162, 163 phenylalanine tRNA, 558 photosynthetic photophosphorylation, 601
petuniasterone A, 437 phenylalanine-cinnamic acid pathway, 209 photosystem I, 496
petunidin, 167 ,B-phenethylamine, 244, 581 photosystem n, 167, 496
Peucedaneae, 134 phenylethylamines, 514, SIS, 517, 581 photosystem n reaction center P680, 496
peyophorine, 581 ,B-phenylethylamines, 58 I phototaxis, 497
peyoruvic acid, 579, 580 2-phenylethylglucosinolate, 303 phototoxic activity, 49, 92, 93,136,317,573,
peyote cactus, see cactus, peyote l-phenylhepta-I,3,5-triyne,49 660
pH, 8, 9, 99,170,171,207,208,217,276, ,B-phenylnitroethane, 290 phototoxins, 134
315,374,483,507,518 phenylpropanoid glycosides, liS Phratora, 124
Phaeelia crenulata, 336 phenylpropanoids,4, 11, 13,54,78, 102, 106, phthalideisoquinoline alkaloids, 600, 603, 610,
Phaedon cochleariae, 309, 311, 445 109,110,111,125,127,136,190,193,324, 615
phaenthine, 606 339, 538, 570 phycology, 12
Phaeophyceae, 260 phenylpropionic acid, 165 Phycomyces, 501
phagocytosis, 591 phenylpyruvic acid, 101, 102, 106 Phycomyces blakesleeanus, 502
phagorepellent, 597, 682, 689 2-phenyl-5-(I'-propynyl)-thiophene,49 phycomycete, 376, 444
phagostimulant, 35, 207, 288, 551 pheromones, 16,32,34,36,37,39,41,111, phyletic problems, 337
Phalarts arundinacea, 514 122, 124, 125, 128, 324, 339, 342-344, 352, Phylica, 610
Phalaris tuberosa, 514, 515 363,365,367,376,383,394,486,501,502, Phyliea rogersj;, 585
phalloidin, 237 542, 551, 552 PhylIanthoideae, 286
phalloin, 237 pheromones, alarm, 324, 339, 343, 383 Phyllanthus, 537
phallotoxins, 237 pheromones, sex, 343, 363, 365, 505 Phyllobates, 677
Phalfus impudicus, 174 Phidippus, 49 phyllocladene,412
pharmaceuticals, 12, 535, 653, 655 phloem, 257, 262, 320, 465, 468, 472, 547, Phyllodectina, 124
phaseic acid, 501 554, 559, 567 phylloquinones, 80, 82, 86, 488
phaseollin, 181-183, 186 phloridzin, 174 Phyllosticta, 72
phaseollinidin, 182 phloroglucinol, 57, 68, 69, 73, 149, 174, 187, Phyllotreta annoraciae, 168
phaseollinisoflavan, 186 200,210 Phyllotreta cruciferae, 308
phaseolotoxin, 238 phlorotannins, 210, 213 Phyllotreta nemorum, 445
Phaseolus, 146,313,341,488,501 Phoebe brenesii, 110 Phyllotreta strio/ala, 308
Phaseolus aureus, 222, 241 Phoma, 378 Phyllotreta tetrastigma, 445
Phaseolus lunatus, 287, 296, 341 Phoradendron flavescens, 244 Phyllotreta undulata, 445
Phaseolus multij1orus, 241 Phoradendron vi/losum, 244 phylogenetic studies, 337, 350, 367, 395, 405,
Phaseo/us radiatus, 313 phorbol, 402, 425 413,485
Phaseolus vulgaris, 156, 167, 183, 184, 190, phorbol esters, 402, 403 phylogeny, viii, I, 11, 12, 164,209
241,242,244,245,261,288,289,488 Phormia, 597, 640, 703 phylogeny, plant, viii, 164
phasin,244 Phormium, 444 physiological activity, 506, 647
phellandrene, 346 Phorodon humuli, 363 physiological effects, 510, 537, 581
a~phellandrene, 344, 345 phosphatases, 330, 488 physiology, plant, 12
,B-phellandrene, 342 phosphatidic acid, 22-24 Physostigma venenosum, 663, 664
Phellinaceae, 610, 625 phosphatidic acid phosphatase, 23 physostigmine, SID, 511, 537, 655, 663, 664
Phelline, 610, 625 phosphatidylcholine, 18, 22-24, 26, 39, 208, phytic acid, 264
Phellodendron, 575, 610 430 phytin, 264
phenacylpyrrolidines, 564 lyso-phosphatidylcholine, 26 phytoaiexins, 8,42,48,72,74, 130, 135, 137,
phenanthrenes, 146, 147, 149,588 phosphatidylethanolamine, 26 138,145,146,148,165,174,178,179,
phenanthroindolizidine alkaloids, 546, 563, 564 phosphatidylglycerol, 17, 19,23 182-184, 186, 188, 261, 262, 309, 367,
phenanthroquinolizidine alkaloid, 546, 564 3'-phosphoadenosine-5'~phosphosulfate 376-378,393,395,397,398,401,408,414,
phenet~yl alcohol, 113 (PAPS):desulfoglucosinolate 415,423,426,510
phenethyi alcohol glycosides, 267 sulfotranserases, 303 phytochelatins, 234, 240, 241
phenethylisoquinoline precursor, 626 phosphodiesterase, 588 phytochrome, 171
phenol, 124 phosphoenolpyruvate, 6, 94, 96, 97 phytodienoic acid, 32, 39
phenolic carboxylic acids, 194 6-phosphogluconate dehydrogenase, 132 phytoecdysteroids, 442, 444
phenolic compounds, 8, 13, 54, 56, 58, 72, 78, 6-phosphogluconic acid, 253 phytoene, 431, 486, 488, 490, 492, 494, 496,
79,108,113,114,120-122,124,125-129, phosphoinositides, 46 499,504
142,170-173,178,187,188,193,194,203, phospholipase, 24 Z-phytoene, 488, 490
206,209,210,212,213,232 phospholipids, 16,17,320 15~Z-phytoene, 490
phenolic glycosides, 124 (5R)-phosphomevalonate, 315 15,15'~E-phytoene, 488, 490
phenols, 170, 171, 190, 193,210,212,213 phosphomevalonate kinase, 315 15,15'-Z-phytoene, 488, 490
phenotypes, 9 N-(phosphonomethyl)glycine, 195 phytoene dehydrogenase, 501
phenyl acetate, 113 phosphopantotheine site of ACP, 19,21 phytoene synthase, 488
phenylacetaldehyde, 113 4'~phosphopantetheine prosthetic group, 19 E-phytofluene, 490
phenylacetic acid, 106, 165 phosphorus, 6 Z~phytofluene, 490
phenylacetothiohydroximate, 303 phosphorylases, 259 phytogeographic distribution, 209
phenylalanine, 3,4,94,96,97, 101, 102, phosphorylation, 315, 518, 520; see also phytohonnone, 33. 98
105-107,118,121,128,130,142,147, 155, dephosphorylation, oxidative phytol, 398, 399, 414, 423
156, 187, 195,203,208,209, 229, 273, 277, phosphorylation, photophosphorylation, Phylolacea, 459, 460, 708
280,286,287,297,300,302,507,509,513, photosynthetic oxidative phosphorylation Phytolacea americana, 244, 460
522,535,540,564,568,617,619,624-626, photocarcinogenic substances, 137 Phytolaeca dodecandra, 459
657,694 photodennatitis, 137,336 Phytolaccaceae, 244, 458-460, 521, 575, 708
D-phenylalanine, 234 photooxidation, 496, 499 phytophagous, 10, 12, 13, 129
 Index 747

