Galactose-derived phosphonate analogues as potential inhibitors of phosphatidylinositol biosynthesis in mycobacteria

Org Biomol Chem. 2007 Mar 21;5(6):952-9. doi: 10.1039/b616450a. Epub 2007 Jan 30.

Abstract

Galactose-based phosphonate analogues of myo-inositol-1-phosphate and phosphatidylinositol have been synthesized from methyl beta-d-galactopyranoside. Michaelis-Arbuzov reaction of isopropyl diphenyl phosphite or triisopropyl phosphite with a 6-iodo-3,4-isopropylidene galactoside afforded the corresponding phosphonates. Deprotection of the diphenyl phosphonate afforded methyl beta-d-galactoside 6-phosphonate, an analogue of myo-inositol-1-phosphate. The diisopropyl esters of the diisopropyl phosphonate were selectively deprotected and the corresponding anion was coupled with 1,2-dipalmitoyl-sn-glycerol using dicyclohexylcarbodiimide. Deprotection afforded a methyl beta-d-galactoside-derived analogue of phosphatidylinositol. The galactose-derived analogues of phosphatidylinositol and myo-inositol-1-phosphate were not substrates for mycobacterial mannosyltransferases (at concentrations up to 1 mM) involved in phosphatidylinositol mannoside biosynthesis in a cell-free extract of Mycobacterium smegmatis. The galactose-derived phosphonate analogue of phosphatidylinositol was shown to be an inhibitor at 0.01 mM of PimA mannosyltransferase involved in the synthesis of phosphatidylinositol mannoside from phosphatidylinositol, and a weaker inhibitor of the next mannosyltransferase(s), which catalyzes the mannosylation of phosphatidylinositol mannoside.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatography, Thin Layer
  • Galactose / analogs & derivatives*
  • Galactose / pharmacology*
  • Inositol Phosphates / chemistry
  • Inositol Phosphates / metabolism
  • Mannosyltransferases / antagonists & inhibitors
  • Mycobacterium smegmatis / drug effects*
  • Mycobacterium smegmatis / enzymology
  • Mycobacterium smegmatis / metabolism*
  • Organophosphonates / metabolism
  • Organophosphonates / pharmacology*
  • Phosphatidylinositols / biosynthesis*
  • Phosphatidylinositols / chemistry
  • Temperature

Substances

  • Inositol Phosphates
  • Organophosphonates
  • Phosphatidylinositols
  • phosphatidylinositol mannoside
  • inositol 1-phosphate
  • Mannosyltransferases
  • Galactose