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Whereas deoxyrhamnojirimycin (LRJ) 1 shows no significant inhibition of naringinase (an α-L-rhamnosidase), its C-5 epimer 2 is a potent and specific inhibitor of the enzyme and demonstrates the value of unambiguous chemical synthesis of such materials in the evaluation of their biological properties. In contrast, moderately weak inhibition towards an α-D-mannosidase is shown by both deoxymannojirimycin (DMJ) 5 and its C-5 epimer 6. Mimics of L- rhamnose which are recognised by enzymes that synthesise or process L- rhamnose may inhibit either the biosynthesis 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 rationale for the surprisingly potent activity of the C-5 epimer 2 compared with LRJ 1 and support a general hypothesis that potent piperidine glycosidase inhibitors mimic the 4H3 conformation of the relevant glycopyranosyl cation intermediate.

Original publication

DOI

10.1016/S0957-4166(98)00317-6

Type

Journal article

Journal

Tetrahedron Asymmetry

Publication Date

21/08/1998

Volume

9

Pages

2947 - 2960