Design, Synthesis and Biological Evaluation of Potent Human Glyoxalase I Inhibitors

Several glutathione derivatives bearing the S-(N-aryl-N-hydroxycarbamoyl) or S-(C-aryl-N-hydroxycarbamoyl) moieties (10, 10′, 13–15) were synthesized, characterized, and their human glyoxalase I (hGLO1) inhibitory activity was evaluated. Compound 10 was proved to be the effective hGLO1 inhibitor with a Ki value of 1.0 nM and the inhibition effect of compound 10 on hGLO1 was nearly ten-fold higher than that of the strongest inhibitor 2 (Ki=10.0 nM) which has been reported in the field of glutathione-type hGLO1 inhibitors. Its diethyl ester prodrug 10′ was able to penetrate cell membrane and had good inhibitory effect on the growth of NCI-H522 cell xenograft tumor model.