INHIBITORS OF ENDO-ALPHA-MANNOSIDASE .3. CONGENERS OF -DEOXY-3-O-(ALPHA-D-GLUCOPYRANOSYL)-MANNOJIRIMYCIN MODIFIED IN THE GLUCOSE UNIT

The syntheses of congeners of -deoxy-3-O-(alpha-D-glucopyranosyl)-mann ojirimycin (1), a strong inhibitor of the glycoprotein-processing endo -mannosidase, are described. The chemical modifications of 1 involved all monodeoxygenations and mono-O-methylations of the glucose unit and the replacement of this unit by D-galactose, D-xylose, and 2-chloro-2 -deoxy-D-glucose. As reported previously, none of the modifications of 1, including deoxygenations and O- and N-methylations of the deoxyman nojirimycin unit, improved the inhibitory properties, but demonstrated the high specificity in the recognition of 1 by the enzyme and allowe d the assignment of intermolecular hydrogen bonds of the inhibitor . e nzyme complex. Essential for complex formation were found NH-5, OH-2, OH-4, and OH-6 of the DMJ unit, as well as OH-3', OH-4', and CH2-6' of the glucose unit. The residual activities on deoxygenating the OH-2' and OH-6' groups of 1 suggest their involvement at the periphery of th e binding site.