Digoxin

A

SEMINAR ON

DIGOXIN, GINSENOSIDES

By

T. Sri Krishna

CONTENTS

History of Digoxin

Structure, Identification tests, Mechanism of action, SAR and Uses of Digoxin

History of Ginsenosides

Structure, Identification tests, Mechanism of action, SAR and Uses of Ginsenosides

HISTORY OF DIGOXIN

Digoxin is used from many year ago.

William Withering(1785) -- the properties

and medicinal uses of Digital.

1799 -- direct action of digitalis on the heart.

GLYCOSIDES

Glycosides – Two part the sugar(glycone)

and the aglycone.

Glycone -- non therapeutic activity and it

contains sugar moieties (ex: galacose,

mannose,arabinose).

Aglycone -- therapeutic activity.

SOURCE FOR DIGOXIN

Digoxin -- Chemical

Component of Digitalis

Lanata.

Source -- Leaves

Scientific name --

Digitalis Lanata.

Common name --

Woolly foxglove , Austrial

digitalis.

Family --

Scrophulariaceae.

CHEMICAL STRUCTURE

These are

composed of

two structural

features:

1) The sugar

(glycone) moiety.

2) The non-sugar

(aglycone -

steroid) moieties.

R - GROUP

The R group at the 17 position difines the class of cardiac

glycoside.

Two class

1.cardenolides

2.bufadienolides

The cardenolides contains unstrutrated butyrolactone ring.

The bufadienolides contains a pyrone ring.

CARDENOLIDES VS BUFADIENOLIDES

Cardenolide

It contains five

membered ring.

It is butyrolactone ring.

Bufadienolides

It contains six

membered ring.

It is a pyrone ring.

STRUCTURAL FEATURES

Steroidal nucleus most be present.

3β-OH group involved in glycosidic linkage.

14β-OH group at C-14.

A/B ring junction cis

B/C ring junction trans

C/D ring junction cis

Additional OH group at C-5,C-11 and C-16 may be present.

The presence of lactone ring.

IDENTIFICATION TESTS :-

General test for Steroids:

Liebermann’s test :

Glycoside in acetic anhydride+ few drop

of conc. H2SO4 Reddish violet

Green.

Test For Deoxysugars:

Keller – kiliani’s Test:

Glycoside in acetic andhydride

containing of FeCl3+ conc. H2SO4 on the

wall of the tube.

Acetice acid layer acquire Bluish

–green colour (Digitalis).

Acetice acid layer acquire red

colour (Squill).

Legal’s test :

Cardenolide in pryidine +Na nitroprusside

+ NaOH deep red colour .

Kedde’s test :

Cardenolide +3,5 dinitrobezoic acid

(kedde’s reagent A)+NaOH (Kedde’s reagent

B)

Violet colour .

MECHANISM OF ACTION

ACTION POTENTIAL

Digoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium.

sodium calcium exchanger (NCX)in turn tries to extrude the sodium and in so doing, pumps in more calcium.

Increased intracellular concentrations of calcium may promote activation of contractile proteins.

Digoxin also acts on the electrical activity of

the heart, increasing the slope of phase 4

depolarization.

And shortening the action potential duration,

and decreasing the maximal diastolic

potential.

STRUCTURE-ACTIVITY RELATIONSHIPS

Steroidal framework :-

The cis junctions between A/B and C/D rings, is

an essential request for the highest interaction

energy.

Modifying A and/or B rings related to B-C plane,

decreases the interaction energy.

The OH group at position C14 is not an

essential feature for inotropic activity, although

when it is replaced by a Hydrogen atom potency

decreases.

Lactone ring :-

The presence of alpha and beta

unsaturated lactone ring increases the

activity.

If we try to saturated it losses the activity.

The lactone ring has been replaced by other

heterocycles like pyridine or piridazine rings,

energetic contribution is only partially.

Sugar :-

The sugar part increases absorption and

distribution of drug in the body.

Ex:- Glucose, Rhamnose ,Cymarose,

Digitose

GINSENOSIDES

HISTORY

Panax ginseng –5000years ago--hills of

Manchuria in China.

The word Panax, from the Greek word

meaning “all-healing”.

Widely distributed in higher plants

Toxic by i.v. injection & harmless by oral

route

SOURCE OF GINSENOSIDES

Ginsenosides is

chemical component of

Panax ginseng.

Source : Main source

is root.

All parts of ginseng.

Family : Araliaceae

ROOT OF GINSENG

CHEMICAL STRUCTRUE

Ginsenosides are mainly divided in two types

based on chemical structure.

One is panaxadiols

And another is panaxatriols

PANAXADIOLS

PANAXATRIOLS

STRUCTURAL FEATURES

Four trans-ring rigid steroid skeleton.

Sugar attachment at positions C-3, C-6, or C-

20.

Ring A and B ,C and D is in Cis.

It contains steroidal nucleus.

And its triterpene .

CHEMICAL TEST

Test for Sugars :

Small quantity of extract was dissolved in 4 ml of distilled water and filtered and the filtrate was subjected to Molisch’s testand Iodine Test.

Test for Glycosides :

A few mg of residue was dissolved 4 ml of distilled water and filtrated and the filtrate was subjected to Legal Test and Borntrager’stest.

CHEMICAL TEST

Froth test:

1 ml of aqueous solution of saponin or plant extract + shake persistent & voluminous froth.

Haemolysis test:

Suspension of RBCs in normal saline + equal volume of plant extract in normal saline + shake gently clear red solution indicating heamolysis of RBCs (compared with blank ).

Test for Terpenoids :-

Knollar’s test:-

5 mg of extract is treated with 2ml of 0.1% anhydrous stannic chloride in pure thionyl chloride. A deep purple color that changes to red indicates the presence of terpenoids.

Salkowski test:-

Treat the extract with few drops of concentrated sulphuric acid ,red color at lower layer indicates presence of steroids and formation of yellow colored lower layer indicates presence of triterpenoids.

STRUCTURE–ACTIVITY RELATIONSHIPS OF

GINSENOSIDES AGAINST CANCER

Number of sugar molecules :-

Anticancer activities increase with the decrease in the

number of sugar moieties.

Ginsenosides with four or more sugar molecules, such

as Rb1 and Rc, show no significant anti-proliferative

effects.

Ginsenosides Rg3 (two sugar residues), Rh2 (one

sugar residue), IH-901 (one sugar residue), PPT (no

sugar residues), and PPD (no sugar residues) inhibit

different types of cancer cells and also enhance the

efficacy of conventional chemotheraphy.

With a sugar substitute at C-6, the anticancer activity of ginsenosides is decreased compared to activity with linkages at C-3 or C-20.

Dehydration at C-20 increases the bioactivity of ginsenosides .

Rg5 differs from Rg3 only by the presence of a hydroxyl group at C-20 in Rg3 and is approximately four times more effective than Rg3 at inhibiting cell proliferation .

MECHANISM OF GINSENOSIDES

Ginsenosides Modulation of Immune

Function:

Different immunomodulatory effects of

ginseng have been reported, including both

immunostimulatory and immunosuppressive

effects.

Ginseng polysaccharides is used for the

Prevention and treatment of the common

cold.

IMMUNOSTIMULATORY EFFECTS

enhances IL-2 interferon gamma (INF-

γ) increased proliferation of (B

lymphocytes

increased plasma level of

immunoglobulin G enhanced macrophage

production , TNF-α, IL-6 elevated the

number of spleen, bone marrow and natural

killer cells.

ANTI CANCER

Cell signaling pathways involved in

apoptotic response targeted by selected

ginsenosides