Pharmaceutical Sciences
PHARMACEUTICAL SCIENCES
Subject : Pharmaceutical Sciences
(For Under Graduate Students)
Paper No. : B. Pharm VIIIth Sem
Paper – 38
Herbal Drug Technology
Topic No. & Title : 450:
Glycosides: Chemistry and Biogenesis of
Digitoxin, Digoxin, Hecogenin, Sennosides
And Diosgenin
Academic Script
INTRODUCTION TO GLYCOSIDES
In chemistry, a glycoside is a molecule in which a sugar is bound to another non sugar
functional group via a glycosidic bond. The sugar group is then known as the glycone
and the non-sugar group as the aglycone. Sugar part of the molecule helps in the
transportation and absorption of aglycone molecule while non sugar part is
responsible for the generation of pharmacological effects so it is also called as
“genin”.
The many plants store chemicals in the form of inactive glycosides; they can be
activated by enzyme hydrolysis, which causes the sugar part to be broken off, making
the chemical available for use. Glycosides play numerous important roles in living
organisms and are used as medications. In animals and humans, poisons are often
bound to sugar molecules as part of their elimination from the body.
Depending on whether the glycosidic bond lies "below" or "above" the plane of the
cyclic sugar molecule, glycosides are classified as α-glycosides or β-glycosides. Some
enzymes such as α-amylase can only hydrolyze α-linkages; others, such as emulsin,
can only affect β-linkages. All the natural glycosides are β-glycosides.
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Classification of Glycosides:
It can be classified depending up on types of linkage or type of aglycone moiety
present or type of sugar present. We will study about each one by one….
01. Depending up on type of linkage:
There are four types of linkages present between glycone and aglycone (OH group
of glycone moiety combine with C, O, N or S atoms of the aglycone, leads to the
formation of glycosidic bond with an elimination of one molecule of water.)
a) C-linkage/glycosidic bond- "Nonhydrolysable by acids or enzymes"
Sugar-OH + HC-Aglycone → Sugar-C-Aglycone + H2O
Example: Aloin in aloe and Cascaroside in Cascara bark
b) O-linkage/glycosidic bond-Hydrolyzed by the acid/ alkali/ or enzymes
Sugar-OH + HO-Aglycone → Sugar-O-Aglycone + H2O
Example: Sennoside from senna leaves.
c) N-linkage/glycosidic bond- Hydrolyzed by the acid/ alkali/ or enzymes
Sugar-OH + HN-Aglycone → Sugar-N-Aglycone + H2O
Example: Nucleosides, where amino group is react with the OH group of ribose
or deoxyribose sugar.
d) S-linkage/glycosidic bond- Hydrolyzed by the acid/ alkali/ or enzymes
Sugar-OH + HS-Aglycone → Sugar-S-Aglycone + H2O
Example: Sinigrin from Black mustard seeds.
02. Depending upon type of aglycone moiety
Depending upon chemical nature of aglycone moiety present they are classified as
a) Steroidal glycosides or cardiac glycosides
b) Anthraquinone glycosides
c) Saponins Glycosides
d) Flavonoid glycosides
e) Coumarin glycosides
f) Cyanogenic glycosides
g) Phenolic glycosides
h) Alcohol glycosides and many other categories.
Dear students, you have understood about definition and classification of glycosides.
In this lecture we have study about chemistry and biogenesis of some important
glycosides like:
a) Cardaic Glycosides:- Such as Digitoxin and Digoxin
b) Steroidal Saponin glycosides:- Such as Diosgenin and Hecogenin
c) Antracene Glycosides:- Such as Sennosides
Before study the about biosynthesis of these glycosides, we have to understand
general reaction involved in the formation of glycosides.
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Biosynthesis of glycosides
The metabolic process of glycosides formation essentially consists of two parts.
a) Biosynthesis of various types of Aglycone moiety and
b) Coupling of Aglycone with Sugar moiety
The synthesis of glycosides in plant cell involves interaction of nucleotide glycosides
such as UDP glucose with alcoholic and Phenolic group of aglycone moiety and such
type of glycoside is called O-type of glycoside. The sugars presents in glycoside are …
a) Monosaccharides: Such as Rhamnose, Glucose and Fucose
b) Deoxysugar: Such as Digitoxose, or Cymarose in case of cardiac glycoside
Principal pathway of glycoside formation involves the transfer of Uridyl group from
Uridyl tri phaphate (UTP) to Sugar-1-Phaphate and lead to synthesis of Uridin
diphasphate (UDP)-Sugar, which is catalyzed by Uridyly transferase. The subsequent
reaction is controlled by the enzymatic system glycosyl transferase involves transfer
of sugar from Uridin diphasphate (UDP)-Sugar to aglycone moiety resulting in
formation of glycoside.
