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Efficient and Specific Strand Scission of DNA by a Dinuclear Copper Complex:  Comparative Reactivity of Complexes with Linked Tris(2-pyridylmethyl)amine Moieties

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journal contribution
posted on 03.05.2002, 00:00 by Kristi J. Humphreys, Kenneth D. Karlin, Steven E. Rokita
The compound [CuII2(D1)(H2O)2](ClO4)4 (D1 = dinucleating ligand with two tris(2-pyridylmethyl)amine units covalently linked in their 5-pyridyl positions by a −CH2CH2− 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 [CuII(TMPA)(H2O)](ClO4)2 (TMPA = tris(2-pyridylmethyl)amine) and [Cu(OP)2]2+ (OP = 1,10-phenanthroline) at equivalent copper ion concentrations. The dinuclear complex, [CuII2(D1)(H2O)2](ClO4)4, is even capable of mediating efficient specific strand scission at concentrations where [Cu(OP)2]2+ does not detectably modify DNA. The unique coordination and reactivity properties of [CuII2(D1)(H2O)2](ClO4)4 are critical for its efficiency and site selectivity since an analogue, [CuII2(DO)(Cl2)](ClO4)2, where DO is a dinucleating ligand very similar to D1, but with a −CH2OCH2− 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.