AMIDINE, AMIDRAZONE, AND AMIDOXIME DERIVATIVES OF MONOSACCHARIDE ALDONOLACTAMS - SYNTHESIS AND EVALUATION AS GLYCOSIDASE INHIBITORS

The synthesis of amidine, amidrazone, and amidoxime derivatives of D-glucono, D-mannono, and D-galactonolactams, which are potent glycosidase inhibitors, is described. With their sugar-like structures and resonance-stabilized, partially positively charged anomeric carbons, these monosaccharide analogs mimic key conformational and electrostatic features of the corresponding glycopyranosyl cations. In the D-gluco series, all three derivatives are potent inhibitors of sweet almond beta-glucosidase. Levels of inhibition remain nearly constant despite a 10(5) change in basicity, indicating that conformational flattening of the hydrolysis intermediate is more important for transition-state binding by the enzyme than charge development. The same D-gluco derivatives also interact with mannose- and galactose-processing enzymes. Considerably weaker inhibition is observed with 1beta-amino-1-deoxynojirimycin, which embodies similar endocyclic and exocyclic nitrogens in an undistorted chair conformation. In the D-manno series, the amidrazone and amidoxime are potent inhibitors of jackbean alpha-mannosidase, mung bean alpha-mannosidase, fungal beta-mannosidase, Golgi alpha-mannosidase I, alpha-mannosidase II, and soluble (or endoplasmic reticulum) alpha-mannosidase. The mannoamidrazone also inhibits Golgi alpha-mannosidase I and the endoplasmic reticulum mannosidase in vivo. In the D-galacto series, significant inhibition of almond beta-glucosidase, bovine liver beta-galactosidase, and green coffee bean alpha-galactosidase is observed, but little or no inhibition of amyloglucosidase.