title: 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.
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 degrees C has been undertaken. A plot of k(obsd) 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, k(2) (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 pK(a) against log k(2) for monothiols shows a linear dependence of k(2) on pK(a), beta(nuc) 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) x 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, k(2) (M(-1) s(-1)) are 5-phenyl-1,2-dithiole-3-thione, 4.7 x 10(-)(4); 5-(4-methoxyphenyl)-1,2-dithiole-3-thione, 4.1 x 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Carey
authors.forename: T W
authors.initials: TW
authors.lastname: Kensler
authors.forename: J C
authors.initials: JC
authors.lastname: Fishbein
mesh_terms: D016588:Anticarcinogenic Agents / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D011719:Pyrazines / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013696:Temperature; D013871:Thiones; D013876:Thiophenes; D014050:Toluene / Q000031:analogs & derivatives / Q000737:chemistry*; D014867:Water
chemical_list: D016588:Anticarcinogenic Agents; D011719:Pyrazines; D013438:Sulfhydryl Compounds; D013871:Thiones; D013876:Thiophenes; D014867:Water; D014050:Toluene; C026209:oltipraz; C004848:dithiol