Steroidal Nucleus Structure and Activity Relationship

Oxygen Substitution on Steroidal Nucleus

• Higher number of -OH groups results in more rapid onset of action and elimination from the body.
• Replacement of -OH groups at C3 and/or C14 by H atoms results in slight reduction of potency.

Structure Activity Relationship

• β-orientation of C17 side chain is necessary for activity, 17α-cardenolides (allocardenolides) are inactive.
• Sugar moiety has no cardiac activity, but when attached to C3 -OH group of steroidal moiety, activity is modified and influences pharmacokinetic behavior.
• Free aglycones are less potent than their glycosides.
• Type and number of sugar units may affect potency.
• Cardiac glycosides with 6-deoxy sugars (6-CH3) are more potent than their 6-CH2OH analogs.
• For oligosaccharide moieties, potency decreases with increase in number of sugar units.

Distribution in Nature

• Scrophulariaceae (Digitalis purpurea leaves - foxglove, Digitalis lanata leaves - white flowers)
• Apocyanaceae (Strophanthus kombe vine seeds - Africa)
• Liliceae (Urginea bulbs - squill, Europe, India)
• In toads (cardiac glycosides are also found in animals only in exceptional cases)

Digitalis

• Digitalis spp (Scrophulariaceae)
• D. lanata: Mediterranean/White, commercially produced in Ecuador, USA, and Holland (total glycosides, 1.5%) with major: Lanatosides A-E (primary glycosides) and digoxin.
• D. purpurea: British/Purple, commercially produced in Holland and Eastern Europe (total 0.5%) with major: Purpurea glycosides A, B, and E, digitoxin, gitoxin, and gitaloxin.

Strophanthidin

• Seeds of East African Strophanthus kombé were formerly official in the BP.
• Principal glycosides: K-strophanthoside, K-strophanthin, and cymarin, all based on the genin strophanthidin.
• Also found in Strophanthus hispidus.

Ouabain

• The principal glycoside of the wood of the African Acokanthera schimperi (A. ouabaio).
• Strophanthus gratus seeds contain 4-8% of ouabain (G-strophanthin), a rhamnose glycoside more stable than those present in other species.

Oleander Glycosides

• Thevetia peruviana (T. neriifolia) - yellow oleander, are a rich source of the glycoside thevetin A.
• Partial hydrolysis and the loss of two glucose units yields peruvoside.
• Peruvoside consists of L-thevetose linked to the aglycone cannogenin.

Other Sources

• Calotropis spp
• Asclepiadaceae
• Convallaria majalis (Liliaceae) - Lily of the Valley

Bufadienolides

• Found in some Liliaceae and Ranunculaceae, and in the toad venoms.
• The genins are partly free and partly combined with suberyl arginine.
• Therapeutically, they find little use as cardioactive drugs because of their low therapeutic index and their production of side effects.

Urginea maritima

• Squill
• Scillaren A, and an amorphous mixture of glycosides, scillaren B isolated.
• Scillaren A is the most important cardiac glycoside.

Chemical Testing

• Colour tests based on the aglycone:
  • Legal's test: deep red color.
  • Raymond's test: violet color - blue color.
  • Kedde's test: violet color.
  • Baljet's test: orange or red.
• Liebermann's test and Antimony test will give a positive reaction.
• Colour tests based on the glycone:
  • Keller-Killiani's test (for 2-deoxy sugar): a blue ring between the 2 layers is a positive reaction.