A

biosynthetic approach of medicinal

natural products
(Chemistry of drugs)

Building blocks
Metabolic pathways
Secondary metabolites
Primary metabolites
Biosynthesis Dr Mohannad Qazzaz
 Biosynthesis

u Biosynthesis: Formation of a chemical compound by a living

organism.
Or

u Biogenesis: Production or generation of living organisms from other

living organisms.
Dr Mohannad Qazzaz
 u The living organism may be considered as a biosynthetic
laboratory not only for chemical compounds (carbohydrate,
proteins and fats) that are utilized as food by humans and
animals

But also for a multitude

of compounds such as
(glycosides, alkaloids
and terpenes) that exert
a physiologic effect.

Dr Mohannad Qazzaz
 u Metabolites are organic compounds synthesized by organisms
using enzyme-mediated chemical reactions called metabolic
pathways.

Biosynthesis
(Metabolic process)

Chemical compounds
(Metabolities)

Dr Mohannad Qazzaz
Dr Mohannad Qazzaz
Dr Mohannad Qazzaz
 u Metabolites are compounds synthesized by plants for both
essential functions, such as growth and development (primary
metabolites).
Dr Mohannad Qazzaz
 u Primary metabolites have functions that are essential to
growth and development and are therefore present in all
plants. It usually performs a physiological functions in the
organism (i.e. an intrinsic function).
u A primary metabolite is typically present in many organisms
or cells. It is also referred to as central metabolite, which has
an even more restricted meaning (present in any autonomously
growing cell or organism).

Dr Mohannad Qazzaz
u primary metabolites:
Comprise many different
types of organic compounds,
including, but not limited to,
carbohydrates, lipids, nucleic
acids and proteins.
They are found universally in
plant kingdom because they
are the components or
products of fundamental
metabolic pathways or cycles
such as glycolysis and the
Krebs cycle.

Dr Mohannad Qazzaz
Dr Mohannad Qazzaz
 u Examples of primary metabolites include energy rich fuel
molecules, such as sucrose and starch, structural components
such as cellulose, informational molecules such as DNA
(deoxyribonucleic acid) and RNA (ribonucleic acid), and
pigments, such as chlorophyll.

u In addition to having fundamental roles in plant growth and

development, some primary metabolites are precursors
(starting materials) for the synthesis of secondary metabolites.

Dr Mohannad Qazzaz
Dr Mohannad Qazzaz
 u A secondary metabolite is typically present in a
taxonomically restricted set of organisms or cells (Plants,
Fungi, Bacteria...).

u Secondary metabolites are organic compounds that are not

directly involved in the normal growth, development, or
reproduction of an organism.

u Unlike primary metabolites, the absence of secondary

metabolites does not result in immediate death, but rather in a
long-term impairment of the organism's survivability,
fecundity, or aesthetics, or perhaps in no significant change at
all.

Dr Mohannad Qazzaz
 u Secondary metabolites often play an important role in:
§ plant defense against herbivory and other interspecies
defenses.
§ Humans use secondary metabolites as medicines, and
flavorings.

Dr Mohannad Qazzaz
Dr Mohannad Qazzaz
u Secondary metabolites largely fall into three classes of
compounds:
§ Alkaloids,
§ Terpenoids,
§ Phenolics.
However, these classes of compounds also include primary
metabolites, so whether a compound is a primary or secondary
metabolite is a distinction based not only on its chemical
structure but also on its function and distribution within the plant
kingdom.

Dr Mohannad Qazzaz
u Many thousands of secondary metabolites have been isolated
from plants, and many of them have powerful physiological
effects in humans and are used as medicines.
u These metabolites give plant & animal drugs their therapeutic
properties.
u Drugs are used as such in their crude form or they may be
extracted, the resulting principles being employed as
medicinal agents. Therefore any study of pharmacognosy must
fulfill a thorough consideration of these entities (constituents),
however, because the plant or animal is composed of many
chemical compounds, it is a common practice to recognize
those compounds that are responsible for the therapeutic effect
& to call them active constituents.
Dr Mohannad Qazzaz
u These active constituents are differentiated from inert
constituents, which also occur in plant and animal drugs.
Cellulose, lignin, suberin, & cutin are usually regarded inert
matter in plant drugs; in addition, starch, albumin, coloring
matters & other substances may have no definite
pharmacologic activity & also are considered inert
constituents. In animal drugs, keratin, muscle fiber &
connective tissue are regarded as inert.

I A
A
I I I
Dr Mohannad Qazzaz
A
u Often the presence of inert substances may modify or prevent
the absorbability or potency of the active constituents. To
eliminate the undesirable effects of inert matter in crude drug
or its preparation, active principles are extracted, crystallised
& purified for therapeutic use. These constituents have been
referred to as secondary metabolites.

