Dinuclear copper(II) complexes of "end-off" bicompartmental ligands: Alteration of the chelating arms on ligands to regulate the reactivity of the complexes towards DNA

Two phenol-based "end-off" biscompartmental heptadentate ligands were designed by introduction of substituents with different electronic and steric properties to the chelating arms, i.e. 2,6-bis{[(2-pyridylmethyl)(2-hydroxyethyl)amino]methyl}-4-methylphenol (L-1) and 2,6-bis{[(2-aminoethyl)(2-hydroxyethyl)amino]methyl}-4-methylphenol (L-2). The dinuclear copper(II) complexes (1 and 2) of the ligands were synthesized and evaluated as potential nuclease models. The basicity behavior and coordination property of each ligand towards Cu(II) ion in aqueous solution were investigated by pH potentiometric titrations accompanied by ESI-MS and spectrometry. Both ligands show a strong tendency to chelate Cu(II) generating dinuclear copper(II) complexes in Cu(II)/L molar ratio of 2:1 in the pH range of 3-11, and when pH is 7.40 the cationic OH--bridged dicopper(II) complexes were determined to be the dominant species. Studies on the interactions of 1 and 2 with Calf Thymus DNA relevant to DNA binding exhibit a pronounced impact of the substituents tethered on the chelating arms of the ligands. Assessment by agarose gelelectrophoresis of the plasmid pBR322 DNA cleavage activity in the presence of Vc under aerobic conditions evidence significant cleavage efficiency of the two complexes, displaying a reactivity order of 1 < 2. The mechanistic studies suggest that the cleavage implements via an oxidative pathway, where hydroxyl radical and hydrogen peroxide are responsible for the cleavage reactions. For 2, additional singlet oxygen seems to be involved in the cleavage. The differences between the two complexes in DNA binding and cleavage were discussed in relation to the electronic and steric properties of the substituents on the chelating arms imposed by each phenoxido ligand.