CHEMISTRY AND BIOGENESIS OF DIGITOXIN AND DIGOXIN
Digitoxin and Digoxin are the Cardenolide type (contains one double bond and five
member unsaturated lacton ring i.e. butyrolactone ring at C-17) of Cardiac glycoside
obtained from the dried leaves of Digitalis purpurea, D. lanata and D. lutea belonging
to the family of scrophulariaceace. They exert a slowing and strengthen effect on the
failing cardiac muscle.
Chemical property of Digitoxin and Digoxin (Cardionoloids):
Both of these compounds have similar structural except digoxin has an OH-group at
C-14 while Digitoxin has H-group at same position.
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Fig: Digitoxin
Fig: Digoxin
These are composed of two structural features:
a) Sugar (glycone) moiety
b) Non-sugar (aglycone-steroid) moieties
Fig: Cardiac Glycoside
c) Acid hydrolysis causes cleavage of glycoside into glycon (sugar) and aglycone
part.
Digitoxin → Digitoxigenin + 3 Digitoxose + 1Glucose
Digoxin → Digoxigenin + 3 Digitoxose + 1 Glucose
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01. The sugar (glycone) moiety: The sugar part increases absorption and distribution
of Cardiac glycoside in the body.
a) Digitoxin and Digoxin, both contains 3 molecule of deoxy sugars i.e. digitoxose
and 1 molecule of glucose.
b) These sugars predominantly exist in the β-conformation.
02. Non-sugar (aglycone-steroid) moieties
a) Digitoxin and Digoxin contains basic steroidal nucleus (C-18).
b) Ring A/B should be in cis-form & Ring B/C should be in trans form while ring
C/D remains in cis-form. The ring junctions Cis, Trans, Cis make the nucleus
very stable so more active.
c) The R group (lactone ring) at the C-17 position defines the class of cardiac
glycoside. Generally, two classes have been observed in nature, those are:
i. Cardenolides: Have an unsaturated butyrolactone ring (C-4) at the C-17
position.
ii. Bufadienolides: Have an α-pyrone ring (C-5) at the C-17 position.
Both Digitoxigenin and digoxingenin have butyrolactone ring (C-4) at the C-17
position, means that they are cardionoloids in nature.
The presence of Alpha & Beta unsaturated lactone ring increases the activity of
Digitoxin and Digoxin, but if we make it saturated, they will loses their activity.
d) They contains β-OH group at C-3, which is involved in the formation of
glycosidic linkage with glycon moiety i.e. digitoxose sugar (O- type of
glycoside).
Example: Digitoxin and Digoxin contains 3 digitoxose and 1 glucose moiety of
sugar molecule
e) Digoxin contain additional β-OH group at C-14. The presence of OH group in C-
14 position makes the glycoside very active and gives rapid action in the body,
but if we change it to (H+) group the drug will be inactive or less active.
f) Additional OH groups at C-5, C-11 and C-16 may be present. Increase in the
number of OH group, results in increase polarity, ultimately increases
solubility, absorption and distribution.
Biosynthesis of Digitoxigenin and Gitoxigenin (Aglycone moiety):
a) Cardiac or steroidal glycosides are obtained from Acetate-Mevolonate
pathway.
b) Acetyl CoA leads to the synthesis of sequalene via Mevalonic acid.
c) Sequalene leads to the synthesis of cholesterol. Oxysequalen and lansoterol
are synthesized as an intermediate using enzyme Epoxyoxidase and
Synthetase.
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d) This Cholesterol molecule act as precursor for the active precursor for the
synthesis of digoxin and Digitoxin.
e) By using SCCE enzyme, this Cholesterol leads to the synthesis Pregnenolone,
which is the key intermediate of the reaction.
f) This Pregnenolone molecule undergoes reduction, oxidation and reduction and
hydroxylation which lead to the synthesis of Digitoxigenin.
g) Sequence of reaction involved during this conversion is as follows
h) Digitoxigenin undergoes hydroxylation at C-14 group and gets converted into
Dioxigenin, which has addition hydroxy group at C14 position.
