Structural variations in the <i>trans</i>-carboxylate/chlorido axis that impact the mode of action of Pt(<scp>ii</scp>) complexes

The design of <i>trans</i>-platinum(ii) complexes marked a significant turning point in the development of unconventional anticancer metallodrugs. Compared to cisplatin, these complexes induce distinctly different cellular responses and are often active against cisplatin-resistant cell lines. In this study, we synthesized and fully characterized two new Pt(ii) complexes, introducing one acetate (^-OCOCH₃) ligand (x) into the <i>trans</i>-PtXX' axis, where X' is either acetate or chlorido. We evaluated their cytotoxicity across a panel of malignant (Capan-1, B16, MCF7, HCT-116, CT26 and P31) and non-malignant (HaCaT, HUVEC, BEC, and MCF10A) cell lines, finding that the complex with only one acetate <i>trans</i> to a chlorido group is more active and selective than the complex with two acetates (X = X'). Furthermore, the two complexes differ from cisplatin in their cellular uptake route as well as mode of action by inducing cancer cell death <i>via</i> non-DNA-associated mechanisms.