Inhibitors of endo-α-mannosidase. Part II. 1-Deoxy-3-O-(α-D-glucopyranosyl)-mannojirimycin and congeners modified in the mannojirimycin unit

Article abstract of DOI:10.1139/v93-240

The syntheses of 1-deoxy-3-O-(α-D-glucopyranosyl)-mannojirimycin (9) and its 2-deoxy, 2-O-methyl, 4-deoxy, 4-O-methyl, 6-deoxy, 6-O-methyl, N-methyl, and N-propyl congeners are described. Since 9 was previously shown to effectively inhibit endo-α-D-mannosidase, a glycoprotein-processing hydrolase, these chemical modifications were designed to assist in the assessment of intermolecular hydrogen bonds of the inhibitor-enzyme complex. The previously reported data require that all hydroxyl groups of the deoxymannojirimycin unit of 9 namely, OH-2, OH-4, OH-6, and also the NH-5 group, interact with charged and polar groupings of the enzyme since deoxygenations and alkylations abolished or significantly reduced activities. Conformational analysis of 9 and some of its congeners based on NMR chemical shifts, experimental and theoretical nuclear Overhauser enhancements and HSEA calculations were performed. The chemical modifications of the glucose unit of 9 are described in the accompanying paper.