Cardenolide analogs. 4. (20R)- and (20S)-cardanolides: on the roles of the 20(22)-ene and 14.beta.-hydroxyl in genin activity
- 1 May 1979
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 22 (5), 529-533
- https://doi.org/10.1021/jm00191a014
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.This publication has 8 references indexed in Scilit:
- Cardenolide analogues. 3. A fast thin layer Chromatographic separation of cardenolide diastereomersSteroids, 1978
- Effects of polyamines on partial reactions of membraneBiochimica et Biophysica Acta (BBA) - Enzymology, 1978
- Membrane Adenosinetriphosphatase: A Digitalis Receptor?Science, 1977
- Cardenolide analogs. 2. 22-Methylenecard-14-enolidesJournal of Medicinal Chemistry, 1977
- Cardenolide analogs. 1. A 17.beta.-unsaturated aldehydeJournal of Medicinal Chemistry, 1976
- Structures of modified cardenolides. II. (20R)-3β-Hydroxy-22-methylene-5β-card-14-enolineActa crystallographica Section B, Structural science, crystal engineering and materials, 1976
- CHEMICAL STRUCTURE AND PHARMACOLOGICAL ACTIVITY OF SOME DERIVATIVES OF DIGITOXIGENIN AND DIGOXIGENINBritish Journal of Pharmacology and Chemotherapy, 1962
- EFFECTS OF DIHYDRO-OUABAIN, DIHYDRODIGOXIN AND DIHYDRODIGITOXIN ON THE HEART-LUNG PREPARATION OF THE DOG1957