Evaluation of isofagomine and its derivatives as potent glycosidase inhibitors

A pseudo-aza-monosaccharide and several pseudo-aza-disaccharide compounds were constructed based on replacement of the anomeric carbon with a nitrogen and the ring oxygen with a carbon. The inhibition constants of these compounds toward five different glycosidases, α-glucosidase, β-glucosidase, isomaltase, α-mannosidase, and glucoamylase, were obtained. Isofagomine, the pseudo-aza-monosaccharide, shows a broad spectrum of strong inhibition against glycosidases. It is the most potent inhibitor of β-glucosidase from sweet almonds reported to date and also a strong inhibitor of glucoamylase, isomaltase, and α-glucosidase. Isofagomine inhibits β-glucosidase, glucoamylase, and isomaltase more strongly than 1-deoxynojirimycin where the ring oxygen has been replaced with a nitrogen. The α-1,6-linked pseudo-disaccharide showed very strong inhibition toward glucoamylase, being nearly as potent an inhibitor as acarbose. Pseudo-disaccharides in which the anomeric nitrogen was methylated to favor formation of either the α or β substrate linkage generally had weakened inhibition for the glycosidases studied most likely due to steric interference with the various active sites. These results indicate that the presence of a basic group at the anomeric center is important for carbohydrase inhibition. The presence of a charged carboxylate group near the anomeric carbon which interacts with the basic nitrogen is suggested for these enzymes, particularly for β-glucosidase. The presence of a second α-linked glucosyl residue is also critical for strong inhibition of glucoamylase.