Cardenolide Analogs. 1. A 17β-Unsaturated Aldehyde

A 17β-unsaturated aldehyde analogue [3β,14β-dihydroxy-5β-pregn-17β-trans-20-en-22-al (7)] of the cardenolides was synthesized and studied. In earlier studies by Rappoport, unsaturated aldehydes were found to be highly active electrophiles, more active, for example, than unsaturated nitriles or methyl esters. The synthesis followed in part a scheme previously reported by Thomas for the syntheses of the 17β-unsaturated nitrile 9 and the 17β-unsaturated methyl and ethyl esters 8 and 10. Both 9 and 8 are more Na⁺,K⁺-ATPase inhibiting and slightly less inotropic than digitoxigenin (lb). However, the unsaturated aldehyde 7 was less Na⁺,K⁺-ATPase inhibiting (I₅₀ = 9.9 ± 0.7 × 10^-7 M) and less inotropic (100% increase in contractile force at 8.5 ± 1.0 × ×10^-6 M) than 1b (I₅₀ = 4.6 ± 1.6 × 10^-7 M; 100% increase at 3.0 ± 1.0 × 10^-7 M).