5-EPI-DEOXYRHAMNOJIRIMYCIN IS A POTENT INHIBITOR OF AN ALPHA-L-RHAMNOSIDASE - 5-EPI-DEOXYMANNOJIRIMYCIN IS NOT A POTENT INHIBITOR OF AN ALPHA-D-MANNOSIDASE

Whereas deoxyrhamnojirimycin (LRJ) 1 shows no significant inhibition o f naringinase (an alpha-L-rhamnosidase), its C-5 epimer 2 is a potent and specific inhibitor of the enzyme and demonstrates the value of una mbiguous chemical synthesis of such materials in the evaluation of the ir biological properties. In contrast, moderately weak inhibition towa rds an alpha-D-mannosidase is shown by both deoxymannojirimycin (DMJ) 5 and its C-5 epimer 6. Mimics of L-rhamnose which are recognised by e nzymes that synthesise or process L-rhamnose may inhibit el ther the b iosynthesis of the sugar or its incorporation into mycobacterial cell walls, providing new strategies for the treatment of diseases such as tuberculosis and leprosy. Molecular modelling studies provide a ration ale for the surprisingly potent activity of the C-S epimer 2 compared with LRJ 1 and support a general hypothesis that potent piperidine gly cosidase inhibitors mimic the H-4(3) conformation Of the relevant glyc opyranosyl cation intermediate. (C) 1998 Elsevier Science Ltd. All rig hts reserved.