PREPARATION AND BIOLOGICAL-ACTIVITY OF MANNO-VALIDAMINES AND GALACTO-VALIDAMINES, NEW 5A-CARBA-GLYCOSYLAMINES AS ALPHA-GLYCOSIDASE INHIBITORS

Manno- and galacto-validamines, which are epimers of validamine, were semi-synthesized by the configurational inversion of validamine, a pse udo-sugar analogue of alpha-D-glucopyranose that has inhibitory activi ty for alpha-glucosidases. The inhibitory activities of these analogue s were determined against several mannosidases and galactosidases. Man no-validamine shows potent inhibition for the alpha-mannosidases (comp etitive, K-i = 4.6 x 10(-5) M for jack beans, and competitive, K-i = 2 .8 x 10(-5) M for almonds), and galacto-validamine shows weak inhibiti on for the alpha-galactosidases (coffee bean and E. coli). The inhibit ory effect of the epimers on the N-linked oligosaccharide-processing m annosidases involved in glycoprotein biosynthesis and lysosomal mannos idase from rat liver were also examined. Mannovalidamine shows potent inhibition on the endoplasmic reticulumal alpha-mannosidase (competiti ve, K-i = 1.2 x 10(-6) M), Golgi mannosidases IA, II (competitive, K-i = 2.8 x 10(-5) M), and lysosomal alpha-mannosidase (competitive, K-i = 1.7 x 10(-5) M). (C) 1997 Elsevier Science Ltd.