Novel bivalent inhibitors with sub-nanomolar affinities towards human glyoxalase I

The zinc metalloenzyme glyoxalase I (GlxI) catalyzes the glutathione-dependent inactivation of cytotoxic methylglyoxal. Two competitive bivalent GlxI inhibitors, polyBHG2-62 (Ki = 1.0 nM) and polyBHG2-54 (Ki = 0.3 nM), were synthesized based on the transition-state analog S-(N-bromophenyl-N-hydroxycarbamoyl) glutathione (BHG). The most effective inhibitor, polyBHG2-54, is the first subnanomolar inhibitor of GlxI, and is over 50-fold more potent than BHG itself.90