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Diterpenes From Gorgonian Corals
Diterpenes From Gorgonian Corals
Diterpenes From Gorgonian Corals
REVIEW
Introduction
Suborder Scleraxonia
Family Anthothelidae
Family Briareidae
Family Subergorgiidae
Suborder Holaxonia
Family Acanthogorgoniidae
Family Gorgoniidae
Family Paramucidae
Family Plexauridae
Suborder Calcaxonia
Family Ellisellidae
Family Primnoidae
Conclusions
References
1 Introduction
Gorgonian octocorals (order Gorgonacea) represent a diverse
group of Cnidaria of great interest to the natural products
community. Tropical reefs are often dominated by these organisms, whose taxonomic identifications have been described as
perplexing and often exasperating by F. M. Bayer (1961) the
author of The shallow-water octocorallia of the West Indian
region. Several reviews focused on various aspects of the terpene
chemistry of corals have been published, with the most recent
comprehensive review on gorgonian natural products reported in
1995.1 Gorgonians belong to the class Anthozoa, the subclass
Octocorallia and the order Gorgonacea, which is composed of
a
Department of Chemistry, Atlantic Veterinary College, University of
Prince Edward Island, Charlottetown, Prince Edward Island, C1A 4P3,
Canada. E-mail: rkerr@upei.ca; Fax: +1 902 566 7445; Tel: +1 902 566
0565
b
Department of Biomedical Sciences, Atlantic Veterinary College,
University of Prince Edward Island, Charlottetown, Prince Edward
Island, C1A 4P3, Canada
Suborder Scleraxonia
Fabrice Berru!
e was born in
Tours, France, in 1977 and
graduated in chemistry in 2000
at
the
Ecole
Nationale
Sup!
erieure de Chimie de Montpellier. He received his Ph.D.
from the University of Nice
where he studied the isolation
and purification of novel antitumoral metabolites from marine
sponges. He is currently a postdoctoral researcher with Prof.
Russell Kerr at the University of
Fabrice Berru!e
Prince Edward Island. His
research interests are focused on
the relationship between marine invertebrates and their associated
microorganism community, and the ability of symbiotic microbes
to produce bioactive natural products.
elucidated by spectroscopic methods, and the structure of excavatolides C (63) and E (65) were further confirmed by X-ray
crystallography.36
Briareum polyanthes. From the non-polar extract of Bermudan
samples of Briareum polyanthes, a novel diterpene hydrocarbon,
emmottene (128) was isolated, the structure of which was elucidated on the basis of detailed spectroscopic data.37 A study of
a Puerto Rican collection of B. polyanthes afforded thirteen new
eunicellin-type diterpenoids, briarellins 129140 and polyanthellin A (141), along with five asbestinane-related diterpenes
(142146) and one briarane-type diterpene (147).38,39 This study
led to the revision of the structure of four previously reported
asbestinin analogues, asbestinin-10, asbestinin-20, asbestinin-21
and 11-acetoxy-4-deacetoxyasbestinin F.
Briareum spp. Bioassay-guided fractionation of the dichloromethane extract from an unidentified species of Briareum has
afforded two new briarane derivatives, violides A and B (148,
149). The structures of these secondary metabolites were determined on the basis of detailed NMR spectroscopic analysis.40
Three new briarane diterpenoids (150152) were identified from
the same gorgonian species, and compounds 150 and 151
exhibited significant cytotoxicity against the human tumor
cell line P-388 with ED50 values of 0.61 and 1.12 mg/mL,
3 Suborder Holaxonia
3.1 Family Acanthogorgoniidae
Acalycigorgia inermis. Four new diterpenoids possessing the
xenicane skeleton, acalycixeniolides DG (249252), have been
isolated from Acalycigorgia inermis from Keomun Island, Korea.
This journal is The Royal Society of Chemistry 2009
These metabolites were identified by the interpretation of spectroscopic data, and compound 251, the most potent of these
metabolites, exhibited cytotoxicity against the human leukemia
cell line K562 with a LC50 of 0.2 mg/mL.58,59 Five new xenicane
metabolites, acalycixeniolides HL (253257), were reported
from a separate collection of A. inermis, and acalycixeniolide I
showed the best cytotoxicity against K562 (LC50 of 1.2 mg/mL).60
In this study, 9-deoxyxeniolide A (258),61 previously reported to
possess antibacterial activity, was also shown to exhibit potent
cytotoxicity against the same cell line (LC50 0.04 mg/mL).
