Flexible vs. rigid bis(2-benzimidazolyl) ligands in Cu(II) complexes: Impact on redox chemistry and oxidative DNA cleavage activity

Cu(II) complexes of bis(2-benzimidazolyl) ligands connected by different linker moieties (disulfide, ethylene, ortho-phenylene) were applied in DNA cleavage reactions. Hydroxyl radicals and hydrogen peroxide were proven as reactive oxygen species (ROS) in a DNA quenching experiment. Thus, an oxidative DNA cleavage mechanism is suggested. The binding affinity of the Cu(II) complexes to DNA was studied by UV–VIS (DNA melting), fluorescence (ethidium bromide displacement assay) and circular dichroism (CD) spectroscopy indicating a correlation between DNA binding and DNA cleavage efficiency. The most important finding was that oxidative nuclease activity correlated with flexibility of the linker between the benzimidazole moieties. A more flexible linker allowed for an easier switch between square planar (Cu(II)) and tetrahedral geometry (Cu(I)) for the complex, and thus resulted in an enhanced ROS generation. EPR spectroscopy and cyclic voltammetry were applied to investigate such changes in geometry and redox state. Cu(II) complexes with flexible and rigid bridged bis(2-benzimidazolyl) ligands exhibit oxidative DNA cleavage by generation of hydroxyl radicals and hydrogen peroxide and by electrostatic DNA interaction. The biological activity correlates with the flexibility of the linker due to facilitation of Cu(II)/Cu(I) redox cycling. [Display omitted] •Cu(II) complexes of bridged bis(2-benzimidazolyl) ligands oxidatively cleave DNA•Hydroxyl radicals and hydrogen peroxide as reactive oxygen species are involved•Cu(II)/Cu(I) redox cycling was easier for a ligand system with a flexible linker•Consequently, this system was more active in oxidative DNA cleavage•Geometry and redox state were investigated by EPR spectroscopy/cyclic voltammetry