Oxidation of 3,6-dioxa-1,8-octanedithiol by platinum(IV) anticancer prodrug and model complex: kinetic and mechanistic studies.
Oxidation of 3,6-dioxa-1,8-octanedithiol by platinum(IV) anticancer prodrug and model complex: kinetic and mechanistic studies.
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DOI：
10.1021/jp302600a
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发表时间：
2012-05
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影响因子：
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通讯作者：
S. Huo;S. Shen;Dongzhi Liu;T. Shi
中科院分区：
文献类型：
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作者：
S. Huo;S. Shen;Dongzhi Liu;T. Shi
硫氧还蛋白是小的氧化还原蛋白，具有Cys-Xaa-Yaa-Cys的活性位点;它们被许多不同的癌细胞过表达。顺铂和Pt（II）类似物可以结合到活性位点并抑制蛋白质的活性，正如其他研究人员所证明的那样。铂（IV）抗癌药物通常被认为是前药，但它们与硫氧还蛋白的相互作用尚未研究。本工作选择3，6-二氧杂-1，8-辛二硫醇（二硫醇）作为硫氧还蛋白活性中心的模型化合物，研究了它与cis-[Pt（NH（3））（2）Cl（4）]和trans-[PtCl（2）（CN）（4）]（2-）（顺铂前药和模型配合物）的反应。在25.0 °C和1.0 M的离子强度下，二硫醇的pK（a）值表征为8.7 ± 0.2和9.6 ± 0.2。反应动力学随后由停流分光光度计在宽pH范围内。建立了总的二级速率定律，-d[Pt（IV）]/dt = k '[Pt（IV）][二硫醇]，其中k'代表所观察到的二级速率常数。当溶液pH值从3增加到9时，k'值增加了几个数量级。还原过程和产物质谱分析的Δ[Pt（IV）]/Δ[二硫醇] = 1：1的化学计量表明，二硫醇被氧化形成分子内二硫化物，与硫氧还蛋白的性质一致。所有的反应特征是合理化的反应机制，涉及三个平行的速率决定步骤取决于反应介质的pH值。评价了速率决定步骤的速率常数。可以得出结论，Pt（IV）抗癌前药可以氧化还原的硫氧还蛋白，其氧化机制与次氯酸/次氯酸盐和氯胺等活性氧物种（ROS）氧化生物学重要还原剂的机制相似。
Thioredoxins are small redox proteins and have the active sites of Cys-Xaa-Yaa-Cys; they are overexpressed by many different cancer cells. Cisplatin and Pt(II) analogues could bind to the active sites and inhibit the activities of the proteins, as demonstrated by other researchers. Platinum(IV) anticancer drugs are often regarded as prodrugs, but their interactions with thioredoxins have not been studied. In this work, 3,6-dioxa-1,8-octanedithiol (dithiol) was chosen as a model compound for the active sites of thioredoxins, and its reactions with cis-[Pt(NH(3))(2)Cl(4)] and trans-[PtCl(2)(CN)(4)](2-) (cisplatin prodrug and a model complex) were studied. The pK(a) values for the dithiol were characterized to be 8.7 ± 0.2 and 9.6 ± 0.2 at 25.0 °C and an ionic strength of 1.0 M. The reaction kinetics was followed by a stopped-flow spectrophotometer over a wide pH range. An overall second-order rate law was established, -d[Pt(IV)]/dt = k'[Pt(IV)][dithiol], where k' stands for the observed second-order rate constants. Values of k' increased several orders of magnitude when the solution pH was increased from 3 to 9. A stoichiometry of Δ[Pt(IV)]/Δ[dithiol] = 1:1 derived for the reduction process and product analysis by mass spectrometry indicated that the dithiol was oxidized to form an intramolecular disulfide, coinciding with the nature of thioredoxin proteins. All of the reaction features are rationalized in terms of a reaction mechanism, involving three parallel rate-determining steps depending on the pH of the reaction medium. Rate constants for the rate-determining steps were evaluated. It can be concluded that Pt(IV) anticancer prodrugs can oxidize the reduced thioredoxins, and the oxidation mechanism is similar to those of the oxidations of biologically important reductants by some reactive oxygen species (ROS) such as hypochlorous acid/hypochlorite and chloramines.