title: Galactose-derived phosphonate analogues as potential inhibitors of phosphatidylinositol biosynthesis in mycobacteria.
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.
authors.affiliation: School of Chemistry, University of Melbourne, Parkville, Australia.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Dinev
authors.forename: Carlie T
authors.initials: CT
authors.lastname: Gannon
authors.forename: Caroline
authors.initials: C
authors.lastname: Egan
authors.forename: Jacinta A
authors.initials: JA
authors.lastname: Watt
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: McConville
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
mesh_terms: D002855:Chromatography, Thin Layer; D005690:Galactose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism; D008364:Mannosyltransferases / Q000037:antagonists & inhibitors; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D063065:Organophosphonates / Q000378:metabolism / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000096:biosynthesis* / Q000737:chemistry; D013696:Temperature
chemical_list: D007295:Inositol Phosphates; D063065:Organophosphonates; D010716:Phosphatidylinositols; C034154:phosphatidylinositol mannoside; C002647:inositol 1-phosphate; D008364:Mannosyltransferases; D005690:Galactose