Phytophthora drechsleri, 48 pine, Virginia, 257 planlains, 514

Phytophthora infestans, 377, 684 pinidine, 543 plantamajoside, 108
Phytophthora megasperma, 178,261,270 ( - )-pinidine, 543 plant-animal interactions, 110, 379
Phytophyta, 242 ( - )-pinidinol, 543 plant-fungal interactions, 376
Phytoseiulus persimilis, 341 D-pinilol, 264, 265 plant-herbivore interactions, 546
phytoslerols, 427, 433, 435-437, 440, 441, D-( + )-pinitol, 264 planthoppers, 173
447,458,582 L-( - )-pinilol, 264 plant-insect interactions, 49. 88,111.118,122,
phytotoxic compound, 175,237 ( - )-pinoresinol. 117 591,597
phytoloxins, 56, 71, 72, 84, 126-128,237, ( + )-pinoresinol, 117 plant-microbe interactions, 261, 272
238,351,367,377,378,398,415,422,423, pinosylvin, 140, 142, 145 plant-plant interactions, 76, 78, 122
459,531,543,562 (+ )-pinpollitol, 264, 265 plants, see aphid host plant compatibility, cell
phytotoxins, sesquiterpenoid, 378, 379 Pinus, 52, 136, 140, 337, 340, 370, 413 culture. cell walls, defense, dicotyledonous
phytOluberin, 377 Pinus banksiana, 338 plants, eggplant, host plants, insect-host
phytyl side chain, 81 Pinus contorta, 338 plant relationships. interplant
Picea, 140, 337 Pinus jeffreyi, 52, 337, 543 communication, monocotyledonous plants,
Picea breweriana, 337 Pinus pinaster, 368 honnones, phylogeny, physiology. plant
Picea engelmanU, 337, 543 Pinus ponderosa, 337, 343 animal interactions, plant fungal interactions,
Picea glauca, 337 Pinus resinosa, 142 plant herbivore interactions, plant insect
Picea mariana, 337 Pinus sabiniana, 543 interactions, plant microbe interactions, plant
Picea pungens, 337 Pinus sylvestris, 142. 340 plant interactions, sterols, sympetalous
Picea rubens, 337 pioneer species, 7 plants, systematics, thermogenic plants,
Picea sitchensis, 337 pipecolic acid, 217-219, 538, 561 tissue culture, tumorigenic plants
piceatannol, 142, 145 L-pipecolic acid, 217, 232, 538 plants, Chinese, 135, 168, 522, 528, 537, 544,
a-picolinic acid, 543 Piper, 36, 104, !lO, !l3, !l4, 538, 539 570, 593, 606, 648, 658, 670, 673, 686, 708
Picralima,640,641 Piper betle. 528, 538 plants, dioecious, 176
Picralima alkaloids, 628, 640, 641 Piper jutokadzura, 113, 118 plants, flowering. 85, 123
Picralima nitida, 641 Piper guineense, 538 plants, herbaceous, 152
picrasin A, 476 Piper hookeri, 104 plants, sympetalous, 108
Picrasma, 660 Piper iongum, 539 plants, thennogenic, 123
Picrasma javanica, 660 Piper methysticum, 136, 139, 140, 538 plants, tumorigenic, 666
Picrasma quassinoides, 473 Piper nigrum, 110, 114,517,538 Planynota flavedana, 92
picric acid, 273, 293, 294 Piperaceae, 36, 104, !lO, !l3, 121, 139, 514, plasma membranes, 574
picropodopbyllotoxin, 120 517,538 plasmid, Ri, 239
Picrorhiza, 444 Piperales, 610 plasmid, Ti, 47, 239
picrotoxinin, 385 pipercide. 114 Plasmodium berghei, 69
picroloxins, 367, 385, 387, 670 piperenone, 113 Plasmodiumfalciparum. 482, 599, 606, 607,
Pieris, 307, 308, 597, 641, 689 .JI-piperideine, 508, 556 614, 625, 640, 649, 651, 652, 660, 666
Pieris brassicae, 307-309, 650 .JI-piperideine carboxylic acid, 538 Plasmodium yoelii, 574. 625
Pieris japonica, 412 piperidine, 340 plastid., 8, 19,94, 106, 107,313,326,401,
Pieris rapae, 307-309, 468, 470, 472 piperidine alkaloids. 525, 529-531, 533, 411,488, 490, 494, 528, 708; see also
pig, 35 537-540, 543-545, 554, 561 proplastids, sieve-tube
pigmen~ 78, 80, 82, 83, 85, 91, 135, 152, 164, .J1-piperidine-2-carboxylic acid, 217 plastids
171, 174, 177, 189, 192,326,380,413,486, .J1-piperidine-6-carboxylic acid, 217 plastoquinones. 76, 86, 488
491,494-499,502,504,506,568,705,708, piperine, !lO, 253, 539, 543 plalydesmine, 573
709 piperlongumine, 539 Platyneris, 420
pilocarpine, 5!l, 692, 693 piperlongwninine, 539 Platyneris dumerilii, 420
Pilocarpus, 692 piperonal, !lO, 344 plalyphylloside, 121, 129
pilocereine, 582 piperonyl butoxide, 110 Platyptilia, 669
Pilocereus, 580 pipoxide, 104 Platyptilia pica, 364, 366, 552, 566
pimara-8(9),15-diene, 407 Piptadenia, 514 Plebejus icarioides, 559
9-,BII-pimara-7,15-diene, 414 Piqueria trinervia, 345 Plenckia, 452
pimaranes, 405, 406, 412 piquerol A, 345 plenolin, 393
pimaric acid, 406 piqnerol B, 345 PleurostyUa africana, 522
Pimelia prostrata, 403 pisatin, 181-183 plumhagio, 63, 64, 80, 84
Pimpinella, 109 (-)-pisatin, 181-183 Piumhaginaceae, 63, 80, 82, 197,571,708
Pimpinella anisum, 122 piscicide., 12, 120, 186, 209, 212, 390, 456, Plumbago, 63, 80
pimpinellin, 133, 135 460 plumeran, 636, 637
Pinaceae, !l7, 136, 173,338,405,413,543 Pissodes strobi, 340 Plumeria obtusifoUa, 361
pine, 315, 375, 393, 543 Pistacia ientiscus, 447 Plumerieae, 637
pinene, 346 pistil,269 Plumerioideae, 636
a-pinene, 331, 340-345 Pisum sativum, 182, 183,220,231,293,369. plumieride, 361
(- )-a-pinene, 331, 342, 343 708 plum., 290
(+ )-a-pinene, 331, 342, 343 Pithecellobium, '127 Plutella "1lostella, 308, 309, 311, 468, 472
d-a-pinene, 331 Pithecellobium lobatum, 227 pluviine, 620
l-a-pinene, 331 Pithecellobium saman, 521 Poaceae, 68, 98, 99, 105, 107, 118, 125,230,
,B-pinene, 331, 340-345 pithecolobine, 521 257,282,285,286,321,346,459,510,522,
(- )-,B-pioene, 331 Pittosporaceae, 45, 46, 134, 337 549, 659, 700
I-,B-pinene, 331 Pituranthos triadiatus, 136 Poanes hobomok, 362
( - )-pinene cyclase I, 331 Pityrogramma, 174 Podalyrieae, 557
(+ )-pinene cyclase I. 331 Plagiochila ovalifolia, 376 Podocarpaceae, 173, 179,405,420,442
d-pinene cyclase, 331 plagiochitin, 376 Podocarpus, 179,405, 420
i-pinene cyclase, 331 plant sterols, see phytosterols Podocarpus elata, 442
pine, jack, 338 Piantaginaceae. 304, 361, 363 Podocarpus !errugineus, 405
pine, lodgepole, 338 Plantago lanceolata, 363 Podocarpus macrophyllus, 405
pine, ponderosa, 343, 420 Plantago major, 358 Podocarpus nubigena, 174
748 Index
podogenin, 463
podophyllotoxin. 117. 118. 120. 128. 618. 676
Podophyllum. 117. 118. 120. 128
Podophyllum hexandrum, 118, 128
Podophyllum peltatum, 117
pods. 174. 182. 193. 194.203.206.324.340.
349.420. 439. 468. 554. 608
Poekilocerus bujonius, 468
Pogonopus, 612, 638, 652
Pogostemon cablin, 373, 393
Pogostemon heyneanus, 373
Pogostemon patchouli, 373, 671, 672
poison. 506. 507. 511. 514. 517. 537. 543.
544. 546. 552. 553. 559. 561. 563. 564. 583.
584.588.596.603.607.617.641.646.658.
659,666; see also arrow poison, fish poison,
mitotic poison, nondepolarizing
neuromuscular poison, poison hemlock,
poison ivy, rat poison
poison hemlock, 543
poison ivy, 67
poison-dart frog, 677
poisoning. 10. 12. 32. 229. 237. 239. 244. 254.
290.294.306.317.390.403.412.447.466.
468. 514. 540. 546. 552. 553. 559. 561. 596.
603.607.646.658.659.676.684.697
poisonous compounds, 417, 223. 232, 235,
237.244. 246. 288. 290. 402. 403. 439. 441.
452.466.506-507.517.537.544.552.559.
583.584.617.641.673.674.676.689.705
Polemoniaceae, 177. 189,444
Polistes metricus, 53
pollen. 30. 39. 176. 352. 389.437.498.515
pollen tube. 132. 389. 439
pollen tube growth. 389
pollination. vii. 9, 26. 30. 151, 165. 171, 176,
177, 189.343.344.352.362.385.393.515.
516. 530. 550
pollinators, 152, 176, 177
polyamine alkaloids. 520. 521. 529
polyamine biosynthesis, 518
polyamines. 517. 518. 520. 521. 564
polychaetes. 381. 420
PolygaJaceae. 149. 458
polygodiaJ. 379
Po1ygonacese. 76. 85. 86. 88. 162. 187. 197.
267. 379. 387. 543. 708
polygonaquinone, 76
Poiygonatum ofjicinalis, 222
Polygonum. 76. 206. 267. 379
Poiygonum stagninum, 209
Polygonum tinctorium. 267
polyhydroxylated tropane alkaloids. 535
polyhydroxypiperidine alkaloids, 531, 544
polyisoprene, 318-322
Z-l.4-polyisoprene, 319
polyisoprene E-allylic diphosphate initiator.
319
polyketide biosynthesis, 58, 139, 142
polyketide derived alkaloids, 543
polyketide synthetase, 57
polyketides. 41. 56-72. 74. 76. 77. 85-87. 91.
92. 121. 139. 148. 155.237.507.538.543.
698
polymeric F-actin, 237
polymerizatioo. 5.115.117.206.237.262.
319.327,370
polymorphism. 7. 296. 298
polymyxin B. 234. 235
polymyxin D, 234
polyneuridine aldehyde. 640
polyols. 247. 262. 264
polypeptides, 19
polyploidy. 5. 588. 597. 619
Po/ypodium glycyrrhiza. 463, 471
Polypodium vulgare. 442, 453. 462 primitive angiospenn families, 19
polypodogenin, 463 Primula, 264
polypodoside A, 462 Primulaceae, 264, 444
Polyporaies. 46 Pristiphora erichsonii, 415, 425
polysaccharides. 3. 244. 247. 252. 256. 257. Pristiphora geniculata, 289
259-262. 270-272 proacaciberin, 282
polysaccharides. algal, 247, 260, 271 (S)-proacaciberin. 282
Polystictus versicolor, 91 proanthocyanidin biosynthesis, 164
polyvinylpyrrolidone, 208 proanthocyanidin dimers, 206
pomegranate, 539 proanthocyanidins. 164. 191. 193. 198. 200.
ponasterone A. 444 20\.203. 204. 206-210. 212. 213
Poncirus, 337 (2R.3S)-proanthocyanidins. 201
poplars. 257 proaporpbine alkaloid. 591. 592
poppies. 593, see also opium poppies Procavia capensis syriaca, 136
Populus. 122-124. 128 procevine, 684
Populus deltoides, 124 procyanidin dimers, 203, 204, 206
Populus grandidentata, 124 procyanidin oligomers, 203
Populus tremuloides, 124 procyanidins. 193.200.203.204.206
Poranthella, 542 2,3-cis-(2R,3R)-procyanidins, 206
Poranthera corymbosa, 554 prodelphbtidins. 200. 206. 2\0
pore, see sieve-tube pores Prodenia, 591
Poronia punctata, 71 Prodenia eridania, 289
Porphyra, 260 profisetinidins, 206
Portulacaceae, 708 (2R)-profisetinidins. 206
postpartum bleeding, 420 (2S)-profisetbtidins. 206
postpartum contractions, 660 progestagens. 427. 433. 437. 439. 463
postpartum hemorrhage, 570 progesterone, 439, 462, 465
potassium. 16.260. 300. 307-309. 348. 517 progoitrin. 307. 308
potassium chloride (KCn. 9 epi-progoitrin, 307
potassium pennanganate, 535 proguibourtinidin, 206
potato. 14. 31. 33. 39. 41. 99. 149. 166. 245. prokaryotic organisms. 4, 5, 18, 19,234
313.314.345.352.372.377.383.397.651. prokaryotic organisms, thennophilic. 26
677.682-684 prokaryotic pathway, 16, 19, 22, 23
potato blight. 269 prolactin release, 640. 659
potato leaves, 682 proline. 207. 208. 213. 215. 217. 219. 222.
potato peels, 684 226. 232. 657. 705. 708
potato peels, fried. 684 prolycopene. 491. 494
potato sprouts. 684 prolyl t-RNA synthetase, 222
potato vines, 684 promelacacidins, 206
potatoes, cull, 684 promOlphinanes, 592
potatoes, "greened," 684 promoter, CaMV 35S, 629
potentillin. 197 promoters. 514
potions, 506 propanaJ. 513
PR transferase, 98 syn-propanethiai S-oxide, 227
preakuammicine, 632, 634 S-(prop-l-enyl)cysteine, 227
precipitation reactions, 507 propionaldehyde. 227
precocenes. 312, 316-318 propionyl-CoA. 27. 65
predators. 343. 361. 382. 447. 466. 470. 498. proplastids. 18. 19.22.26.401
551.552 S-n-propy1cysteine. 227
pregnenolone. 439. 465. 686 prorobinetinidin, 206
prehelminthosporai, 378 Prosopis, 218, 543, 562
prelnnularic acid. 143 prostaglandins. 29. 32. 34.40. 123. 167.420
prenyl pyrophosphate hydrolases. 488 Proteaceae. 68. 82. 286. 537
4'-prenyloxyresvemtrol, 145 proteacin, 280
prenylated proteins 321 protease. 242
prenylation. 82. 86. 87. 132-134. 173. 182. protein. 156. 158. 167. 184. 193.206-210.
186 212.213.215.217.220-222.231.232.234.
3-prenylindoles, 663 240. 242. 244-246. 259. 261. 272. 276. 280.
prenyltransferase. 316. 319. 322. 326. 329. 300.312.320-322.371.373.444.490.492.
368-370 498. 503. 532. 549. 557. 561. 709. 710; see
prephenate aminottansferase, 106 acyl camer proteins, ADP/ATP carrier
prephenate dehydrataae. 101. 177 protein, chromoproteins, flavoproteins,
prephenate dehydrogenase, 173 glycoproteins, jasmonate-induced proteins,
prephenic acid, 101, 102. 104, 106 fJ-.k.etoacyl acyl carrier proteins, microtubule
prephytoene. 348. 488 protein polymerization, non-protein amino
prephytoene pyrophosphate, 488, 490 acids, prenylated proteins, proteinase
presquaIene, 350, 430 inhibitors, proline-rich proteins, protein
presqualene alcohol, 348. 350, 430, 455 amino acids, toxic proteins
presqualene pyrophosphate, 428, 430, 431, 488 protein amino acids, 215, 216, 226, 231, 232,
press cake. 244, 307 303
pre-tazettine. 621, 623 protein biosynthesis, 613, 623
prickly pear. 582 protein synthesis. 323. 452. 482. 520. 623.
primeverose. 254, 266, 280 625. 627. 645. 676. 696. 700
2-fJ-.primeverosyloxy-2-phenyl-2S-acetonitrile. proteinase inhibitors, 33, 39, 40, 245
277 proteins, prenylated, 321
 Index 749

proteins, proline-rich, 207 Psychotria beccarioides, 665 pyruvate dehydrogenase, 19

