Mechanistic Insights Into the Factors That Influence the DNA Nuclease Activity of Mononuclear Facial Copper Complexes Containing Hetero-Substituted Cyclens

The factors that influence the DNA nuclease activity of mononuclear facial copper complexes containing heterosubstituted cyclens were systematically investigated in this work using density functional theory (DFT) calculations. The heterosubstitution of cyclens were found to significantly affect the dimerization tendency of the mononuclear Cu(II) complexes examined and their respective pK(a) values of the metal-bonded water molecules. The Cu(II)-oxacyclen complex was found to be more favorable for the hydrolytic cleavage of the DNA dinucleotide analogue BNPP-(bis (p-nitrophenyl) phosphate). This was due to this species having a higher dimerization resistance to give rise to a higher concentration of the active catalyst and a lower pK(a) value of the Cu(II)-coordinated water molecule to facilitate an easier generation of the better nucleophile hydroxyl ion, which gave a lower reaction barrier. The dimerization of the Cu(I) complexes studied and their corresponding redox potentials were determined, and a remarkable reaction barrier was observed for the generation of a superoxide ROS (reactive oxygen species) mediated by the Cu(I) -oxacyclen complex. This behavior was attributed to the higher electronegativity of the O heteroatom, which facilitates the nucleophilic attack of the oxygen molecule and the Cu-O(OH2) bond fission via an enhancement of the Lewis acidity of the metal center and the formation of a significant hydrogen bond between the heterocyclic oxygen and the metal-bonded water molecule. The theoretical results reported here are in good agreement with the literature experimental observations and more importantly help to systematically elucidate the factors that influence the DNA nuclease activity of mononuclear facial copper complexes containing heterosubstituted cyclens in detail.