Acceleration of Hydrolytic DNA Cleavage by Dicopper(II) Complexes with p-Cresol-Derived Dinucleating Ligands at Slightly Acidic pH and Mechanistic Insights

Abstract

Abstract Four dicopper(II) complexes, [Cu2(µ-X)(bcmp)](ClO4)2 [X = OH (1a) and X = Cl (1b)], [Cu2(µ-OH)(Me4bcmp)](ClO4)2 (2), and [Cu2(bcc)](ClO4)3 (3), were synthesized with three p-cresol-derived ligands, 2,6-bis(1,4,7-triazacyclononylmethyl)-4-meth-ylphenol (Hbcmp), 2,6-bis(1,4,7-triaza-4,7-dimethylcyclonon-ylmethyl)-4-methylphenol (HMe4bcmp), and 2,6-bis(1,4,7,10-tetrazacyclododecylmethyl)-4-methylphenol (Hbcc) to study hydrolytic DNA cleavage. Crystal structures of 1a, 1b, 2, and 3 were determined by X-ray analysis. The pH titrations and spectroscopic studies in the complexations of the ligands with copper(II) perchlorate revealed that the dicopper core structures of 1a, 2, and 3 in the solid state are kept at pH 5–9 in an aqueous solution. DNA binding abilities of 1a, 2, and 3 were examined by isothermal titration calorimetry (ITC). DNA cleavage studies were carried out by using supercoiled plasmid pUC19 DNA. 1a largely accelerated hydrolytic DNA cleavage at pH 5–6 but not at pH 7–8. This is the first example of pH-dependent DNA cleavage by a dicopper complex. Inhibition studies with specific DNA binders, 4′,6-diamidino-2-phenylindole and methyl green, suggested that 1a accelerates the DNA cleavage via GC-specific binding. The mechanistic insights into the pH-dependent DNA cleavage are proposed on the basis of the crystal structures, structures in aqueous solutions, DNA binding modes, and DNA cleavage activities of 1a, 1b, 2, and 3.