A divergent synthesis of 2-acyl derivatives of PUGNAc yields selective inhibitors of O-GlcNAcase

Abstract

A divergent route facilitating the rapid synthesis of a series of O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenylcarbamate (PUGNAc)-based inhibitors, bearing different N-acyl groups has been developed. All compounds of this series are inhibitors of both human O-GlcNAcase and human β-hexosaminidase, yet some effectively exploit differences between the active site architectures of these two human enzymes which render them selective for O-GlcNAcase. Such inhibitors may be valuable tools in dissecting the role of the O-GlcNAc post-translational modification at the cellular and organismal level since these compounds may have different pharmacokinetic properties when compared to other inhibitors of β-N-acetyl-glucosaminidases.