Basics of Natural Products

(PHG220)

1
Glycosides
(Part 1)
 Definition

Glycosides are non-reducing substances, which result from

the establishment of a bond between a sugar
(Monosaccharide or Oligosacchaide) and a non-sugar
(aglycone or genin)
 Classification
According to the glycosidic linkage, the following glycosides can
be distinguished:
1- O-glycoside:
If this bond involves an alcoholic or phenolic hydroxyl group of the aglycone
(such as the case of saponins, flavonoids among others)
2- N-glycoside:
If the bond involves a nitrogen-containing function in the aglycone such as the
case of nucleosides
 Classification
3- C-glycoside:
in which the saccharide-aglycone bond is established directly
between two carbon atoms (For example aloin of aloe).
4- S-glycoside:
the sulfur-containing analogues of O-glycoside, and known as
glucosinolates.
 Classification
According to the nature of the aglycone (chemical structure of the
aglycone), glycosides may conveniently be classified to the :
1- Steroidal glycosides
2- Antraquinone glycosides
3- Flavonoid glycosides
4- Saponine glycosides
5- Thioglycosides (Sulphur gly.)
6- Cyanogenitic glycosides
7- Phenolic glycosides
8- Alcoholic glycosides
9- Aldehydic glycosides
 Pharmacological activity
The physiological action of glycosides is intimately associated with and due to
the aglycone.
Role of sugar: stabilization and solubility, modify pharmacodynamic properties
of the aglycone.
Some of them affect the heart e.g. digitoxin.
Some are laxative e.g. sennosides.
Others are analgesics e.g. salicin. Salicin
some act against capillary fragility e.g. rutin, hesperidin.
Others are antiinfalmmatory e.g. glyccerhezin.

Salix alba ‫الصفصااف‬

Functions of glycosides in the plant

They represent stored food reserve (sugar reserve).

They play an important regulating roles in plants.
They may serve as means of detoxifying many substances by
transforming them to glycosides.
Some glycosides have a role of defense against the invasion of
the tissues by microorganisms subsequent to wounding.
(many aglycones are antiseptic).
Steroidal Glycosides
(Cardiac glycosides)
 What are Steroidal Glycosides ???

Definition:
Cardiac glycosides are C23 or C24 steroid derivatives which exert
on the failing heart a slowing and strengthening effect.
They constitute a well-defined and highly homogeneous group
from a structure, as well as pharmacological standpoint.

Structure:
The structures are remarkably homogenous, and comprise a
steroidal aglycone of the (C23) cardenolide or of the (C24)
bufadienolide, and a sugar moiety.
Structure of the aglycones:
- Have in common the classic, tetracyclic, steroidal nucleus.
- A, B, C, and D rings normally have a cis-trans-cis configuration
- All aglycones have two hydroxyl groups.
- Presence a  substituent (an unsaturated lactone) of at C-17.
- The size of the lactone ring distinguishes two groups of glycosides:
1- Cardenolides with an ,-unsaturated -lactone (butenolide)
2- Bufadienolides with a di-unsaturated -lactone (pentadienolide)
O O
12 CH3 R 21
18 R= 23 Cardenolide
17 20
11
C 13
22
1 CH3 9 H 14 D 16
19
2
10
H 8 15 O O
A OH 21
3 5
B 7 R=
24
Bufadienolide
20
HO 4 6 23
H 22
Structure of the Sugar Moiety:
The majority of the saccharides found in cardiac glycosides are
highly specific. They are:

1- 6-deoxyhexoses (such as L-rhamnose, D-fucose)

2- 6-deoxy-3-methylhexoses (such as L-thevetose, D-digitalose)
3- 2,6-dideoxyhexoses ( such as D-digitoxose)
4- 2,6-dideoxy-3-methylhexoses (such as L-oleandrose, D-
cymarose)
5- Glucose may also be found in the glycosides

Note, that one hydroxyl group on a sugar can be acetylated.

