Department of Chemistry and Chemical Technologies , Università della Calabria , 87036 , Arcavacata di Rende , CS , Italy.
Inorg Chem. 2019 Mar 18;58(6):3851-3860. doi: 10.1021/acs.inorgchem.8b03486. Epub 2019 Mar 7.
The reduction mechanism of Pt(IV) anticancer prodrugs, still today a matter of debate, assisted by one of the dominant reductants in human plasma, that is l-ascorbic acid in its monodeprotonated form, has been computationally examined in this work. In order to check what should be the influence on the reduction rate of the identity of the ligands in axial and equatorial position, both cisplatin and oxaliplatin derivatives have been studied, varying the ligands in axial position in connection with the role they should play as bridges, trans leaving species, and proton acceptors. OH, OAc, Cl, and Br ligands have been tested as bridging/leaving ligands, whereas Cl and aspirin have been used as trans labile and less labile ligands, respectively. The most recent theoretical and experimental investigations have demonstrated that the generally adopted grouping of reduction mechanisms into inner- and outer-sphere does not properly take into account all the viable alternatives. Therefore, inner-sphere mechanisms, classified as ligand-bridged, ligand-bridged-H transfer and enolate β-carbon attack, have been explored for all the complexes under investigation. Concerning the outer-sphere mechanism, redox potentials have been calculated adopting a recently proposed procedure based on the separation between electrochemical and chemical events to evaluate their propensity to be reduced. Moreover, according to the hypothesis that the outer-sphere reduction mechanism involves the sequential addition of two electrons causing the formation of a Pt(III) intermediate, the possibility that singlet and triplet pathways can cross for the Pt(IV) cisplatin derivative having two chlorido ligands in axial position has been explored in detail. Results show that the mechanism indicated as base-assisted outer sphere can become competitive with respect to the inner one if two singlet-triplet spin inversions occur. Results presented here are helpful in addressing synthetic strategies as they show that Pt(IV) prodrugs propensity to be reduced can be properly tuned and give indications on how this aim can be accomplished.
这项工作计算研究了由人血浆中主要还原剂之一（以单质子化形式存在的抗坏血酸）辅助的 Pt(IV) 抗癌前药的还原机制。为了检验轴向和赤道配体的身份对还原速率的影响，研究了顺铂和奥沙利铂的衍生物，同时改变轴向配体，以研究它们作为桥联配体、反式离去物种和质子受体的作用。已经测试了 OH、OAc、Cl 和 Br 配体作为桥联/离去配体，而 Cl 和阿司匹林分别用作反式不稳定和较稳定的配体。最近的理论和实验研究表明，通常采用的将还原机制分为内球和外球的分组方法并不能恰当地考虑所有可行的替代方案。因此，已经探索了所有研究配合物的内球机制，包括配体桥联、配体桥联-H 转移和烯醇化物β-碳攻击。对于外球机制，采用了一种最近提出的基于电化学和化学事件分离的程序来计算氧化还原电位，以评估它们被还原的倾向。此外，根据外球还原机制涉及两个电子的顺序添加导致 Pt(III) 中间体形成的假设，详细探索了轴向位置具有两个氯配体的 Pt(IV) 顺铂衍生物中可能发生单重态和三重态途径交叉的情况。结果表明，如果发生两个单重态-三重态自旋反转，被称为碱基辅助外球的机制可以与内球机制竞争。这里呈现的结果有助于确定合成策略，因为它们表明 Pt(IV) 前药的还原倾向可以得到适当的调节，并提供了如何实现这一目标的指示。
