title: Efficient and specific strand scission of DNA by a dinuclear copper complex: comparative reactivity of complexes with linked tris(2-pyridylmethyl)amine moieties.
abstract: The compound [Cu(II)(2)(D(1))(H(2)O)(2)](ClO(4))(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)](ClO(4))(2) (TMPA = tris(2-pyridylmethyl)amine) and [Cu(OP)(2)](2+) (OP = 1,10-phenanthroline) at equivalent copper ion concentrations. The dinuclear complex, [Cu(II)(2)(D(1))(H(2)O)(2)](ClO(4))(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 [Cu(II)(2)(D(1))(H(2)O)(2)](ClO(4))(4) are critical for its efficiency and site selectivity since an analogue, [Cu(II)(2)(DO)(Cl(2))](ClO(4))(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.
authors.affiliation: Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors.forename: Kristi J
authors.initials: KJ
authors.lastname: Humphreys
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Karlin
authors.forename: Steven E
authors.initials: SE
authors.lastname: Rokita
mesh_terms: D000588:Amines / Q000737:chemistry*; D001483:Base Sequence; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D016166:Free Radical Scavengers / Q000737:chemistry; D006147:Guanine / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry*; D019163:Reducing Agents / Q000737:chemistry; D013379:Substrate Specificity
chemical_list: D000588:Amines; D016166:Free Radical Scavengers; D009942:Organometallic Compounds; D011725:Pyridines; D019163:Reducing Agents; D006147:Guanine; D003300:Copper; D004247:DNA; D010100:Oxygen