Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Michel 11, 15121 Alessandria, Italy.
Dalton Trans. 2018 Jun 25;47(25):8268-8282. doi: 10.1039/c7dt04614f.
Multi-action cisplatin-based mono- (1) and di-clofibric acid (2) Pt(iv) "combo" derivatives were synthesized via both traditional and microwave assisted procedures. The two complexes offered very good performances (IC50 values in a nanomolar range) on a panel of human tumor cell lines, including the highly chemoresistant malignant pleural mesothelioma ones. Moreover, both 1 and 2 bypass the cisplatin resistance. Indeed, cisplatin and clofibric acid, the metabolites of the Pt(iv) → Pt(ii) intracellular reduction, proved to act synergistically. The adjuvant action of clofibric acid relies on the activation of peroxisome proliferator-activated receptor α (PPARα) that, in turn, decreases the level of Hypoxia-Inducible Factor-1α. Both compounds induced extensive apoptosis in tumor cells, also via oxidative stress. Finally, 2 exhibited excellent performances also under the hypoxic conditions typical of solid tumors, where cisplatin is less effective.
通过传统和微波辅助方法合成了具有多种作用的顺铂单（1）和双氯非布酸（2）Pt（iv）“组合”衍生物。这两种配合物在一组人类肿瘤细胞系中表现出非常好的性能（IC50 值在纳摩尔范围内），包括高度耐药的恶性胸膜间皮瘤。此外，1 和 2 都绕过了顺铂耐药性。事实上，顺铂和氯非布酸是 Pt（iv）→Pt（ii）细胞内还原的代谢物，被证明具有协同作用。氯非布酸的辅助作用依赖于过氧化物酶体增殖物激活受体α（PPARα）的激活，而 PPARα 又会降低低氧诱导因子-1α 的水平。这两种化合物在肿瘤细胞中也通过氧化应激诱导广泛的细胞凋亡。最后，2 在肿瘤中典型的缺氧条件下（顺铂在这种条件下效果较差）也表现出优异的性能。
