Structure-activity relationship studies of prostate-specific membrane antigen (PSMA) inhibitors derived from alpha-amino acid with (S)- or (R)-configuration at P1 ' region

Abstract

Prostate-specific membrane antigen (PSMA), a type II membrane glycoprotein, is considered an excellent target for the diagnosis or treatment of prostate cancer. We previously investigated the effect of beta and gamma-amino acids with (S)or (R)-configuration in the S1 pocket on the binding affinity for PSMA. However, comprehensive studies on the effect of alpha-amino acid with (R)-configuration in the S1 ' pocket has not been reported yet. We selected ZJ43 (1) and DCIBzL (5) as templates and synthesized their analogues with (S)or (R)-configuration in the P1 and P1 ' regions. The PSMA-inhibitory activities of compounds with altered chirality in the P1 ' region were dropped dramatically, with their IC50 values changing from nM to mu M ranges. The compounds with (S)-configuration at both P1 and P1 ' regions were more potent than the others. The findings of this study may provide insights regarding the structural modification of PSMA inhibitor in the S1 ' binding pocket.