Glycosides

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 Introduction
• Glycosides are natural products composed of
sugar (glycone) parts and non-sugar parts
(aglycone or genin).
• The term glycoside may also refer to any
natural product which can potentially occur
bound to sugars.

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General formula of glycosides

Sugar Non-sugar
glycosidic bond Glycoside
(glycone) (aglycone)

Hydrolysis

Sugar Non-sugar
(glycone) + (aglycone)

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Why do we study glycosides?
 A number of glycosides are medicinally
useful.
 They are widely distributed in plants and
apparently responsible, at least in part, for
the medicinal values of many plants.
 Many glycosides are toxic
oThey could also serve as potential source
of new drugs.
 Some glycosides serve as starting materials
for semi-synthetic drugs.
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 General properties of glycosides
a. Distribution
 Glycosides are mostly found in plants and
microorganisms, however, very few important
glycosides are obtained from animals.
 could be found in any part plants.
 are generally present in vacuoles of cells
(intracellular).
 The amount of glycosides may vary in the same
plant due to seasonal and climatic conditions and
also depending on the growth stage of the plant.
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 b. Chemical properties
 Generally, glycosidic compounds occur as a
combination of an aglycone with a glycone(s).
However, sometimes the aglycone part could be
found free.  
 D-glucose is the most common sugar that occurs
in glycosides.
 In most glycosides the sugar moiety is a true
sugar, however, there are several glycosides in
which the sugar moiety is not a true sugar but
rather a sugar derivative such uronic acids.
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 Glycosidic linkages in natural glycosides have
the β-form.
 More than one sugar molecule may be
present in glycosides.
o The sugar molecules may be attached to the
aglycone at different points or
o They may be attached to each other as
disaccharides, trisaccharides etc.
 Most glycosides are hydrolysable by boiling on
acids.

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 Almost all glycosides are accompanied by
enzymes which can hydrolyze them.
 The enzymes can be found in different part or
cell of the plant or in the same cells being
membrane bound.
o During injury to the tissue, germination or
other physiological activity, the enzymes
may come in contact with the glycosides,
and the hydrolysis of the glycosides take
place.

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 c. Physical property
• Most glycosides are crystalline compounds.
• Solubility profile

Hydroalcoholic Organic solvents

Water Alcoho
solution (e.g. pet. ether, chloroform,
l
(80% acetone, carbon
methanol) tetrachloride)
Glycosides    

Free aglycones    

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 The higher the sugar content, the less soluble
are glycosides in organic solvent.
 Glycosides form levorotatory solutions in
water and alcohol.
 Most glycosides have bitter taste.

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 d. Function of glycosides in plants
 In plants, glycosides may be involved in
regulatory, sanitary (detoxification) or
protective activities.
  Glycosides may be used to
o modify solubility of compounds.
o stabilize some liable compounds.
o Store some organic compounds.

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 Some glycosides also serve as sugar reserves,
for example, for germinating seeds.
 Some colored flavonoids such as
anthocyanins which are found in flowers may
serve as pollinator attractants.

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 e. Pharmacological activity
 Pharmacological activity of glycosides is
intimately associated with the aglycone.
 The sugar part influences stability and
solubility and ultimately pharmacokinetic
phenomena (absorption and distribution) of
the drug in the body.

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 F. GLYCOSIDIC LINKAGE
I. O-glycosides:
 In these glycosides the sugar is condensed
with alcoholic or phenolic hydroxyl group, or
carboxylic group of the aglycone.
 O-glycosides could be regarded as sugar
ethers.

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 O-glycosides are the most abundant glycosides.
 They can easily be hydrolyzed by boiling in
mineral acids.

Sugar OH HO Another molecule

H2O

Sugar O Another molecule

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 II. S-glycosides:
 In these glycosides the sugar is condensed with
a sulfahydral (thiol) group of the aglycone.
 Natural S-glycosides are very few.
 They can easily be hydrolyzed by boiling in
mineral acids.

Sugar OH HS Another molecule

H2O

Sugar S Another molecule

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 III. N-glycosides:
 In these glycosides the sugar is condensed
with an amine or amino (–NH2 or –NH) group
of the aglycone. E.g. nucleosides.
 They can easily be hydrolyzed by boiling in
mineral acids.

Sugar OH HN Another molecule

H2O

Sugar N Another molecule

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 IV. C-glycosides:
 In these glycosides the sugar is condensed
directly to a carbon atom.
 They are highly resistant to acid hydrolysis.
They can only be hydrolyzed oxidatively.

