5-epi-Deoxyrhamnojirimycin is a potent inhibitor of an α-L- rhamnosidase: 5-epi-Deoxymannojirimycin is not a potent inhibitor of an α- D-mannosidase

Benjamin G. Davis, Andrew Hull, Colin Smith, Robert J. Nash, Alison A. Watson, David A. Winkler, Rhodri C. Griffiths, George W J Fleet

Research output: Contribution to journalArticleOther

45 Citations (Scopus)

Abstract

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 languageEnglish
Pages (from-to)2947-2960
Number of pages14
JournalTetrahedron-Asymmetry
Volume9
Issue number16
DOIs
Publication statusPublished - 21 Aug 1998
Externally publishedYes

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