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.

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.

Mechanisms of decomposition of alpha-hydroxydialkylnitrosamines in aqueous solution.

A study of the decomposition of alpha-hydroxydialkylnitrosamines in aqueous 9% acetonitrile, with an ionic strength of 1 M (NaClO(4)), at 25 degrees C is reported. Plots of the logarithm of the buffer-independent rate constant, k(o), against pH are concave up and indicate a three-term rate law for the solvent reaction, including acid (k(H+)-, base (k(OH))-, and pH-independent (k(HOH)) terms. Secondary alpha-deuterium isotope effects for compound 1a, (N-nitrosomethylamino)phenylmethanol, are as follows: k(alpha)(H)/k(alpha)(D) = 1.12 +/- 0.03 and 1.19 +/- 0.02 for k(H+) and k(OH), respectively. General acid (k(HA)) and general base (k(A-) catalysis by more acidic carboxylic acid buffers is also observed. Structure reactivity and other parameters obtained in this study, and their changes with substrate and catalyst structure, permit the assignment of mechanisms for the k(H+) k(OH), k(HA), and k(A-) processes.

Predicted exocyclic amino group alkylation of 2'-deoxyadenosine and 2'-deoxyguanosine by the isopropyl cation.

Diisopropyltriazene in aqueous 10% acetonitrile (pH 7.0 +/- 0.4) yields N(6)-isopropyl-2'-deoxyAdo as the predominant product and N(2)-isopropyl-2'-deoxyGuo in yields comparable with the O(6) adduct in reactions with 2'-deoxyAdo and 2'-deoxyGuo, respectively. These observations are inconsistent with what is expected on the basis of the regnant hypothesis concerning factors that determine atom site selectivity in diazonium ion-mediated alkylations. An alternative explanation based on the fleeting existence of the reactive intermediates involved is consistent with these observations.