University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Waehringer Strasse 42, 1090, Vienna, Austria.
Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.
Angew Chem Int Ed Engl. 2019 May 27;58(22):7464-7469. doi: 10.1002/anie.201900682. Epub 2019 Apr 25.
Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, Pt complexes are considered to define the future of anticancer platinum drugs. The aqueous stability of a series of biscarboxylato Pt complexes was studied under physiologically relevant conditions. Unexpectedly and in contrast to the current chemical understanding, especially oxaliplatin and satraplatin complexes underwent fast hydrolysis in equatorial position (even in cell culture medium and serum). Notably, the resulting hydrolysis products strongly differ in their reduction kinetics, a crucial parameter for the activation of Pt drugs, which also changes the anticancer potential of the compounds in cell culture. The discovery that intact Pt complexes can hydrolyze at equatorial position contradicts the dogma on the general kinetic inertness of Pt compounds and needs to be considered in the screening and design for novel platinum-based anticancer drugs.
由于其高动力学惰性，因此与生物分子的副反应减少，Pt 配合物被认为定义了未来的抗癌铂类药物。在生理相关条件下研究了一系列双羧酸盐 Pt 配合物的水稳定性。出人意料的是，与当前的化学理解相反，特别是奥沙利铂和沙铂配合物在赤道位置（甚至在细胞培养基和血清中）快速水解。值得注意的是，所得水解产物在还原动力学方面有很大差异，这是 Pt 药物激活的关键参数，也改变了化合物在细胞培养中的抗癌潜力。完整的 Pt 配合物可以在赤道位置水解的发现与 Pt 化合物普遍动力学惰性的教条相矛盾，需要在新型基于铂的抗癌药物的筛选和设计中加以考虑。
