Efficient and specific strand scission of DNA by a dinuclear copper complex: comparative reactivity of complexes with linked tris(2-pyridylmethyl)amine moieties.

The compound Cu(II)(2)(D(1))(H(2)O)(2)(4) (D(1) = dinucleating ligand with two tris(2-pyridylmethyl)amine units covalently linked in their 5-pyridyl positions by a -CH(2)CH(2)- bridge) selectively promotes cleavage of DNA on oligonucleotide strands that extend from the 3' side of frayed duplex structures at a site two residues displaced from the junction. The minimal requirements for reaction include a guanine in the n (i.e. first unpaired) position of the 3' overhang adjacent to the cleavage site and an adenine in the n position on the 5' overhang. Recognition and strand scission are independent of the nucleobase at the cleavage site. The necessary presence of both a reductant and dioxygen indicates that the intermediate responsible for cleavage is produced by the activation of dioxygen by a copper(I) form of the dinuclear complex. The lack of sensitivity to radical quenching agents and the high level of site selectivity in scission suggest a mechanism that does not involve a diffusible radical species. The multiple metal center exhibits a synergy to promote efficient cleavage as compared to the action of a mononuclear analogue Cu(II)(TMPA)(H(2)O)(2) (TMPA = tris(2-pyridylmethyl)amine) and Cu(OP)(2) (OP = 1,10-phenanthroline) at equivalent copper ion concentrations. The dinuclear complex, Cu(II)(2)(D(1))(H(2)O)(2)(4), is even capable of mediating efficient specific strand scission at concentrations where Cu(OP)(2) does not detectably modify DNA. The unique coordination and reactivity properties of Cu(II)(2)(D(1))(H(2)O)(2)(4) are critical for its efficiency and site selectivity since an analogue, Cu(II)(2)(DO)(Cl(2))(2), where DO is a dinucleating ligand very similar to D(1), but with a -CH(2)OCH(2)- bridge, exhibits only nonselective cleavage of DNA. The differences in the reactivity of these two complexes with DNA and their previously established interaction with dioxygen suggest that specific strand scission is a function of the orientation of a reactive intermediate.