title: Further probing of the substrate specificities and inhibition of enzymes involved at an early stage of glycosylphosphatidylinositol (GPI) biosynthesis.
abstract: 1-D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-1-O-hexadecyl-myo-inositol (14), 1-D-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-myo-inositol 1-(octadecyl phosphate) (18), 1-D-6-O-(2-amino-2-deoxy-beta-D-glucopyranosyl)-myo-inositol 1-(1,2-di-O-hexadecanoyl-sn-glycerol 3-phosphate) (24), 1-D-6-O-(2-amino-2-deoxy-alpha-D-mannopyranosyl)-myo-inositol 1-(1,2-di-O-hexadecanoyl-sn-glycerol 3-phosphate) (30) and the corresponding 2-amino-2-deoxy-alpha-D-galactopyranosyl analogue 36 have been prepared and tested in cell-free assays as substrate analogues/inhibitors of alpha-(1 --> 4)-D-mannosyltransferases that are active early on in the glycosylphosphatidylinositol (GPI) biosynthetic pathways of Trypanosoma brucei and HeLa (human) cells. The corresponding N-acetyl derivatives of these compounds were similarly tested as candidate substrate analogues/inhibitors of the N-deacetylases present in both systems. Following on from an early study, 1-L-6-O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-2-O-methyl-myo-inositol 1-(1,2-di-O-hexadecanoyl-sn-glycerol 3-phosphate) (44) was prepared and tested as an inhibitor of the trypanosomal alpha-(1 --> 4)-D-mannosyltransferase. A brief summary of the biological evaluation of the various analogues is provided.
authors.affiliation: School of Life Sciences (Chemistry), Carnelley Building, University of Dundee, Dundee DD1 4HN, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Crossman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Paterson
authors.forename: Michael A J
authors.initials: MA
authors.lastname: Ferguson
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.forename: John S
authors.initials: JS
authors.lastname: Brimacombe
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis*; D006367:HeLa Cells / Q000201:enzymology; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D008364:Mannosyltransferases / Q000037:antagonists & inhibitors; D013379:Substrate Specificity; D014344:Trypanocidal Agents / Q000138:chemical synthesis; D014346:Trypanosoma brucei brucei / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D017261:Glycosylphosphatidylinositols; D014344:Trypanocidal Agents; D007294:Inositol; D008364:Mannosyltransferases