5-Thio-d-glycopyranosylamines and their amidinium salts as potential transition-state mimics of glycosyl hydrolases: synthesis, enzyme inhibitory activities, X-ray crystallography, and molecular modeling

Abstract

Listen

Translate article

The synthesis of new glycosidase inhibitors, namely, the glycosylamines of 5-thioglucose and 5-thiomannose and their corresponding amidinium salts are described. We report also the crystal structures of 5-thio-d-mannopyranosyl amine 1 and 5-thio-d-mannopyranosylamidinium bromide 2 bound in the enzyme active site of Golgi α-mannosidase II (GM II). Compounds 1 and 2 have been found to be inhibitors with IC50 values of 0.07 and 0.9mM, respectively. We also report the docked structures of 5-thio-d-glucopyranosylamine 3 and 5-thio-d-glucopyranosylamidinium bromide 4 in the active site of glucoamylase G2, derived by molecular modeling. Compounds 3 and 4 were found to be inhibitors with Ki values of 0.015 and 0.098mM, respectively. The results led to conclusions about the nature of the transition state and strategy for the inhibition of glycosyl hydrolases in general.