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

Four dicopper(II) complexes, [Cu-2(mu-X)(bcmp)](ClO4)(2) [X = OH (1a) and X = Cl (1b)], [Cu-2(mu-OH)(Me(4)bcmp)]- (ClO4)(2) (2), and [Cu-2(bcc)](ClO4)(3) (3), were synthesized with three p-cresol-derived ligands, 2,6-bis(1,4,7-triazacyclononyl-methyl)-4-meth-ylphenol (Hbcmp), 2,6-bis(1,4,7-triaza-4,7-dimethylcyclonon-ylmethyl)-4-methylphenol (HMe(4)bcmp), 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.