Development of Cu(II) complexes of substituted polypyridyl and salicylaldehyde ligands as anticancer agents

A comprehensive panel of mixed ligand Cu(II)-complexes with general formula Cu(X-dppz)(X2-sal)(NO3) was synthesized and properly characterized through elemental analysis, FT-IR, mass spectrometry, UV–Vis and EPR spectroscopy. Theoretical calculations using DFT and TD-DFT methods were carried out to support the interpretation of the absorption spectra, revealing that most of the observed absorptions exhibit either Ligand Centered (LC) or Ligand-to-Ligand Charge Transfer (LLCT) character. The study was aimed to investigate them as anticancer agents against three cancer cell lines selected based on the incidence (MDA-MB 231) and aggressiveness (U87 and MG 63) of the related tumor type, and to investigate the effect of substitutions on both ligands (i.e., the polypyridyl diimine ligand, dppz, and the auxiliary ligand, sal) on antiproliferative activities of the complexes. The results showed that complexes bearing the –NO₂ group on the dppz ligand exhibited significantly higher cytotoxicity, particularly against MDA-MB 231 cells, compared to their Cl-substituted counterparts, with the exception of the complex with the 3-bromo-5-chloro-salicylaldehyde as auxiliary ligand. The latter also turned out to be essential for the cytotoxicity (comparative analysis with sal-free Cu(II)-complexes) as well as the complete structure of the complexes (comparative analysis with pure polypyridyl ligands). Mechanistic studies (in vitro and in silico) revealed that these complexes induce cytotoxicity through Reactive Oxygen Species (ROS) generation and intercalation into the DNA double helix, as well as through G-quadruplex stabilization. Among the synthesized compounds, complexes Cl2CuBrCl (4) and NO2CuBrCl (14) demonstrated the most promising biological activity, making them compelling candidates for further investigation as anticancer agents.