Fine-tuning alkyl chain length in copper(II) complexes: effects on DNA binding and catalytic cleavage

Metal complexes are well known for their DNA cleavage activity. Copper is a metal that stands out for this purpose because it is able to perform cleavage through oxidative mechanisms using the Haber-Weiss cycle. We report two unprecedented copper(II) complexes (2 and 3) with long-chain ligands and compare the results with those of a previously reported complex (1), which we use as a reference in our studies. They were all properly characterized using a set of physicochemical methods, including elemental analysis, electron paramagnetic resonance, spectroscopic and electrochemical analysis. Density functional theory (DFT) modeling revealed a pseudo-octahedral environment where the ligands are trans to each other. The interaction of 1, 2, and 3 with salmon sperm DNA was monitored spectrophotometrically, and the binding constants (K_b) were 4.24 × 10⁴ L mol^-1, 1.92 × 10⁴ L mol^-1, and 1.15 × 10⁴ L mol^-1, respectively. The interactions were supported by docking studies conducted with the CCDC GOLD® docking suite. Finally, all complexes exhibited DNA binding and cleavage properties, but 2 stood out as the most active one (2, k_obs = 0.88 ± 0.09 h^-1 > 1, k_obs = 0.54 ± 0.06 h^-1 > 3, k_obs = 0.50 ± 0.03 h^-1). These results support the idea that fine-tuning the length of the alkyl chain can enhance DNA-targeting activity and contribute to the development of efficient strategies for catalytic cleavage of nucleic acids.