Biological studies of a substituted bipyridine-coordinated Zn(II) ion: In vitro cytotoxicity, ROS-induced apoptosis, anti-metastatic and nuclease-like activity plus in silico binding affinity towards cancer-related proteins

Abstract A new dimethyl-substituted bipyridine-Zn(II) complex was synthesized and structurally characterized. Single-crystalline structure of the complex was successfully elucidated as [Zn(2Mebpy)3](ClO4)2•1.5(dioxane) by X-ray diffraction, where 2Mebpy represents 4,4′-dimethyl-2,2′-bipyridine. Also, the three-dimensional electrostatic potential maps (3D ESP) were plotted for [Zn(2Mebpy)3]2+ cation and [Zn(2Mebpy)3](ClO4)2 molecule. The in vitro cytotoxicity of the complex, compared with cisplatin, was evaluated towards the human breast (MCF-7) and glioblastoma (U-87MG) cancer cells as well as normal murine embryo cells (NIH/3T3). Noteworthily, great cytotoxicity and selectivity of the Zn(II) complex against MCF˗7 cells was confirmed by IC50 value of 5.1±0.5 μM and selectivity index of 3.2 over 48 h. The complex-induced MCF-7 and U-87 cells death mostly proceeded through an apoptotic pathway in a dose-dependent manner as evidenced by the flow cytometric results. The complex demonstrated potential anti-metastatic activity against MCF-7 cells as evidenced by inhibition of colony formation and cell migration. The apoptotic mechanism in the complex-treated MCF-7 cells was probably associated with the overproduction of reactive oxygen species (ROS). The comet assay results also showed that the complex could induce DNA damage in MCF-7 cells. Moreover, the complex exhibited hydrolytic cleavage of pUC19 DNA, which may be responsible for their observed cytotoxic effect to some extent. Finally, binding affinity of the complex towards cancer therapeutic targets such as anti-apoptotic proteins, estrogen receptor α, tubulin, and topoisomerase II was predicted by in silico molecular docking. In conclusion, the complex can be introduced as a potential therapeutic agent in breast cancer. This work indicate that other metal-cored complexes baring bypyridine derivatives can also exhibit promissing anticancer effects, opening the window towards a battery of similar candidate structures.