Sugar OH HC Another molecule

H2O

Sugar C Another molecule

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 G. PRIMARY AND SECONDARY GLYCOSIDES
 Primary glycosides are those which have an
oligosaccharide unit and are extracted intact,
without losing any sugar unit.
 Extraction and drying processes can result in
the removal of 1 or 2 sugars from primary
glycosides giving rise to a new glycoside with
less number of sugar units. These type of
glycosides are refereed to as secondary
glycosides.

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 Classification of glycosides
• The classification of glycosides is highly
challenging and often not completely
successful.
• For practical purposes, however, the
following classification approached have
been followed.

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 I. Based on the sugar part
Example:
 glucosides are those glycosides which have
only glucose as their sugar part.
 rhamnosides are those glycosides which
have only rhamnose as their sugar part.
 rhamnoglucosides are those glycosides
which have only rhamnose and glucose as
their sugar parts.
II. Based on pharmacological activity
• Example: Cardiac glycosides are those which
have pharmacological effects on the heart.
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 III. Based on the chemical nature of the aglycone
 Accordingly we have the following types of glycosides.
o Anthraquinone glycosides
o Saponin glycosides
o Flavonoid glycosides
o Terpene glycosides
o Alcohol glycosides
o Simple phenolic glycosides
o Cyanogenetic (cyanophoric) glycosides
o Aldehyde glycosides
o Isothiocyanate glycosides
o Ester glycosides
o Lactone glycosides
o Amino glycosides
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 Medicinally and Pharmaceutically important
glycosides

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 continue
I. Anthraquinone glycosides (anthracene glycosides)
 Anthraquinone glycosides are those glycosides which
have anthraquinone derivative aglycones. They are
also called anthracene glycosides but anthracene
does not occur naturally.
 The anthraquinone aglycones can exist in different
oxidation state.
 They are mostly O-glycosides but some C-glycosides
also occur. A very small amount of free aglycones
could also be obtained with the glycosides.
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 O O OH
8 1
7 9 2
4H
10
6 3
5 4
O H H H
Anthraquinone Anthrone Anthranol

2H -2H

O O

H OH
Oxanthrone

O
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 H OH OH O OH
H
O
HO
HO O O OH
H OH CH2OH
H H HO

O
CH2OH
OH
O
OH
Aloe-emodin 8-glucoside HO
(an O-glycoside)
Barbaloin
(a C-glycoside)

 Pharmacological activity/ therapeutically uses

o Stimulant cathartics

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 Glycosides of anthranols and anthrones elicit a
more strong action than do the corresponding
anthraquinone glycosides.
 The glycosides are hydrolyzed by the enzymes of
the microflora to the pharmacologically active free
aglycones.
 They act on the large bowel.
o Their effect may be delayed up to 6 hrs or longer.
 They increase the strength of peristaltic
contractions but not the frequency.
o at larger doses, they cause colic pain.
 They are habit forming. They must not be
prescribed for more than 15 days.
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 Chemical tests for anthraquinone glycosides
a. Borntrager's test
 This test requires free anthraquinone-type aglycones.
 Anthraquinone-type aglycones produce pink, red or
violet color with ammonium hydroxide solution or
sodium bicarbonate solution.
 A little powder is shaken with water immiscible solvent
like ether or chloroform and then filtered. To the
filtrate in a test tube an equal amount of ammonium
hydroxide is added and shaken. The development of
pink, red or violet colors in the aqueous phase indicates
the presence of free anthraquinone-type
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 Glycosides and reduced anthraquinone
aglycones (anthrones, anthranols,
oxanthrones and dianthrones) do not give
positive result in this test.
 O-glycosides should be hydrolysed first by
boiling the sample in 2 mole acid.
o C-glycosdes are hydrolysed by boiling the sample
in 2 mole acid in the presnce of ferric chloride.
 Oxanthrones are treated with fuming nitric
acid to convert them to anthraquinones. After
that ammonium hydroxide is added.
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 Table1. Examples of crude drugs containing anthraquinone glycosides

crude drug Botanical source Active constituents Pharm act/ Med.

use
Senna Dried leaflets of Cassia acutifolia or Sennosides A and B Stimulant
C. angustifolia cathartics
(fam. Fabaceae)
Rhubarb Dried rhizomes and roots of Rheum Sennosides, Laxative
officinale or other spices of Rheum chrysophanol glycosides, aloe-
except R. raponticum emodine glycosides and emodin
(fam. Polygonaceae) glycosides

