An improved synthesis of the potent and selective γ-glutamyl transpeptidase inhibitor GGsTop together with an inhibitory activity evaluation of its potential hydrolysis products

Abstract

A previously reported synthetic route to 2-amino-4-{[3-(carboxymethyl)phenoxy](methoxy)phosphoryl}butanoic acid (GGsTop), a potent, highly selective, non-toxic, and irreversible inhibitor of γ-glutamyl transpeptidase (GGT) was substantially improved. This route furnishes GGsTop in four steps with an overall yield of 32% from inexpensive starting materials, i.e., the yield is increased approximately sixfold relative to the previous protocol. The synthesis and inhibitory activity evaluation of potential hydrolysis products of GGsTop clearly demonstrated that GGsTop is the active inhibitor, and the conceivable hydrolysis products barely affect the activity of human GGT.