prothoracic glands, 439 psychotridine, 665 Pythium aphanidermatum, 47
protoalkaloids, 513 Psychotrieae, 612, 638 Pythium ultimum, 26
protoanemonin, 269 psychotrine, 613, 616
protoberberine, 586-601, 610 Ptaeroxylaceae, 478, 575, 576 quadrigeminine A, 665
proIoberberine alkaloids, 586-601 Ptaeroxylon, 478 quail, 179,517
protoberberine alkaloids, quaternary, S99 ptaquiloside, 375 Quassia amara, 482
prolOcatechualdehyde, 619-621 Ptectinophora gossypiella, 169 quassimarin, 482
protocatechuic acid, 96 Pte/ea, 571, 573, 574 quassin, 473, 477
protohyperlcin, 91 Pteiea trifoliata, 571 quassinoids 473, 476-478, 482, 484, 485
protolimonoids, 473 Pteridium aquilinum, 414, 442 Quebec, 378
proton extrusion, 415 pterocarpans, 179, 181, 182, 184, 186 ( - )-qoebrnchamine, 635
proton pumps, 520 Pterodon pubescens, 420 ( + )-quebrachamine, 635
protopine, 594, 600, 601, 603, 610, 616 Pterophoridae, 364 L-( - )~quebrachitol, 264
protopine alkaloids, 600, 601 Puccinia coronata, 98 quebrncho, 204, 208, 213
protoplasts, 2, 9, 15, 518 pulchellidine, 672 quercetin, 152, 159, 160, 166, 167, 195
prolOSlepbenine, 592, 613 pulchellin, 672 quercetin 3-glucoside, 169
protoveratrine A, 684-686 pulegone, 333, 345 quercetin 3-0-galactoside, 167
protoveratrine B, 684-686 (+ )-pulegone, 333, 345 quercetin 3-rhanmoside, 169
protoverine, 684, 686 Pulsatilla, 269 quercetin glycosides, 172
protoverine, polyesters, 684, 686 pumiliotoxin A, 560 D-quercitol, 264
protozoans, 392, 431 pumiliotoxin B, 560 proto-quercitol, 195
prnnasin, 272, 217, 279, 280, 286-289, 294, pumpkin, 33, 315, 370, 399 scyllo-quercitol, 195
297 pungeot principle, llO, ll4, 300, 302, 452, Quercus, 195, 264
(R)-pronasin, 277, 280 517,530,538 Quercus robur, 195, 196
prunasin 2'-glucoside, 277, 280 Punica granatum, 539 Quercus rubra, 252
pronasin hydrolase, 280, 296 Punicaceae, 539 Quercus suber, 447
prunasin-6-malonate, 277 pupa, 99, 440, 552, 591 quinazoline allraloids, 568-570, 575, 576, 610
Prunus, 269, 272, 274, 277. 280, 286, 288, 363 pupil dilation, 537 quinazolinocarboline alkaloids, 568, 571, 576
Prunus domestica, 280 purgative, 69,444, 445, 452 quinic acid, 94, 95, 99, 102, 104, 108, 121,
Prunus laurocerasus, 274 purine alkaloids 700 171, 195,210
Prunus maximowiczii, 269 pnrine bases, 507, 700, 702, 703 ( - )-quinic acid, 94
Prunus persica, 288 purine nucleoside phosphorylase, 702 quinic acid esters, 108
Prunus serotina, 277, 280, 287, 288, 295, 299 puromycin, 234 quioidine, 506, 5ll, 649-651
Prussian blue assay (tannins), 210 Purshia, 444 quinine, 10, 175, 361, 506, 5ll, 569, 571,
pseudoaconitine, 673 Purshia tridentata, 208 649-651, 653
Putranjiva roxburghii, 304
pseudoalkaloids, 668 quinine sulfate, 650
pntrescine, 510, 517, 518, 521, 526, 529, 531,
pseudocereals, 460 quinoline alkaloids, 568, 570, 571, 573, 575,
534,547-549, 565
Pseudococcus iongispinus, 561 610, 612, 615, 638, 649
putrescine-N-methyltransferase, 531
pseudocopulation, 344, 381 quinolizidine alkaloid biosynthesis, 554, 561.
Putterlickia verrucosa, 695
pseudocyanogenic glycosides, 273, 294 567
Pyracantha, 499
pseudoguaianes, 374 quinolizidine alkaloids, 2, 3, 364, 544, 546,
Pyralidae, 390
pseudohypericin, 91 pyranocoumarin, 137
552-554, 556-560, 564-567, 690, 709
pseudojervine, 686 pyranoquinoline alkaloids, 570, 571, 573 quinolizidine ring systems. 693, 694
pseudolycorine, 620, 623 quinolone alkaloids, 568, 570, 571, 573-575
pyranoquinoline alkaloids, linear, 570
Pseudomonas, 83 pynmoses, 247, 248 4-quinolone alkaloids, 568, 570, 571, 574
Pseudomonas syringae, 98, 237, 238 pyrazine alkaloids, 692, 703 quinonemethide structures, 63, 117, 212
Pseudomyrmex, 289 pyrazines, 703, 711 quinonemethides, pentacyclic nortriterpene,
Pseudomyrmex !errugineus, 53 pyrelhrins, llO, 346, 348, 430 452
d-pseudonorephedrlne, 522 Pyrethrum, 348 quinones, 8, 14,56,65,76-80,92,93,97, 104
pseudopelletierine, 539 Pyricularia oryzae. 414, 423, 543 ortho-quinones, 76
pseudopurpurio, 87 pyridine alkaloids, 513, 525 para-quinone, 77. 78
Pseudotsuga, 337 pyridoxamine-5~phosphate, 508
quinovose, 456
Pseudotsuga menziesii, 200, 338 D~quinovose, 251
pyrimidine bases, 135, 700
D-psicose, 250 Pyrolaceae, 361
Psila rosae, 113, 136 pyrolysis, 312 rabbit, 380, 451, 600, 646, 658, 674, 685
psilocin, 525 pyrooes, 155 Rabdosia, 408, 415, 419
Psilocybe, 525 2-pyrones, 139, 140 Rabdosia japonica, 432, 447
psilocybin, 513, 525 pyrophosphatases, 9, 330 races, 8
psilostachyin, 387 pyrophosphomevalonate decarboxylase, 315 radial diffusion method (tannins), 212
psilostachyin B, 387, 388 pyranoquinoline alkaloids, angular, 570 radical coupling, 64 , 82, 117
psilostachyin C, 388 Pyrrhallta luteola, 88 radicle, 78, 175, 317, 346, 390, 523, 526, 537,
Psilotales, 173 Pyrrhocoridae, 383 540, 558, 599, 601, 641, 650, 673, 697
Psi/otum, 173 Pyrrhocoris apteris, 383 radish, 300, 303, 306, 309, 314
PSMO inhibitors, see mixed function oxidase pyrrole esters, 552, 553 Radula variabilis, 174
inhibitors pyrrolidine alkaloids, 531-534, 538-540, 545 raffinose, 256, 261
PSMOs, see mixed function oxidases A1-pyrroline-5-carboxylic acid, 226 ragweed, 388
Psophocarpus tetragonolobus, 293 pyrrolizidine alkaloids, 321, 364, 466, ragwort, 550
psoralen, 133-135, 137, 138 546-554,559,564-567,683,703 Ranales, 576
psoralen synthase, 133 8a-pyrrolizidioe, 549 Rangifer tarandus, 207
psorospennin, 148 pyrrolizidine N-oxides, 546, 547 Rannnculaceae, 267, 269, 272, 277, 286, 290,
Psorospermum!ebrifugum, 148 pyrroloquinazoline alkaloids, 568, 569, 570 408,466,510,549,557,568,581,588,592,
psychoactive substances, 336 Pyrus serofina, 238 598, 600, 603, 605, 606, 610, 660, 673
psychotomimetic activity, 660, 694 pyruvate, 6, 19,97, 101,273,274,578-580, Ranunculales, 576, 610
Psychotria, 611, 612, 638 660,697 ranunculin, 269, 272
750 Index

ranunculoside, 269 resistance, disease, 174, 184,300,309 Rhizophora man~/e, 204

Ranuncu{us, 269, 363 resistant effects, 179, 183, 184, 193,207,210, Rhizophoraceae, 88, 197, 537, 549
rapanone, 77 221,242,269,288,308,309,526,535,607, Rhizopus, 658
rape, 30, 35, 306 614,652,659,660,676 Rhizopus stoionifer, 261, 401, 414
rapeseed, 307 resorcinol, 200 rhodanese, 290
Raphanus sativus, 306, 309, 345, respiration, 3, 4, lO, 16,59,92,99, 120, 166, rhodanine, 212. 213
raspberry, 110, 128,209 338,361,515,517,601,645, '103 Rhodnius prolixus, 479
raspberry ketone, 110 respiratory arrest, 597, 640 Rhododendron japonicum, 411
rat, see bush rats, rat liver. rat poison respiratory failure, 607, 674 Rhododendron mol/e, 412
rat poison, 641 respiratory paralysis, 675 rhodojaponin III, 412
Rathbunia alamosensis, 582 respiratory stimulation, 702 Rhodophyceae, 260, 260, 513, 515
rats, 29, 35, 132,209,460,553,591,641,651, resveratrol. 140, 142, 145 rhodopsin, 497
682, 685, 698, 702 E-resveratrol, 145 Rhodymenia palmata, 260
rattle box, 705 Z-resveratrol, 145 rhoeadane alkaloids, 603
rattle bush, 705 Retanilla, 610 rhoeadine, 603
Rauvolfia, 640 reticuline,9 rhombifoline, 556
Rauvolfia canescens, 33
(- )-reticuline, 561, 585, 595 Rhopalosiphum padi, 99
(+ )-reticuline, 561, 585, 592, 598, 600
Rauvoifia serpentina, 242, 354, 355, 366, 629, rhubarb, 76, 91
( - )-(R)-reticuline, 586, 592, 594, 595, 598,
640,653 Rhus, [95, 196,206
600
Rauvolfia tetraphylla, 640 Rhus typhina, 195, 196
(+ )-(S)-reticuline, 586, 588, 590, 595, 599,
Rauvolfia vomitoria, 640 ribalinine, 573
603
Rauvolfieae, 637 (R)-reticuline, 586, 592 ribose, 99, 250
reaction, see Diels Alder reaction, elimination, (S)·reticuline, 586-588, 590, 598, 600 D-ribose, 250
phytosystem IT reaction center, preciptiation Reticulothermes flavipes, 340 ribosomal subunit, 60-S, 623
reaction, transamination reaction retina, 497 ribosomal subunit, 80-S, 700
rearrangement, ally lie, 43 retinal, 497 ribosomes, 19, 318, 482, 488, 558
rearrangement, Claisen, 101, 106 E-retinal. 497 ribulose 5-phosphate, 253
rearrangement, dienol-benzene, 591, 592 l1-Z-retinal,497 ribulose-l,S-bisphosphate carboxylase, 208,
rearrangement, dienone-phenol, 591, 592, 608 E-retinoic acid, 497 213,242
rearrangement, E-Z (trans-cis), 131 retinol, 497 rice, 6, 14,33,35,52,53,70, 173,408,414,
rearrangement, merolimonol, 477 retronecine, 548-550, 552, 565 423,437
rearrangements, Wagner-Meerwein, 329 retrorsine, 548, 549 Richardella dulcijera, 245
Reboulia hemisphaerica, 368 (9S)-retrorsme, 548 Richardsonia,612
receptor, 510, 525, 591, 609, 649, 659, 660, retroviruses, 561 ricin, 244
664, 675, 698, 708; see also acetylcholine Retziaceae, 361 ricinine 513, 528
receptors, antennal reverse transcriptase, 521, 599-601, 616, 623 Ricinocarpoideae,412
receptors, dopamine receptors, glutamate reward,550 ricinoleic acid, 24, 26, 35
receptors, glycine receptors, muscarinergic reynosin, 392 ricinoleyl phosphatidylcholine, 24. 26
acetylcholine receptors, nicotinic Rhabdodendraceae, 197 ricinoleyl-CoA, 24
acetylcholine receptors, nicotinic receptors, Rhabdodendroideae, 575 Ricinus communis, 24, 26, 244, 261, 401, 407,
opiate receptors, postsynaptic receptors, Rhabdodendron, 197 408, 414, 424, 425, 528, 530
tarsal receptors Rhabdosia, 420 rimuene, 412
receptor, postsynaptic, 510 Rhagoletis cerasi, 37, 39 rinds, 337
red blood cells, 244 Rhamnaceae, 85, 86, 88, 149, 173,240,244, Rio Japuras, 588
reductant, 21, 22, 51 575, 581, 585, 610, 695, 700 rishitin, 376
reductive pentose cycle, 248 6'-0-( a-L-rhamnopyranosides of epivolkenin Rivea, 658
regulators, see growth regulator and taraktophyllin, 285 Rivea corymbosa, 655, 658
regulatory processes, 7 26-0-a-L-rhamnopyranosylpolypodogenin·3-0- RNA, 4, 237, 520, 618
Rehmannia glutinosa, 108 a-L-rhamnopyranosyl-(1-2)-/3-D- mRNA, 134, 156, 184,237
Reichsteinia cardinalis, 164 glucopyranoside, 462, 463 tRNA, 520, 558, 601
reindeer, 207 rhamnose, 172, 456 RNA polymerase, 521
Reinecke salts, 507 L-rhamnose, 247, 250, 251, 260, 456 RNA synthesis, 135, 452, 520, 599, 648, 676,
Rejoua,637 4(a-L-rhamnosyloxy)benzylisothiocyanate. 306 696
relaxant, see also muscular relaxant 7-a-L-rhamnosyl-6-methoxyluteolin, 168 rRNA transcription, 45 S, 648
Rhamnus, 85, 88, 610
relaxant, skeletal muscle, 136, 607 RNA-dependent DNA polymerase, 623
Rhamnusjrangula,91
relaxant, smooth muscle, 600, 702 RNA-polymerase IT, 237
Rhamnus purshianus, 91
religious practice, 139,647,697 roasted materials, 700, 703
Rhapheolepis, 206
Remija, 611, 649 Robillia pseudoacacia, 244
Rhazya stricta, 242, 629
repellents, 10,35, 169,212,309,324,339,
Rheum, 76, 85
robustaol A, 69
340,342,346,350,361,365,395,484,511, Rheum officinale, 91 rock hyrax, 136
522, 542, 582, 591, 682, 683; see mosquito rheumatism, 564, 673 rodenticide, J32
repellent, phagorepellent rhexifoIine, 364, 552. 669 rodents, 132, 136, 345, 380
repolarization, 685 rhipocephaJio, 381, 420 Rollinia,67
reproduction, 340, 395, 398, 419, 444, 455, rhipocephanal, 381, 420 Romans, 658
479,498,501,502 rhizobitoxin, 238 Rondeletieae, 612. 638
reproductive failure, 420 Rhizobium, 167, 191,244 root, 2, 5, 7, 8, 18,26,30,42,46-48,50,78,
reptiles, 511 Rhizobium japonicum, 238 83,85,92,99,104,109,111,117,125,127,
Resedaceae, 304 Rhizobium leguminosarum, 167 129, 130, 136, 139, 140, 152, 155, 165, 167,
reserpiline, 630 Rhizobium meUloti, 189, 190,261 183, 187, 190, 191, 193,209,231,238,242,
reserpine, 511, 628, 640, 647 Rhizoctonia, 253 256,257,261,270,290,291,310,311,313,
reserve carbohydrate, 257 Rhizoctonia leguminicola, 561, 565 320,335,345,346,351,353,364,391,396,
resins, 30, 40, [20, 136,3[8,324,339,340, Rhizoctonia repens, 148 411,413,419,423,439,447,452,457,460,
342,343,350,375,398,401,405,412,413, rhizoma iris, 452 462,468,479,482,490,492,494,526,528,
426 rhizome, 117, 147,364,444,452,462,463, 529,531,532-535,537,544-547,553,554,
resistance, 517, 607, 682, 689 471,600,670,681 559,561,562,566,588,597,601,608,610,
 Index 751