Dr Mohannad Qazzaz
Dr Mohannad Qazzaz
 The building blocks

u The building blocks for secondary metabolites are derived from

primary metabolism.

u The most important building blocks employed in the biosynthesis

of secondary metabolites are derived from the intermediates:
1. Acetyl coenzyme A (acetyl-CoA)
2. Mevalonic acid
These are utilized respectively in the
3. Shikimic acid acetate,
4. 1-deoxyxylulose 5-phosphate shikimate,
mevalonate,
5. Amino acids and deoxyxylulose phosphate pathways.

Dr Mohannad Qazzaz
Mevalonic acid

Dr Mohannad Qazzaz
 1. Acetate pathway
Ø 4 acetate groups when linked together they gives rise to the
formation of 6-methyl salicylic acid.

4x

Ø Acetate occupies a central position in relation to the general

metabolism of plants. Acetate condensation occurs in many
possible routes which give rise to variety of aromatic
compounds.
Dr Mohannad Qazzaz
 • The form in which acetate is used in most of its important
biochemical reactions is acetyl coenzyme A (acetyl-CoA).

• Acetyl-CoA is formed by oxidative decarboxylation of the

glycolytic pathway product pyruvic acid.

Dr Mohannad Qazzaz
• Important secondary metabolites formed from the acetate
pathway includes:

Phenols,
Prostaglandins,
Macrolide antibiotics

Dr Mohannad Qazzaz
2. Mevalonate pathway

u Mevalonic acid is itself formed from three molecules of

acetyl-CoA, but the mevalonate pathway channels acetate into
a different series of compounds than does the acetate pathway.

u Acetate-mevalonic acid pathway: mevalonate pathway to

isopentenyl diphosphate.

u Terpenoids is the major product of Mevalonate

Dr Mohannad Qazzaz
 Isopentenyl diphosphate is the precursor of terpenoids.
Dr Mohannad Qazzaz
3. Deoxyxylulose phosphate pathway

u Deoxy-xylulose phosphate arises from a combination of two

glycolytic pathway intermediates, namely pyruvic acid and
glyceraldehyde 3-phosphate.

u The mevalonate and deoxyxylulose phosphate pathways are

together responsible for the biosynthesis of a vast array of
terpenoid and steroid metabolites.

Dr Mohannad Qazzaz
Dr Mohannad Qazzaz
Dr Mohannad Qazzaz
 4. Shikimic acid (Shikimate) pathway
u The shikimate pathway (shikimic acid pathway) is a seven
steps metabolic route used by bacteria, fungi, algae, some
protozoan, and plants for the biosynthesis of folates and
aromatic amino acids (phenylalanine, tyrosine, and
tryptophan).

Shikimic acid Phenylalanine Tyrosine

Dr Mohannad Qazzaz
• phosphoenolpyru
vate (from
glycolysis)
• D-Erythrose 4-
phosphate (from
the pentose
phosphate cycle)

Dr Mohannad Qazzaz
 Ø The path gives the aromatic substitution patterns para-
hydroxy, ortho-dihydroxy, or 1,2,3 trihydroxy of meta
substitution in polyphenols from acetate
Ø Shikimic acid through a series of phosphorylated
intermediates yield chorismic acid which is an important
branch-point intermediate.
Ø One branch leads to anthranilic acid then to tryptophan.
Ø The other leads to prephenic acid which is the last
nonaromatic compound in the sequence.
Ø Prephenic acid can be aromtized in 2 ways:
§ The first proceeds by dehydration and simultaneous
decarboxylation to yield phenyl pyruvic acid, the direct
precursor of phenylalanine.
§ The second occurs by dehydrogenation and
decarboxylation to give p-hydroxy phenyl pyruvic acid ,
the precursor of tyrosine.
Dr Mohannad Qazzaz
 The shikimate pathway leads to a variety of:
1. Phenols
2. Cinnamic acid derivatives
3. Lignans
4. Alkaloids

Alkaloids derived from phenyl alanine, tyrosine Biosynthetic pathway to flavonoid aglycones
and their derivatives

Dr Mohannad Qazzaz
5. Amino acids pathway

u Peptides, proteins, alkaloids and many antibiotics are derived

from amino acids.

u The aromatic amino acids phenylalanine, tyrosine, and

tryptophan are themselves products from the shikimate
pathway.

Dr Mohannad Qazzaz
u Secondary metabolites can be synthesized by combining several
building blocks of the same type, or by using a mixture of
different building blocks.
u Many of secondary metabolites also contain one or more sugar
units in their structure.

u To appreciate how a natural product is elaborated, it is of

value to be able:
1. To divide its structure into the basic building blocks from which it
is made up.
2. To propose how these are mechanistically joined together.

Dr Mohannad Qazzaz
Structural type of building blocks
1. C1: the simplest of the building blocks:
• Is composed of a single carbon atom, usually in the form of a
methyl group.
• Most frequently it is attached to oxygen or nitrogen, but
occasionally to carbon.
• It is derived from the S-methyl of L-methionine.

Dr Mohannad Qazzaz
Structural type of building blocks
2. C2:
• A two-carbon unit
• May be supplied by acetyl-CoA. Acetyl-CoA is first converted
into the more reactive malonyl-CoA before its incorporation.