Acalycigorgia sp. A series of eunicillin-type diterpenes was isolated from the octocoral gorgonian Acalycigorgia sp. collected by
the Australian Institute of Marine Science scientists in Thailand.
The structure of compound 259a was determined by 2D NMR
analysis, and a series of homologues with the same terpene core
as 259a but with a fatty acid side chain from 6 to 20 carbons
(259b) were identified using tandem mass spectroscopy.62
3.2 Family Gorgoniidae
Eunicella cavolinii. Massileucellins AC (260262) were isolated
from Eunicella cavolinii harvested near Marseille, France. Identification of the structures, which possess two oxa bridges in the
eunicellane skeleton, was based on NMR and MS data.63
A further chemical investigation of the extracts from Eunicella
cavolinii described above led to the purification and characterization of eight new eunicellane-type diterpenes (263270).64
From an acetone extract of a Mediterranean collection of
Eunicella cavolinii, one new eunicellin-type diterpene (271) was
isolated and identified by interpretation of spectroscopic data.65
Eunicella labiata. Five new diterpenoids belonging to the eunicellan class, labiatamides AB (272273) and labiatins AC
Nat. Prod. Rep., 2009, 26, 681710 | 689
a new pseudopteroid, bipinnapterolide A (325), with the rare 2,3epoxy-1,4-dione moiety, were reported from P. bipinnata
collected off San Andres Island, Colombia. Their structures were
determined through a combination of spectroscopic and X-ray
crystallographic methods.86 From the same location, two new
diterpenes a seco-furanocembranolide (326) and the highly
oxygenated cembranolide bipinnatolide K (327) were isolated
and identified by detailed spectroscopic methods.87 An investigation of P. bipinnata collected near San Andres Island
(Colombia) has resulted in the identification of a new diterpene
named verrilin (328), which possesses the novel verrillane carbon
skeleton.88
In 2000, a report described the novel bisditerpenoid ether
biskallolide A (329), which appears to be produced by dehydration of two units of kallolide A (330).88 This report also
indicated that 2-C-alkoxylation and 2-C acyloxylation of kallolide A occur spontaneously in certain solvents. The chemical
structures of kallolide A (330) including the dimeric ether 329
were established by detailed analysis of the spectral data and
comparisons with kallolide A.89 The structures of six new bilactone diterpenoids, caucanolides AF (331336), were elucidated
on the basis of spectroscopic data. Caucanolide A (331) and D
(334) demonstrated significant in vitro antiplasmodial activity
against chloroquine-resistant Plasmodium falciparum W2 with an
IC50 value of 15 mg/mL.90 Moreover, caucanolide B (332)
constitutes the only example from Nature of a secondary
metabolite possessing N1,N1-dimethyl-N2-acylformamidine
functionality. A unique oxapolycyclic diterpenoid, bipinnapterolide B (337), was purified from Colombian samples of
P. bipinnata collected from Old Providence Island. The structure
was deduced from 2D NMR studies and confirmed by singlecrystal X-ray diffraction.91 Compound 337 exhibited moderate
the serrulatane ring system to the amphilectane skeleton. Secopseudopterosins were shown to be precursors in pseudopterosin
biosynthesis, and their dehydro-derivatives, the amphilectosins,
were demonstrated to be the key intermediate linking these two
classes of diterpenes.107 This study also provided an explanation
for the occurrence of pseudopterosins with a- and b-isobutenyl
substituents. cis-Amphilectosin (378) gave rise specifically to
a pseudopterosin with the b-isobutenyl group, while the transderivative (379) afforded the a-isobutenyl pseudopterosin 380
in biosynthetic experiments. Elisabethatrienol (370) has been
reported from a specimen of P. elisabethae collected in Colombia,101 suggesting that this may be involved in the conversion of
the cyclase product (374) to erogorgiaene; however, this has not
been confirmed experimentally.
