Oxidative DNA Cleavage, Formation of μ-1,1-Hydroperoxo Species, and Cytotoxicity of Dicopper(II) Complex Supported by a p-Cresol-Derived Amide-Tether Ligand

Abstract

Metal complexes to promote oxidative DNA cleavage by H₂O₂ are desirable as anticancer drugs. A dicopper(II) complex of known p-cresol-derived methylene-tether ligand Hbcc [Cu₂(bcc)]³⁺ did not promote DNA cleavage by H₂O₂. Here, we synthesized a new p-cresol-derived amide-tether one, 2,6-bis(1,4,7,10-tetrazacyclododecyl-1-carboxyamide)-p-cresol (Hbcamide). A dicopper(II) complex of the new ligand [Cu₂(μ-OH)(bcamide)]²⁺ was structurally characterized. This complex promoted the oxidative cleavage of supercoiled plasmid pUC19 DNA (Form I) with H₂O₂ at pH 6.0-8.2 to give Forms II and III. The reaction was largely accelerated in a high pH region. A μ-1,1-hydroperoxo species was formed as the active species and spectroscopically identified. The amide-tether complex is more effective in cytotoxicity against HeLa cells than the methylene-tether one.