Preparation and biological activity of manno- and galacto-validamines, new 5a-carba-glycosylamines as α-glycosidase inhibitors

Manno- and galacto-validamines, which are epimers of validamine, were semi-synthesized by the configurational inversion of validamine, a pseudo-sugar analogue of α-d-glucopyranose that has inhibitory activity for α-glucosidases. The inhibitory activities of these analogues were determined against several mannosidases and galactosidases. Manno-validamine shows potent inhibition for the α-mannosidases (competitive, Ki = 4.6 × 10−5 M for jack beans, and competitive, Ki = 2.8 × 10−5 M for almonds), and galacto-validamine shows weak inhibition for the α-galactosidases (coffee bean and E. coli). The inhibitory effect of the epimers on the N-linked oligosaccharide-processing mannosidases involved in glycoprotein biosynthesis and lysosomal mannosidase from rat liver were also examined. Mannovalidamine shows potent inhibition on the endoplasmic reticulumal α-mannosidase (competitive, Ki = 1.2 × 10−6 M), Golgi mannosidases IA, II (competitive, Ki = 2.8 × 10−5 M), and lysosomal α-mannosidase (competitive, Ki = 1.7 × 10−5 M).