Design and biological evaluation of a histidine-bearing cyclometalated Pd(II) complex derived from 2-phenylpyridine

A rationally designed approach was employed to synthesize a new C^N-cyclometalated Pd(II) complex (C^N = 2-phenylpyridine) as a potential anticancer metallodrug. The incorporation of histidine in the coordination sphere of metal complex offers dual effect, balancing hydrophobic and hydrophilic properties while enhancing biocompatibility. The structure of histidine-bearing C^N-cyclometalated Pd(II) complex was characterized using elemental analysis, FT-IR, and NMR spectroscopy. In vitro cytotoxic activity was evaluated against HEP G2 human hepatoma and MCF7 human breast cancer cells revealing high selectivity of complex toward HEP G2 compared to MCF7 cancer cells. The effect of complex on NIH-3T3 mouse embryonic fibroblast normal cells were also assessed. To elucidate the mechanism of action, binding interactions with DNA were investigated using UV-Vis and fluorescence spectroscopy demonstrating preferential binding to the minor groove of DNA, suggesting a DNA-targeting mechanism. Additionally, the complex exhibited strong affinity for bovine serum albumin (BSA) with through a static quenching process. These findings suggest that the integration of amino acids into the coordination sphere of cyclometalated complexes can address the limitations of traditional metal-based anticancer agents by improving drug stability and biocompatibility.