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.

DNA hydrolysis promoted by di- and multi-nuclear metal complexes

“…Moreover, these copper complexes might be mononuclear. The dinuclear Cu 2+ compound [Cu 2 (D 1 )(H 2 O) 2 ](ClO 4 ) 4 (see Table 1, 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) reported by Karlin group selectively promotes DNA cleavage on oligonucleotide strands that extend from the 3 side of frayed duplex structures at a site two residues displaced from the junction [67]. The DNA cleavage mechanism does not involve a diffusible radical species, whereas both a reductant and dioxygen are necessary.…”

Synthesis, Structure, Cytotoxic Activities and DNA-Binding Properties of a 1D Copper(II) Complex Bridged both by Oxamidate and Terephthalato Groups

“…Flow times were measured with a digital stopwatch; each sample was measured three times, and an average flow time was calculated. Relative viscosities for HS-DNA in the presence and absence of the complex were calculated from the relation g = (t-t 0 )/t 0 , where t is the observed flow time of DNA-containing (7) b (Å ) 15.3143 (9) c (Å ) 13.6514(9) b (°) 110.9460(10)…”

“…It is well known that modes of DNA non-covalent interaction with metal complexes include electrostatic effect, groove binding and intercalation; and effectiveness mainly depends on the mode and affinity of the binding between the complexes and DNA [8,9]. Along this line, many of transition metal complexes have been synthesized and their interactions with DNA studied [10][11][12][13][14][15][16][17][18][19]. Furthermore, significant developments have occurred in recent years in the chemistry of polymer-metal complexes.…”

The DNA cleavage and antimicrobial studies of Co(II), Ni(II), Cu(II) and Zn(II) complexes of 4-pyridinecarboxaldehyde with 4-aminopyridine

“…The interaction of these complexes with DNA has gained much attention due to their possible applications as new therapeutic agents. Because ligands both influence the reactivity of transition metal complexes with DNA and can also be varied in an easily controlled fashion, their presence and manipulation greatly facilitate the interaction between the complexes and DNA [10][11][12]. Many potent antibacterial and antifungal Schiff base compounds of heterocyclic compounds were reported [13][14][15].…”