Cascara Dried bark of Rhumnus purshina O-glycosides (10-20%), Laxative

(fam. Rhamnaceae) C-glycosides (80-90%) and some
free anthraquinones:
e.g. cascarosides

Aloe Dried juice of the leaves of various Two fractions: an anthraquinone Purgative
spp of Aloe like Aloe barbadensis fraction called "aloin" and
(fam. Liliaceae) resins. barbaloin is the major
constituent of the aloin.
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II. Saponin glycosides
 Saponin glycosides have pentacyclic
triterpenoid derivative or steroidal derivative
as their aglycone part. Saponin aglycones are
commonly refereed to as sapogenines.
 Based on the sapogenine unit, saponin
glycosides are classified into pentacyclic
triterpenoid glycoides and steroidal
glycosides.

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 Sapogenins

Pentacyclic skeleton Steroidal skeleton

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 General physical properties of saponin glycosides
o Produce foam (froth) in aqueous solutions.
o Produce hemolysis in red blood cells.
 General chemical properties of saponin
glycosides.
o In plants, steroidal sapogenins are the derivatives of
pentacyclic sapogenins (triterpenes).
o All saponin glycosides have β-O-glycosidic linkage at
C-3. Some may have O- or C-glycosidic linkage at
other sites.
o They form a 1:1 addition complex (precipitate) with
cholesterol, especially in the presence of Ca2+.
This is the basis for their hemolytic activity
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 Pharmaceutical applications of saponin
glycosides
o Steroidal glycosides, because of their structural
resemblance, they are used as starting material for
the semi-synthesis of steroid based drugs such as
Sex hormones (for replacement therapy and
preparation of oral contraceptives),
Cortisones (steroidal anti-inflammatory drugs),
Diuretic steroids (e.g. Spironolactone),
Cardiac glycosides and
Vitamin D

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 Examples of crude drugs containing pentacyclic
triterpenoid glycosides.
a. Licorice
 Dried unpeeled roots and rhizomes of Glycyrrhiza
glabra (fam. Fabaceae)
 Contains glycyrrhizin (glycyrrhizinic acid) which yields
glycyrrhetic acid (glycyrrhetinic acid) on complete
hydrolysis.
 Uses:
o As sweetening agent
o Treatment of rheumatoid arthritis and other
inflammatory condition
o As stomachic (incases appetite)
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 COOH

D-Glucuronic acid O D-Glucuronic acid O

glycyrrhizin (glycyrrhizinic acid)

glycyrrhetic acid (glycyrrhetinic acid)

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 b. Quilli bark
 Dried inner bark of Quillia saponaria (fam.
Rosaceae/ Caryphayllaceae)
 Contains quillia saponins
 Uses:
o As emulsifier for coal tar.
o As detergent in shampoos OH O OH

O O
O
4 1

O -L-Ara
-D-Fuc
H
O 2
1 2 OH 1
-D-Gal -D-GlcA O -L-Rha 4
3 CHO 1 3 1
1 -D-Xyl -D-Api
-D-Xyl
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 III. Cardiac glycosides
 The aglycones of these glycosids have a steroid
nucleus with a lactone functional group.
 According to the size of the lactone ring,
cardiac glycosides are classified into two
groups:
o Cardenolides, which have 5-membered lactone (γ-
lactone)
o Bufadienolides, which have 6-membered lactone
(δ-lactone)

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General formula
R
CH3
C
CH3 H D

A H OH
B
O
H
O O
O R=

Cardenolides
O
O O
R=
O

Bufadienolides
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 Cardenolides are obtained almost entirely
from plants.
 Most bufadienolides are obtained from frogs
and very few come from plants.
 Secondary glycosides are very common in the
extraction of cardiac glycosides. If drying is not
carried out with precaution, β-glucosidase
removes the terminal glucose in many primary
glycosides.

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 Sugars occurring in cardiac glycosides
o The aglycone part is almost always found β
substituted at position 3.
o The sugar moiety could be a monosaccharide but
often an oligosaccharide (2-4 units).
o Besides common sugars such as D-rhamnose (a 6-
deoxysugar) cardiac glycosides usually have 2,6-
dideoxy sugars such as digitoxose and cymarose
which only occur in cardiac glycosides.
o When there is D-glucose unit, it is always terminal.
H3C H3C
O O
HO OH HO OH

HO H3CO

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 Pharmacological activity and therapeutic uses
o As their name implies cardiac glycosides, have
specific and strong action on the muscles of the
heart.
o Cardenolides are commonly used for treatment.
The bufadienolides tend to be highly toxic. 
o They increase the strength of the contraction of
the heart and thus used for cardiac insufficiency
and congestive heart failure .
o They increase cardiac out put and decrease heart
rate and heart volume.

