Inhibition of Glycosidases by Lactam Oximes: Influence of the Aglycon in Disaccharide Analogues

Abstract

The influence of a substituent at the hydroximo function of the lactam analogue 1 on the inhibition of β- and α-glucosidases is evaluated. In contrast to 1, the O-alkyl oximes 5, 6, 9, and 10 are selective inhibitors of β-glucosidases. Alkylation of the D-gluconohydroximo-1,5-lactam 19 with the triflate 12, or condensation of the thiogluconolactam 20 with the hydroxylamines 14 or 18 afforded the benzylated cellobioside analogues 21 and 23, respectively. The O-alkyl oximes 33 and 39 were prepared similarly (Scheme 3). Deprotection afforded the cellobioside analogues 5 and 6, and the O-alkyl oximes 9 and 10. The lactam O-alkyl oximes 5, 6, 9, and 10 are strong inhibitors of the β-glucosidase from C. saccharolyticum (IC50 = 0.3-8 μM) and, with exception of the dodecyl analogue 9 (IC50 = 2 μM), moderate-to-weak inhibitors of β-glucosidases from sweet almond (IC50 = 60-1000 μM; see Table). In contrast to the strong inhibition of α-glucosidase from brewer's yeast by 1 (Ki = 2.9 μM), the ethers 5,6, and 10 are weak inhibitors of this enzyme (IC50 between 2500 and > 5000 μM). Similarly, the D-galactohydroximo-1,5-lactam 7 is a potent inhibitor of the α-galactosidase from coffee beans and of the β-galactosidases from bovine liver and E. coli (Ki = 5, 10, and 0.1 μM, resp.), while the lactoside analogue 8 is a strong inhibitor of the E. coli β-galactosidase (Ki = 0.1 μM), but a moderate-to-weak inhibitor of coffee-bean α-galactosidase and bovine-liver β-galactosidase (Ki = 250 μM and IC50 = 2500 μM, resp.). The galacto-configured lactam oximes 7 and 8 are good inhibitors of the β-glucosidase isolated from C. saccharolyticum (Ki = 2.5 and 3.3 μM, resp.).