Synthesis of thiodisaccharides related to 4-thiolactose: Specific structural modifications increase the inhibitory activity against E. coli β-galactosidase

Abstract

In the search for new glycosidase inhibitors, a set of benzyl β-d-Gal-S-(1→4)-3-deoxy-4-thio-α-d-hexopyranosides was synthesized. Diverse configurations were installed at C-2 and C-4 of the glucose residue. The benzyl glycosidic group was kept intact or substituted by an electron-donating or electron-withdrawing group that could also participate in hydrogen bonding. All thiodisaccharides were found to be inhibitors of E. coli β-galactosidase. In general, benzyl thiodisaccharides were better inhibitors than those substituted (NO2 or NH2) on the benzyl ring. Thiodisaccharides containing a hexopyranoside, instead of a pentopyranoside, showed a weaker inhibitory activity, except for those having the α-d-xylo configuration, which exhibited inhibition constants of the same order of magnitude. These and previous results indicated that the inhibition process by thiodisaccharides is strongly dependent on the configuration of the 3-deoxy-4-thiopyranoside, as well as its substitution pattern (such as the presence of a benzyl glycoside). The enzyme-inhibitor interaction during the hydrolysis process involves a conformational selection resulting from rotation around the thioglycosidic bond and the flexibility of the terminal six-membered ring. Thus, the mentioned structural features of the inhibitor could give rise to favorable ground state conformations for the interaction with the enzyme, similar to those found for selected thiodisaccharides in the bound state. These studies demonstrated that the performance of thiodisaccharides as enzyme inhibitors could be increased by selecting the appropriate configuration and substitution of the hexopyranoside replacing the glucose moiety of 4-thiolactose.