ROS-mediated antitumor activity, apoptosis, and molecular docking studies of platinum (II) coordination complexes bearing 2-(diphenylphosphino)pyridine ligand

Abstract

Abstract In this study, the cytotoxicity of platinum (II) complexes containing 2-(diphenylphosphino)pyridine (dppy) ligands with a general formula of [cis- PtX2(κ1 P-dppy)2], (X = Cl (1a), p-tolyl (1b) and Me (1c)) on human lung (A549), ovarian (SKOV3), breast (MCF-7) cancer and normal breast (MCF-10A) cell line have been studied using MTT assay. Since the coordination sphere of metal complexes certainly affects the biological behavior, a series of platinum-phosphine complexes with diverse types of auxiliary ligands (Cl, p-tolyl, and Me) were employed to investigate their effect on biological activity. Based upon the in vitro cytotoxicity results, 1b exhibits a marked cell growth-inhibitory effect against ovarian and lung cancer cell lines with an IC50 value of 9.40 and 5.58 µM, respectively, which were significantly better than that observed for cisplatin (19.02, and 8.64 µM). Additionally, all complexes achieved significantly lower cytotoxicity towards MCF-10A. To investigate the interaction of complexes with DNA, an electrophoresis mobility shift assay was conducted on 1b, which indicated that complexes bind to DNA and affect its electrophoretic mobility. An analysis of apoptosis in A549 cells supported the conclusion that 1b inhibits cell proliferation via induction of apoptosis at a concentration-dependent manner. As a result of excessive production of reactive oxygen species (ROS), DNA was further damaged by these complexes. In order to determine the binding mode and binding site as well as binding energies, Molecular docking was also used to investigate the interactions of compounds with four different DNA structures (PDB IDs: 1BNA, 1LU5, 3CO3, and 198D). According to this study, 1b may have important applications in biopharmaceuticals.