Amphiphilic Cu(II) Oxacyclen Complexes: From Oxidative Cleavage to Condensation of DNA

Cu(II) complexes with monoalkylated oxacyclen ligands (C₁₂, C₁₆, and C₁₈) have been investigated regarding their interaction with DNA by different methods: circular dichroism, UV/VIS (ultraviolet-visible) and fluorescence spectroscopy as well as by gel electrophoresis. The results demonstrate that the complexes can cleave DNA through both hydrolytic and oxidative mechanisms, with hydroxyl radicals and hydrogen peroxide identified as the reactive oxygen species involved. The targeted incorporation of alkyl chains significantly enhances the DNA-binding affinity of the Cu(II) complexes, and the length of the alkyl substituents plays an important role, as they can interact with the major groove of the DNA. Alkylation is the determining structural factor responsible for the enhanced DNA interaction, since such an interaction is not observed with unsubstituted complexes. Moreover, the length of the alkyl chains significantly influences this behavior, as longer substituents induce a concentration-dependent DNA aggregation, a phenomenon absent in the nonalkylated analog. This aggregation and condensation behavior is examined using atomic force microscopy and dynamic light scattering. Moreover, DNA/small molecule interactions are also investigated using molecular dynamics simulations.