Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz.
Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz.
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癌症化学预防药物奥替普拉主要代谢物的替代前体的硫解化学。
DOI：
10.1021/jo020588n
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Fishbein,JamesC
中科院分区：
文献类型：
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作者：
Navamal,Mettachit;McGrath,Colleen;Stewart,Jennifer;Blans,Patrick;Villamena,Frederick;Zweier,Jay;Fishbein,JamesC
化合物7-甲基-6，8-双（甲基二硫烷基）吡咯并[1，2-a]吡嗪（5;“双二硫化物”）和甲硫基磺酸（（6-（甲磺酰基硫烷基）-7-甲基）吡咯并[1，2-a]吡嗪-8-基）酯（六）“双甲磺酸硫酯”）作为癌症化学预防剂奥替普拉，1，以测试它们是否具有相似的生物活性。在目前的工作中，这些化合物与谷胱甘肽反应的机制进行了研究，以验证假设，即它们将在生物硫醇的存在下化学上有能力得到奥替普拉代谢产物。在37 °C下，主要在水性介质（≤ 15体积%乙醇）中进行动力学和产物研究。通过电喷雾HPLC/MS对中间体进行的动力学分析和鉴定表明，化合物5通过硫醇-二硫键交换（包括去除两个硫代甲基）在两个连续反应中分解。与此相反，6分解在三个连续的步骤中，首先需要形成的二谷胱甘肽加合物，随后由两个后续的硫醇二硫键交换反应，涉及损失的谷胱甘肽部分。两者5和6，以及奥替普拉本身，在与谷胱甘肽的反应中给出了几乎定量的代谢产物4。通过EPR自旋捕获方法对6的衰变进行分析表明，小于0.2%的反应通量通过比羟基自由基更稳定的自由基进行。
The compounds 7-methyl-6,8-bis(methyldisulfanyl)pyrrolo[1,2-a]pyrazine (5; “bis disulfide”) and methanethiosulfonic acidS-((6-(methanesulfonylsulfanyl)-7-methyl)pyrrolo[1,2-a]pyrazin-8-yl) ester (6; “bis methanesulfonic acid thioester”) have been synthesized to serve as alternative precursors to the major metabolite,4, of the cancer chemopreventive oltipraz,1, to test whether they possess similar biological activities. In the present work the mechanisms by which these compounds react with glutathione have been investigated in order to validate the assumption that they would be chemically competent in the presence of the biological thiols to give the oltipraz metabolite. A kinetic and product study was carried out in mainly aqueous media, ≤15% ethanol by volume, at 37 °C. The kinetic analysis and identification of intermediates by electrospray HPLC/MS indicate that compound5decomposes in two sequential reactions via thiol−disulfide interchange involving removal of the two thiomethyl groups. In contrast,6decomposes in three sequential steps, the first entailing formation of the diglutathionyl adduct, followed by two subsequent thiol disulfide interchange reactions involving loss of the glutathionyl moieties. Both5and6, as well as oltipraz itself, give nearly quantitative yields of the metabolite4in reactions with glutathione. Analysis of the decay of6by EPR spin trapping methods indicates that less than 0.2% of the reaction flux proceeds through radicals more stable than the hydroxyl radical.