MEDICINAL CHEMISTRY

efractory periods. These are mainly used for CHF, arterial fibrillation, arterial flutter and
paroxysmal arterial
Chemistry of aglycone part
Aglycone portion of the cardiac glycosides is a steroid nucleus with a unique set of fused
rings, which makes these agents easily distinguished from the other steroids. Rings A-B
and C-D are cis fused, while rings B-C have a trans fusion. Such ring fusion gives the
aglycone nucleus of cardiac glycosides the characteristic "U" shape as shown in the
figure. The steroid nucleus also carries, in most cases, two angular methyl groups at C-10
and C-13. Hydroxyl groups are located at C-3, the site of the sugar attachment, and at C-
14. The C-14 hydroxyl is normally unsubstituted. However, additional hydroxyl groups
may be found at C-12 and C-16, the presence or absence of which distinguishes the
important genins: digitoxigenin, digoxigenin, oubagenin and gitoxigenin (107, 111-113).
The lactone ring at C-17 is another major structural feature of the cardiac aglycones. The
size and degree of unsaturation of the lactone ring varies with the source of the glycoside.
(i) In digitalis glycosides: The anellation of the A - B and C - D rings is cis (Z), the 3
-OH is axial and all of these steroids carry a 14β-OH group. The C-17 side chain
is an unsaturated lactone ring. The sugar part, binding to the 3-OH, -is a tri or
tetrasaccharide consisting mainly of digitoxose and glucose.
(ii) Strophanthin aglycone has a 5β-OH group in addition to other hydroxyls, upto a
maximum of 6 in ouabain. The 19-CH3 is replaced by a CHO or primary alcohol
and the sugars are the unusual rhamnose cymarose.
(iii) The squill aglycones carry a six-membered lactone ring with two double bonds.
None is used because of high toxicity.
(iv) The lactone ring is not essential. The coplanar Compounds with marginal
activity: where side-chains instead of a ring have even higher activity.
(v) The activity of a compound depends to a great extent on the position of the 23 rd
carbonyl oxygen, which is held quite rigidly by ring D and the double bond.
(vi) Removal of the sugar portion allows epimerization of the 3β-OH group, with a
decrease in activity and an increase in toxicity due to changes in polarity.
The lactone ring at C-17 is another major structural feature of the cardiac aglycones. The
size and degree of unsaturation of the lactone ring varies with the source of the glycoside.
Mechanism of action
Cardiac glycosides exert positive inotropic effect on heart. At the cellular level, digitalis
inhibits membrane-bound Na + , K + -activated adenosine triphosphatase. This inhibition
increases intracellular Na + . This Na + in turn exchanges with extra cellular Ca ++ , thus
increasing intracellular Ca 2+ levels. Inhibition of the enzyme also decreases outward
pumping of both Na + . The net effect is an increase in the Ca ++ pool available for
excitation-contraction coupling.
Official drugs:
Digoxin, B.P., I.P. 3β-[(O-2, 6-Dideoxy-β-D-ribo-hexopyranosyl-(1-4)-O-2 ,6-dideoxy-β-
D-ribo-hexopyranosyl-(1 -4)-O-2, 6-dideoxy-β-D-ribo-hexopyranosyl)-oxy]- 12β,14dihydroxy-5
β, 14β-card-20(22)-enolide. It has the aglycone digoxigenin and