EVALUATION OF ISOFAGOMINE AND ITS DERIVATIVES AS POTENT GLYCOSIDASE INHIBITORS

A pseudo-aza-monosaccharide and several pseudo-aza-disaccharide compou nds 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, alpha-glucosid ase, beta glucosidase, isomaltase, alpha-mannosidase, and glucoamylase , were obtained. Isofagomine, the pseudo-aza-monosaccharide, shows a b road spectrum of strong inhibition against glycosidases. It is the mos t pol:ent inhibitor of beta-glucosidase from sweet almonds reported to date and also a strong inhibitor of glucoamylase, isomaltase, and alp ha-glucosidase. Isofagomine inhibits beta-glucosidase, glucoamylase, a nd isomaltase more strongly than 1-deoxynojirimycin where the ring oxy gen has been replaced with a nitrogen. The alpha-1,6-linked pseudo-dis accharide showed very strong inhibition toward glucoamylase, being nea rly as potent an inhibitor as acarbose. Pseudo-disaccharides in which the anomeric nitrogen was methylated to favor formation of either the alpha or beta substrate linkage generally had weakened inhibition for the glycosidases studied most likely due to steric interference with t he various active sites. These results indicate that the presence of a basic group at the anomeric center is important for carbohydrase inhi bition. The presence of a charged carboxylate group near the anomeric carbon which interacts with the basic nitrogen is suggested for these enzymes, particularly for beta-glucosidase. The presence of a second c c-linked glucosyl residue is also critical for strong inhibition of gl ucoamylase.