The effect of 16 beta-substitution on the structure and activity of digitoxigenin: is there an additional binding interaction with Na+,K+-ATPase?
We have studied the basis of the effect of 16 beta-substitution on the structure and activity of digitoxigenin derivatives by examining the crystal structures of these compounds and their inhibitory activity toward the receptor for these drugs, Na+,K+-ATPase. To understand the increase in inhibitory activity of the 16 beta-ester compounds and the decrease in activity of gitoxigenin (16 beta-hydroxydigitoxigenin), both with respect to digitoxigenin, we have compared the observed conformations of gitoxigenin, gitoxigenin 16 beta-formate, and other 16 beta-esters to that of digitoxigenin. Our data do not support the possibility of hydrogen bonding between the 16 beta-hydroxyl of gitoxigenin and the lactone ring, previously suggested to account for the decreased activity of gitoxigenin vis à vis digitoxigenin, but, rather, suggest that the decreased activity may be due to an intramolecular hydrogen bond between the hydroxyls on C-14 and C-16 and an unusual D-ring conformation which combine to alter the carbonyl oxygen of the lactone ring away from the putative active position. In contrast, the 16 beta-ester moiety has a preferred conformation which may serve to fix the lactone ring in the active conformation. Thus, the increased activity of the 16 beta-esters cannot be explained by altered carbonyl oxygen position and may be related to an additional receptor binding site for the ester moiety.
D000818:Animals; D001665:Binding Sites; D004073:Digitoxigenin / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013552:Swine
D004073:Digitoxigenin; D000254:Sodium-Potassium-Exchanging ATPase