Synthesis and evaluation of eight aminodeoxy trisaccharide inhibitors for N-acetylglucosaminyltransferase-V.
N-Acetylglucosaminyltransferase-V is an important enzyme controlling the branching pattern of N-linked oligosaccharides. This enzyme recognizes the trisaccharide octyl 2-acetamido-2-deoxy-beta-D-glucopyranosyl-(1-->2)-alpha-D-mannopyranosyl -(1-->6)-beta-D-glucopyranoside (5) as a substrate and adds a beta-linked GlcNAc residue to OH-6 of the central alpha-Man unit. Eight analogs of 5 were chemically synthesized where C-6 of the alpha-Man residue in 5 was deoxygenated, and structurally diverse modifications were introduced at C-4 of the same residue. The key intermediate prepared for this purpose was octyl 2-acetamido-2-deoxy-beta-D- glucopyranosyl-(1-->2)-4-amino-4,6-dideoxy-alpha-D-mannopyranosyl- (1-->6)-beta-D-glucopyranoside (7a) where the original 4'-amino group was readily derivatized on the unprotected sugar. The eight analogs 7a-7h were evaluated as inhibitors for GlcNAcT-V, both isolated (from hamster kidney) and cloned (from rat kidney). All of the compounds were found to be competitive inhibitors with Ki in the range of 3-106 microM. The conclusion of this work is that recognition of acceptor 5 does not involve contact of the C-6--C-4 end of the alpha-Man residue with the protein in the E-I (or E-S) complex.
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Department of Chemistry, University of Alberta, Edmonton, Canada.
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D000606:Amino Sugars; D000818:Animals; D002240:Carbohydrate Sequence; D006224:Cricetinae; D003837:Deoxy Sugars; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D007668:Kidney / Q000201:enzymology; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors*; D014312:Trisaccharides / Q000138:chemical synthesis / Q000494:pharmacology*
D000606:Amino Sugars; D003837:Deoxy Sugars; D004791:Enzyme Inhibitors; D014312:Trisaccharides; D017351:N-Acetylglucosaminyltransferases; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase