Abstract
A substantial amount of attention has been paid to chemical research on cyclometalated platinum compounds that contain diphosphine ligands due to their coordination behavior and reactivity. To introduce new anticancer metallodrugs, a series of synthesized mononuclear and dinuclear cycloplatinated(II) complexes derived from deprotonated 2,2´-bipyridine N-oxide (bipyO) bearing 1,1′-bis(diphenylphosphino)alkanes (alkane: methane (dppm), ethane (dppe) and propane (dppp)) were biologically evaluated to probe the effect of diphosphine ligands on their anticancer behavior. The antitumor effects of (1a, 1b, 1c, 2a, 2b, and 2c) were evaluated against human lung (A549), ovarian (SKOV3), breast (MCF-7) cancer cell lines as well as normal breast (MCF-10A) cell line. The interactions of complexes with DNA structures (PDB IDs: 1BNA, and 1LU5) as term of binding modes and binding sites were determined using molecular docking. Compound [Pt(p-tolyl)(κ2N,C- bipyO)(κ2P-dppe)], 1b, inhibited cell proliferation significantly more effectively than cisplatin and exhibited significantly greater in vitro cytotoxicity against A549, SKOV3, and MCF7 cell lines. Complexes [Pt(p-tolyl)(κ2N,C- bipyO)(κ2P-dppp)], 1c and [Pt2(p-tolyl)2(κ2N,C- bipyO)2(µ2P-dppe)], 2b also displayed stronger cytotoxic activity than cisplatin on SKOV3, and MCF7 cancer cell lines. In evaluating cytotoxic effects on MCF-10A cells, all compounds showed low toxicities with higher selectivity index than cisplatin. EMSA, and Comet assay showed that 1b, can intercalate with DNA and targets the genomes of cancerous cells. The apoptosis assay of 1b on MCF-7 cancer cells showed that by increasing the concentration of this compound from 1 to 3 and then 5 µM, the percentage of cells entering the apoptotic stage increases from about 9.4% to 61.39% and then to 74.10%. Based upon the biological analyses, the alkyl linker chain length in 1,1′-bis(diphenylphosphino)alkanes appear to be a key factor controlling the biological activity. Interestingly, cloplatinated(II) complexes bearing 1,1′-bis(diphenylphosphino)ethane (dppe), revealed promising anticancer potentials, which makes them be good candidates for future studies in the cancer treatment field.
Published Version
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