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CHEMISTRY AND BIOGENESIS OF DIOSGENIN AND HECOGENIN
Diosgenin and Hecogenin are the Steroidal sapogenins consists of C27 steroidal
nucleus. Steroidal saponins are of great pharmaceutical importance because of
their relationship to compounds such as the sex hormones, cortisone, diuretic
steroids, vitamin D and the cardiac glycosides. Diosgenin is obtained from various
species of Dioscorea such as Dioscorea deltoidea, D. composite, D. floribunda, D.
zingiberensis belonging family Dioscoraceae. Diosgenin also obtained from various
other species such as Solanum xanthocarpum, S. indicum. Trigonella foenum gracum
and Costus speciosus while Hecogenin is obtained from the leaves of various species
of Agave genus, including Agave sisalana, Agave cantala and Agave aurea belonging
to the family Asparagaceae.
Chemical Nature of Steroidal Saponins: Diosgenin and Hecogenin
a) Saponins have a high molecular weight compounds with high polarity.
b) Both Diosgenin and Hecogenin, contain basic steroidal nucleus with 5 methyl
group.
c) The steroidal sapogenins have 27 carbons and are internal ketals of 16, 26-
dihydroxy-22-keto-steroids.
d) They have two additional rings, which are heterocyclic in nature those are;
e) Ring E is five-membered tetrahydro furan
f) Ring F is six membered tetrahydro pyran
g) The Rings are joined at 22-carbon in spiroketal fashion, and the parent
structure is therefore called spirostan.
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h) Sugar moiety attached at C-3 position of the steroidal ring. Different sugars are
different in different type of steroidal sapogenin such as Disogenin contain 2
Rha and 1 Glu molecule.
i) Frothing property: Both of these molecules are capable of lowering surface
tension in water.
j) Hemolytic property: destroys RBC by hemolysis (toxic to cold-blooded animals
–so act as fish poison).
Chemical Nature of Diogenin Chemical Nature of Hecogenin
Synonym(s): Dioscorea sapogenin or Synonym(s): Hecogenin Sapogenin or
3-βhydroxy-5-spirostene, 25R- 3-βhydroxy-5-spirostene, 25R-
spirostene-3β-ol. spirostene-12-one.
Molecular Weight: 414.627 Molecular Weight: 430.619
Molecular Formula: C27H42 O3 Molecular Formula: C27H42 O4
Physical Description: Fine white Physical Description: Off white
powder Powder
O
Melting Point: 204-207 C Melting Point: 240-245OC
Solubility: Soluble in Methanol, CHCl3; Solubility: Soluble in Methanol, CHCl3;
Poorly soluble in H 2 O. Poorly soluble in H 2 O.
k) Diosgenin and Hecogenin, both are chemically transformed to C21 products
(16-dehydropregnenolone (16-DPA), which are convenient intermediates in
the synthesis of 4 different groups of steroidal drugs namely
Corticosteroids: like cortisone, hydrocortisone, prednisolon which are mainly used
for the production of drugs used in the treatment of rheumatic disease and
ophthalmic disorders.
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Pregnanes: like Progesterone and 17-α-Hydroxy Progesteron. This is the main
ingredient for the production of oral contraceptives.
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Androstenes: like testosterone and methyl testosterone, sex hearmones.
19-Nor Steroids: like Ethiesteron, Nor-esteron acetate
a) Hecogenin with C-ring substitution provides with a starting material for the
synthesis of corticosteroids however Diosgenin is suitable for the synthesis of
contraceptives and the sex hormone.
b) Diosgenin in unmodified form exhibit estrogenic activity. Along with that it is
also used to reduce blood cholesterol level, blood pressure as well as in small
dose it increase fertility.
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Biogenesis of Steroidal Saponin: Diosgenin and Hecogenin
a) Steroidal saponin arises from the Mevalonic acid pathway. Acetate CoA
obtained from the TCA cycle is act as a precursor for the biosynthesis of both
steroidal sapogenins. It leads to the synthesis of Squalene via Mevalonic acid.
b) Subsequently sequalene gets converted in to cholesterol. Following steps takes
place in the cyclization of sequalene to synthesise cholesterol.
c) This cholesterol leads act as a direct precursor for the synthesis of both
Diosgenin and Hecogenin.
d) In D. floribunda, Cholesterol leads to the synthesis of Diosin (glycoside) which
on hydrolysis yields Diosgenin (aglycone moiety).