 CHO CH2OH CHO CHO CH3
OH O OH OH OH O OH
OH OH O OH
HO OH OH CH3 HO OH
OH HO HO
OH OH HO OH
OH OH OH
CH2OH CH3 OH
CH3
D-Glucose L-Rhamnose D-Fucose

CHO
CHO CH3 CHO CH3 CH3
OH OH O OH
CH2 O OH CH2 O OH CH3O
OH OCH3 OCH3
HO
OH OH
OH
OH OH OH OH
CH3 OH
CH3 OH CH3 OCH3

D-Cymarose D-Digitalose
D-Digitoxose

CHO CHO
HO OH O OH CH2 OH O OH
OCH3 OH OCH3
HO CH3 CH3
HO
HO HO
CH3 OCH3 OCH3
CH3
L-Thevetose L-Oleandrose
 Structure-activity Relationships
The presense of a certain number of structural elements is required for the
activity:
1- The lacton ring
O
- unsaturated lacton ring at C-17 21 O
- The lacton must be in the  configuration
23
12
18
CH 3 20
22
2- The configuration of the cycles 11
C 13
17

CH3 D 16
- The activity is maximized with the cis-trans-cis 2
1
19
9 H 14

15
configuration. A
10
H 8
OH
3 5
B
- The activity is diminished when the A and B rings HO
7
4 6
are trans fused (uzarigenin) H
- The C and D rings must be cis fused. Digitoxigenin (H-5 beta)
Uzarigenin (H-5 alpha)
3- The substituents
- The OH groups at C-3 and C-14 must be in the  configuration
- The inversion of the configuration at C-3 or at C-14 diminishes the activity,
but 3- or 14-deoxy compounds are not completely inactive.
 Distribution
Cardenolides
They are the more common and are particularly in the Apocynaceae (e.g.
Adenium, Strophanthus) and Asclepiadaceae (e.g. Calotropis), but are also found
in some Liliaceae (e.g. Convallaria), Scrophulariaceae (e.g. Digitalis),
Ranunculaceae (e.g. Adonis and Helleborus) and in the Moraceae and Tiliaceae.

Bufadienolides
They occur in some Liliaceae (e.g. Urginea), in some Ranunculaceae (e.g.
Helleborus), and in some toad venoms.

Digitalis sp. Urginia maritima Strophanthus sp.

Adonis vernalis
Convaleria majalis
Calotropis procera Adenum obesum
 Pharmacological activities and Indications
Pharmacological properties:
The cardiac effects are:
1- Positive inotropic effect.
- increase the force and speed of contraction of the
heart.
2- Negative chronotropic effect.
- decrease the heart rate by the affecting the
autonomic nervous system.
3- Negative dromotropic effect.
-decrease in the conduction velocity at the atrium-
ventricle (A-V) junction and by an increase in the
refractory period of the A-V node.
Therapeutic indications:
Cardiac glycosides are indicated for:
1- cardiac insufficiency with low output
2- Supraventricular rhythm abnormalities: to slow
down or decrease atrial fibrillation or flutter.
 Identification of cardiac glycosides

I- Color reactions of the Sugars.

1- Reaction with a xanthydrol
(Xanthydrol in concentratrd acetic acid, development red color).
2- Keller-Kilani-Reaction
(conc. acetic acid containing two drops of 5% FeCl3 solution and
conc. H2SO4, blue color )

II- Color reaction of the Aglycones

1- Baljet reaction (uses picric acid and yields an orangy color)
2- Kedde reaction (3,5-dinitrobenzeoic acid and yields a reddish-
violet color)
3- Raymond reaction (m-dinitrobenzene yields a blue color)
 Drugs containing cardenolides
1- Digitalis purpurea
- The concentration of cardenolides in the leaves is about 0.2-0.5%
- The chief cardenolides of the leaf of D. purpurea fall into three series
defined by the structure of their aglycone:

(Aglycone)
Sugar
components Series A Series B Series E
(attched at C-3) (Digitoxigenin) (Gitoxigenin) (Gitaloxigenin)
Purpurea glycoside Purpurea glycoside
-Dx-Dx-Dx-Glu Glucogitaloxin
A B
-Dx-Dx-Dx Digitoxin Gitoxin Gitaloxin
-Dtl-Glu Gluco-odoroside H Digitalinum verum Glucoverodoxin
-Dtl Odoroside H Strospeside Verodoxin

