title: Cardenolide analogues. 4. (20R)- and (20S)-Cardanolides: on the roles of the 20(22)-ene and 14beta-hydroxyl in genin activity.
abstract: (20R)-20,22-Dihydrodigitoxigenin (3a) and (20S)-20,22-dihydrodigitoxigenin (3b) were isolated from (20R,S)-20,22-dihydrodigitoxigenin (3) by three fractional crystallizations each from ethyl acetate. The two diastereomers have distinct NMR spectra and similar (Na+,K+)ATPase inhibitory activities (I50 = 1.1-1.4 X 10(-5) M)--about 1/100 as active as digitoxigenin (1). Their activity compared with other cardenolide analogues 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 found to be equivalently active in inhibiting (Na+,K+)ATPase, with I50 values of 7.0 x 10(-5) M. Although it has been usually believed that the 14 beta-hydroxyl of cardenolides increases binding to the receptor, 2b (the 14-ene derivative of 7b) was more than twice as active (I50 = 3.0 X 10(-5)) than either 7a or 7b.
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D002297:Cardanolides / Q000138:chemical synthesis / Q000494:pharmacology*; D002298:Cardenolides / Q000494:pharmacology; D004073:Digitoxigenin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002297:Cardanolides; D002298:Cardenolides; D004073:Digitoxigenin; D000254:Sodium-Potassium-Exchanging ATPase