The study of Pt(IV) antitumor prodrugs able to circumvent some drawbacks of the conventional Pt(II) chemotherapeutics is the focus of a lot of attention. This paper reports a thorough study based on experimental methods (reduction kinetics, electrochemistry, tandem mass spectrometry and IR ion spectroscopy) and quantum–mechanical DFT calculations on the reduction mechanism of cisplatin-based Pt(IV) derivatives having two hydroxido (1), one hydroxido and one acetato (2), or two acetato ligands (3) in axial position. The biological reductants glutathione and ascorbic acid were taken into consideration. The presence of a hydroxido ligand resulted to play an important role in the chemical reduction with ascorbic acid, as verified by ¹⁵N-NMR kinetic analysis using ¹⁵N-enriched complexes. The reactivity trend (1 > 2 > 3) does not reflect the respective reduction peak potentials (1 < 2 < 3), an inverse relationship already documented in similar systems. Turning to a simplified environment, the Pt(IV) complexes associated with a single reductant molecule (corresponding to the encounter complex occurring along the reaction coordinate in bimolecular reactions in solution) were characterized by IR ion spectroscopy and sampled for their reactivity under collision-induced dissociation (CID) conditions. The complexes display a comparable reduction reactivity ordering as that observed in solution. DFT calculations of the free energy pathways for the observed fragmentation reactions provide theoretical support for the CID patterns and the mechanistic hypotheses on the reduction process are corroborated by the observed reaction paths. The bulk of these data offers a clue of the intricate pathways occurring in solution.Graphic abstract

中文翻译：

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基于顺铂的Pt（IV）衍生物在生物还原剂存在下的行为的多方法学研究，重点是孤立的相遇复合物。

能够克服常规Pt（II）化疗药物某些缺点的Pt（IV）抗肿瘤前药的研究是许多关注的焦点。本文基于实验方法（还原动力学，电化学，串联质谱法和IR离子光谱法）以及基于量子力学DFT计算的基于顺铂的具有两个羟基的Pt（IV）衍生物的还原机理进行了详尽的研究（1），在轴向位置上有一个羟基和一个乙酰基（2）或两个乙酰基配体（3）。考虑了生物还原剂谷胱甘肽和抗坏血酸。羟基配体的存在在抗坏血酸的化学还原中起着重要作用，如¹⁵使用¹⁵种富氮复合物进行N-NMR动力学分析。反应性趋势（1  >  2  >  3）不能反映出各自的还原峰电位（1  <  2  <  3），在相似系统中已经记录了逆关系。转向简化的环境，通过IR离子光谱表征与单个还原剂分子相关的Pt（IV）配合物（对应于溶液中双分子反应中沿着反应坐标发生的相遇配合物），并在碰撞诱导下对其反应性进行采样解离（CID）条件。该络合物显示出与溶液中观察到的相当的还原反应性排序。观察到的裂解反应的自由能途径的DFT计算为CID模式提供了理论支持，并且所观察到的反应途径证实了还原过程中的机理假说。这些数据的大部分提供了溶液中发生的复杂途径的线索。图形摘要