The question of the inducibility of diterpene biosynthesis in
gorgonians has been addressed in two systems. Firstly, various
This journal is The Royal Society of Chemistry 2009
carbocyclic skeleton.123 The structures and relative configurations of cumbiasins were elucidated by interpretation of
2D-NMR and mass spectroscopic data.
In 2000, elisabatin C (405) and p-benzoquinone 406 were
reported as new representatives of the amphilectane and
serrulatane families of diterpenes, respectively. In addition,
elisapterosin C (407) and two new related amphilectane nor- and
tetrisnor-diterpenes, 4-(acetyl)amphilectolide (408) and amphiphenalone (409), were identified from the same organism.124 In
2003, the structures of elisabatin C (405) and elisabatin B (389)
were established by X ray analysis.115 A novel C40 bisditerpene
(410) was reported to co-occur with erogorgiaene (375) and
7-hydroxyerogorgiaene (376).105 The bisditerpene is apparently
derived from the alcohol 376.
A new diterpene possessing an unprecedented perhydroacenaphthene carbon skeleton was isolated and characterized
by combined spectroscopic data. This compound, named ileabethin (411), contains a fully substituted aromatic ring, whose
substitution pattern resembles that of the pseudopterosin class of
diterpene glycosides. Moreover, the isobutenyl side chain typically found in P. elisabethae metabolites appears in 411 masked
as a spiro gem-dimethyldihydrofuran moiety.125 The structure
and synthesis of a novel serrulatane diterpene, O-methylelisabethadione (412), has been reported.126 This publication also
cytotoxic activity against several cancer cell lines from the NCI
60 cell-line tumor panel.
Eunicea tourniforti. Five new diterpenoids (477481) were
isolated from the gorgonian Eunicea tourniforti collected off the
southwest coast of St. Thomas, US Virgin Islands, elucidation
of their structures being achieved by interpretation of 1D and
2D NMR data.149 From collections of E. tourniforti along the
southwest coast of Barbados, four new cembrane diterpenes
(482485) were reported.150
This journal is The Royal Society of Chemistry 2009
Suborder Calcaxonia
Gorgonella umbraculum. A new briarane diterpene, umbraculolide A (532), was isolated from Gorgonella umbraculum collected
from Tuticorin, India.161 A second collection of G. umbraculum
collected from Tamil Nadu, India, led to the isolation of three
new umbraculolides BD (533535), which were characterized by
interpretation of spectroscopic data.162
Junceella fragilis. Gorgonian corals of the genus Junceella are
common in the subtropical and tropical waters of the IndoPacific Ocean and are well known as a source of highly oxidized
Conclusions
genera and likely also a consequence of the high natural abundance of these gorgonians in accessible reef habitats. A range of
biological activities have been reported for diterpenes derived
from gorgonians over the past 13 years, including: anti-cancer
(most common), anti-inflammatory, antiplasmodial, antibacterial, antiviral, antimalarial and antioxidant, as well as ecologically
relevant activities such as fish-feeding deterrence.
There is substantial structural diversity of diterpenes isolated
from gorgonians. Compounds reported during the period
covered by this review can be classified as belonging to one of
40 skeletal classes (Fig. 3). While some of these natural products
were previously known, a substantial number represent new
classes of diterpenes unique to organisms of the marine environment. The classification of diterpenes in the terpene literature
is somewhat confusing and many new compounds are very
similar to ones previously identified.
These classes of diterpenes contain carbocyclic rings with 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13 and 14 carbons as well as acyclic skeletons
with novel branching patterns, indicating significant diversity in
terpene biosynthesis in gorgonians. Fig. 4 shows the distribution
of the nine most common carbon skeletal types (amphilectane,
briarane, cembrane, cladiellane, dolabellane, gerenylgeranane,
pseudopterane, serrulatane and xenicane) amongst the genera
studied. Details of the skeletal types isolated from the genus
Pseudopterogorgia clearly the source of the greatest structural
diversity are shown in Fig. 5. Examples of diterpenes spanning
28 of the 40 diterpene classes have been isolated from
Pseudopterogorgia spp. during the time-frame of this review.
