Platinum(II) Complexes Bearing Triphenylphosphine and Chelating Oximes: Antiproliferative Effect and Biological Profile in Resistant Cells

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Abstract
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 the proposed (SP4‐3) configuration for 1. Study of the antiproliferative activity, performed on a panel of human tumor cell lines and on mesothelial cells, highlighted complex 2 as the more effective. In particular, it showed a remarkable cytotoxicity in ovarian carcinoma cells (A2780) and interestingly, a significant antiproliferative effect on cisplatin resistant cells (A2780cis). Investigation into the intracellular mechanism of action demonstrated that 2 had a lower ability to platinate DNA than did cisplatin, which was 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 mitochondrion‐mediated pathway as responsible for the interesting cytotoxic profile of complex 2.

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