Synthesis and evaluation of eight aminodeoxy trisaccharide inhibitors for N-acetylglucosaminyltransferase-V

Article abstract of DOI:10.1016/S0008-6215(97)00174-2

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-β-D-glucopyranosyl-(1 → 2)-α-D-mannopyranosyl-(1 → 6)-β-D-glucopyranoside (5) as a substrate and adds a β-linked GlcNAc residue to OH-6 of the central α-Man unit. Eight analogs of 5 were chemically synthesized where C-6 of the α-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-β-D-glucopyranosyl-(1 → 2)-4-amino-4,6-dideoxy-α-D-mannopyranosyl-(1 → 6)-β-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 K(i) in the range of 3-106 μM. The conclusion of this work is that recognition of acceptor 5 does not involve contact of the C-6-C-4 end of the α-Man residue with the protein in the E-I (or E-S) complex.