Hydrazonate‐Based Copper(II) Metallodrugs: Insights into Solution Behavior, G‐Quadruplex DNA Interaction, and Anticancer Potential

Here, two mixed-ligand mononuclear [Cu(L¹)py] (1), [Cu(L²)Him] (2) and one dinuclear copper(II) complex [Cu₂(L³)₂(DMSO)(MeOH)] (3) were isolated in solid state and characterized through single-crystal X-ray diffraction. Herein, we highlight the solution behavior of these complexes in solution medium through HRMS and ESR. Though the complexes maintain their integrity with respect to the ligand coordination, there is solvent or co-ligand exchange and generation of both [Cu(L)(py/Him)] or [Cu(L)(H₂O)] species. G-quadruplex (G4-DNA) structures in the human telomeric DNA (hTelo) and promoter regions of oncogenes (c-MYC) can behave as potential therapeutic targets for the cancer treatment. Hence, the interaction of these complexes with G4-DNA and also duplex DNA was investigated through spectroscopy and molecular docking studies. The results reveal that the copper complexes show higher affinity for G4-DNA over duplex DNA, with 3 demonstrating the strongest binding among them. The complexes have also been tested for DNA nuclease activity against pUC19 plasmid DNA. Finally, the complexes showed significant cytotoxicity towards cancerous cell lines, namely HeLa and MCF-7 in comparison to the noncancerous cell line NIH-3T3. Annexin V/PI double staining assay demonstrated the apoptotic mode of cell death caused by the complexes. Overall, the results of G4-DNA interaction and anticancer activity are consistent, suggesting G4-DNA is the target for their biological activity.