Burst of DNA Double-Strand Breaks by Dicopper(II) Complex with a p-Cresol-2,6-Bis(amide-tether-dpa) Ligand via Reductive O2-Activation

Abstract

Abstract We found bursts of DNA double-strand breaks by a dicopper(II) complex with a p-cresol-2,6-bis(amide-tether-dpa) ligand (HL) [Cu2(μ-1,1-OAc)(μ-1,3-OAc)(L)]2+ (1) via reductive O2-activa-tion with sodium ascorbate (AscNa) under air, where 26% of supercoiled plasmid DNA was converted to linear form in 1 min. The reasons for bursts of DNA double-strand breaks by 1 were clarified in comparison with a Robson type dicopper complex [Cu2(μ-OH)(bpmp)]2+ (2) and an iron complex of N4Py ligand [Fe(MeCN)(N4Py)]2+ (3). Spectroscopic, electrochemical, and kinetic studies revealed that upon reaction with AscNa, 1 is rapidly reduced to Cu(I)Cu(II) and Cu(I)Cu(I) species, which are involved in rate-limiting three electron reduction of O2 to HO• responsible for the DNA cleavage. The HO• formation was monitored by emission spectral change of terephthalic acid (TA). DNA binding abilities of 1 and 3 were examined by isothermal titration calorimetry (ITC) and electronic absorption spectral and IR spectral changes. These revealed that the rapid HO• formation and the large binding number and rigid binding to DNA are key features of 1 to enable the burst of DNA double-strand breaks.