INHIBITORS OF ENDO-ALPHA-MANNOSIDASE .1. DERIVATIVES OF 3-O-(ALPHA-D-GLUCOPYRANOSYL)-D-MANNOPYRANOSE

Golgi membrane endo-alpha-D-mannosidase releases the disaccharide alph aDGlc(1 --> 3)DMan (34) from the GlcMan9Glc-NAc2 oligosaccharide of im mature N-linked glycoproteins. To convert the hydrolysis product 34 in to a potent inhibitor of the enzyme, chemical modifications at the 1- and 2-positions of the mannose unit of 34 were performed. These includ e replacement of OH-1 by hydrogen (6), fluorine (12), and p-nitropheno xy (5). Two potent inhibitors resulted, as reported recently, when bot h OH-1 and OH-2 of 34 were replaced by a double bond (glucal derivativ e 8) or replaced by hydrogen (1,2-dideoxy 9). 9 proved 40 times strong er as an inhibitor than 1-deoxy 6. However, further modifications at t he 4- and 6-positions of 9, namely deoxygenation, methylation, and rep lacement 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.