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

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 (K_i=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 (K_i=5, 10, and 0.1 μM , resp.), while the lactoside analogue 8 is a strong inhibitor of the E. coli β-galactosidase (K_i=0.1 μM ), but a moderate-to-weak inhibitor of coffee-bean α-galactosidase and bovine-liver β-galactosidase (K_i=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 (K_i=2.5 and 3.3 μM , resp.).