Dx = Digitoxose, Glu = Glucose, Dtl = Digitalose

 O O O O O O
CH3
CH3 CH3 O
CH3 H OH O C H
CH3 H CH3 H
H OH
H OH H OH
HO
H HO HO
H H

Digitoxigenin Gitoxigenin Gitaloxigenin

(Series A) (Series B) (Series E)
2- Digitalis lanata

Glycoside Aglycone Sugar moieties

Lanatoside A Digitoxigenin -Dx-Dx-Dx(Ac)-Glu
Lanatoside B Gitoxigenin -Dx-Dx-Dx(Ac)-Glu
Lanatoside C Digoxigenin -Dx-Dx-Dx(Ac)-Glu
Digoxin Digoxigenin -Dx-Dx-Dx
Lanatoside D Diginatigenin -Dx-Dx-Dx(Ac)-Glu
Lanatoside E Gitalioxigenin -Dx-Dx-Dx(Ac)-Glu

Dx = Digitoxose, Glu = Glucose,

 O O O
O OH
OH
CH3
CH3

CH3 H OH
CH3 H

H OH H OH

HO HO H
H
Digoxigenin Diginatigenin
(Serie C) (Serie D)
Digitalis lanata Digitalis purpurea
Digoxin

D. lanata
 O
3- Strophanths kombe O
H CH3
The seeds contain 7-10% cardenolides. O
C
The principal glycosides are K-strophanthoside, K- H

strophanthin- and cymarin, all based on the genin H OH

strophanthidin. O OH
They are used intravenously in emergency for its Cymarose-(beta)-Glucose-(beta) Glucose
cardiac effects. Cymarin

It is absorbed too poorly to be used orally. k-Srophanthin-(beta)

k-Strophanthosid

4- Strophanthus gratus O O
The seeds contain 4-8 % of ouabain (g-
OH CH3
strophanthin). OH
OH

This compound is very polar, practically not CH2 H

absorbed orally. H OH
It is a heart tonic with a rapid onset and short O OH
duration of action.
Rhamnose
g-Strophanthin (Ouabain)
Strophanthus gratus Strophanthus kombe
Bufo Bufo
 Bufadienolides
Therapeutically they find littel use as cardioactive drugs because of
their low therapeutic index and their production of side-effects.
1- Squill
The bulb of the Urginia maritima contains up to 4 % bufadienolides.
The chief glycosides of the white variety are glucoscillaren A,
scillaren A and proscillaridin A.
Proscillaridin A is active orally and is eliminated rapidly and is not
cumulative, therefore it is safe to use.
The chief glycoside of the red variety is the scilliroside, which gives by
hydrolysis the aglycon scillirosidine and glucose.
The red squill is considered a rat poison.
 O O
O O
CH 3
CH 3

CH 3 OH
CH 3 H
H OH
H OH
O
O
Rhamnose - Glucose - Glucose O-COCH3
Glucose
Proscillaridin A
Scilliroside
Scillaren A
Glucoscillaren A
Urginea maritima
Basics of Natural Products
(PHG220)
Anthraquinone glycosides
(Part 2)
 What are Anthraquinones ??
Definition:
They derived from anthracene and have a variable degree of oxidation (anthrones,
anthranols, anthraquinone).

They are a natural group of purgative drugs.

Distribution:
Liliaceae (aloe), Polygonaceae (rhubarbs), Rhamnaceae (buckthorn,
cascara), Leguminosae (senna).

They are found too in Rubiaceae, Ericaceae, Euphorbiaceae,

Scrophulariaceae.
 Chemical Strcture and classification
1- The aglycones
A- Anthrones and anthranoles
They are isomeric (tautomeric forms)
They designated by the term „reduced forms“

B- Anthraquinones
The oxidized form of Anthranols and anthrones.

C- Dianthrones
(derived from two anthrone molecules)
1- Homodianthron: composed of 2 identical anthrons.
2- Heterodianthron: composed of 2 differnt anthrons .
They form as a result of mild oxidation of the anthrone .
They have two chiral centres (at C-10 and C-10´)
2- The glycosides
In fresh plant occur glycosides of monomeric anthrones.
During desiccation, two transformation processes come to play:
1- Oxidation, which leads to anthraquinone glycosides
2- Dimerization, which yields glycosides of dianthrones.
O O OH

Oxid.

