Cardiac glycosides. 7. Sugar stereochemistry and cardiac glycoside activity

Abstract

Digitoxigenin alpha-L-, beta-L-, alpha-D-, and beta-D-glucosides; alpha-L-, beta-L-, alpha-D-, and beta-D-mannosides; and alpha-L- and beta-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-beta-D-digitoxoside, digitoxigenin beta-D-galactoside, and digitoxigenin beta-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 alpha-L- and possibly beta-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 alpha-L isomer. However, with the beta-L isomer, some influence of 4'-OH, 3'-OH, and 2'-OH binding remains. With beta-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 beta-D-glycosides, an equatorial 4'-OH, axial 3'-OH, and equatorial 2'-OH groups appear to contribute to binding.

Selectivity of Digitalis Glycosides for Isoforms of Human Na,K-ATPase

“…In the case of digitoxigenin glycosides the addition of either two or three digitoxoses to digitoxigenin has a similar effect on affinity and ␣2/a3:␣1-selectivity. Group C consists of nine synthetic monoglycosyl derivatives of digitoxigenin (20). Several of these derivatives show a higher affinity for all three isoforms compared with the parent digitoxigenin, but only the ␤-L-rhamnosyl derivative, evomonoside, seems to show significant selectivity, in this case for ␣3:␣1.…”

Direct and stereoselective synthesis of β-d-mannosides using 4,6-O-benzylidene-protected mannosyl diethyl phosphite as a donor

“…2,3,4,6-Tetra-O-benzyl-D-mannosyl and 2,3-di-O-benzyl-4,6-O-benzylidene-D-mannosyl donors were prepared from the corresponding mannoses 1a 26 and 1b 27 according to standard procedures. Phosphorylation with diphenyl chlorophosphate under the Sabesan conditions 28 (DMAP, CH 2 Cl 2 , 0 °C) provided diphenyl phosphates 2a and 2b in good yields (Eq.…”

A Short Review on Cardiotonic Steroids and Their Aminoguanidine Analogues

“…Moreover, an equatorial 4'-OH group is also important for binding, and not a 3'-OH, while the 4'-OH axial group is much less effective [71]. In spite of these general considerations, the influence of different substituents depends on the regarded sugar [72]. Sugars as rhamnose or thevetose can increase potency several times, while mannose has no effect [73].…”