Kinetic constraints for the thiolysis of 4-methyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (oltipraz) and related dithiole-3-thiones in aqueous solution

K. A. Carey, T. W. Kensler, J. C. Fishbein

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)939-945
Number of pages7
JournalChemical research in toxicology
Volume14
Issue number8
DOIs
StatePublished - Sep 11 2001

ASJC Scopus subject areas

  • Toxicology

Fingerprint Dive into the research topics of 'Kinetic constraints for the thiolysis of 4-methyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (oltipraz) and related dithiole-3-thiones in aqueous solution'. Together they form a unique fingerprint.

Cite this