H H
O
Anthranol
Anthraquinone Anthrone
Dimerization

Dianthrone

O
- The importent saccharides are D-glucose, D-galactose, L-rhamnose and in
rare cases D-apiose.

- The bond with the aglycone normally involves the phenolic OH-gruop in 8-
position (in the case of glucose), or in the 6-position (in the case of rhamnose
and apiose).

- The aglycone may be linked to 2 sugars (e.g. glucofrangulin A)

- It is not rare for 1,8-dihydroxyanthrones to occur as C-glycosides, with the bond

forming between the C-1 of glucose and the C-10 of the aglycone (aloin A
and B)
OH O OH OH O OH
OH O OH
8 1 8 1
8 9 1

7 10 10
CH2OR CH2OR
3 H Glc Glc H

R1 5
10
4 R2 Aloin A: R = H Aloin B: R = H
Aloinoside A: R = Rhamnose Aloinoside B: R = Rhamnose
O
 Physico-chemical Properties

Anthraquinones are colored, orange-red compounds, springly

soluble in cold water and soluble in organic solvents and alcohols.

The glycosides are soluble in water and hydroalcoholic solutions.

Treating the O-glycosides in acidic medium causes their

hydrolysis.

Cleavage of the C-C bond of C-glycosides can only be obtained

in the presence of ferric chloride.
 Chemical Characterization
1- Bornträger reaction: (for aglycone)
- upon dissolving the anthraquinone derivatives in alkaline aqueous
medium (KOH), a red color, more or less purplish, develops.
- only positive with the free anthraquinone forms.

2- Modified Bornträger reaction (for glycosides) 2

Acid hydrolysis of the glycoside prior to addition of KOH Mg

O O OH

3- With magnesium acetate

- specific to 1,8-dihydroxyanthraquinones. O
- intense red color Mg- chelat-complex

- Like the Bornträger reaction, this reaction is positive only with the
oxidized and free forms.
 Pharmacological action
Pharmacological properties:
They exert a more or less violent laxative activity.
They affect intestinal motility (they increase peristalsis,
particularly in the left colon and in the sigmoid).
They affect the absorption of water and electrolytes.

Mechanism of the action:

By inhibting the Na-K ATPase activity of the enterocytes, they cause
an inhibition of water, sodium and chloride resorption.

Uses:
As laxative, they are used crude (as herb teas), or as galenicals
(powders and extracts).
Main anthraquinone glycoside-containing drugs:

1- Senna
- leaves and fruits of Cassia senna (C. acutifolia)
known as Alexandrian senna and of Cassia
angustifolia known as Tinnevelly senna.

- The dried drug contains:

1- 3-4 % dianthrone glycosides (sennosides A-D),
Sennosides A and B are the major components

2- Traces of free anthraquinones and anthraquinone

glycosides
Glc Glc
OH O O OH
O O
1
1 8
8
3
3 10
10
COOH COOH
H
H H H
R 10´ R
10´
3´
3´
8´ 1´
8´ 1´

O O O OH
O OH
Glc Glc
Sennoside A: R = COOH Sennoside B: R = COOH
Sennoside C: R = CH 2OH Sennoside D: R = CH 2OH

OH O OH

10
COOH
H H
Rhein-anthrone

Laxative drugs containing Senna extract.

2- Cascara bark (sacred bark):
- It is the bark of Rhamuns purshianus (Fam.
Rhamnaceae).
- The drug contains 6-9 % anthraquinone glycosides.
- The chief constituents are O-glycosides of C-
glycosides, namely cascarosides A, B, C and D.
- Also present as anthraquinone and dianthrone O-
glycosides.

Glc Glc
O O OH O O OH

8 1 8 1

10 10
CH2R CH2R
H Glc Glc H

Cascaroside A: R = OH Cascaroside B: R = OH
Cascaroside C: R = H Cascaroside D: R = H
Rhamuns purshianus
3- Aloes
Aloe is the concentrated juice from the transversely cut
leaves of various Aloe-species (Fam. Liliaceae).
About 180 species of aloe are known, the drug is mainly
obtained from the following:
1- Cape variety from Aloe ferox (from South Africa and
Kenya). (dark-brown or greenish-brown glassy masses).
2- Curacao variety from Aloe barbadensis (A. vera) (from
West Indian Islands). (yellowish-brown to chocolate-
brown).
3- Socotrine and Zanzibar varieties from Aloe perryi (no
longer official).
Aloe ferox

Cape aloe
 Aloe contains 15-40 % C-glydosides (aloe-
emodin-anthrone 10-C-glucosides).
The chief constituent is aloin (barbaloin), which
is a mixture of aloin A and aloin B.

