Inhibition of Glutamate Carboxypeptidase II by Phosphonamidothionate Derivatives of Glutamic Acid

Abstract

A limited series of N-thiophosphonyl-glutamates were found to be inhibitors of the prostate-specific membrane antigen (PSMA) form of glutamate carboxypeptidase II. Comparative inhibitory profiles of an analogous O-thiophosphonyl-2-hydroxygluta-rate revealed that the amido-linkage of the N-thio-phosphonyl-glutamate provides a significant enhancement of inhibitory potency presumably due to significant hydrogen-bonding interactions with acceptor groups in the active-site of PSMA resulting in tighter binding. An analogous N-phosphonyl-glutamate exhibited significantly greater inhibitory potency than the parent N-thiophospho-nyl-glutamate indicating that the sulfur ligand of the N-thiophosphonyl-glutamates is responsible for less favorable active-site interactions than oxygen, potentially due to steric crowding from the longer P-S bond or as a result of active-site metal substitution of Co(II) for Zn(II) arising from assay conditions.

Key Words:

• Prostate-specific membrane antigen inhibition
• Glutamate carboxypeptidase II inhibition
• Phosphonamidothionate
• Phosphonamidoic acid
• Phosphonothionate
• Phosphonothioic acid