Binuclear platinum(ii) complexes bearing various bridging 1,1′-diphosphinoferrocene ligands as potential anticancer agents: synthesis and biological evaluation

Abstract

Novel binuclear platinum(II) complexes driven by C^N cyclometalated ligands with the general formula [Pt₂(C^N)₂Cl₂(μ-L)], where C^N = 2-phenylpyridine (ppyH) or 2-(2,4-difluorophenyl)pyridine (dfppyH) and L = 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis(diisopropylphosphino)ferrocene (dippf), and 1,1′-bis(dicyclohexylphosphino)ferrocene (dcpf), have been designed, synthesized, and characterized. Single crystal X-ray analysis confirmed the molecular structures of complexes. The electronic absorption spectra of these Pt(II) complexes are examined, and density functional theory (DFT) and time-dependent DFT (TD-DFT) were employed for geometry optimization and electronic structure computations, respectively. To evaluate the potential of these complexes as anticancer agents, the biological activities including cytotoxic activity, DNA interaction and molecular docking were accomplished. The cytotoxic activity of the prepared complexes was assessed against A549, HeLa, and MCF-7 tumor cell lines using the MTT assay. The results demonstrated that 2c and 3c had reasonable cytotoxic activities, while the other complexes revealed less cytotoxic activity. In comparison to cisplatin, 3c showed significantly higher cytotoxicity against A549 cells. Additionally, the SAR results established that the dfppy ligand, which contains fluorine atoms improved the cytotoxic activity of these complexes. To understand the antiproliferative mechanism of 3c, analyses of DNA damage (comet assay) and apoptosis were carried out. In addition to this, the detection of cellular reactive oxygen species (ROS) was evaluated. Moreover, molecular docking simulations suggested reasonable interactions between these complexes and DNA. This study suggests that metal-based drug design can be developed utilizing the scaffold of 3c as a valuable anticancer agent.