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

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.