611,614,640,645,647,653,658,663,666, rutin, 164-167, 169 Santolina chamaecyparissus, 348

667, 673, 678, 700, 708, 709; see also rutinose, 266 santolinyl skeleton, 346
bloodroot. celery root, root cultures, ipecac Rutoideae. 571, 573. 575, 576 santonin, 392
root, root beer, root nodulation, root-rot Rwanda, 652 a-santonin, 393
nematode, rootwonn, white snakeroot Ryania speciosa, 418 sap, 514, 591
root beer, 110 ryanodine, 418 Sapindaceae, 46, 217, 222, 223, 231, 273,
root nodulation, 165 rye, 98, 99, 658-660 284-287,458
rootwonn, northern corn, 113 ryegrass, annual, 659 Sapium, 403
rootwonn, southern com, 113 Sapium japonicum, 403
rootwonn, western corn 113 sabinene, 332, 333, 338 Sapium sebiferum. 45, 50
raridins, 379 d-sabinene, 332, 333 sapogenins, 456-458, 470, 472, 678
Rorippa indica, 310, 311 sabinol, 333, 346 (25R)-sapogenins. 678
Rorippa nasturtium-aquaticum, 304 cis-sabinol, 333 (25S)-sapogenins, 678
Rosa, 265, 499 d-sabinyl acetate, 332 saponic alkaloids, 457, 460
Rosa canina, 242 saccharides, 244, 247, 261 saponic materials, 582
Rosa damascena, 326 saccharin, 462 saponification, 16
Rosa dilecta, 328 Saccharomyces cerevisiae, 245 saponins, 441, 447, 456-460, 462, 463, 468,
Rosaceae, 125, 134, 148, 175, 179, 197,208, Saccharum officinarum, 145 470-472
244,264,269,279,284,286,287,289,337, safflower, 48 saponins, bidesmosidic, 458
444,499,514,515,673 saffron, 499 saponins, ginseng. 460. 462
Rosales, 197 safrole,ll0 Sapotaceae, 245, 279, 318, 321,458,549,639,
rosane, 406, 412 safynol,48 703
rose hips, 265 sage, 319, 326, 330, 346, 371, 393 sapwood, 324, 591. 613
roselle, 171 sagebrush, 552, 559 Sarcocca, 686
rosenonolactone.412 sago, viii Sarcococca, 677
rosewood oil, 528 saguaro cactus, see cactus. saguaro Sarcopharyngia, 637
Rosidae, 277, 576 saikosaponin a, 460 D-sannentose, 250, 251, 465
Rosiflorae, 197 saikosaponin d. 460 sannentosin, 282
rosin, 398, 413 Salada, 452 sannentosin epoxide, 282
rosmarinic acid, 108 salannin, 479 Sarothamnus scoparius, 554, 559
rotenoids, 110, 151, 186-188,316 Salicaceae, 121-124 sarpagine alkaloid, 640
rotenone, 120, 186. 187 salicin, 121, 124 Sarracenia, 240, 543
roundwonns, 392, 539 salicortin,124 Sarraceniaceae, 360, 361
rubber, viii, 288, 296, 312, 318-323 salicylaldehyde. 124 sativan. 179, 186
rubber biosynthesis, 318, 319 salicylic acid, 104, IDS, 122, 123. 126, 129, sawfly, 340
rubber, natural, 318-321 650 sawfly, larch, 415, 425
rubber transferase enzyme, 319 saligenin, 122, 124 sawfly, mountain ash, 289
ruberytbric acid, 87, 89 saliva, 207, 208, 212, 561, 664, 697 sawfly, turnip, 418
Rubia akane, 700 salivation, 561, 697 Saxifragaceae, 88, 355, 359
Rubia cordl/olia, 700 Salix, 122, 124, 363 saxitoxin, 703
Rubia tinctoria, 85, 87, 89 Salpiglossideae, 537 scallop, giant, 498
Rubiaceae, 10, 76, 85-89, 108, 187, 229, 353, salts, see N-methyl-J'-pyrrolinium salt, Scarabaeidae. 179
358,360,361,363,405,412,444,458,481, Reinecke salts, sodium salts, lithium salts sceletenone, 624
510, 533, 579, 598, 610, 611, 615, 636-638, salutaradine. 592, 595 Scelelium, 623
640, 648, 649, 652, 653, 655, 660, 662, 664, salutaradinol I, 595 Sceletium alkaloids, 624
665, 700, 708 Salvadoraceae, 304 Scenedesmus, 494
rubijervine, 681, 684-686 Sa/via, 77, 345, 346, 371, 375, 394, 407, 413 scent glands, 670
Rubioideae, 612, 637 Salvia leucophylla, 345 Schelhammera, 625
RuBPC, 208 Salvia miltiorrhiza, 413 schelhammeridine, 626
Rubus idaeus, 209 Salvia offidnafis, 326. 330-332, 346, 371, Schiff base, 98, 497, 507, 509, 518, 531
Rudbeckia hirta, 125, 177 375,393 Schiff base formation, 507, 531, 620, 628
rugosin D, 208 Salvia sciarea, 407 Schiff-base intermediates, see intermediates,
rugosin E, 210 SAM, see S-adenosylmethionine Schiff-base
Rumex, 76, 85, 91, 363 samandarine, 677 Schinopsis, 204, 206
Rumex crispus, 91 Samanea saman, 521 Schinopsis balansae, 204
Rumex tenuifolius, 439 Sambucaceae, 361 Schinopsis lorentzii, 204
ruminants, 120, 340. 460 Sambucus, 499 Schistocerca, 686
RuspoJia hypercrateriformis, 533, 545 sambunigrin, 277, 279, 287 Schistocerca gregaria, 444, 460. 478-480
ruspolinone, 533 (S)-sambunigrin. 277 Schistosoma, 393
rust. see carrot rust fly. crown rust, rust sandalwood, 384 Schistosoma japonicum. 230
diseases. rust fungi, rusHed flour beetle sandaracopimaradiene, 407, 414 Schistosoma mansoni, 209, 420
rust diseases, 414 d-sandaracopimara-8(14)-diene, 408 schistosomiasis, 209. 380, 393, 420, 459, 460,
Ruta,574 d-sandaracopimara-8(14),16-diene, 408 612
Ruta graveolens, 133, 134, 138, 510, 571, 574 ent-sandaracopimara-8(14),15-diene.407 schistosomula, 230
rutabaga. 306 sandaracopimaridiene, 414 Schizachyrium scoparium, 125, 346
Rutaceae, 11, 12,36,117.133-135.138,158, sandaracopimaric acid, 407, 415 Schizaeaceae, 414
175,337,458,473,475-478,510,514,515, Sanguinaria canadensis, 601 Schizaphis graminum, 113, 129, 173, 363, 365
568-571,573-577,598,601,610,660,662, sanguinarine. 26, 961, 594, 601, 603 Schizolobium parahybum. 222
663, 692, 693 Saniculoideae, 134 schizophrenia, 514
rutacridone alkaloids, 8 Santalaceae, 45,197,521.549,557 Schotia brachypetaia, 145
rutacridone epoxide, 510, 574 Santalales. 45 schottenol, 441, 582
rutaecarpine, 570 santalenes, 384 Sdrpophaga incertu/as, 480
Ruta1es, 197,337,473,483-485,568,577, (+ )-(E)-a-santalen-12-oic acid, 381 Scirpus maritimus, 145, 149
616,667 Santa/um album, 521 scIareol. 405, 407. 412, 414
Ruteae,575 santamarin, 392 13-epi-scIareol. 406, 407, 414
752 Index

