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 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-1 (or E-S) complex. Eight amino-trisaccharides (7a–7h) were chemically synthesized and found to be competitive inhibitors of GlcNAcT-V with K i values ranging from 3 to 106 μM.