Structural variations in the trans-carboxylate/chlorido axis that impact on the mode of action of Pt(II) complexes

Abstract

The design of trans-platinum(II) complexes marked a significant turning point in the design of unconventional anticancer metallodrugs. Compared to cisplatin, these complexes exhibit 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 trans-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, MCF10A) cell lines, finding that the complex with only one acetate in trans to a chlorido group is more active and selective than the complex with two acetates (X=X’). Furthermore, the two complexes differ in their cellular uptake route as well as mode of action from cisplatin by inducing cancer cell death via non-DNA-associated mechanisms.