sclerotia, 658 seeds, vii, 5-7, 9, 13, 14, 16-19,22-33,35, 501,517,575,670,671; see also
Sclerotinia sclerotiorum, 137 39-43,47,49,51-53,55,73,78,83,84, homosesquiterpenes, sesquiterpene
Scolypopa australis, 385 99, 105, 109, 118, 121, 122, 125-127, 130, phytotoxins
Scolytus, 40, 72, 342 132,136,137,152,167,171,175,179,183, sesquiterpenes, acyclic, 370, 382
Scolytus multistriatus, 83, 168 189,190,203,206,208,215,217,219,220, sesquiterpenes, eremophilane, 371
Scolytus quadrispinosus, 84 222,223,226-229,231,232,241,242,244, sesterterpenes, 370, 398, 415, 420, 422-424,
Scoparia dulcis, 101, 104 245,249,251,256,260,264,265,277,279, 488
scopolamine, 511, 534, 535, 537 280,282,287,288,294-300,305-307, Sevin, 110
scopoletin, 130-133,288 309-311,345,376,379,390,391,396,402, sex cells, 376
( - )-scoulerine, 600 403,411,414,435,445,459,460,468,472, sex detennination, 439
( - )-(S)-scoulerine, 603 473,478-481,483,499,528,529,537,544, sex expression, 437
(S)-scoulerine, 9, 588, 598, 600 552-554,558,559,561,565,567,568,597, shade, 7, 177,219
(13R)-scoulerine, 603 609,615,617,627,634,635,641,645,653, sheep, 136,212,220,390,411,451,466,515,
(13S)-scoulerine, 603 655,658-660,663,667,669,671,700,705, 559, 676, 685, 705
14-S-scoulerine, 603 710,711 shikimate-3-phosphate, 94, 97
Scrophularia raamosa, 358 Selaginaceae, 361 (- )-shikimate-3-phosphate. 97
Scrophulariaceae, 78, 85, 88, 92, 101, 108, Selaginallales, 173 shikimic acid, 3, 8, 11,64,65,76.77,80,82,
158,173,174,177,179,358,361,363,364, Seiaginella, 173 85-87,94-97, 102, 104, 121, 126, 139, 142,
366,387, 391,444,452,458,466,468,500, selection pressure, 9, 11, 12 148, 193, 195, 215, 324, 507, 568
522,549,552,557,559,566,569,570,669 selenium, 229 (- )-shikimic acid, 94, 195
Scrophulariales, 88 selenocystathlonine, 229 shikimic acid pathway, 11, 64-66, 76, 77, 94,
scrub, Florida, 125, 127 self-inhibition, vii, 125 95,97, 125
scutellum, 240 Semiaqui/egia, 269 shikimi-no-ki, 94
Scutia buxifolia, 700 semiochemical, 339, 365, 367 shikonin, 85
scutianine A, 700 sendanin, 480 shiromodiol diacetate, 380
scutianine B, 700 senecic acid, 549 shoots, 136, 138, 145, 175,231,238,345,408,
scutianine C, 700 Senecio, 510, 547, 549-552, 559 411,415,423
scutianine D, 700 Senecio jacobaea, 553 Siberia, 673
scutianine F, 700 Senecio longilobus, 553 Sibine stimulea, 390
scutianine G, 700 Senecio spathulatus, 552 sickness, see milk sickness, motion sickness,
sea cucumbers, 458 Senecio triangularis, 552, 559 vomiting sickness
sea urchin, 340, 381, 420, 696 Senecio vulgaris, 546, 547, 549. 550, 553, 565, Sida, 569, 570
seasonal variations, 543
566 Sideritis, 420
Secale, 99, 101
Senecioneae, 46, 387, 510, 549. 552 Sideritis mugronensis, 168
Secale cerale, 99
senecionine, 548. 549, 550, 552, 553, 559. 566 siderophores, 230, 240, 521
Sechium edule, 31
senecionine N-oxide, 550, 553, 566 Sierra Leone, 29
secodine, 632, 635
senepoxide, 104 sieve plates, 259
secoiridoid glucosides, 353, 358
senescence, 518, 554 sieve tubes, 320
secoiridoid glycosides, 359
seniciphylline N-oxide, 552 sieve-tube plastids, 708
secoiridoids, 354, 358-361, 365
Senna. 88, 91 sieve-tube pores, 259
(- )-secoisolariresinol, 117, 118
sepals, 91 signal transducer, 33, 39
secologanin, 2, 353, 358, 359, 366, 579, 610,
sequestration, 9, 124, 208, 220, 324, 340, 353, signals, 8, 33, 41, 53, 165, 167, 191,261
611,628,630,636-638,641,648,652,668,
361,363,364,418,442,466,550-552,564, Silene cucubalus, 242
669
secondary compounds, viii, 1,3-12, 14.40, 683,703 silk, 136, 341, 361
76,85,94,97,98, 101, 138, 139,232,249, sequoyitol, 264 silkwonn, 35, 128, 169, 187, 341, 440, 454
287, 296, 311 serendipity berries, 245 silkworm, cecropia, 444
secondary metabolites, vii, 1-16,32,34,53, serine, 215, 217, 220, 222, 226, 290 silybin, 168
58,76,77,80,92,94, 101, 102, 104, 106, D-serine, 215, 217 Silybum marianum, 168
136, 179,247,252,254 L-serine. 215, 217 silychristin, 168
secondary phloem, 320 (2-serine )tabtoxin, 238 silydianin, 168
secophthalideisoquinoline alkaloids, 603, 610 serotonergic, 510 silymarin, 168
secret societies, 647 serotonin, 228, 229. 510, 514, 516, 517, 525. Simaba multiflora, 481, 482
secretory canals, 324 640, 659, 660 simalikalactone D, 482
secretory cells. 326 serotonin antagonist, 640 simarolide, 476
Securinega alkaloids, 703 serpentine, 630-632, 645, 653, 654 Simaroubaceae, 46. 88,197,337,473,
Securinega suffruticosa, 703 sesamin, 118, 120 475-478,481,482,485,575,576,660,662,
securinine, 703 Sesamum indicum, 118 666
sedamine, 540 Sesbania, 705 Simmondsia chinensis, 51, 52
sedative. 460, 640, 670, 673 Sesbania alkaloids, 705 Simmondsiaceae, 51, 293
sedges, 384, 659 Sesbania drummondii, 705, 711 sinalbin, 300, 308, 310
Sedum, 531, 539 sesbanimide, 705, 711 sinapic acid, 108. 113. 115
Sedum cepaea, 282 sesbanimide B, 705 sinapine, 300, 302, 310
Sedum sarmentosum, 282 sesbanimide C, 705 Sinapis alba, 308, 310
seed coats, 275, 277 sesbanine, 705 sinapyl alcohol, 115
seed dispersal, see dispersal, seed seselin, 130 Sindris albimaculatus, 29
seed dormancy, see dormancy, seed sesquiterpene alkaloids, 375, 525. 670, 671 ,B-sinesal, 370
seed germination, see germination, seed sesquiterpene biosynthesis. 370, 371, 401 sinigrin, 266, 303, 307-309
seed oil. 35, 36, 45, 118, 285 sesquiterpene cyclase, 368 Sinningia cardinalis, 164
seedlings, 34, 47, 78, 92, 99, 109, 125, 127, sesquiterpene glycosides, 378 sinoacutine, 592
132, 135, 145, 158, 178, 183,220,229,230, sesquiterpene lactones, 316, 351, 365, 367, sinomenine, 592
238,275,276,280,282,287,288,290,296, 376,386-397,415,425,454 Sinomenium, 592, 593
310,314,315,317,344,345,369,376,390, sesquiterpene olefin cyclase, 374 Sinomenium acutum, 592
401,407,408,413-415,424,425,436,437, sesquiterpenes, 13,30,46,78.312,335, siphonidin, 269
444,452,484,501,504,634,645,652,673, 337-339,342,344,346,350,367-387, Siphonodon australe, 269, 272
702, 703, 708 391-394,396-398,412,415,419,420,500, siphonoside, 269
 Index 753

sirenin, 376 Solanum X ajanhuiri, 684, 690 spindle-tree, 269, 270

I-sirenin, 376 solasodine, 677, 678, 680, 683, 684 Spiraea, 673
Sitophilus zeamais, 437 (25R)-solasidine, 680 Spiraea japonica, 673
sitosterol, 436, 459, 582 solasonine, 683 Spiraeoideae, 264, 284
,B-sitosterol, 35, 320, 427, 435, 436, 439, 441, Solenopsis, 533, 542 spirobenzylisoquinoline, 610
458 Soienopsis saevissima, 35 Spirodela po!yrhiza, 162
skeleton, see artemisyl skeleton, cadalane Soienopsis xenovenenum, 552 spirosolanes, 677, 678. 680, 681
skeleton, cevane skeleton, chrysanthemyl Solidago, 418, 423 spirostanols, 681
skeleton, santolinyl skeleton Solidago altissima, 49 Spodoptera, 591, 603
Skimmia japonica, 573 solon, 168 Spodoptera eridania, 135,361,390
skimmianine, 573 solorinic acid, 86 Spodoptera exempta, 361, 380, 415, 418, 481
skin, 381, 498 solvent, 324, 326, 339, 348, 439, 496 Spodoptera exigua, 390
,B-skytanthine, 669 solvent extraction, 324, 326 Spodopterajrugiperda .. 145,390,412,480,
slaframine, 561 Sonneratiaceae, 88 481,658,666
slime mold, 71 Sonora, 582, 615 Spodoptera littoralis, 379,418,550
slobbering, 561 Sophora secundiflora, 559 Spodoptera fitura, 113, 136, 138,396,417,
smallpox, 237 Sophora subprostrata, 168 425,480
smartweed,76 sophoradin, 168 Spodoptera ornithogalli, 390
smooth muscle tonus, 588 Sophoreae, 557 Spondias mombin, 210, 212
snail gut acetone powder, 294 sophorose, 266 sponges, 380, 700
snails, 209, 289, 380, 393, 459, 460 soporific drug, 136, 538 spores, 110, 167,377,414,503,520
snake bites, 591 Sorbaria arborea, 284 Spreckeliajormosissima, 621
snakes, 179 sorbitol, 262, 264 spruce, 337, 543
snapdragon, 158, 189 D-sorbitol, 264 spruce, black, 337
snuff, 462, 514 D-sorbose, 250 spruce, blue, 337
soap, 16 L-sorbosone, 265 spruce, Engelmann, 337
sodium, 207, 260, 348, 468 Sorbus, 269, 289 spruce, red, 337
sodium carbonate, 294 Sordaria fimicola, 71 spruce, Sitka, 337
sodium channels, 348, 560, 674, 675, 677, 685, sorghum, 101,208,210,213,274-276,280, spruce, white, 337
703 282, 288, 290, 299 squalene, 3, 427, 428, 430-432, 444, 447, 452,
sodium channels, voltage-dependent, 560 Sorghum bie%r, 78, 274, 275 455, 490, 689
sodium metabisulfite, 207 Soulamea soulameoides, 481, 482 squalene biosynthesis, 428
sodium picrate paper (HCN test), 294 soulameolide, 477 squalene epoxidase, 431
sodium potassium-ATPase (Na+ +K+- squalene 2,3-epoxide, 427, 431, 432, 444, 447,
sour oranges, 340
ATPase), 468, 601, 603, 615, 660, 676 473
South America, 120, 139, 179, 229, 296, 388,
sodium salt, 16 437,460,525,535,550,561,605,6\0,643, (3S)-squalene epoxide, 447
sodium transport, 660 (3S)-2,3-squa1ene epoxide, 431, 432
649, 660, 684, 696, 700
softwood, 37, 115 squalene mono-oxygenase, 431
South American leaf blight, 288
soil, 4, 8, 26, 53, 83, 125-127, 191,207,229, squalene-2,3-oxide-cycloartenol cyclase, 432
South Pacific, 226. 294, 538
242,262,340,345,378,391,441,459,700 squalene synthase, 372, 428, 430, 452, 455
southeastern Asia, 210, 319
soil nutrients. 8 St. Anthony's fIre. 658
South-West Cape Province, 623
soil organisms, 4 S1. John's wort, 91
Soviet Asia, 210
solacauline, 682 Stachelameisen (ants), 703
solacongestidine, 681, 683 Soviet Union, 378, 623
stachyose, 256, 261
soladulcidine, 678, 683 soyasapogenol B, 78, 452
Stachyuraceae, 442
soiadulcine, 682 soybean, 178, 181, 182, 184, 188, 191, 192, Stachyurus, 442
solafloridine, 683 238,245,256,261,265,270,290,472 stalking game, 647
solamargine, 682, 683 spadix, 515 stalks, 608
Solanaceae, 3, 30, 31, 88, \08, 110, 134, 163, Spanish fly, 382 Stanhopea pulla, 344
183,242,377,395,453,458,494,506,5\0, Sparganothis sulfureana, 291 Stanhopea tricornis, 344
517,525,533,534,537,539,544,550,557, sparteine, 9, 554-556, 558, 559 Stanleya, 305
560,660,671,677 ( - )-sparteine, 554, 555 Staphyleaceae, 514
Solaneae, 537 sparteine sulfate, 558 Staphylococcus aureus, 69
solanidanes, 677 Spartium junceum, 559' starch, 249, 254, 257, 259, 260, 270-272, 290;
5a,22,BH,25,BH-solanidan-3,B-ol, 684 spasmolytic. 136, 591 also see floridean starch
22,BH,25aH-solanid-5-en-3,B-ol, 684 spathe, 515 starch synthesis, 249
solanidine, 458, 677-683 Spathelia, 477 starch synthetase, 259
solanidine alkaloids, 680, 684 Spathelioideae, 571, 575 starch, floridean, 260
Solaniflorae, 360 speannint, 335, 351 starfish, 458
solanine, 682 sperm tube growth, 340 steam distillation, 324, 452
a-solanine, 458, 682-684 sperm whale, 52 stearic acid, 17,22,26,35,51,53
soianocapsine, 678, 683 Spermacoce,612 stearoyl desaturase, 21
Solanum, 535, 677, 678, 680, 681, 683, 684 Spennacoceae, 612, 638 stearoyl-ACP, 19,21, 22
Solanum alkaloids, 249, 668, 678, 680, 681, spennicide, 376, 460 stearyl-ACP,51
683,684 spermidine, 517, 518, 520, 521, 529, 547 stearyl-CoA, 51
Solanum berthaultii, 269, 383 spermidine alkaloids. 521 Stegnospermaceae, 708
Solanum eleagnifolium, 683 spermine, 517, 518, 529 stemborer, yellow, 480
Solanum lycocarpum, 557 spermine-DNA complexes, 520 Stemmadenia pubescens, 632
Solanum malacoxylon, 437 sphondin, 133. 135, 136 stemmadenine, 632, 634, 635
Solanum mammosum, 460 spices, 12,47, 110, 130,340,346,379 stemofoline, 533
Solanum marginatum, 242 spider, 49, 80, 551, 564 Stemonaceae, 179
Solanum melongena, 677 spider, giant tropical orb, 551 Stemonaceae, 531, 533
Solanum nodiflorum, 460 spiders, jumping, 49 stemonine, 533
Solanum rostraturn, 677, 683 Spilanthes oiearacea, 36 stemospironine, 533
Solanum tuberosum, 31, 41, 377, 535, 677, spinach, 40, 94, 99, 442, 520 stems, 7, 30,117,152,193.207.269.514,
683,684 Spinacia o/eracea, 3, 557 522, 608, 658, 700
754 Index

