Double-strand DNA cleavage by copper complexes of 2,2′-dipyridyl with guanidinium/ammonium pendants

Two ligands with guanidinium/ammonium groups were synthesized and their copper complexes, [Cu(L¹)Cl₂](ClO₄)₂·H₂O (1) and [Cu(L²)Cl₂](ClO₄)₂ (2) (L¹ = 5,5′-di[1-(guanidyl)methyl]-2,2′-bipyridyl cation and L² = 5,5′-di[1-(amino)methyl]-2,2′-bipyridyl cation), were prepared to serve as nuclease mimics. X-Ray analysis revealed that Cu(II) ion in 1 has a planar square CuN₂Cl₂-configuration. The shortest distance between the nitrogen of guanidinium and copper atoms is 6.5408(5) Å, which is coincident with that of adjacent phosphodiesters in DNA (ca. 6 Å). In the absence of reducing agent, supercoiled plasmid DNA cleavage by the complexes were performed and their hydrolytic mechanisms were demonstrated with radical scavengers and T4 ligase. The pseudo-Michaelis–Menten kinetic parameters (k_cat, K_M) were calculated to be 4.42 h⁻¹, 7.46 × 10⁻⁵ M for 1, and 4.21 h⁻¹, 1.07 × 10⁻⁴ M for 2, respectively. The result shows that their cleavage efficiency is about 10-fold higher than the simple analogue [Cu(bipy)Cl₂] (3) (0.50 h⁻¹, 3.5 × 10⁻⁴ M). The pH dependence of DNA cleavage by 1 and its hydroxide species in solution indicates that mononuclear [Cu(L¹)(OH)(H₂O)]³⁺ ion is the active species. Highly effective DNA cleavage ability of 1 is attributed to the effective cooperation of the metal moiety and two guanidinium pendants with the phosphodiester backbone of nucleic acid.