S-(N-Aryl-N-hydroxycarbamoyl)glutathione derivatives are powerful competitive inhibitors of the anticancer target enzyme glyoxalase I. Indeed, the N-p-bromophenyl derivative is the strongest inhibitor of the enzyme from human erythrocytes yet reported (Ki = 1.4 x 10(-8) M). Structure-activity correlations indicate that the high affinities of the derivatives for both human and yeast glyoxalase I are due to the fact that the derivatives are hydrophobic analogs of the enediol(ate) intermediate associated with the glyoxalase I reaction. The derivatives also proved to be slow substrates for the thioester hydrolase glyoxalase II (bovine liver). Compounds of this type are of interest as potential tumor-selective anticancer agents, based on the abnormally low levels of glyoxalase II activity in some types of cancer cells.
Several recent developments suggest that the GSH-dependent glyoxalase enzyme system deserves renewed interest as a potential target for antitumour drug development. This summary focuses on the design and development of new classes of tumoricidal agents that specifically target this elementary detoxification pathway in order to induce elevated concentrations of cytotoxic methylglyoxal in tumour cells. Special emphasis is placed on structure- and mechanism-based inhibitors of GlxI (glyoxalase I), the first enzyme in the pathway. A new class of bivalent transition-state analogues is described that simultaneously bind the active site on each subunit of the homodimeric human GlxI, resulting in K (i) values as low as 1 nM. Also described is a new family of bromoacyl esters of GSH that function as active-site-directed irreversible inhibitors of GlxI. Newer prodrugs for delivering the GSH-based inhibitors into tumour cells include reactive sulphoxide esters that undergo acyl exchange with endogenous GSH to give the inhibitors, and polymethacrylamide esters of the inhibitors that are potentially tumour-selective on the basis of the "enhanced permeability and retention effect". Finally, a preliminary evaluation of the efficacy of selected GlxI inhibitors in tumour-bearing mice is given.
Human glutathione (GSH) transferase (hGSTP1-1) processes with similar kinetic efficiencies the antitumor agents 2-crotonyloxymethyl-2-cyclohexenone (COMC-6), 2-crotonyloxymethyl-2-cycloheptenone (COMC-7), and 2-crotonyloxymethyl-2-cyclopentenone (COMC-5) to 2-glutathionylmethyl-2-cyclohexenone, 2-glutathionylmethyl-3-glutathionyl-2-cycloheptenone, and 2-glutathionylmethyl-2-cyclopentenone, respectively. This process likely involves initial enzyme-catalyzed Michael addition of GSH to the COMC derivative to give a glutathionylated enol(ate), which undergoes nonstereospecific ketonization, either while bound to the active site or free in solution, to a glutathionylated exocyclic enone. Free in solution, GSH reacts at the exomethylene carbon of the exocyclic enone, displacing the first GSH to give the final product. This mechanism is supported by the observation of multiphasic kinetics in the presence of high concentrations of hGSTP1-1 and the ability to trap kinetically competent exocyclic enones in aqueous acid using COMC-6 and COMC-7 as substrates. That the exocyclic enone is formed by nonstereospecific ketonization of an enol(ate) species is indicated by the observation that COMC-6 (chirally labeled with deuterium at the exomethylene carbon) gives stereorandomly labeled exocyclic enone. The isozymes hGSTP1-1, hGSTA1-1, hGSTA4-4, and hGSTM2-2 catalyze the conversion of COMC-6 to final product with similar efficiencies (K(m) = 0.08-0.34 mM, k(cat) = 1.5-6.1 s(-)(1)); no activity was detected with the rat rGSTT2-2 isozyme. Molecular docking studies indicate that in hGSTP1-1, the hydroxyl group of Tyr108 might serve as a general acid catalyst during substrate turnover. The possible significance of these observations with respect to the metabolism of COMC derivatives in multidrug resistant tumors is discussed.
[reaction: see text] Data are presented indicating that the potent antitumor activity of 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxy-2-cyclohexenone (COTC) and 2-crotonyloxymethyl-2-cyclohexenone (COMC) is not likely the result of glyoxalase I inhibition, as has long been assumed. An alternative hypothesis is presented, based on the finding that COMC is a substrate for human glutathionyl transferase, which produces a transient, highly electrophilic glutathionylated 2-exomethylenecyclohexanone that can covalently modify proteins and nucleic acids.
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