This report summarizes an investigation of the reactions of biological and other thiols with the cancer chemopreventive oltipraz and other dithiolethiones. Analysis of the kinetics of reaction of 4-methyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (oltipraz) 1 with monothiols and dithiols in the range of 0.75-20 mM in aqueous 15% ethanol, at pH 7.5 (0.1 M Tris buffer) and at 37 °C has been undertaken. A plot of kobsd against [thiol] shows that reactions of mono- and dithiols are first order in thiol concentration. The dependence on pH of these reactions shows that the active species is the thiolate anion. Specific second-order rate constants, k2 (M-1 S-1) for reaction of the thiolate anions with oltipraz have been determined to be cysteine, 0.040 ± 0.001; 2-mercaptoethanol, 2.0 ± 0.02; glutathione, 0.099 ± 0.001; mercaptoacetic acid anion, 4.0 ± 0.01; dithiothreitol, 1.33 ± 0.02; 1,3-propanedithiol, 10 ± 0.5; 1-mercaptopropane-3-ol, 6.5 ± 0.1; 1-mercaptopropane-2,3-diol, 1.26 ± 0.05. A plot of pKa against log k2 for monothiols shows a linear dependence of k2 on pKa, βnuc 1.1 ± 0.07, which accounts for most of the reportedly enhanced reactivity of dithiols over monothiols. The pseudo-first-order rate constant for the solvolysis of oltipraz has been measured as 2.2 (±0.2) × 10-8 S-1. The kinetics of reaction of three other dithiole-3-thiones with glutathione has also been studied for comparison with oltipraz. The specific second-order rate constants, k2 (M-1 S-1) are 5-phenyl-1,2-dithiole-3-thione, 4.7 × 10-4; 5-(4-methoxyphenyl)-1,2-dithiole-3-thione, 4.1 × 10-4; and 1,2-dithiole-3-thione 0.08. Important implications for the mode of biological action of these compounds and the nature of the putative biological targets of the compounds are discussed.
ASJC Scopus subject areas