Effect of the chelate ring size on the cleavage activity of DNA by copper(II) complexes containing pyridyl groups

Square pyramidal five-coordinate copper(II) complexes of the general formula [Cu(N4)ClO4]ClO4, N4 represents a tetradentate ligand where N4 = pzdpy (1,4-bis(2-pyridylmethy)piperazine), 1; hpzpy (1,4-bis(2-pyridylmethyl)homopiperazine), 2; pmap, (bis(2-(2-pyridylethyl))-(2-pyridylmethyl)-amine), 4; and [Cu(N4)Cl]ClO4 with N4 = pmea (bis(2-pyridylmethyl)-2-(2-pyridylethyl)amine), 3; pmap, 4a; tepa (tris (2-(2-pyridyl)ethyl)amine), 5 were structurally characterized. The single crystal X-ray crystallography of 3 was determined. The molar conductivity studies of the complexes in H2O reveal the presence of [Cu(N4)(H2O)]2+ as the reactive species in the aqueous solutions. The synthesized complexes were used to study the DNA cleavage activity at pH 7.0 and 37 °C. Under pseudo Michaelis–Menten conditions, the constant for the catalytic cleavage of DNA, kcat decreases in the following order: 1 > 3 > 2 > 4 ≫ 5. Complex 1 showed very high nuclease activity with a rate enhancement of 25-million-fold over the non-catalyzed DNA. The results demonstrated that an increase in the number of six-membered rings in the complexes suppresses the cleavage process. Although the mechanistic studies of DNA cleavage by the complexes in presence of oxidative scavengers indicate that the mechanism of the cleavage in complexes 2–4 is most likely hydrolytic in nature, an oxidative mechanism via hydroxyl radical was revealed with complex 1.

A systematic study for the DNA cleavage by square pyramidal copper(II) complexes, [Cu(N4)ClO4/Cl]ClO4, derived from tetradenate pyridyl ligands, where N4 = pzdp, hpzpy, pmea, pmap or tepa was undertaken. The reactivity of the DNA cleavage decreases with increasing the number of six-membered chelate rings in the complexes. Complex 1, containing N4 = pzdp showed nuclease activity with rate enhancement of 25-million-fold over the non-catalyzed DNA. The mechanism of the DNA cleavage by the complexes is reported.Figure optionsDownload as PowerPoint slideHighlights
► The reactive species of [Cu(N4)ClO4/Cl]ClO4 in aqueous solutions is the aqua species.
► DNA cleavage activity decreases with increasing the number of six-membered chelate rings in complexes.
► Complex based piperazine, N4 = pzdp showed very high catalytic cleavage.
► Hydrolytic and oxidative DNA cleavages are reported.