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e) Same in case of Agave sisalana, cholesterol leads to the synthesis of hecogenin.
CHEMISTRY AND BIOGENESIS OF SENNOSIDE
Sennosides are the anthraquinone type of glycoside obtained from the dried leaves
of Cassia anugstifolia (Tinnevelly senna) and Cassia acutifolia belonging to the family
of Leguminoseae. Leaves contain not less than 2 % of Anthracene derivative
calculated as calcium Sennoside B.
Chemical Nature of Sennoside
a) Sennoside are dianthrone glycoside derived from two Anthracene moieties, which
are…
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b) Which occurs as Yellow-brown powder with a slight odor and taste. It has melting
point approx 3920F.
c) Sennoside consist of mixture of four anthracene glycoside i.e. Sennoside A, B, C
and D, which are the dianthrone glycoside having their aglycone composed of
rhein and / or aloe emodin moieties i.e. 10, 10’-bis (9, 10-dihydro -1,8-dihydroxy-
9-oxanthracene-3-carboxylic acid)
d) Sennoside A and B consist of dimeric glucoside of the rhein (2 molecule of rhein
anthrone moieties condensed through C-10 atom) while Sennoside C and D
consist of Hetro- Diantrone moiety i.e. 1 moiety of each, aloe emodin anthrone
and rhein anthorne.
e) Sennoside A & B glycoside, on hydrolysis yields one molecule of glucose and
aglycone i.e. Sennidin A and Sennidin B, respectively.
f) Sennoside A and B are the stereo-isomeres of each other, Sennoside A is
levoroatory in nature and water insoluble while Sennoside B exist in Meso form
i.e. optically inactive and more water soluble. Sennoside C and D are also isomers
of each other. Sennoside C is is levoroatory in nature and Sennoside D is optically
inactive.
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g) Sennoside glycoside, on treatment with Calcium chloride gets converted into
calcium salt of sennoside A and B.
h) Purgative activity of sennosides is mainly due to presence of Sennoside B, which
hydrolyzed in intestine. Due to irritant nature of Anthracene derivative, it increase
the peristaltic movement of large intestine and produces purgative effect.
i) Purgative activity of Sennoside glycoside is due to its glycoside form rather than
that of free aglycone moiety because sugar moiety is essential to transport the
aglycone molecule up to large intestine.
j) Hydroxylation at C-1 and C-8 carbon atom increases the solubility of drug, as a
result increase the activity.
k) Unlike Anthrone and Anthranol, on prolong storage, Sennoside do not undergoes
oxidation and not converted in to less active anthraquinones. They retain their
activity on prolong storage.
l) Dianthrone i.e. Sennoside A, B, C & D are more active in nature as compared to
monomers like Aloe emodein, Rhein etc.
Biosynthesis of Sennoside
Sennoside are dianthrone type of anthracene derivative, which are synthesized
actate-mevalone pathway. In this Pathway, head and tail condensation of 8 acetate
unit or Acetyl CoA with 7 Malony CoA, leads to the synthesis of poly-β-
ketomethylene acid. The resulting polyketide chain can bend in different ways,
depending on the number of-CH2-CO units, with the subsequent cyclization or
aromatization. Other anthraquinones are produced from them upon oxidation of the
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β-methyl group or upon alkylation and hydroxylation, for example,
CH3→CH2OH→CHO→COOH
(the transition from chrysophanol to aloe-emodin, emodinic aldehyde, fallasinal,
rhein, emodinic acid) or OH→OCH3 (from emodin to physcion).
Aloe emodin and emodin anthrone on condensation about C-10 carbon atom leads
to the synthesis of dianthrone molecule of Sennoside A and B.
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CONCLUSION
Glycoside are the naturally occurring secondary metabolites, which produces verity
of pharmacological effects and used medicinally in the treatment of human beings. In
this lecture we have already studies in detail about chemistry and biogenesis of
Digitoxin, Digoxin, Hecogenin, Diosgenin and Sennosides. Digoxin is a very potent
drug and is used medicinally to treat cardiac disease while Sennosides are used to
produce the purgative effects. Disosgenin and Hecogenin is used to produce
synthetically oral contraceptives, sex hormones, steroidal diuretics etc. By
understanding the chemical nature and steps involved in the biogenesis of these
molecule, we can produce artificially a new molecule with more efficacy.
With all these information here we came’s to end of today's lecture. Do keep in mind
what we discussed today. Time for you to elf-study.
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