Bivalent transition-state analogue inhibitors of human glyoxalase I.

A new class of competitive inhibitors of homodimeric human glyoxalase I has been created by cross-linking two molecules of the transition-state analogue S-(N-4-chlorophenyl-N-hydroxycarbamoyl)glutathione (CHG) through their gamma-glutamyl-NH(2) groups with poly-beta-alanyl tethers of differing length: [CHG(beta-ala)n](2) suberate diamide (n = 1-7). The strongest inhibitors of this antitumor target enzyme likely bind simultaneously to the active site on each subunit to give K(i) values as small as 0.96 nM (n = 6). [structure: see text]