Electronic effects of 4'-aryl substitution in terpyridine copper(II) complexes: structural insights, DNA-binding affinity, and cytotoxic evaluation.

Ever since the early success of anticancer medications, DNA has been one of the major target molecules in chemotherapeutic drug development. Herein, three new mononuclear Cu(II) complexes [Cu(L1)(L')](ClO4)2; 1, [Cu(L2)(L')](ClO4)2; 2 and [Cu(L3)(L')](ClO4)2; 3 [where, L1 = 4'-phenyl-2,2':6',2″-terpyridine, L2 = 4'-(naphthalen-1-yl)-2,2':6',2″-terpyridine, L3 = 4'-(anthracen-9-yl)-2,2':6',2″-terpyridine and L' = 2-(2-pyridyl)-1,8-naphthyridine] have been synthesised and comprehensively characterised. Spectroscopic (FT-IR, UV-vis, ESI-MS, and EPR) and analytical data confirm the formation of the complexes, while single-crystal X-ray diffraction analyses reveal distorted square-pyramidal geometries around the Cu(II) centres. Electrochemical investigations by cyclic and differential pulse voltammetry demonstrate quasi-reversible Cu(II)/Cu(I) redox behaviour. DNA-binding studies employing electronic absorption, fluorescence emission and circular dichroism spectroscopy indicate that all complexes interact effectively with DNA, with binding affinity increasing in the order 1 < 2 < 3. The enhanced interaction of 3 is attributed to the extended π-conjugation of the anthracenyl substituent, facilitating stronger π-π stacking interactions. Agarose gel electrophoresis experiments show that complexes 2 and 3 form high-molecular-weight DNA-protein aggregates at higher concentrations. Intrinsic DNA cleavage was observed after the metal complex was induced with a reductant, which suggests that cleavage occurred through a reduction-mediated mechanism. In vitro cytotoxicity studies (MTT assay) against MCF7 and HEK293 cell lines reveal dose-dependent growth inhibition, with complexes 2 and 3 exhibiting enhanced activity, correlating with their stronger ROS producing propensity. The ability to generate cellular ROS was also examined and complex 2 was found to be efficient in ROS generation in a cancer cell line. These results highlight the influence of aryl substitution on the structural, electronic, and biological properties of terpyridine-based copper(II) complexes.