Stenocarpus, 82 strawberries, 346 sulfuretin, 173

Stenocereus alamosensis, 582 Streptanthella, 305 sulfuric acid, 227, 535
Stenocereus gummosus, 441, 582 Streptanthus, 305 Sumatra, 187
Stenocereus thurberi, 441, 582 streptimidone, 705 sunflower, 390, 415
Stenosolen, 637 Streptocarpus dunnii, 87 surface active agents, 459, 460
Stephania, 592, 593 Streptomyces, 65, 97, 105,234,253,568 sutherIandin, 284
Stephania tetrandra, 606 Streptomyces erythreus, 65 Swainsona, 254, 561
stephanine, 591 Streptomyces griseus, 262 Swainsona canescens, 561
steptomycin, 253 Streptomyces verticillus, 235 swainsonine, 254, 270, 561, 562, 565
Sterculia foetida, 35 streptomycin, 262 swainsonine N-oxide, 561
Sterculiaceae, 28, 46, 304, 444, 466, 571, 581, streptovitacin A, 705 Swartzia madagascariensis, 460
655, 666, 700 stress, 8,13,134,174,184,189,190,274, sweet clover, 130, 132, 137
sterculic acid, 27 290,296,337,339,495,517; also see sweet compounds, 99,175,209,245,253,257,
stereochemistry, 21, 37, 40, 67, 97, 101, 117 abiotic stress, water stress resistance 261,264,367, 385, 398, 408, 420, 424, 444,
sterigmatocystin, 65 Strictocarpia, 658 456,462,463,471
Sternechus tuberculatus, 220 strictosamide, 648 sweet potato, 7, 72, 313, 377
steroid glycosides, 441 strictosidlne, 2, 359, 628-631, 635, 645, 648, Sweetenioideae, 488
steroid saponins, 456 649, 652-654 sweroside, 359
steroidal alkaloids, 510, 560, 668, 675, 677, strictosidine synthase, 2, 629 Swertia caroliniensis, 359
682, 686, 689, 690 Striga, 78, 92, 391, 392 swertiamarin, 359
steroidal sapogenins, 456 Striga asiatica, 78, 92, 392 swine, 460, 480
steroids, 3, 10,37,312,322,348,397,427, strigol, 78, 391, 396 Sylvifagus floridana, 390
428,432,433,439,440,447,453,455,471, stroma, 8, 19,23 sympathetic nervous system, 510
501,504; see also, corticosteroid, strophanthidin glycosides, 468 Symphonia globubfera, 148
ecdysteroid, steroid alkaloids, steroidal Strophanthus, 463, 465, 468 Symphytum, 552, 553
Strophanthus boivinii, 463 Symphytum officinale, 3, 557
glycosides, phytoecdysteroids
Symplocaceae, 361, 575, 610
sterol esters, 18 Strophanthus gratis, 469
sterol-J22-desaturase, 436 Symplocos, 610
Strophanthus kombe, 465, 469
synapse, 510, 662
J14_sterol reductase, 436 strychnan, 636
synergists, 13,35,50,110,111,113,128,348,
sterols, 312-314, 349, 370, 401, 427, 431, 433, Strychneae, 638
435-437,439-442,452-455,458,471,582; strychnine, 511, 607, 628, 641-643, 703
383
synomones, 9, 30, 39, 110, 176, 324, 339, 343,
see also C2rsterols, C29-sterols, campesterol, Strychnos, 511, 638, 640, 643, 652, 660
Strychnos alkaloids, 631-635
344,367,380,381,498,516
cholesterol, cholesterol binding, 20,22-
Synsepalum dulcificum, 245
dihydroxycholesterol, ergosterol, fucosterol, Strychnos dinklagei, 645
Syntermes na, 372
(25R)-26-hydroxycholesteroI, 20- Strychnos nux-vomica, 641
synthetase complexes, 19
hydroxycholesterol, 22,8-hydroxycholesterol, Strychnos usambarensis, 652
Syntomis, 591, 597, 603, 613, 619, 640, 641,
26-hydroxycholesterol, lanosterol, 411'- Stylidiaceae, 257, 360, 361
650, 658, 662, 664, 686, 703
methylergosta-8,24(28)-dien-3,8-01 to 24- stylopine, 600 syringic acid, 78, 126
methylenelophenol (J8_.J7)-sterol (S)-stylopine, 600
syringin.115,117
isomerase, 1411'-methylsterol 1411'- Stylopyga rhombifolia, 136 systematics, plant, 12
demethylase, 2,3-oxidosqualene:lanosterol Styraceae, 412 Syzygium aromaticllm, 59
cyclase. phytosterols, ,8-sitosterol, styrylpyrones, 139
stigmasterol, taraxasteroI, UDP:sterol suberin, 51, 53-55, 127
T -2 toxin, 378
transglucosylase subterranean clover, 179
Tabebuia guayacan, 85, 92
sterol-S-adenosylmethionine methyl transferase, succinic acid, 160
Tabemaemontana, 635, 637, 640, 645, 647,
436 succinic semi aldehyde, 81
652,654
steryl ferulates, 437 o-succinylbenzoic acid (OSB), 80-82, 87, 93
Tabemaemontaneae, 637
Stevia, 407 o-succinylbenzoic acid (OSB) CoA synthetase.
Tabernanthe iboga, 628, 647
Stevia rebaudiana, 420 81 Tabernanthe subsesselis, 647
stevio!, 408, 420, 425 o-succinylbenzoic acid (OSB) synthase, 81 tabersonine, 632, 634, 635, 645, 652
stevioside, 420 N'-succinyl-2,6-diaminopimelic acid, 217 tabtoxin, 237
7 -stigmastenol, 582 sucrose, 175,245,247,253-257,261,270, tachycardia, 674
stigmasterol, 427, 435, 436 271, 385, 420, 460, 462, 463 tadpoles, 460
Stilbaceae, 361 sucrose esters, 269 taeniacide, 539
stilbene biosynthesis, 142, 155, 156 sucrose synthetase, 256 D-tagatose, 250
stilbene glycosides, 140 sugar, 3, 15, 24, 30, 52, 96, 108, 132, 160, Tageteae, 387
stilbene synthases, 142, 156 164,170-172,175,194,197,208,244, Tagetes, 47
stilbenes, 8, 136, 139, 140, 142, 143, 145, 147, 247-253,256,257,259-262,264,266,270, Tagetes erecta, 48
149,156 273, 279, 280, 287, 290, 544, 583; see also tagetone, 346
stimulants, 12, 78, 128; see also feeding blood sugar, 2-deoxy sugars Talguenea, 610
stimulants, phagostimulants sugar beets, 3, 222, 256, 260, 460; also see tall fescue. 510, 659, 667
stimulants, central nervous system, 703 sugar beet wire worm tall morning glory, 7
stimulants, ganglionic, 540 sugar cane, 52, 78, 145,256,290,414 L-ta!omethylose, 251
stimulants, growth, 53 sugar carboxylic acids, 247, 463 talose, 250
stimulants, heart, 392 sugar mimics, 253 tamarack, 415
stimulants, skeletal muscle, 702 sugars, amino, 247, 253 Tanacetum. 328, 331, 332, 348
stimulants, uterine, 640 sugars, branched-chain, 247, 251 Tanacetllm vulgare, 88, 326, 328, 330-332
stinging hairs, 517 sugars, methoxy, 247, 251 tannase, 212
Stipa,659 sugars, nucleotide, sugars, phosphorylated, 248 tannic acid, 208
Stipa robusta, 659, 667 sulfatase, 160, 188, 294 tannin assays, see acid butanol assay, Folin-
stipitatonic acid, 59 sulfation of desulfoglucosinolates, 303 Denis assay, hide powder method
stizolobic acid, 706 sulfoquinovosyl diglyceride, 18 tanning, 200, 206, 207, 210
stomatal closure, 500, 501 sulforaphane, 306 tannins, 8, 12, 102, 152, 159, 163, 170, 171,
stomatal opening, 415 sulforaphene, 310 191, 193-197,204,206-210,212,213,289;
storage, 220, 240, 241, 247, 257, 259, 264, sulfur, 42, 45, 173, 226, 227, 229, 231, 266, see also condensed tannins. ellagitannins,
287,295 303,309 gallotannins, phlorotannins
 Index 755

tansy ragwort, 553 a-terthienyl, 48 Thelypodieae, 305

Tanzania, 652 Tessaria dodoneifolia, 175 Thelypodium, 304. 305, 310
tapewonn, 539 testosterone, 53, 440 Thelypodium paniculatum, 305
tapping, 320 tetanus, 607 Thelypodium eucosmum, 305
taraktophyllin, 285, 286 tetrabase, 294 Theobroma, 700
Taraxacum kok-saghyz, 319 tetracycline, 56, 65, 67, 74, 234 Theobroma cacao, 700
Taraxacum officinaie, 159 12-0-tetradecanoylphorbol-13-acetate, 403 theobromine, 700, 702, 703
taraxasterol, 447 Tetradium, 569, 570, 574, 575, 610 Theophrastaceae, 452
taraxerol, 447 Tetradium rutaecarpa, 570 theophylline, 511, 700, 702, 703
tarennoside, 358 l,2,3,6-tetragalloylglucose, 196 therapeutic function, 511, 612, 613, 642, 645.
taro, 26 Tetragono[obus, 184 648, 698, 708
tarsal receptors, 309 tetrahydroalstonine, 630, 631 thennopsine, 558
tartaric acid, 265 tetrahydroanabasine, 507, 508 Thermopsis, 552, 558
taspine, 591 tetrahydrobenzylisoquinoline alkaloids (TBIQ), Thermopsis divaricarpa, 552, 559
taste, 171, 175,210,237,245,253,261,264, 578,584,585,587,588,598,610 Thevetia thevetioides, 468, 472
267,269,300,302,316,339,340,346,361, I-tetrahydrobenzylisoquinoline alkaloids, 575, D-thevetose, 251, 465
L-thevetose, 251, 465
380,386,389,390,417,444,452,456,460, 610
thiamine pyrophosphate, 81
462,463,466,478,483,511,525,539,552, tetrahydroberberine, 598, 599
thiarubrine A, 48
641,673,684; also see bittersweet taste, (- )-L1-1-tetrahydrocannabinol, 336
thioctic acid, 237
bitter taste, distasteful properties, peppery L1 1(6ttetrahydrocannibinol, 336
thiocyanates, 266, 290, 302, 305, 306, 310
taste, sweet compounds tetrahydrocolumbamine, 598, 599
thioesterases, 21, 23
Taxaceae, 401, 402, 413, 626, 676 (S)-tetrahydrocolumbamine, 598 thioglucosidases, 300
taxane alkaloids, 402 tetrahydrohannan, 660 f3-thioglucosidases, 302
taxanes, 398, 401, 402, 413 tetrahydroisoquinoline alkaloids, 575, 581, 605 thiohydroximate O-sulfonates, 306
taxifolin, 159 tetrahydrolathyrine, 226, 232 thiohydroximates, 303-304
taxine, 626 tetrahydropalmatine, 599 thiohydroximates, S-glucosylation, 303
taxine I, 676 tetrahydroprotoberberine alkaloids, 598 thiohydroximic acids, 303
taxine II, 676 (S)-tetrahydroprotoberberine oxidase, 598 thiokinases, 23
taxiphyllin, 276, 277, 280, 286 tetrahydropteridine cofactor, 132 thiophene, 45, 48, 49
(R)-taxiphyllin, 276, 277, 280 4,2' ,4'.6'-tetrahydroxychalcone, 158 thioredoxin, 8
Taxodium distichum, 420 2a,3a,22a,23a-tetrahydroxy-24a-methyl-f3- thiosulfate sulfur transferase, 290
taxo1, 676, 677 homo-7-oxa-5a-cholestan-6-one, 437 Thladiantha grosvenorii, 463
taxonomists, 12 1,6,7 ,8-tetrahydroxyoctahydroindolizine, 562 threonine, 217, 220, 234
Taxus, 288, 402, 499, 626, 676, 677 1,3,5,6-tetrahydroxyxanthone, 148 threose, 249
Taxus alkaloids, 668, 676, 689 tetrahymanol, 431 Thuja, 337
Taxus brevifolia, 677, 691 Tetrahymena pyriformis, 431 Thuja occidentalis, 346
Taxus wallichiana, 677, 690 tetraketides, 58, 59 Thuja p!icata, 340
tazettine, 622, 623 4,4'-tetramethyldiaminodiphenylmethane, 294 a-thujaplicin, 340
TBIQ, see tetrahydrobenzylisoquinoline tetrandrine, 606 ,B-thujaplicin, 340
alkaloids ( + )-tetrandrine, 606, 607 thujaplicinol, 339
TCA cycle, see tricarboxylic acid cycle tetranortriterpenes, 473, 475, 477, 484 a-thujene, 333
tea, 165, 171, 172, 191,210,213,219,506, Tetranychus urticae, 67, 341, 445 l-a-thujene, 332
553, 700, 702 tetraphyllin A, 285, 286 thujic acid, 340
tea, black, 172, 210 tetraphyllin B. 285, 286, 298 thujone, 340, 346
teak. 88 tetraphyllin B sulfate, 285 3-thujone, 332, 333
Teclea,574 tetraploid. 337 (+ )-3-thujone, 340
Tecoma slans, 568, 669 tetraterpene biosynthesis, 431 d-3-thujone, 332, 333
Tectona grandis, 88 tetraterpenes, 46, 348, 367, 384, 431, 486-488, Thunbergiaceae, 361
telemagrandin I, 197 490 thylakoid membranes. 17, 18, 326, 518
telemagrandin II, 197 tetrodotoxin, 674 ThymeJaeaceae, 134,398,401-404,413,419,
teleology, 4 teucrein, 358 423, 424, 444
tendril,33 Teucrium, 358, 406 thymol,346
Tenodera ardifolia sinensis, 468 Teucrium marum, 358 thyroid glands, 220
Ti-plasmid, see plasmid, Ti
Tenthredinidae, 289 Texas, 338, 380, 387, 388, 472, 540
tigliane, 402, 403, 424
tenuiin, 390, 392, 394 Thailand, 698, 711
tiglic acid, 321
Tephrosia, 186 L1-1-THC, see L1-1-tetrahydrocannabinol
13-tigloyloxylupanine, 558
Tephrosia elala, 187 thalicarpine, 606
tigogenin, 680. 681
tephrosin, 187 thalicmine, 591
Tiliaceae, 466
teratogenic, 538, 543, 558, 559, 668, 684 Thalictrum, 242, 269, 588, 592, 605, 667 tingenone, 452, 671
teratological. 685 Thalictrum aquilegifolium, 277 tirucalloi, 473, 473
teratomas, testicular, 235 Thalictrum dipterocarpum, 242 apo-tirucaUol, 473
Terminalia chebula, 194 Thalictrum faheri, 606 L11 -tirucallol. 473, 476
tennites, 53, 85, 89, 340, 343, 372, 419, 500 Thalictrum foetidum, 660 tissue culture, 33, 85, 153, 326, 350, 365, 370,
Ternstroemia japonica, 460 thalidasine, 606 394,447,457,465,470,506,526,529,534,
Temstroemiaceae, 460 thaumatin, 245 544,546,554,576,610,645,652,666
terpenes, 177,312,327,345,384,396,424, Thaumatococcus danie/li, 245 tissue culture, plant, 2. 3, 13, 50, 80, 85, 86,
425,427, 428, 452, 483, 485, 504 THBIQ, see tetrahydrobenzylisoquinoline 92, 127, 137, 149,526,593,594,629,645,
terpenoid biosynthesis, 8, 313, 327, 370 alkaloids 649
terpenoid metabolism, 312-314, 507 L11(6tTHC, see L1'(6)-tetrahydrocannibinol 1LC, see chromatography, thin layer
terpenoids, 8, 11, 104, 507; see also Thea sinensis, 171, 210, 460, 700, 702 toads, 466, 560, 708
hydroquinone terpenoids Theaceae, 171, 197,460,700 tobacco, 30, 49, 50, 105, 110, 121, 128, 129,
terpinen-4-oI. 333 theaflavins, 172, 210 131,132,171,221,237,372,401,414,415,
a-terpineol, 331, 333 thearubigins, 172, 210 462,500,525,526,529,531,533,538,545,
terpinolene, 331, 342, 343 thebaine, 593, 595-597, 615 648, 653; see also tobacco smoke, tobacco
terramycin, 65 Theligonaceae, 361, 708, 711 homwonn, Indian tobacco
756 Index

