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-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 Ki 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-1 (or E-S) complex.