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 In addition, the improved circulation increases renal
secretion which relives edema.
 Their activity is due to their aglycones. Both the
glycosides and the free aglycones show more or less
equal activity.
 However, the sugar units greatly influence
absorption, on set of action and half-life of the
glycosides in the body since they affect water
solubility.
Number of sugars Water Route of On set Elimination
solubility administration of action
Less Less Oral Slow Slow
More More Parentral (IV) Very fast Fast
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 H3C
R
H
H3C
OH H
H

HO Target

H
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 Remarks
o Cardiac glycosides are very potent and toxic drugs i.e. their
margin of safety is very narrow. Usually the therapeutic level is
approximately 50-60% of the toxic dose.
o Crude drugs containing cardiac glycosides and their galenicals
are not used because of their irreproducible activity.
o Pure glycosides are extracted from plants for medicinal use.
o Dose has to be adjusted experimentally.
o They accumulate in the body and cause chronic toxicity and
therefore continuous monitoring of serum level is mandatory.
o Orally administered cardiac glycosides have variable
bioavailability and therefore changing brands is not
recommended.

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 O

OH OH
OH
HO O O O
O O

OH

Digitoxin: R= H
Digoxin: R= OH

Preparations containing cardiac glycosides

official in Ethiopia
Digoxin……..elixir, injection and tablet.
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 IV. Flavonoid glycosides
 Flavonoids are glycosides in which the aglycone has a C 6­
C3-C6 nucleus. They are usually substituted by hydroxyl
groups.
 They are responsible for the color of flowers, fruits and
sometimes leaves.
 Flavonoidal compounds occur mainly as O-glycosides,
sometimes as C-glycosides and free aglycones.
 The major structural categories are flavones, flavanones,
flavonols, anthocyanidins, catechins
 Natural products normally discussed together with
compounds include isoflavonoids, chalcones and
aurones.
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 3'
2' 4'
B O
8
O 2 5' O
7 1'
A C 6'
4 OH
6 3
5 O
O O

flavone flavanone flavonols

O
O
O

OH
O

anthocyanidin catechin (flavan-3-ol) isoflavanoid

5
6 4
3'
4' 2' 3 O
2
5'
6'
O O

chalcone aurones
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 Many flavonoids have yellow color but
anthocyanins (glycosides of anthocyanidins) have
red, blue or purple color.
 Most flavonoids absorb in the UV region
o The function of flavonoids in plants could be
protecting leaves from the damaging effects of
ultraviolet light.
 Flavonoids exhibit various pharmacological
activities including antioxidant, anti-
inflammatory, anti-HIV etc

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 Some medicinally important flavonoids.
o Rutin
o Used as for the treatment of capillary bleeding
and increased capillary fragility

OH

OH

HO O

O 4 1
-D-Glc -D-Rha
OH O

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 o Silybin
Silybin is the major active compound isolated
from silymarin, a hepato-protective Flavonoidal
fraction obtained from Silybum marianum
(Asteraceae) (Milk Thistle, St. Mary Thistle) .
Silybin and also silymarin are used for wide
range of liver problems.

O OH

HO O OMe
O
H

OH OH

OH O
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 V. Coumarin glycosides (lactone glycosides)
 These are glycosides which have coumarin
based aglycone.
5 4
6 3

7
O 2 O
8
Coumarin
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 In the plant, coumarin is believed to exist in a
glycoside form but upon injury to the plant, it
losses the sugar part.
 Pharmacological activity
o Some coumarin derivatives have anticoagulant
activity
used as oral anticoagulant agents.
oRemark:
On set of action is somewhat slow: lag period
4-12 hrs.
Duration of action is also longer: up to days
after withdrawal.
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  Occurrence and common sources
o They are widely distributed in nature.
o Note that most of naturally occurring coumarins
lack anticoagulant activity but they are converted
to derivatives with such activity, by microbial
action (e.g. dicoumarol).

OH OH

O O O OO O

Coumarin Dicoumarol (bishydroxycoumarin)

does not have have strong
anticoagulant activity anticoagulant activity
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 The structural requirements for a coumarin
derivative to exhibit anticoagulant activity are
the 4-hydroxy group and a substituent at C3.
 Dicoumarol is very potent anticoagulant which
can not be used for treatment purpose.
However, it was used as a lead compound for
the synthesis of coumarin based oral
anticoagulants such as warfarin.

OH O

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O O
Warfarin 65
 •Thank u!!!

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