tobacco smoke, 526 triacetic acid lactone, 58 tnsporic acid C, 502

tocopherols, 488 I-triacontanol,53 trisporic acid E, 502
a-tocopherol, 86 triacylglycerides, 16,23,24,26,27,42,43,45 trisporic acids. 501, 502, 504
Tocoyena, 611, 612, 638 triacylglycerols, 16-18,24-26,38,43,49 trisporin. 502
Toddalia, 610 trial by ordeal, 663, 673, 676; also see ordeal trisporol, 502
Toddalioideae, 571, 573, 575 ceremonies triterpene biosynthesis, chair-hoat-chair-boat
tomatidenol, 683 Tribolium castaneum, 35, 460 transition state, 427, 432
tomatidine, 458, 678, 680, 682 Tribolium confusum, 562 triterpene biosynthesis, chair-chair-chair-boat
(25S)-tomatidine, 680 Tribulus terrestris, 457 transition state, 427, 447, 473
tomatilladine, 683 tricarboxylic acid (TCA) cycle, 3, 24, 81 triterpene glycosides, pentacyclic, 459
tomatine, 458, 510, 690 tricetinidin, 172 triterpene glycosides, 441, 453, 456, 459, 460,
a-tomatine, 681, 682, 684, 689, 690 Trichilia, 477 463, 470, 582, 583
tomato, 30, 33, 39-41, 83, 109, 126,237,381, Trichilia emetica, 480 triterpenes, 78, 39, 322, 348, 369, 370, 380,
415,479,482,486,488,490,491,494,499, Trichilia roka, 480 422,427,428,431,432,444,447,451-456,
501,510,677,681,682,689,690 trichilin A, 480 458, 470, 473, 477, 483, 504, 575
tonic, 364, 670 trichirokanin, 480 triterpenes, B,D-seco-limonoids, 476
tonoplast membrane, 9, 598 Trichocereus pachanoi. 523 tnterpenes, B,D-seco structures, 477
toonacilin, 480, 484 Trichoderma viride, 459 tnterpenes, metabolically altered, 379, 473,
toosendanin, 480 Tricholomataceae, 35. 700 478
toothpastes, 603 trichomes, 30, 269, 324, 351, 383 triterpenes, pentacyclic, 431, 447
topoisomerase I, 645, 648 trichomes, glandular, 324, 386, 394, 395, 414, triterpenoid sapogenins, 458
topoisomerase II, 645 423 triterpenoid saponins, 456, 458, 460, 470
Torreya nucifera, 382 Trichomycetes, 260 Triticale, 101
Torricelliaceae, 361 Trichophyton rubrum, 683 Triticum, 101
Tovariaceae, 304 Trichoplusia, 660 Triticum monococcum, 282
toxic proteins, 244 Trichopsenius, 53 Triton X-loo (detergent), 432
toxic substances, 168, 169, 173, 227, 228, 242, trichothecenes, 378, 379, 395 trixagol, 500
244,340,591,640,650,676,683,685 Trichothecium, 378 Trogoderma granarium, 35
toxicity, vii, viii, 12,72,111,117,120, trichotomine, 666 Trollius, 269
135-137,316,317,346,348,380,411,415, Triclisia patens, 606 Tropaeolaceae, 303, 304, 308
441,456,459,460,479,480,482,510,529, tricoccin 5 22 , 476 Tropaeo/um majus. 303, 308, 309
552,553,559,564,583,591,612,613,619, Tricop/usius ni, 390 tropane alkaloids, 528, 531-535, 537, 539,
640, 646, 673, 683, 708 2-tridecanone, 30, 40, 41, 682 544, 545, 678
toxicity, mammalian, 187 trifarin, 380, 419 tropic acid, 535, 545
Toxicodendron radicans, 67 Trifoliumpratense, 179, 186,460 (S)-tropic acid, 535
toxiferine, 643 Trifolium repens, 179,289,296,297 tropine, 511, 535
C-toxiferine, 643 Trifolium subterraneum, 179 tropinone, 535
C-toxiferine I, 643 1 ,2,6~trigalloylglucose, 196 tropoloisoquinoline alkaloids, 588
toxin, 29, 30, 72, 78-80, 83, 125, 126, 138, Triglochin maritima, 275, 277 trout, 35
342,345,351,377,378,396,439,441,466 triglochinin, 277, 280, 290 trypanocidal, 599
TPP, see thiamine pyrophosphate triglycerides, vii, 16,26,27,35,41,262,320 Trypanosoma cruz;, 452, 479, 599, 645, 650,
ent-trachylobane, 408 Trigonella, 184 660
I-trachylobane, 408 Trigonellafoenum~graecum, 457, 528 trypanosomes, 479
trachyloban-19-oic acid, 415 trigonelline, 231. 528, 708 trypsin, 208, 242, 245
trachylobanoic acids, 415 3,5,3'~trihydroxybibenzyl, 147 trypsin inhibitors, 245
trail marking pheromone, 324, 343, 419, 437, 4,2',4'-trihydroxychalcone, 179 tryptamine, 2, 10, 359, 514-517, 525, 563,
542 2,5,7-trihydroxyflavanone, 162 628,629,630,648,649,652,654,655,660,
tranquilization, 139, 364, 640 7,2',4'-trihydroxyisoflavan, 184 663, 665, 667, 668
transamination, 101,508,513,581,681 5,7,4'-trihydroxyisoflavone, 178 tryptophan, 3, 94, 97-99, 209, 228, 267, 300,
transamination reaction, 217 6,7,4'-trihydroxyisoflavone, 179 302,507,515,516,525,568,570,575,656,
transcription, 568 1,4,5-trihydroxynaphthalene,83 660,665
transduction, 8, 16 9,12, 13-trihydroxy-(E)-1 O-octadecenoic acid, L-tryptophan, 3, 656
transglycosylation, 303 27,40 tryptophan amino transferase, 98
translation, 8, 226 9,1O,18-trihydroxystearic acid, 53 tryptophan dimethylallyltransferase (DMAT), 3
translocated, 256 Trimeniaceae, 610 tryptophan dimethylallyltransferase synthetase
transport, 3, 6, 8,9,18,19,65,114,115,117, 2,4,5~trimethoxy-l-propenylbenzene, 113 (DMAT) syntetase, 3, 656
166, 190,230,231,240,241,257,266,271, 2,6,6~trimethylcyclohex-2-ene-l,4-dione, 124 tryptophan 2-monooxygenase, 98
287,288,328,345,483,488,521,528,534, (2E,4E,6E,8E)-3,5,7-trimethyl-2,4,6,8- L-tryptophan synthase, 98
546,547,554,562,567,574,588,618,640, decatetraene, 37 Tsuga, 337
645, 660; see also cardiomuscular calcium 1-(2,3,6-trimethylphenyl)-but-2-ene-l-one, 500 T-toxins,72
transport, electron transport chain, sodium 4,5',8-trimethylpsoralen, 137 tuberculostatic effects, 149, 599, 600, 603
transport (3E,7E)-4,8,12-trimethyl-I,3,7,11- tuberculostearic acid, 27
transposable elements, 9 tridecatetraene, 341 tubers, 14, 31, 33, 147, 148, 166,257,314,
traumatin, 32 1,3,7-trimethylxanthine, 700 345,397
Trautvetteria, 269 tripdiolide, 420 Tubiflorae, 359
tree, see neem tree, spindle-tree, tulip tree tripeptides, 657 tubocurarine, 511, 605, 607, 675, 676
a,a-trehalose, 254 Triphyophyllum, 698 (+ )-tubocurarine, 676
trematode, 393 Triplostegiaceae, 361 d-tubocurarine, 643
tremetone, 317 Tripsacum, 101 tubulin, 120,617,618,645
tremulacin, 124 Tripterygium wilfordii, 420, 528, 671 tubulosine, 613, 652
tremuloidin, 124 TriptoIide, 420 tulip tree, 591
Trewia, 528 Trirhabda canadensis, 418 Tulipa, 269
Trewia nudijlora, 695-697 triricinoleoylglycerol, 26 tuliposide A, 269
trewiasine, 696, 697, 711 trisaccharide esters, 108 tuliposide B, 269
triacanthine, 700 trisporic acid B, 502 tumor, Ehrlich ascites, 210
 Index 757

