Inhibitors of endo-α-mannosidase. Part I. Derivatives of 3-O-(α-D-glucopyranosyl)-D-mannopyranose

Abstract

Golgi membrane endo-α-D-mannosidase releases the disaccharide αDGlc(1 → 3)DMan (34) from the GlcMan9GlcNAc2 oligosaccharide of immature N-linked glycoproteins. To convert the hydrolysis product 34 into a potent inhibitor of the enzyme, chemical modifications at the 1- and 2-positions of the mannose unit of 34 were performed. These include replacement of OH-1 by hydrogen (6), fluorine (12), and p-nitrophenoxy (5). Two potent inhibitors resulted, as reported recently, when both OH-1 and OH-2 of 34 were replaced by a double bond (glucal derivative 8) or replaced by hydrogen (1,2-dideoxy 9). 9 proved 40 times stronger as an inhibitor than 1-deoxy 6. However, further modifications at the 4- and 6-positions of 9, namely deoxygenation, methylation, and replacement of OH-6 by an amino group, were now found to largely abolish the activity, demonstrating that OH-4 and OH-6 of 9 are involved in H-bonding with the enzyme.