The Cardiac GlycosidesCardio-active Glycosides

A Group of steroidal glycosides act as cardiotonic agent. They increase tone, excitability and

contractility of cardiac muscles.

Structural features:

-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

present.

-The presence of lactone ring:

R

OH

sug-O

R2

R1

3 5

12

16

17

R3

H

H

H

BA

CD

14

• According to the type of lactone ring Cardiac Glycosides are classified into:– Cardinolides:They are C-23 containing 5-membered

unsaturated lactone ring

e.g. Digitalis & Strophanthus

– Bufadienolides:They are C-24 containing 6-membered

unsaturated lactone ring

e.g. Squill

OO

17

17

O

O

The Sugar Part:

• The glycosides usually contain 3 to 4 sugars attached at C-3 OH.

• Beside Glucose and Rhamnose they usually contain deoxysugars.

CHO

CH

CH

CH

CH

CH2OH

OH

OH

HO

OH

Glucose

CHO

CH

CH

CH

CH

CH3

OH

OH

HO

Rhamnose

HO

CHO

CH2

CH

CH

CH

CH3

OH

OH

Digitoxose

OH

CHO

CH2

CH

CH

CH

CH3

OH

OH

Cymarose

OCH3

The Cardinolides1- Digitalis Glycosides

• Digitalis is Known as “foxglove”

• The most important species includes:

• 1) Digitalis purpurea

• 2) Digitalis lanata

OO

OH

HO

R2

R1

3 5

12

16

17R1=R2=H DigitoxigeninR1=H, R2=OH GitoxigeninR1=OH, R2=H Digoxigenin

Digitalis contain three major aglycones:

Digitoxigenin derived Glycosides: (Glycosylation at 3 OH)

Lanatoside A DX-DX-DX(Ac)-Gl

Purpurea glycoside ADX-DX-DX-Gl

Acetyl-digitoxinDX-DX-DX(Ac)

DigitoxinDX-DX-DX

Gitoxigenin derived Glycosides: (Glycosylation at 3 OH)Lanatoside B

DX-DX-DX(Ac)-GlPurpurea glycoside B

DX-DX-DX-Gl

Acetyl-gitoxinDX-DX-DX(Ac)

GitoxinDX-DX-DX

Digoxigenin derived Glycosides: (Glycosylation at 3 OH)LanatosideC

DX-DX-DX(Ac)-GlDeacetyl lanatoside C (Deslanoside)

DX-DX-DX-Gl

Acetyl-digoxinDX-DX-DX(Ac)

DigoxinDX-DX-DX

-Ac (Alkaline hydr.)

-Ac (Alkaline hydr.)

-Gl (Enzymatic Hydr.)-Gl (Enzymatic Hydr.)

-Ac (Alkaline hydr.)

-Ac (Alkaline hydr.)

-Gl (Enzymatic Hydr.) -Gl (Enzymatic Hydr.)

-Ac (Alkaline hydr.)

-Ac (Alkaline hydr.)

-Gl (Enzymatic Hydr.) -Gl (Enzymatic Hydr.)

2- Strophanthus Glycosides

• Obtained from Strophanthus kombé

• The used part is the seeds.

• The common aglycone is K-strophanthidin

OO

OH

CHO

O

3 5

12

16

17

OH

Cymarose

-Glucose

-Glucose K-Strophanthoside

K-Strophanthin

Cymarin

K-Strophanthidin

10

14

Bufadienolides1- Squill Glycosides

• They have 6-membered lactone ring.

• Obtained from Squill bulbs.

• Aglycone contains only two hydroxyl groups at C-3 and C-14.

OH

O

3

5

12

16

17

Rhamnose

-Glucose

-Glucose Glucoscillarin A

Scillarin A

Proscillaridin A

Scillaridin A

O

O

Physical and Chemical properties of cardiac glycosides:

• Solubility:– Glycosides are soluble in water and alcohols.– Increase number of sugars increase water

solubility.

– Aglycones soluble in CHCl3 and EtOAc.

• Stability:– 1) Acid hydrolysis:

• Split sugars from the aglycone first.

– 2) Enzymatic hydrolysis:• Split sugars stepwise starting from the terminal

sugar.

– 3) Elevated temperature:• Cause dehydration by removal of C-14 OH group to

give inactive anhydro-form

OO

OH

Sug-O

OO

Sug-O

High temperature

Anhydro-form

Medicinal Importance:

• -They are Cardiotonics used to treat Congestive heart failure.

• -They increase force of contraction of cardiac muscles without increasing oxygen consumption.

• -Increase cardiac output.• The diastolic phase lasts longer, thus decreases

heart rate.• -Have diuretic effect due to increase amount of

blood passing through the kidney.

Chemical Identification:

General test for steroids:Liebermann’s test:

Glycoside in acetic anhydride + Few drops of conc. H2SO4 Reddish violet Green

Test for Deoxysugars:Keller-Kiliani’s Test:

Glycoside in gl. acetic containing traces of FeCl3 + conc. H2SO4 on the wall of the tube

Acetic acid layer acquire Bluish-green colour (Digitalis)

Acetic acid layer acquire Red colour (Squill)

• Test for 5-membered lactone ring:

– Legal’s test: • Cardenolide in pyridine + Na nitroprusside + NaOH

deep red colour.

– Kedde’s test : • Cardenolide + 3,5 dinitrobenzoic acid (Kedde’s reagent A) + NaOH

(Kedde’s reagent B) violet colour.COOH

NO2O2N