M Pharm (Pharmaceutical Chemistry) students
Akshintala. Sree Gayatri
Thota. Madhu latha
University college of pharmaceutical sciences
Department of pharmaceutical chemistry
Acharya Nagarjuna University
These are an important class of naturally occurring drugs whose
actions include both beneficial and toxic effects on the heart.
Plant glycosides with specific action on heart.
to assasinate people, arrow poisons
South American toad skins, African plant extracts
to treat congestive heart failure (dropsy).
for treatment of atrial fibrillation and flutter.
aglycone structure important for activity.
Digitalis purpurea leaves (foxglove)
Digitalis lanata leaves – white flowers
Strophanthus vine seeds – Africa
Urginea bulbs (squill) – Europe, India
Convallaria leaves (lily of the valley) – also
produces a volatile oil perfume
•Group of steroidal glycosides act as cardiotonic agent.
•They increase tone, excitability and contractility of cardiac
General properties of Cardiac Glycosides :
Solubility in H2O
Insolubility in Organic solvents
Very toxic compounds
PHYSICAL AND CHEMICAL PROPERTIES OF
Glycosides are soluble in water and alcohols.
Increase number of sugars increase water solubility.
Aglycones soluble in CHCl3 and EtOAc.
Split sugars from the aglycone first.
Split sugars stepwise starting from the terminal sugar.
Cause dehydration by removal of C-14 OH group to give inactive
A small group of plant
glycosides act directly
on the heart muscle.
These include (but are
not limited to cardiac
exert a slowing and
on the failing cardiac
CLASSIFICATIONS OF GLYCOSIDES:
According to their therapeutic effects:
CHF(congestive heart failure) and cardiac muscle
stimulators such as:
Digitalis glycosides: digoxin, digitoxin, gitoxin (Fox
Ouabain: Strophanthus gratus seeds.
K-strophanthin: Strophanthus kombe seeds.
Scillaren A,B which isolated from red and white
Convolloside:Convallaria majalis: Lily of the Valley.
According to the type of lactone ring:
1. Cardenolide (one double bond, lactone ring) :
Has five member lactone ring (unsaturated) attached at C17 B position of
Strophanthus gratus glycoside :
Strophanthus Kombe glycoside :
2. Bufadienolide: (contain two double bonds, lactone ring):
Has six member ( unsaturated ) lactone ring attached at C-17 alpha –
Squill bulb glycoside
The cardiac glycosides occur mainly in plants from which the
names have been derived.
Strophanthus kombe are the major sources of the
The term 'genin' at the end refers to only the aglycone portion
(without the sugar).
The aglycone portion of cardiac glycosides is more important
than the glycone portion.
Aglycone part has steroidal nucleus
Sugar moiety(glycone) :
The glycosides usually contain 3 to 4 sugars attached at C-3
The sugars most commonly used include L-rhamnose, D-
glucose, D-digitoxose, D-digitalose, D-digginose.
Beside Glucose and Rhamnose they usually contain
These sugars predominantly exist in the cardiac glycosides in
These are composed of two structural features :
the sugar (glycone) moiety and
the non-sugar (aglycone - steroid) moieties.
The R group at the 17-position defines the class of cardiac
Two classes have been observed in Nature:
1. cardenolides and
2. bufadienolides .
The cardenolides have an unsaturated butyrolactone ring
While the bufadienolides have an a-pyrone ring.
Steroidal nucleus must be present.
3 -OH group involved in glycosidic linkage.
14 -OH group at C-14.
A/B ring junction cis
B/C ring junction trans
C/D ring junction cis
Additional oH groups at C-5, C-11 and C-16 may be
The presence of lactone ring
Structural actiity and relationship :-
1) 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
2) The presence of Alpha & Beta unsaturated lactone ring
increases the activity of Cardiac Glycosides, but if we make it
saturated the Cardiac glycosides will lose its activity.
3) The ring junctions Cis, Trans, Cis make the nucleus very
stable so more active.
4) The sugar part increases absorption and distribution of
Cardiac glycoside in the body.
Sugar part : Glucose, Rhamnose, Cymarose, Digitoxose
foxglove - biennial flowering plants
cases of poisoning rare
natural emetic if eaten in excess
Digitalis purpurea leaf – purple, British
Digitalis Tablets B.P.
Tincture of Digitalis B.P.
commercially grown Holland, E. Europe
NB no extraction for these products
Digitalis lanata leaf – white,
used for manufacture of pure glycosides
i.e. digoxin, lanatoside C
Holland, Equador, USA 17
DIGITALIS PURPUREA – PURPLE FOXGLOVE
Digitalis consists of the
dried leaves of Digitalis
It is required to contain at
least 0.3% of total
cardinolides calculated as
Parts Used: Leaves
Habitat: Native to Western
Europe. Although the plant
is cultivated, wild plants are
thought to be superior. 18
CHEMISTRY OF D.PURPUREA
purpurea glycoside A
purpurea glycoside B
contains 30 glycosides, 6 main ones
only has 3 aglycones
At C-3 of the genin: a linear chain of 3 digitoxose sugar moieties
terminated by glucose.
On drying: enzyme degradation takes place loss of the terminal
also contains anthraquinone glycosides
CHEMISTRY OF D.LANATA
compounds belong to
5 membered lactone ring
approx 96 compounds
worked on structures]
R1 R2 Names 1y 2y
H H digitoxigenin A A digitoxin
H OH gitoxigenin B B gitoxin
OH H digoxigenin C C digoxin
OH OH diginatigenin D D diginatin
H formylester gitaloxigenin E E gitaloxin
* Acetyl group
properties - makes
Some cardioactive glycosides from D.lanata:
sugar found on primary glycosides of D.lanata.
glucose on the end of a chain of O-linked digitoxose sugars
expect about 10 compounds from D.lanata
Digoxin “Lanoxin” – Wellcome – 0.25 μg white tablet
Digitoxin “Digitalin” 0.25 μg small pink tablet
Lanatoside “Cedilanid” 0.10 μg – less well absorbed
but used for rapid digitalisation
Others not marketed, used experimentally
This glycone part found in both species.
only strospeside important as emergency injection for heart attacks.
quickest acting cardiac glycoside.
Biochemical Mechanism of Action:
The mechanism whereby cardiac glycosides cause a positive
Several mechanisms have been proposed.
but the most widely accepted involves the ability of cardiac
glycosides to inhibit the membrane bound Na+-K+-ATPase
pump responsible for Na+-K+ exchange.
The process of membrane depolarization / repolarization is
controlled by the movement of three cations, Na+, Ca+2, and
K+, in and out of the cell.
They are Cardiotonics used to treat Congestive heart
They increase force of contraction of cardiac muscles
without increase oxygen consumption.
Increase cardiac output.
The diastolic phse last longer so decrease heart rate.
Have diuretic effect due to increase amount of blood passing
through the kidney.
General test for steroids:
Glycoside in acetic anhydride + Few drops of conc. H2SO4
Reddish violet Green
Test for Deoxysugars:
Glycoside in acetic anhydride containing traces of FeCl3 +
conc. H2SO4 on the wall of the tube
Acetic acid layer acquire Bluish-green colour
Acetic acid layer acquire Red colour (Squill) 27
Test for 5-membered lactone ring:
Cardenolide in pyridine + Na nitroprusside + NaOH deep
Kedde’s test :
Cardenolide+ 3,5 dinitrobenzoic acid (Kedde’s reagent A) +
NaOH (Kedde’s reagent B) violet colour.