Phosphonate and phosphinate analogues of N-Acylated γ-glutamylglutamate: potent inhibitors of glutamate carboxypeptidase II

Phosphonate and phosphinate analogues of N-acylated γ-glutamylglutamate were tested for the ability to inhibit glutamate carboxypeptidase II (GCP II). All of the compounds inhibit GCP II with IC50 values in the low nanomolar range. The comparison of the results to previously reported inhibitory studies of the same compounds toward folylpoly-γ-glutamyl synthetase (FPGS) and γ-glutamyl hydrolase (γ-GH) provides insight into structural and mechanistic features of each enzyme. Potential utility of these compounds as diagnostic agents and probes to understand folate or antifolate poly-γ-glutamates metabolism is also described.