Platinum(II) complexes bearing triphenylphosphine and chelating oximes: antiproliferative effect and biological profile in resistant cells

Platinum(II) complexes of the type [Pt(Cl)(PPh3){(κ2-N,O)-(1{C(R)=N(OH)-2(O)C6H4})}] with R = Me, H, (1 and 2) were synthesized and characterized. Single crystal X-ray diffraction confirmed for 1 the proposed (SP4-3) configuration. The study of the antiproliferative activity, performed on a panel of human tumor cell lines and on mesothelial cells, highlighted complex 2 as the most effective. In particular, it showed a remarkable cytotoxicity on ovarian carcinoma cells (A2780) and interestingly, a significant antiproliferative effect on cisplatin resistant cells (A2780cis). The investigation on the intracellular mechanism of action demonstrated for 2 a lower ability to platinate DNA with respect to cisplatin, taken as reference, and a notably higher uptake in resistant cells. A significant accumulation in mitochondria, along with the ability to induce concentration-dependent mitochondrial membrane depolarization and intracellular reactive oxygen species production, allowed us to propose a mitochondria-mediated pathway as responsible for the interesting cytotoxic profile of complex 2.