Cardenolide analogs. 4. (20R)- and (20S)-cardanolides: on the roles of the 20(22)-ene and 14.beta.-hydroxyl in genin activity

Abstract

(20R)-20,22-Dihydrodigitoxigenin (3a) and (20S)-20,22-dihydrodigitoxigenin (3b) were isolated from (20R,S)-20,22-dihydrodigitoxigenin by 3 fractional crystallizations each from ethyl acetate. The 2 diastereomers have distinct NMR spectra and similar (NA+,K+)ATPase [rat brain, EC 3.6.1.3] inhibitory activities (I50 [median inhibitory concentration] = 1.1-1.4 .times. 10-5 M)-about 1/100 as active as digitoxigenin. Their activity compared with other cardenolide analogs suggests a passive geometric role for the 20(22) double bond in eliciting (Na+,K+)ATPase inhibition, keeping the lactone carbonyl in the proper orientation. (20S)-3.beta.,14.beta.-Dihydroxy-22-methylene-5.beta.,14.beta.-cardanolide (7a) was then synthesized from 3a, and (20R)-3.beta.,14.beta.-dihydroxy-22-methylene-5.beta.,14.beta.-cardanolide (7b) from 3b. They were equivalently active in inhibiting (Na+,K+)ATPase, with I50 values of 7.0 .times. 10-5 M. Although it has been usually believed that the 14.beta.-hydroxyl of cardenolides increases binding to the receptor, (the 14-ene derivative of 7b) was more than twice as active (I50 = 3.0 .times. 10-5 M) than either 7a or 7b.