Department of Chemistry and Chemical Technologies, Università della Calabria, Arcavacata di Rende, Italy.
J Comput Chem. 2021 Apr 5;42(9):608-619. doi: 10.1002/jcc.26483. Epub 2021 Jan 20.
A detailed computational exploration of the most relevant steps of iodido Pt(IV) complexes reduction and Pt(II) drugs mechanism of action and eventual deactivation is presented here inspired by the recent findings on iodido Pt(II) complexes and surprising re-evaluation of their cytotoxic activity. Pt(II) and Pt(IV) model systems are investigated and compared with cisplatin and its Pt(IV) derivative. Both monodeprotonated ascorbic acid and l-cysteine are used as reducing agents in the inner-sphere reduction mechanism of Pt(IV) complexes. Aquation mechanism of iodido Pt(II) complexes, interaction with guanine and sulfur containing compounds and reaction with the model protein hen egg white lysozyme are explored, due to a detected different behavior with respect to classical platinum drugs. The outcomes of such exploration allow to shed light on the role that the increased soft character together with bridging and leaving abilities of iodide over chloride could play in determining the cytotoxic profile of iodido Pt drugs.
本文受碘代 Pt(II) 配合物的最新研究结果和对其细胞毒性活性的惊人重新评估的启发，对碘代 Pt(IV) 配合物还原和 Pt(II) 药物作用机制及最终失活的最相关步骤进行了详细的计算研究。研究了 Pt(II) 和 Pt(IV) 模型体系，并将其与顺铂及其 Pt(IV) 衍生物进行了比较。在 Pt(IV) 配合物的内球还原机制中，使用单质子化抗坏血酸和 L-半胱氨酸作为还原剂。由于与经典铂类药物相比表现出不同的行为，还探索了碘代 Pt(II) 配合物的水合机制、与鸟嘌呤和含硫化合物的相互作用以及与模型蛋白鸡卵清溶菌酶的反应。这种探索的结果可以阐明增加的软特性以及碘化物相对于氯化物的桥接和离去能力在确定碘代 Pt 药物的细胞毒性特征方面可能起的作用。
