Cardiac glycosides. 6. Gitoxigenin C16 acetates, formates, methoxycarbonates, and digitoxosides. Synthesis and Na+,K+-ATPase inhibitory activities.
A series of 17 gitoxigenin 16 beta-formates, acetates, and methoxycarbonates was synthesized, including their 3 beta-acetates, formates, and digitoxosides. A 16 beta-formate group was generally found to increase activity 30 times, a 16 beta-acetate group 9-12 times, while a 16 beta-methoxycarbonate decreased activity by two-thirds. 3 beta-Formates and acetates had little effect on activity by themselves, but sometimes reduced the activity-increasing properties of 16 beta-formates and acetates. A 3 beta-digitoxoside increases the activity of gitoxigenin by 15 times, but the effect is less if the 16 beta-group is esterified. And finally, a 16-one decreases activity dramatically. These data suggest an important role for C16 esters and possibly the presence of a separate binding site on Na+,K+-ATPase corresponding to the cardenolide C16 position.
D000818:Animals; D002298:Cardenolides / Q000138:chemical synthesis* / Q000494:pharmacology; D002301:Cardiac Glycosides / Q000138:chemical synthesis* / Q000494:pharmacology; D004071:Digitalis Glycosides / Q000138:chemical synthesis* / Q000494:pharmacology; D004077:Digoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013552:Swine
D002298:Cardenolides; D002301:Cardiac Glycosides; D004071:Digitalis Glycosides; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase; C021029:gitaloxin