Analogues of d -glucosaminylphosphatidylinositol: synthesis of the glycosyl donors

Dix, Alexander P.; Borissow, Charles N.; Ferguson, Michael A. J.; Brimacombe, J. S.

doi:10.1016/s0040-4039(00)01900-6

Cited by 9 publications

(5 citation statements)

References 6 publications

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“…The compounds shown in Figure 1 were synthesized as previously described (Cottaz et al ., 1993; Crossman et al ., 1997, 1999; Borissow et al ., 2001; Dix et al ., 2001), except for D ‐GlcNα1‐6 L ‐2‐ O ‐methyl‐ myo ‐inositol‐1‐HPO 4 ‐ sn ‐1,2‐dipalmitoylglycerol (GlcN‐[L]‐(2‐ O ‐methyl)‐ PI), which was prepared in a similar manner to the corresponding D ‐ myo ‐inositol analogue (Crossman et al ., 1997), and D ‐GalNα1‐6 D ‐ myo ‐inositol‐1‐HPO 4 ‐ sn ‐1,2‐dipalmitoylglycerol (GalN‐PI), D ‐ManNα1‐6 D ‐ myo ‐inositol‐1‐HPO 4 ‐ sn ‐1,2‐dipalmitoylglycerol (ManN‐PI), D ‐Glc Nβ1‐6 D ‐ myo ‐inositol‐1‐HPO 4 ‐ sn ‐1,2‐dipalmitoylglycerol (GlcN‐β‐PI), D ‐GlcNα1‐6 D ‐ myo ‐inositol‐1‐HPO 4 ‐octadecyl (GlcN‐I‐ P ‐C18) and D ‐GlcNα1‐6 D ‐ myo ‐inositol‐1‐HPO 4 ‐octyl (GlcN‐I‐ P ‐C8) (A.Crossman, M.J.Paterson and J.S.Brimacombe, details to be published elsewhere). N ‐acetyl derivatives of the compounds were prepared by standard procedures (Smith et al ., 1996).…”

Section: Methodsmentioning

confidence: 99%

Specificity of GlcNAc-PI de-N-acetylase of GPI biosynthesis and synthesis of parasite-specific suicide substrate inhibitors

et al. 2001

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The substrate speci®cities of Trypanosoma brucei and human (HeLa) GlcNAc-PI de-N-acetylases were determined using 24 substrate analogues. The results show the following. (i) The de-N-acetylases show little speci®city for the lipid moiety of GlcNAc-PI. (ii) The 3¢-OH group of the GlcNAc residue is essential for substrate recognition whereas the 6¢-OH group is dispensable and the 4¢-OH, while not required for recognition, cannot be epimerized or substituted. (iii) The parasite enzyme can act on analogues containing bGlcNAc or aromatic N-acyl groups, whereas the human enzyme cannot. (iv) Three GlcNR-PI analogues are de-N-acetylase inhibitors, one of which is a suicide inhibitor. (v) The suicide inhibitor most likely forms a carbamate or thiocarbamate ester to an active site hydroxy-amino acid or Cys or residue such that inhibition is reversed by certain nucleophiles. These and previous results were used to design two potent (IC 50 = 8 nM) parasite-speci®c suicide substrate inhibitors. These are potential lead compounds for the development of anti-protozoan parasite drugs.

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Section: Methodsmentioning

confidence: 99%

Specificity of GlcNAc-PI de-N-acetylase of GPI biosynthesis and synthesis of parasite-specific suicide substrate inhibitors

et al. 2001

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“…d -GlcNα1−6- l -2- O -methyl- myo -inositol-1-HPO 4 - sn -1,2-dipalmitoylglycerol (GlcN-[ l ]-(2- O -methyl)-PI) was prepared in a manner similar to that of the corresponding d - myo -inositol analogue (). 3-Deoxy- d -GlcNα1−6- d - myo -inositol-1-HPO 4 - sn -1,2-dipalmitoylgly-cerol (3-dGlcN-PI), 4-deoxy- d -GlcNα1−6- d - myo -inositol-1-HPO 4 - sn -1,2-dipalmitoyl-glycerol (4-dGlcN-PI), 6-deoxy- d -GlcNα1−6- d - myo -inositol-1-HPO 4 - sn -1,2-dipalm-itoylglycerol (6-dGlcN-PI), and 4- O -methyl- d -GlcNα1−6- d - myo -inositol-1-HPO 4 - sn -1,2-dipalmitoylglycerol (GlcN4Me-PI) were synthesized as described recently ( , ). The preparation of d -GalNα1−6- d - myo -inositol-1-HPO 4 - sn -1,2-dipalmitoylglycerol (GalN-PI), d -ManNα1−6- d - myo -inositol-1-HPO 4 - sn -1,2-dipalmitoylglycerol (ManN-PI), and d -GlcNβ1−6- d - myo -inositol-1-HPO 4 - sn -1,2-dipalmitoylglycerol (GlcN- β -PI) will be published elsewhere (Crossman and Brimacombe, unpublished data).…”