tumor, human non-small cell lung, 420 Umbellularia cail/ornica, 340 veatchine, 673, 674
tumor-promoting substances, 402, 403 umbels, 135, 136 vegetables, 171, 306
(umon;, 209, 321, 402, 403, 511, 512, 546, Uncaria, 204, 206 velvetleaf, 309, 310, 697, 711
553,559,564,566,568,574,577,617,660, Uncaria gambia, 204, 481 venecurine, 645
671,695,696,711; see also antitumor 2-undecanone, 30 venereal warts, 120
substances, cancer, carcinomas, cell cultures, undecylamine, 513 Venezuela, 645
tumorigenic plants, tumor-promoting Ungnadia speciosa, 6, 14, 287, 298 venom, 179,343
substances United States, 35, 39, 52, 78, 84, 91, 92, 127, veno-occlusive disease, 552, 553
tumors, colon, 420 130, 136, 165,210,213,235,237,244,246, Vepris, 570, 573, 574
tumors, colo-rectal, 306 294,296,297,311,317,320,322,362,378, veratramine, 684, 686
tumors, crown gall, 239 383,390,396,460,549,559,561,582,615, veratric acid, 674
tumors, nasopharyngial, 591 646, 648, 673, 684, 705 veratridine, 675, 685, 686
tung, 35, 39, 74 unsaturation, 3, 16, 26 veratrine, 684, 686
tung nut, 244 uracil, 226 veratrole, 113, 124
tung oil, 244, 402 Uragoga, 611 Veratrum, 677, 684-686
turgorins, 123, 193 urea, 220, 221, 305 Veratrum alkaloids, 668, 677, 684-686, 690
turkey red, 89 uredospores, 110 Veratrum grandiflorum, 681, 684
Tumeraceae, 285, 286, 287 urinary antiseptics, 392 verazine, 677, 680, 681, 686
turnip, 306, 309 urine, 174,288 Verbena hybrida, 159
turnover, 324, 351, 510, 526, 574, 594 uronic acids, 456, 456 Verbena o/ficinalis, 355
turpentine, 312, 398, 412 ursolic acid, 346, 447, 452 Verbenaceae, 86, 88, 159, 337, 361, 364, 385,
turreanthin, 473 Urtica dioica, 517 405,406,413,415-418,442,447,458,655,
Turreanthus africanus, 473 Urticaceae, 88, 517, 563, 693, 700 666
tutin, 385, 670 urushiol, 68 verbenalin, 355
tyiocrebrine, 564 usambarensine, 652 verbenol, 343
Tylophora, 533, 563, 564, 576 uscharidin, 466 cis-verbenol, 343
Tylophora asthmatica, 571, 573 usnic acid, 58 verbenone, 343
tylophorine, 563, 564 usumbarensine, 652 verbenyl acetate, 343
tylophorinine, 564 uterine bleeding, 600 vernalization, 411
tyramine, 244, 515, 518, 522, 523, 579, 587, uterine contracting agents, 420, 600, 660 vemolepin, 389, 393
592, 620, 624 uterine muscle, 600 vernolic acid, 26, 27
Tyria jacobaea, 550 Utetheisa ornatrix, 551 vemolide, 392
tyrosine, 3, 64, 80, 94, 97, 101, 102, 104, 106, UV, see ultraviolet radiation Vernonia, 387, 389, 390
107,220,229,273,280,286,300,302,507, Uvaria, 67 Vernonia colorata, 392
509,522,523,564,579,587,591,595,608, Uvaria catocarpa, 175 Vernonia jlaccidifolia, 390
617,619,620,624-626,703,705 Uvaria zeylanica, 105 Vernonia gigantea, 390
L-tyrosine, 274, 275, 277, 290 Vernonia glauca, 390
tyrosine ammonia lyase (TAL), 107,509 vaccenate, 35 Vernonia hymenolepis, 389
L-tyrosine ammonia lyase (TAL), 107 Vaccinium, 171 Vernonieae, 387
tyrosine decarboxylase, 515, 599 Vaccinium myrtillus, 554 Veronica, 387
tyrosine hydrolase, 229 vacuoles, 9,13-15,131,151,152,155,177, versicolorin A, 65
tyrosine kinase, 145 186, 193,319,465,526,546,557,588,598, vertebrates, 510
629,631,652,705 verticillatine, 694
ubiquinone, 76, 86, 104, 125 vaginidiol, 135 vertigo, 640
Udoteaceae, 381, 420 valepotriates, 364, 365 vertine, 694
UDP-L-arabinose, 253 valerian, 353, 361, 364 vesicate, 137
UDP-D-galactose, 249 Valeriana, 353, 365 vesication, 307
UDP-galactose:diacylglycerol Valeriana edulis, 364 vesicles, 9, 596, 598, 618
galactosyltransferase, 23 Valeriana ojficinalis, 364, 670 Vespa, 343
UDP-D-galacturonic acid, 253, 260 Valeriana wallichii, 364 Vestia, 660
UDP-glucose, 162, 190, 196,249,256,266, Valerianaceae, 46, 353, 361, 364 vestitol, 184
267,276,277,293,296,299,303,335 Valerianella discoidea, 353 (- )-vestitol, 179
UDP-D-glucose, 249 Valerianella locusta, 353 ( - )-(3R)-vestitol, 179
UDP-glucose:aldehyde cyanohydrin ,B-glucosyl valerie acid, 35, 36 vestitone, 181
transferase, 282 valine, 234, 273, 274, 276, 282, 286, 287, 300, Vibumaceae, 361
UDP-glucose o-dihydroxycoumarin 7-0- 302,513 vicenin-2, 173
glucosyltransferase, 132 L-valine, 234 Vicia, 223, 226, 229, 280, 700
UDP-D-glucose-4-epimerase, 249 Vallesia,640 Vicia angustifolia, 287
UDP-glucosyl transferase, 276, 277 vallesiachotaman, 636, 638 Vicia Jaba, 48, 223, 229, 244, 309, 363, 623
UDP-D-glucuronic acid, 253 valonea, 195 Vida sativa, 223, 226, 232
UDP-D-xylose, 253 valpotriates, 353 vicianin, 254, 287
UDPG:sterol transglucosylase, 456 vanilla, 122 (R)-vicianin, 280, 287
UDPG:thiohydroximate glucosyltransferases, vanillic acid, 95, 113, 125, 126 vicianose, 266
303 vaniJIin, 122, 344 vicine, 700
ulcer, 420, 460, 462 vanillin assay, 212 Victoria, 516
ulceration, 420 Vanillosmopsis, 390 Vietnam. 379
Ulmaceae, 244 variation, 1,3-5,7,8, 10, 14,35,47,52, 121, Vigna unguiculata, 215, 217
ultraviolet light (UV), 1,4,42, 129, 131, 135, 136, 177, 198,206,212,213,286,287,294, vinblastine, 511, 645. 653, 654
137,138,145,159,177,179,188,188,212 305,311,337,338, 342, 395, 457, 480 Vinca, 637, 645
ultraviolet spectrophotometry, 1 varnishes, 413 Vinca minor, 640
ultraviolet-A radiation, 49, 135 vasicine, 570 vine amine, 640
ultraviolet -B radiation, 166 vasicinol, 570 ( + )-vincamine, 640
Ulva, 495 vasicinone, 570 Vincetoxicum, 563
Umbelliferae, see Apiaceae vasoconstriction, 517, 660 vincosan, 636, 638
umbelliferone, 130-135 vasodilation, 137,346,517,528,640,697 vincoside, 629
758 Index

vincristine, 506, 511, 645, 653, 676, 696 water cress, 304 xanthone, 65, 139, 148, 149
vindoline, 355, 630, 632, 634, 635, 645 water hemlock, 47 xanthone aglycones, 148
a-viniferin, 145 water stress resistance, 500 xanthophyll cycle. 497
e-viniferin, 145 water-beetles, 439 xanthophylls, 367, 494, 497, 501
(S)-5-vinyloxazolidine-2-thione, 307 watermelon, 499 X8nthorrheaceae, 88
Viola, 290 wattle, 204, 206 xanthotoxin, 113, 127, 128, 133-138
Violaceae, 290 wattle, black, 206 xanthotoxol, 133, 134
violaxanthin, 486, 494, 496, 497 wax ester, 51, 52, 54, 55 xanthoxin,501
E-violaxanthin, 501 wax, camauba, 52 xanthyletin, 130
9'-Z-violaxanthin, 501 wax, leaf. 53 Xeranthemum annuum, 26, 27
violaxanthin de-epoxidase. 497 wax, jojoba, 51, 52, 55 Xeranthemum cylindraceum, 280, 297
violaxanthin pool, 497 wax, sugar cane, 52 xeranthin, 280
viral activity 184, 191, 192 waxes, 16, 17, 51-55, 152, 191,422 x-ray crystallography, I, 610
viral infectivity, 562 webwonn, parsnip, 136, 137 D-xylan, 259
Virola, 514 Wedelia asperrima, 420 xylans, 260
virotoxins, 440 wedeloside, 420 Xyleborus ferrugineus, 442
virulence (Vir) gene, 123 weeds, 92, 99, 300, 310, 317, 351, 390, 391, meso-xylitol, 264
virus, 49, 105, 120, 121, 128, 129, 134, 520, 394, 396, 418, 466, 471, 472; also see Xylocarpus, 361, 481, 571
535,616,648; see also adenovirus, alligator weed, duckweed, Klamath weed, Xylocarpus granatum, 361,481
cytomegalovirus, retrovirus, RNA viruses locoweed, ragweed, smartweed Xylocarpus moluccensis, 361, 481
virus, avian myeloblastosis, 623 weevil, bean, 245 xylomollin,361
virus, herpes simplex, 210, 623, 648 weevil, bean, adult, 340 xylose, 172,248,249,456
virus, herpes simplex type I, 120 weevil, rice grain, 437 D-xylose, 248, 259, 260, 456
virus, human immunodeficiency (mv), 210 weevil, southern cow pea, 215, 217 6-0-P-D-xylosyl-D-glucose,254
virus, Moloney murine leukemia. 254 weevil, white pine, 340
virus, potato X, 651 Welwitschia, 140, 149 yage,660
virus, Rauscher leukemia, 623 West Indian cherry, 265 yarn, 33, 105, 147
virus, Rauscher NIH/3T3, 623 West Indies, 177 Yang, 460
virus, vaccinia, 648 wheat, 35, 41, 70, 98, 105, 115, 173,238,245, yangonin, 140
viruses, RNA, 648 361,415,501,517,553 yeasts, 261, 264, 270, 313, 428, 430, 441, 452,
viscotoxin A, 244 wheat germ, 245 517,520,582,583,601,613
viscotoxin B, 244 white snakeroot, 317, 321 yeasts, cactophilic, 583
viscotoxin, 244, 246 Wieland-Gumiich aldehyde, 643 yellow jessamine, 646
Viscum album, 244, 246 wighteone, 179 yellow rain, 379
vision, 344, 365, 382, 486, 497, 498 wildfire toxin, 237 yellow rice disease, 63
vision, insect, 498 wilfordic acid, 528 yellow starthist1e, 317, 322
visnadine, 137 wilIardiine, 700 yellow wooly bear, 390
Vitaceae, 140, 171 willow, 121, 122, 124 Yemen, 522
vitamin A, 312,497 wilt, verticillium, 378, 395 yerba mate, 213, 700
vitamin A aldehyde, 497 wine, 165, 171,210,708 yew, 676
vitamin B6, 508 Winteraceae, 387, 610 yingabaosu A, 392
vitamin C, 265 wintergreen, 122 ylangenes, 375
vitamin D, 437 witch hazel, 252 yobimban system, 640
vitamin K, 80 witchcraft, 537 yohirubine, 511, 628, 630, 640, 654
vitamin KJ. 80, 81 Withania somnifera, 539 yolks,498
vitamin K2, 81 woad,267 Yponomeuta cagnagellus, 269
vitamins, 167 wood, 11, 13,37,39,40,50,53-55,77-79, Yponomeuta evonymellus, 288
vitamins, group B, 264 85, 88, 92, 93, 105, 114, 115, 136, 143, 145, yuan-hoa, 404
vitellogenin, 221 149, 194, 340,473 yuanhuacine, 404
Vitex, 442 workers, grocery, 137 yuanhuarline, 404
vitexin, 162, 173 World War II, 649 yuanhuafme, 404
Vitis vinifera, 145, 171 wonn, see also bollwonn, budwonn, cutwonn, yuanhuatine, 404
(+ )-vitrenal, 376 giant silkwonn moth, homwonn, rootwonn, yuechukene, 575
vittae. 130, 136 roundwonn, silkwonn, tapewonn, webwonn, Zabrotes subfasciatus, 245
Voacanga africana, 635 wonnwood
Vochysiaceae, 533 wonn, sugar-beet wire, 36 Zaire,662
volatile fractions, 324, 326 wonn, tomato, 682 Zamia floridana, 294
vole, montaine meadow, 101 wonnwood, 346 Zanlhorhiza, 269
volkenin, 285, 286, 296 wort, 315 Zanthoxylum, 569, 570, 575, 610, 662
vomiting, 452, 612, 697 wot tip glycoside, 459 Zanthoxylum chalybaea, 573
vomiting sickness, 222 wound healing, 591 Zanthoxylum coco, 573
Vonones sayi, 80 wound infections, 591 Zanthoxylum holstii, 573
Vouacapoua, 145 wounds, vii, 8, 32, 39, 40, 104, 319, 324, 339, Zea, 65, 70, 101
342, 398, 420, 445 Ze. mays, 65, !O5, 173,435,504,700,703
walking stick, 341 Wrightia tomentosa, 686 zearalenol, 70
wallflower, 309 Wunnbaeiodeae, 617 zearalenone, 70
walnut, 83, 265 wyerone,48 zeatin,7oo
Waltheria, 700 wyerone epoxide, 48 trans-zeatin, 700
warburgana1, 379, 380, 419 zeaxanthin, 494, 496-498
Warburgia stuhlmannii, 379 xanthine, 700, 702 zeaxanthin epoxidase, 497
Warburgia ugandensis, 379 xanthine alkaloids, 700 zierin, 280, 287, 297
warlarin, 132, 138 xanthine base, 692 (S)-zierin, 280
Washington, 338 xanthinin, 389 zierinxyloside, 280
wasps, 41, 53, 54, 177, 343, 514 Xanthium, 389 zinc, 242, 543
waste product hypothesis, 1,5,7 Xanthocercis, 253 Zingiber officinale, 114
 Index 759

Zingiberaceae, 87, 88, 114, 179,337 zoapatie, 420 Zygaena, 289

zingiberene, 30 zombies, 537 Zygaenajilipendulae, '517,529
ziziphin, 700 Zonocerus variegatus, 290, 551, 564 Zygaena lonicerae, 703
zizyphi fructus, 700 zooparasites, 533 Zygaena trifolii, 9
Zizyphus, 610, 700 Zosteraceae, 533 Zygomycetes, 502
Zizyphus jujuba, 460, 700 zwitterions, 217, 705 Zygophyllaceae, 120, 458, 459, 569, 570, 576,
zoapatanoi, 420 Zygadenus, 677 660