OH O OH OH O OH

8 1 8 1

10 10
CH2OR CH2OR
H Glc Glc H

Aloin A: R = H Aloin B: R = H
Aloinoside A: R = Rhamnose Aloinoside B: R = Rhamnose
Basics of Natural Products
(PHG220)
Saponin glycosides
(Part 3)
 Saponins
They are widely distrubuted glycosidic compounds which are
characterized by:
1- Their surface-active properties.
2- Their property of producing a frothing in aqueous solution.
3- They have also haemolytic properties.
4- Some have piscicidal activity.
Classification:
The major classes of saponins can be considered:
1- Steroid glycosides (present mainly in the Monocotyledons ).
2- Triterpene glycosides (present in the Dicotyledons) .
3- Steroidal alkaloid glycosides.
 Chemical structure
1- Steroidal saponins glycosides:
Skeletons with 27 C-atoms, we distinguish two types:
1- Spirostane glycosides (16,22:22,26-Diepoxy-cholestan)
2- Furostane glycosides (16,22-Epoxy-cholestan).

R1
21 O 26

25 R2 21 H 26

20 22 23
20 23
18 H 22
O 18 H
16
O
H H 16
19
19 H H

H H
3 5 H H
3 5

H
H
 Chemical structure

2- Triterpene glycosides: (C30-derivatives)

The triterpenoid saponines may be classified into 2 groups:

1- Tetracyclic triterpenoid saponins (e.g. dammarane derivatives).
2- Pentacyclic trietrpenoid saponins.
The triterpenoid sapogenins that are by far the most common are in
fact pentacyclic compounds
Structure of the glycosides:
All classes have the existence of one or more sugar chains.
The chains may be linear or branched.
D-glucose, D-galactose, D-glucuronic acid, L-rhamnose, and D-fucose are
commonplace.
Monodesmosidic saponins have a single sugar chain normally attached
at carbon C-3.
Bidesmosidic saponins have two sugar chains, usually with one
attached through C-3 and one attached through C-28 (in case of
triterpenoid saponins) or at C-26 (in case of steroidal saponins).

Bidesmosidic saponins are easily transformed into monodesmosidic

saponins by hydrolysis of the esterified sugar at C-28 or C-26.
 Distribution

The steroidal saponins are less widely distributed in nature than

the pentacyclic triterpenoid type.

The steroidal saponins are found in many families, e.g.

Dioscoreaceae, Amaryllidaceae, Liliaceae and Leguminosae.

The steroidal alkaloids are found in Solanaceae, Buxaceae, Liliaceae

and Apocynaceae.

The pentacyclic triterpenoid saponins are rare in monocotyledons

but are abundant in many dicotyledonous families.
 Characterization and identification
1- Haemolysis
One of the properties of saponins, namely their ability to rupture
erythrocytes, has been for decades as a detection and quantitation
method.

2- Froth test
Saponins and drugs containing saponins give persistent froth (foam)
when shaken with water.

3- Color reaction and thin layer chromatography

No color reaction is particularly specific to these compounds.
- Liebermann for steroidal saponins.
- Reaction with antimony trichloride, vanillin or Anisaldehyde in the
presence of sulfuric acid) can be used for triterpenoid saponins.
Pharmacological activities and Indications

Antibiotic activity against both bacteria and fungi, e.g. -hederin

from ivy (Hedera helix).
Haemolytic properties, which are attributed to the interaction
with the sterols of the erythrocyte membrane that induces an
increase in permeability and a loss of hemoglobin.
Anti-inflammatory and anti-rheumatic activity (Glycyrrhiza galbra
and Aesculus hippocastanum).
Anti-exudative activity such as in Aesculus hippocastanum and
Glycyrrhiza glabra
 Pharmacological activities and Indications

