SYNTHESIS AND EVALUATION OF 8 AMINODEOXY TRISACCHARIDE INHIBITORS FORN-ACETYLGLUCOSAMINYLTRANSFERASE-V

N-Acetylglucosaminyltransferase-V is an important enzyme controlling t he branching pattern of N-linked oligosaccharides. This enzyme recogni zes 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 ce ntral alpha-Man unit. Eight analogs of 5 were chemically synthesized w here C-6 of the alpha-Man residue in 5 was deoxygenated, and structura lly 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-man nopyranosyl-(1 --> 6)-beta-D-glucopyranoside (7a) where the original 4 '-amino group was readily derivatized on the unprotected sugar. The e ight analogs 7a-7h were evaluated as inhibitors for GlcNAcT-V, both is olated (from hamster kidney) and cloned (from rat kidney). All of the compounds were found to be competitive inhibitors with K-i in the rang e of 3-106 mu M. The conclusion of this work is that recognition of ac ceptor 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. (C) 1997 Publish ed by Elsevier Science Ltd.