Section: Methodsmentioning

confidence: 99%

“…D-GlcNR1-6-L-2-O-methyl-myo-inositol-1-HPO 4 -sn-1,2-dipalmitoylglycerol (GlcN-[L]-(2-O-methyl)-PI) was prepared in a manner similar to that of the corresponding D-myo-inositol analogue (58). 3-Deoxy-D-GlcNR1-6-D-myo-inositol-1-HPO 4 -sn-1,2-dipalmitoylglycerol (3-dGlcN-PI), 4-deoxy-D-GlcNR1-6-D-myo-inositol-1-HPO 4 -sn-1,2-dipalmitoyl-glycerol (4-dGlcN-PI), 6-deoxy-D-GlcNR1-6-D-myo-inositol-1-HPO 4 -sn-1,2-dipalmitoylglycerol (6-dGlcN-PI), and 4-O-methyl-D-GlcNR1-6-D-myo-inositol-1-HPO 4 -sn-1,2-dipalmitoylglycerol (GlcN4Me-PI) were synthesized as described recently (60,61).…”

Section: Methodsmentioning

confidence: 99%

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Substrate Specificity of thePlasmodium falciparumGlycosylphosphatidylinositol Biosynthetic Pathway and Inhibition by Species-Specific Suicide Substrates

et al. 2002

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The substrate specificities of the early glycosylphosphatidylinositol biosynthetic enzymes of Plasmodium were determined using substrate analogues of D-GlcN(alpha)1-6-D-myo-inositol-1-HPO(4)-sn-1,2-dipalmitoylglycerol (GlcN-PI). Similarities between the Plasmodium and mammalian (HeLa) enzymes were observed. These are as follows: (i) The presence and orientation of the 2'-acetamido/amino and 3'-OH groups are essential for substrate recognition for the de-N-acetylase, inositol acyltransferase, and first mannosyltransferase enzymes. (ii) The 6'-OH group of the GlcN is dispensable for the de-N-acetylase, inositol acyltransferase, all four of the mannosyltransferases, and the ethanolamine phosphate transferase. (iii) The 4'-OH group of GlcNAc is not required for recognition, but substitution interferes with binding to the de-N-acetylase. The 4'-OH group of GlcN is essential for the inositol acyltransferase and first mannosyltransferase. (iv) The carbonyl group of the natural 2-O-hexadecanyl ester of GlcN-(acyl)PI is essential for substrate recognition by the first mannosyltransferase. However, several differences were also discovered: (i) Plasmodium-specific inhibition of the inositol acyltransferase was detected with GlcN-[L]-PI, while GlcN-(2-O-alkyl)PI weakly inhibited the first mannosyltransferase in a competitive manner. (ii) The Plasmodium de-N-acetylase can act on analogues containing N-benzoyl, GalNAc, or betaGlcNAc whereas the human enzyme cannot. Using the parasite specificity of the later two analogues with the known nonspecific de-N-acetylase suicide inhibitor [Smith, T. K., et al. (2001) EMBO J. 20, 3322-3332], GalNCONH(2)-PI and GlcNCONH(2)-beta-PI were designed and found to be potent (IC(50) approximately 0.2 microM), Plasmodium-specific suicide substrate inhibitors. These inhibitors could be potential lead compounds for the development of antimalaria drugs.

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“…(II) and (IV) were prepared as described for the d-enantiomers (Dix et al, 2001) Analysis of (IV), found: C 49.34, H 7.59, N 13.18%; calculated: C 49.20, H 7.31, N 13.24%. [] D À291 (c = 1, CHCl 3 ).…”

Section: Methodsmentioning

confidence: 99%

Methyl (2′R,3′R)-2-azido-2,6-dideoxy-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-α-L-glucopyranoside

et al. 2002

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Unlike other α‐mannopyranoside‐2‐sulphonates, the 2‐O‐trifluoromethylsulfonyl (trifluoromethanesulfonate) derivative, (II), underwent an SN2 displacement with an azide ion to give methyl (2′R,3′R)‐2‐azido‐2,6‐dideoxy‐3,4‐O‐(2′,3′‐dimethoxybutane‐2′,3′‐diyl)‐α‐l‐glucopyranoside, C13H23N3O6, (IV), in preference to the E2 reaction.

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Analogues of d -glucosaminylphosphatidylinositol: synthesis of the glycosyl donors

Cited by 9 publications

References 6 publications

Specificity of GlcNAc-PI de-N-acetylase of GPI biosynthesis and synthesis of parasite-specific suicide substrate inhibitors

Specificity of GlcNAc-PI de-N-acetylase of GPI biosynthesis and synthesis of parasite-specific suicide substrate inhibitors

Substrate Specificity of thePlasmodium falciparumGlycosylphosphatidylinositol Biosynthetic Pathway and Inhibition by Species-Specific Suicide Substrates

Methyl (2′R,3′R)-2-azido-2,6-dideoxy-3,4-O-(2′,3′-dimethoxybutane-2′,3′-diyl)-α-L-glucopyranoside

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