Anti-tussive and expectorant activity (Glycyrrhiza galbra, Polygala

senega, Hedera helix and Primula veris)
Some saponins have been found to possess CNS-stimulating
activity and anti-fatigue action (saponins from ginseng)
Stimulating action on the circulation (extract of Aesculus
hippocastanum)
A number of plants with spermicidal activity have a long history of
use as anti-fertility agents in indigenous medical systems.
Natural steroidal saponins for the production of pharmaceuticals

They are of great pharmaceutical importance because of their

relationship to compounds such as the sex hormones, cortisone,
diuretic steroids and vitamin D and the cardiac glycosides.
Some used as starting materials for the synthesis of these
compounds.
Diosgenin is suitable for the manufacture of oral contraceptives
and the sex hormones. It can also be used for corticosteroid
synthesis.
Hecogenin provides a practical starting material for the synthesis of
the corticosteroids.
 H
O

Sources of Diosgenin: O

Yams
The drug consists of the tuberous roots RO
of Dioscorea species Diogenin, R=H Rham
Dioscin, R= -Gluc
(Dioscoreaceae), such as D. Rham

esculenta, D. alata and D. opposita.

Untile 1970 diosgenin isolated from
the Mexican Dioscorea was the sole
source for steroidal contraceptive
manufacture.
Diosgenin occurs as dioscin, which
comprises two molecules of rhamnose
and one molecule of glucose.
 Sources of hecogenin:
Agave, Sisal
Hecogenin is obtained commercially as the acetate form
about 0.01% yield from sisal leaves (Agave sisalana, Fam.
Amaryllidaceae).

H
O
O
O

HO
Hecogenin
Chief triterpenoid saponins-containing drugs
1- Saponin-containing drugs as expectorant and anti-tussive

1- Liquorice
- roots and stolons of the Glycyrrhiza glabra (Fam. Leguminosae).
- It contains glycyrrhizin (a mixture of K- and Ca-salts of glycyrrhizinic
acid). Glycyrrhizinic acid is the diglucopyranosiduronic acid of
glycyrrhetic acid.
COOH

Glucorunic acid
O
Glucorunic acid
Glycyrrhizinic acid
Uses:
- flavoring agent, mild expectorant and as demulcent, and for the
treatment of rheumatoid arthritis, Addisons´s disease and various
inflammatory conditions.
- Glycyrrhizinic acid exhibits inhibiting of the Δ4-5-β- reductase
activity, which is responsible for the degradation of corticoids.
Saponin-containing drugs with anti-exudative activity

Seeds of Horse chestnut

seeds of Aesculus hippocastanum (Fam. Hippocastanaceae).
10 % Triterpen saponins, referred to as Aescin, (a mixture of several
glycosides derived from 2 triterpenoid aglycones from the olean-12-ene
series protoaescigenine and barringtogenol C).
The drug showed anti-inflammatory, anti-edema and anti-exudative
activity.
It is used to treat the symptoms of varicose symptom complex (VSC)
such as pains, heaviness, tension in the legs and pruritus.
 O-R1

O-R2
CH2O-R3
COOH OH
O O
OH CH2-R4
Glu-O
Protoaesigenin: R1=R2=R3= H; R4= OH
O-Glu Barringtogenol: R1=R2=R3=R4= H
Aescin- and Aesculus extract-containing drugs
 Saponin-containing drugs as Adaptogens
Ginseng
The drug consists of the dried roots of Panax
ginseng (Korean ginseng) or Panax
quinquefolium (American ginseng) Fam.
Araliaceae.

Ginseng contains 2-4 % saponins. (about 20

glycosides of tetracyclic aglycones of the
dammarane-series (ginsenosides).
important types are:
1- Trihydroxylated type (protopanaxadiol)
2- Tetrahydroxylated type (protopanaxatriol).
 OH
O
OH 20 S
OH
20 S

HO HO
R R
R=H: Protopanaxadiol R=H: Panaxadiol
R=OH: Protopanaxatriol R=OH: Panaxatriol

Uses:
- CNS stimulant (used as adaptogen).
(increase resistance to fatigue and stress and improve memory)
- used for the symptomatic treatment of functional asthenia, for the
treatment of anemia, diabetes and sexual impotence and
conditions arising from the onset old age.
- improves general health and lack of concentration.
Panax ginseng Roots
Ginseng-containing drugs