Synthesis of evaluation of beta-glycosyl-1,2,3-triazole derivatives as beta-glycosidase inhibitors

Glycosidases are enzymes which hydrolyze glycosidic (carbohydrate) bonds and are involved in various biological processes. The enzymes exhibit preferences toward both the glycone (sugar) and the aglycone (nonsugar) substituents of a glycoside. Glycosidase inhibitors can provide information about the structure and mechanism of an enzyme and are of interest for the treatment of a variety of diseases, including HIV, diabetes, and cancer. beta-Glycosyl triazoles were examined as aglycone-modified beta-glycosidase inhibitors.;The copper (I) catalyzed 1,3-dipolar cycloaddition click reaction was utilized to regiospecifically prepare 1-glycosyl- and 1-galactosyl-4-phenyl-1,2,3-triazoles from beta-azidoglycopyranoside and phenylacetylene. These compounds were evaluated as inhibitors against four beta-glycosidases. The inhibition constants, Ki, of the compounds were determined to be within a low millimolar range, corresponding to poor to moderate glycosidase inhibitors. Each of the beta-glycosidases has unique interactions with the aglycone, which would account in part for the different inhibition activities of the compounds.;The inhibition activity of glycosyl triazoles was explored further with a library of 1-glycosyl-4-(aryl/alkyl)-1,2,3-triazoles, prepared from beta-azidogalactopyranoside or beta-azidoglucopyranoside and various terminal alkynes under click conditions. The strongest glycosyl triazole inhibitor had a Ki value of 3muLM against E. coli beta-galactosidase. The micromolar inhibitor served as a structural scaffold for the construction of a second library. Two hit compounds were identified from the second library, with Ki values of approximately 5muM and 14muM against E. coli beta-galactosidase. Modeling studies were done to examine the possible enzyme-aglycone interactions that can be targeted in future glycosyl triazole libraries.;We have demonstrated 1-glycosyl-1,2,3-triazoles are glycosidase inhibitors and can be used to examine the unique aglycone preferences of a glycosidase. Glycosidase inhibition was improved by modification of the aglycone, thereby highlighting the importance of the aglycone group within glycosidase binding events. By taking into consideration both the glycone and aglycone preferences of a glycosidase, a potent and selective inhibitor can result.