Cardiac Glycosides. 7. Sugar Stereochemistry and Cardiac Glycoside Activity

Digitoxigenin α-L-, β-L-, α-D-, and β-D-glucosides; α-L-, β-L-, α-D-, and β-D-mannosides; and α-L- and β-L-rhamnosides were stereoselectively synthesized from the corresponding sugar tetrabenzyl trichloroacetimidates. The Na⁺,K⁺-ATPase receptor inhibitory activities of these glycosides (as a measure of receptor binding) were compared with those of digitoxigenin, digitoxigenin 6'-hydroxy-β-D-digitoxoside, digitoxigenin β-D-galactoside, and digitoxigenin β-D-digitoxoside. The observed activities reveal that a given sugar substituent may have a role in binding of some glycoside stereoisomers, but not others. With α-L- and possibly β-L-rhamnosides, the 5'-CH₃ and 4'-OH appear to have a predominant role in binding to the Na⁺,K⁺-ATPase receptor. Addition of a 6'-OH to form the corresponding mannosides dramatically disrupts the effect of both the 5'-CH₃ and 4'-OH in prompting receptor binding of the α-L isomer. However, with the β-L isomer, some influence of 4'-OH, 3'-OH, and 2'-OH binding remains. With β-D-glycosides, binding via the “5'-CH₃ site” appears to be of little importance and addition of a 6'-OH diminishes activity only slightly. With these β-D-glycosides, an equatorial 4'-OH, axial 3'-OH, and equatorial 2'-OH groups appear to contribute to binding.