Synthesis of deoxygenated alpha(1-->5)-linked arabinofuranose disaccharides as substrates and inhibitors of arabinosyltransferases of Mycobacterium tuberculosis

Bioorg Med Chem. 2009 Jan 15;17(2):872-81. doi: 10.1016/j.bmc.2008.11.027. Epub 2008 Nov 18.

Abstract

Arabinosyltransferases (AraTs) play a critical role in mycobacterial cell wall biosynthesis and are potential drug targets for the treatment of tuberculosis, especially multi-drug resistant forms of M. tuberculosis (MTB). Herein, we report the synthesis and acceptor/inhibitory activity of Araf alpha(1-->5) Araf disaccharides possessing deoxygenation at the reducing sugar of the disaccharide. Deoxygenation at either the C-2 or C-3 position of Araf was achieved via a free radical procedure using xanthate derivatives of the hydroxyl group. The alpha(1-->5)-linked disaccharides were produced by coupling n-octyl alpha-Araf 2-/3-deoxy, 2-fluoro glycosyl acceptors with an Araf thioglycosyl donor. The target disaccharides were tested in a cell free mycobacterial AraTs assay as well as an in vitro assay against MTB H(37)Ra and M. avium complex strains.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacology
  • Arabinose / analogs & derivatives*
  • Arabinose / chemistry
  • Arabinose / pharmacology
  • Disaccharides / chemical synthesis*
  • Disaccharides / pharmacology
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Pentosyltransferases / antagonists & inhibitors*
  • Pentosyltransferases / metabolism
  • Substrate Specificity

Substances

  • Anti-Bacterial Agents
  • Disaccharides
  • arabinofuranose
  • Arabinose
  • Pentosyltransferases
  • arabinosyltransferase