Synthesis, DNA binding profile and DNA cleavage pathway of divalent metal complexes

Abstract

Graphical AbstractDivalent metal complexes of dipyridylamine ligand with an anthracene moiety induced considerable oxidative DNA cleavage in the presence hydrogen peroxide and dioxygen. AbstractComplexes of dipyridylamine based ligand with an anthracene moiety containing divalent metal ions Co(II), Cu(II), Ni(II), Zn(II) and Cd(II) were characterized structurally. The experimental results showed that they can induce considerable oxidative DNA cleavage in the presence hydrogen peroxide and dioxygen. The Zn(II) complex did not show any appreciable cleavage activity, whereas the Cd(II) and Ni(II) complexes were moderately active. On the other hand, Cu(II) and Co(II) complex showed the formation of a significant quantity of linear DNA resulting from the double-strand breaks. Mechanistic studies revealed the involvement of HO• and the superoxide anion to be the reactive species in the scission process in aerobic media. A mechanism involving either the Fenton or the Haber-Weiss reaction was proposed for the DNA cleavage mediated by these complexes. The Cu(II) complex could also cleave the double stranded calf thymus DNA (ds DNA) in the presence of activators, most likely via an oxidative mechanism, whereas the activity of the other complexes was negligible under similar reaction conditions. The kinetic aspects of ds DNA cleavage with the Cu(II) are detailed. The interaction of the five metal complexes with ds DNA was investigated by UV absorption and linear dichroism studies, and the mode of complexes binding to ds DNA is proposed. 4 species. 21,25-29 The chemistry of nucleic acid degradation by synthetic nucleases has been the subject of numerous studies. 18,30-36 On the other hand, only a limited number of reports have examined the actual rates of product formation (kinetics) during chemical nuclease induced DNA scissoring. 37-40 A recent development in the field of DNA cleavage are measurements of the reaction kinetics of the drug-mediated DNA cleavage by the linear dichroism (LD)technique. [41][42][43][44] Here, we report the synthesis and characterization of various transition metal complexes containing a dipyridylamine-based ligand bearing the anthracene moiety (Fig. 1).Anthracene moiety is one of fused aromatic hydrocarbons and is expected to intercalate between DNA base pair, thereby, enhance the binding efficiency to DNA. The ability of the complexes to promote the cleavage of two different DNA, namely, pBR322 plasmid DNA, and calf thymus DNA, was investigated. In the latter case, the detailed degradation kinetics were evaluated using the LD technique. The binding mode of the metal complexes to calf thymus DNA was also examined by absorption and LD spectroscopy.All chemicals were used as received unless stated otherwise. Calf thymus DNA (referred to as dsDNA) was purchased from Sigma and dissolved in a 5 mM cacodylate buffer (pH 7.0) containing 1 mM EDTA and 100 mM NaCl by gentle shaking at 4 °C. The dsDNA solution was dialyzed several times against 5 mM cacodylate buffer (pH 7.0) at 4 °C. The dsDNA concentrat...

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