There are interesting correlations between certain phylogenetic
groups of gorgonians and classes of diterpenes. For instance, the
amphilectane skeleton of the pseudopterosins, and the biosynthetically related serrulatane framework of the seco-pseudopterosins, have only been reported from one species,
P. elisabethae. Further, dolabellane diterpenes are restricted to
the genus Eunicea, pseudopteranes are restricted to the genus
Pseudopterogorgia, and xenicane diterpenes have only been
reported from Acalycigorgi inermis. The organisms described in
this review belong to the order Gorgonacea and are representatives of three suborders, Scleraxonia, Holaxonia and Calcaxonia.
As is evident from Fig. 4, the diterpene chemistry of the Scleraxonia is dominated by briaranes and the closely related cladiellanes.
With the exception of two compounds from Plumarella sp.,
gorgonians of the suborder Calcaxonia only produce diterpenes of
the briarane class. While briaranes are common in the suborders
Scleraxonia and Calcaxonia, members of the Holaxonia do not
contain briaranes but rather contain terpenes with cembrane and
geranylgeranane skeletons. Thus, there appear to be some key
differences in the classes of terpene skeletons at the suborder level,
and progressively less at the levels of family and genus.
A report by Dorta and co-workers suggests that the oxidation
of C-18 of furanocembranolides may be useful as a chemotaxonomic marker for several genera of octocorals,71 and this review
suggests that diterpene chemistry may be of use in certain cases in
assisting with taxonomic assignments at the levels of suborder,
family and possibly genus. To further develop the classification
of gorgonians, various molecular methods are now being used
for taxonomic purposes, and such approaches have recently been
applied to understand relationships within the family Plexauridae.189 It therefore appears that a combination of molecular,
chemical and classical morphological analysis should be used
Fig. 4 Classification of carbon skeletal types (amphilactane, briarane, cembrane, cladiellane, dolabellane, gerenylgeranane, pseudopterane, serrulatane
and xenicane) by genus of gorgonian. A total of 592 diterpenes have been reported from gorgonians in the period 1995 to April 2008. Numbers in
parentheses indicate the total number of terpenes isolated from the associated phylogenetic groups and skeletal classes.
6 References
1 A. D. Rodriguez, Tetrahedron, 1995, 51, 45714618.
2 D. Banjoo, A. R. Maxwell, B. S. Mootoo, A. J. Lough, S. Mclean
and W. F. Reynolds, Tetrahedron Lett., 1998, 39, 14691472.
3 S. A. Look, W. Fenical, D. Van Engen and J. Clardy, J. Am. Chem.
Soc., 1984, 106, 50265027.
4 D. Maharaj, K. O. Pascoe and W. F. Tinto, J. Nat. Prod., 1999, 62,
313314.
5 E. O. Pordesimo, F. J. Schmitz, L. S. Ciereszko, M. B. Hossain and
D. Van der Helm, J. Org. Chem., 1991, 56, 23442357.
6 R. Dookran, D. Maharaj, B. S. Mootoo, R. Ramsewak, S. McLean,
W. F. Reynolds and W. F. Tinto, J. Nat. Prod., 1993, 56, 10511056.
7 B. Cinel, M. Roberge, H. Behrisch, L. van Ofwegen, C. B. Castro
and R. J. Andersen, Org. Lett., 2000, 2, 257260.
8 M. Roberge, B. Cinel, H. J. Anderson, L. Lim, X. Jiang, L. Xu,
C. M. Bigg, M. T. Kelly and R. J. Andersen, Cancer Res., 2000,
60, 50525058.
9 R. Britton, M. Roberge, H. Berisch and R. J. Andersen, Tetrahedron
Lett., 2001, 42, 29532956.
10 O. Taglialatela-Scafati, U. Deo-Jangra, M. Campbell, M. Roberge
and R. J. Andersen, Org. Lett., 2002, 4, 40854088.
11 D. Banjoo, B. S. Mootoo, R. S. Ramsewak, R. Sharma, A. J. Lough,
S. McLean and W. F. Reynolds, J. Nat. Prod., 2002, 65, 314318.
12 O. Taglialatela-Scafati, K. S. Craig, D. Reberioux, M. Roberge and
R. J. Andersen, European Journal of Organic Chemistry, 2003, 3515
3523.
13 P. Sung, P. Chang, L. Fang, J. Sheu, W. Chen, Y. Chen and M. Lin,
Heterocycles, 2005, 65, 195204.