Carey K A, Kensler T W, Fishbein J C
Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
Chem Res Toxicol. 2001 Aug;14(8):939-45. doi: 10.1021/tx0100340.
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.
本报告总结了对生物硫醇及其他硫醇与癌症化学预防剂奥替普拉及其他二硫杂环戊烯酮反应的研究。已对4-甲基-5-(吡嗪-2-基)-1,2-二硫杂环戊烯-3-硫酮（奥替普拉）1与单硫醇和二硫醇在15%乙醇水溶液中、pH 7.5（0.1 M Tris缓冲液）及37℃条件下，浓度范围为0.75 - 20 mM时的反应动力学进行了分析。以k(obsd)对[硫醇]作图表明，单硫醇和二硫醇的反应对硫醇浓度呈一级反应。这些反应对pH的依赖性表明活性物种是硫醇盐阴离子。已确定硫醇盐阴离子与奥替普拉反应的特定二级速率常数k(2)（M⁻¹ s⁻¹）分别为：半胱氨酸，0.040 ± 0.001；2-巯基乙醇，2.0 ± 0.02；谷胱甘肽，0.099 ± 0.001；巯基乙酸阴离子，4.0 ± 0.01；二硫苏糖醇，1.33 ± 0.02；1,3-丙二硫醇，10 ± 0.5；1-巯基丙烷-3-醇，6.5 ± 0.1；1-巯基丙烷-2,3-二醇，1.26 ± 0.05。单硫醇的pK(a)对log k(2)作图显示k(2)对pK(a)呈线性依赖性，β(nuc)为1.1 ± 0.07，这解释了据报道二硫醇比单硫醇反应活性增强的大部分原因。已测得奥替普拉溶剂解的准一级速率常数为2.2(±0.2)×10⁻⁸ s⁻¹。还研究了其他三种二硫杂环戊烯-3-硫酮与谷胱甘肽的反应动力学，以便与奥替普拉进行比较。特定二级速率常数k(2)（M⁻¹ s⁻¹）分别为：5-苯基-1,2-二硫杂环戊烯-3-硫酮，4.7×10⁻⁴；5-(4-甲氧基苯基)-1,2-二硫杂环戊烯-3-硫酮，4.1×10⁻⁴；以及1,2-二硫杂环戊烯-3-硫酮，0.08。讨论了这些化合物生物作用模式及假定生物靶点性质的重要意义。