Dr Mohannad Qazzaz
3. C5:
• The branched-chain C5 “isoprene” unit is a feature of
compounds formed from mevalonate or deoxyxylulose
phosphate.

Dr Mohannad Qazzaz
4. C6C3:
• This refers to a phenylpropyl unit.
• Is obtained from the carbon skeleton of either L-phenylalanine
or L-tyrosine.

Dr Mohannad Qazzaz
5. C6C2N: again, this building block is formed from either L-
phenylalanine or L-tyrosine.

6. Indole.C2N:

Dr Mohannad Qazzaz
7. C4N: the C4N unit is usually found as a heterocyclic pyrrolidine
system and is produced from L-ornithine (non-protein amino
acid).

8. C5N: it is produced by using L-lysine and the unit tends to be

found as a piperidine ring system.

Dr Mohannad Qazzaz
 u Simple examples of how compounds can be visualized as a
combination of building blocks are shown in Figure below.

Dr Mohannad Qazzaz
The construction mechanisms
u Natural product molecules are biosynthesized by a sequence of
reactions which are catalyzed by enzymes.
u Enzymes have the power to affect these transformations:
1. More efficiently and more rapidly than the chemical analogy.
2. Under very much milder conditions.
3. Carry out reactions in a stereospecific manner.

Dr Mohannad Qazzaz
1. Alkylation reactions
2. Wagner-Meerwein rearrangements
3. Aldol and Claisen reactions
4. Schiff base formation and the Mannich reaction
5. Transamination
6. Decarboxylation reactions
7. Oxidation and reduction reactions
8. Phenolic oxidative coupling
9. Glycosylation reactions
Dr Mohannad Qazzaz
Biosynthesis of Anthraquinone glycosides:

Sugar + aglycone = glycoside

u Knowledge of the biosynthesis has been obtained from studies
of microorganisms. Feeding of labeled acetate to Penicillium
islandicum , a species that produces several anthraquinone
derivative, revealed that head to tail condensation of acetate
units. H C H2
C
H2
C
H2
C HC
3
H
C
2 H
C
2 H
C
2
3
C C C C C C

O O O O O O

u A poly – β – ketomethylene acid intermediate is probably first

produced and then gives rise to the various oxygenated
aromatic compounds after intra molecular condensation.
Dr Mohannad Qazzaz
 H2 H2 H2 H2 H2 H2
H3C C C C H3C C C C
C C C C C C

O O O O O O

H2 H2 H2 H2 H2 H2
H3C C C C H3C C C C
C C C C C C

O O O O O O

Dr Mohannad Qazzaz
u Anthranols and anthrones are likely intermediates in the
formation of anthraquinones.
u The emodin like anthraquinones is formed in the higher plants
by a similar pathway.
u The transglycosylation reaction, which creates a glycoside
probably occur at a late stage in the pathway after the
anthraquinone molecule has been formed.

Dr Mohannad Qazzaz
Biosynthesis of Saponin glycosides

u The main pathway for both steroid and triterpenoid saponin

glycosides are similar.
Acetate Acetyl COA Aceto acetate COA
sequalene cholesterol Steroid Steroidal saponins

or from

Sequalene pentacylclic compounds ( triterpenoid )

Dr Mohannad Qazzaz
 Biosynthesis of Nicotine:
COOH
ornithine Putrescine N-methyl transferase
H decarboxylase
H2N NH2 H2N NH2 S-adenosyl metionine
Putrescine
Ornithine

N-methyl Putrescine
oxidase
+
CH
N
H2N NHCH3 NHCH3
O CH3
N-methyl Putrescine N-methyl aminobutanol
N-methyl Pyrrolonium ion

O CH2OH COOH
HO
H2N CH C OH COOH
CH OH
CH2 +
N COOH
C O CH2OP N COOH
Quinolinic acid
OH
Aspartic acid Glyceraldehyde
3-phosphate

COOH
-CO2

N
Nicotinic acid

COOH
COOH
-CO2
+ + N
-H
N
CH3
N
CH3 N

N
CH3
Dr Mohannad Qazzaz N
Nicotine
 Biosynthesis of tropine and hyoscyamine:
COOH
H2N NH2 COOH
Ornithine
NH2
phenyl alanine
COOH
S-adenosyl methionine

+ O
N
CH3

N-methyl pyrollonium ion COOH

O
OH
C _ CH3 2 (CH3COOH)
_ COOH
+ CH
N CH2OH
C_CoA C
CH3
O Tropic acid
H

H3CN
O
H
+ C-CH3
O
N CH CO
H3CN CH2OH
CH3 C-CoA CH
O OH

-CO2 Tropine
-CoA Hyoscyamine

N
H 3C
C COCoA
Dr Mohannad Qazzaz O
Dr Mohannad Qazzaz
Dr Mohannad Qazzaz
Dr Mohannad Qazzaz