Synthesis of isosteric and isopolar phosphonate substrate analogues designed as inhibitors for phosphatidylinositol-specific phospholipase C from bacillus cereus

Vinod, Thottumkara K.; Griffith, O. Hayes; Keana, John F. W.

doi:10.1016/0040-4039(94)85358-4

Cited by 33 publications

(20 citation statements)

References 16 publications

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“…21 Thus, the dibenzyl phosphonate 8 was monodebenzylated to afford 9 by prolonged treatment with 2-mercaptobenzothiazole 22 or, preferably, by treatment with DABCO at reflux in toluene. 23 While 9 could be condensed with simple alcohols such as 1-octanol under the agency of BOP or DCC to give 10, even after extensive investigation we were unable to effect efficient condensation with 1,2-dipalmitoyl-sn-glycerol using any of a range of coupling reagents (BOP, 24 PyBOP, 25 HATU, DCC, EDC, triisopropylbenzenesulfonyl chloride 26 or trichloroacetonitrile 27 ). This troublesome road block therefore demanded an alternative approach.…”

Section: Resultsmentioning

confidence: 95%

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

et al. 2007

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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.

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Section: Resultsmentioning

confidence: 95%

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

et al. 2007

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“…In vivo , most forms of bacterial PI-PLC work extracellularly by cleaving the headgroup from glycosyl-PtdIns (GPI) linkages that anchor GPI-targeted proteins to the outer leaflet of the plasma membrane (PM; Low and Saltiel, 1988; Ferguson and Williams, 1988; Sharom and Lehto, 2002); although intracellular functions of these enzymes have also been documented (Wadsworth and Goldfine, 1999; Wei et al, 2005; Poussin et al, 2009). Consequently, extensive structural and biochemical investigations of PI-PLCs were undertaken in hopes of generating strain-specific antibiotics or small molecules that could selectively target these secreted enzymes (Vinod et al, 1994; Martin and Wagman, 1996; Morris et al, 1996). Moreover, PI-PLCs were also recognized as ideal models for understanding how peripheral membrane proteins interact with membrane surfaces to carryout catalysis (Griffith and Ryan, 1999; Roberts et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Defining the Subcellular Distribution and Metabolic Channeling of Phosphatidylinositol

Pemberton

Kim

Sengupta

et al. 2019

Preprint

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1 Pemberton et al. characterize a molecular toolbox for the visualization and manipulation of 2 phosphatidylinositol (PtdIns) within intact cells. Results using these approaches define the steady-state 3 distribution of PtdIns across subcellular membrane compartments as well as provide new insights into the 4 relationship between PtdIns availability and polyphosphoinositide turnover. 5 6 7 Abstract 8Phosphatidylinositol (PtdIns) is an essential structural component of eukaryotic membranes that also 9 serves as the common precursor for polyphosphoinositide (PPIn) lipids. Despite the recognized importance 10 of PPIn species for signal transduction and membrane homeostasis, there is still a limited understanding of 11 how the dynamic regulation of PtdIns synthesis and transport contributes to the turnover of PPIn pools. To 12 address these shortcomings, we capitalized on the substrate selectivity of a bacterial enzyme, PtdIns-specific 13 PLC, to establish a molecular toolbox for investigations of PtdIns distribution and availability within intact cells. 14 In addition to its presence within the ER, our results reveal low steady-state levels of PtdIns within the plasma 15 membrane (PM) and endosomes as well as a relative enrichment of PtdIns within the cytosolic leaflets of the 16 Golgi complex, peroxisomes, and outer mitochondrial membranes. Kinetic studies also demonstrate the 17 requirement for sustained PtdIns supply from the ER for the maintenance of monophosphorylated PPIn 18 species within the PM, Golgi complex, and endosomal compartments. 19

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“…The (α,α-difluoroalkyl)phosphonate analogues of glycerol 3-phosphate, 2 , and of phosphoenolpyruvate, 3 , bind to glycerol 3-phosphate dehydrogenase (alternative substrate) and EPSP synthase (irreversible inhibitor), respectively. Syntheses of the (α,α-difluoroalkyl)phosphonate analogues of ribonucleoside monophosphates, 6a,b AZT-triphosphate,6c phosphatidylinositol, and phosphatidylcholine 8 have also appeared. Perhaps, most impressively, Burke and co-workers have shown that a hexapeptide containing difluorinated phosphotyrosine analog 4b inhibits protein phosphotyrosine phosphatase 1B with K i = 100 nM .…”

Section: Introductionmentioning

confidence: 99%

Ready Access to Fluorinated Phosphonate Mimics of Secondary Phosphates. Synthesis of the (α,α-Difluoroalkyl)phosphonate Analogues of l-Phosphoserine, l-Phosphoallothreonine, and l-Phosphothreonine

et al. 1996

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In addition to the previously recorded reactions of diethyl lithio(difluoromethyl)phosphonate (8) with primary triflates and aldehydes, we report here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (-78 degrees C, THF) with the following methyl esters (product, yield): methyl (S)-isopropylideneglycerate (14, 99%), methyl (S)-3-O-(tert-butyldimethylsilyl)-2 -O-tetrahydropyranylglycerate (16, 85%), and the Garner ester derived from D-serine (15, 77%). Expeditious treatment of the resultant alpha,alpha-difluoro-beta-keto phosphonates with hydride or Grignard reagents followed by alcohol deoxygenation provides a general method for the synthesis of (alpha,alpha-difluoroalkyl)phosphonate analogues of secondary phosphates. For tertiary alcohols, Dolan-MacMillan deoxygenation conditions are employed. The requisite methyl oxalate esters are obtained by an improved procedure wherein the lithium alkoxide of the hindered tertiary alcohol is irreversibly generated at low temperature and then condensed with methyl oxalyl chloride. Relative stereochemistry is assigned via conversion of the Garner ester derived Boc-amino alcohols to the corresponding cyclic, six-membered phosphonate esters and examination of their (1)H NMR spectra. The relevant vicinal coupling constants are extracted from these spectra by performing double quantum-filtered phase-sensitive COSY experiments. This new (difluoromethylene)phosphonate anion-methyl ester condensation, Grignard (hydride) addition, deoxygenation sequence has been applied to the synthesis of (alpha,alpha-difluoroalkyl)phosphonate analogues of L-phosphoserine (>/=96% ee) and L-phosphoallothreonine (93% ee) from D-serine and of L-phosphothreonine (91% ee) from L-glycerate, respectively.

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Synthesis of isosteric and isopolar phosphonate substrate analogues designed as inhibitors for phosphatidylinositol-specific phospholipase C from bacillus cereus

Cited by 33 publications

References 16 publications

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

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

Defining the Subcellular Distribution and Metabolic Channeling of Phosphatidylinositol

Ready Access to Fluorinated Phosphonate Mimics of Secondary Phosphates. Synthesis of the (α,α-Difluoroalkyl)phosphonate Analogues of l-Phosphoserine, l-Phosphoallothreonine, and l-Phosphothreonine

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