title: Optimised chemical synthesis of 5-substituted UDP-sugars and their evaluation as glycosyltransferase inhibitors.
abstract: We have investigated the applicability of different chemical methods for pyrophosphate bond formation to the synthesis of 5-substituted UDP-galactose and UDP-N-acetylglucosamine derivatives. The use of phosphoromorpholidate chemistry, in conjunction with N-methyl imidazolium chloride as the promoter, was identified as the most reliable synthetic protocol for the preparation of these non-natural sugar-nucleotides. Under these conditions, the primary synthetic targets 5-iodo UDP-galactose and 5-iodo UDP-N-acetylglucosamine were consistently obtained in isolated yields of 40-43%. Both 5-iodo UDP-sugars were used successfully as substrates in the Suzuki-Miyaura cross-coupling with 5-formylthien-2-ylboronic acid under aqueous conditions. Importantly, 5-iodo UDP-GlcNAc and 5-(5-formylthien-2-yl) UDP-GlcNAc showed moderate inhibitory activity against the GlcNAc transferase GnT-V, providing the first examples for the inhibition of a GlcNAc transferase by a base-modified donor analogue.
authors.affiliation: King's College London, School of Biomedical Sciences, Institute of Pharmaceutical Science & Department of Chemistry, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Tedaldi
authors.forename: Michael
authors.initials: M
authors.lastname: Pierce
authors.forename: Gerd K
authors.initials: GK
authors.lastname: Wagner
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D011756:Diphosphates / Q000737:chemistry; D004789:Enzyme Activation; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005695:Galactosephosphates / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013777:Tetrazoles / Q000737:chemistry; D013997:Time Factors; D014530:Uridine Diphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D014531:Uridine Diphosphate Galactose / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D011756:Diphosphates; D004791:Enzyme Inhibitors; D005695:Galactosephosphates; D011994:Recombinant Proteins; D012997:Solvents; D013777:Tetrazoles; C029973:galactose-1-phosphate; C045574:1H-tetrazole; D014531:Uridine Diphosphate Galactose; C107241:diphosphoric acid; D014537:Uridine Diphosphate N-Acetylglucosamine; D014530:Uridine Diphosphate; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase