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Inhibitors of glyoxalase I: design, synthesis, inhibitory characteristics and biological evaluation.

Glyoxalase I (EC 4.4.1 .S lactoylglutathione lyase) catalyses the formation of S-u-lactoylglutathione from methylglyoxal and glutathione [ 11. The molecular species that binds to the active site of glyoxalase I is the hemithioacetal, formed nonenzymically from methylglyoxal and reduced glutat hione, y-L-glutamyl-S-( 1 -hydroxy-2-oxopropyl)L-cysteinylglycine. The isomerization of the hemithioacetal to S-1 Aactoylglutathione in the active site of glyoxalase I is thought to proceed via an endiolate intermediate. The reaction mechanism involves a shielded proton transfer from C-1 to C-2 of the hemithioacetal and rapid ketonization to the thioester product [2]. The S-u-lactoylglutathione formed is optically pure; generally, S(R)-2hydroxyacylglutathione derivatives are formed from glutathione and a-oxoaldehydes [3]. Recent evidence suggests that both Rand S-stereoisomers of the hemithioacetal bind to the active site of glyoxalase I and are converted to enediolate intermediates followed by stereospecific protonation to form the thioester [4]. The active site of glyoxalase I contains a glutathione-recognition site, a general-base catalyst (thought to be the imidazole moiety of a histidine residue [S]) and a proximate zinc ion, Zn2+, with co-ordinated water molecules that interact with the hemithioacetal and enediolate intermediate. The glutathione-recognition site is thought to form a complementary surface of counter-charged groups, lysine (mammalian enzyme) or arginine (yeast enzyme) residues and aspartate or glutamate residues, which bind the glutathionyl moiety of the hemithioacetal substrate by salt-bridge linkages (Figure 1). The charge characteristics of the glutathionyl moiety and the structural characteristics of the putative enediolate mechanistic intermediate have been conserved in developing potent, competitive, substrate-analogue inhibitors and transitionstate analogue inhibitors.