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

Dicopper complexes [Cu2(μ-OH)(Ln)](ClO4)2 [n = 1 (1) and 2 (2)] with a novel phenanthrene amide-tether ligand conjugate (HL1) and the original p-cresol-2,6-bis(amidecyclen) (HL2) were synthesized. A phenanthrene unit of 1...

Four dicopper(II) complexes, [Cu2(µ-X)(bcmp)](ClO4)2 [X = OH (1a) and X = Cl (1b)], [Cu2(µ-OH)(Me4bcmp)](ClO4)2 (2), and [Cu2(bcc)](ClO4)3 (3), were synthesized with three p-cresol-derived ligands, 2,6-bis(1,4,7-triazacyclononylmethyl)-4-meth-ylphenol (Hbcmp), 2,6-bis(1,4,7-triaza-4,7-dimethylcyclonon-ylmethyl)-4-methylphenol (HMe4bcmp), and 2,6-bis(1,4,7,10-tetrazacyclododecylmethyl)-4-methylphenol (Hbcc) to study hydrolytic DNA cleavage. Crystal structures of 1a, 1b, 2, and 3 were determined by X-ray analysis. The pH titrations and spectroscopic studies in the complexations of the ligands with copper(II) perchlorate revealed that the dicopper core structures of 1a, 2, and 3 in the solid state are kept at pH 5–9 in an aqueous solution. DNA binding abilities of 1a, 2, and 3 were examined by isothermal titration calorimetry (ITC). DNA cleavage studies were carried out by using supercoiled plasmid pUC19 DNA. 1a largely accelerated hydrolytic DNA cleavage at pH 5–6 but not at pH 7–8. This is the first example of pH-dependent DNA cleavage by a dicopper complex. Inhibition studies with specific DNA binders, 4′,6-diamidino-2-phenylindole and methyl green, suggested that 1a accelerates the DNA cleavage via GC-specific binding. The mechanistic insights into the pH-dependent DNA cleavage are proposed on the basis of the crystal structures, structures in aqueous solutions, DNA binding modes, and DNA cleavage activities of 1a, 1b, 2, and 3.

Dicopper complexes of a new p-cresol-2,6-bis(dpa) amide-tether ligand (HL1), [Cu 2 (μ-OH 2 )(μ-1,3-OAc)(L1)](ClO 4 ) 2 (1) and [Cu 2 (μ-1,1-OAc)(μ-1,3-OAc)(L1)]X (X = ClO 4 (2a), OAc (2b)) were synthesized and structurally characterized. 2b rapidly cleaves supercoiled plasmid DNA by activating H 2 O 2 at neutral pH to a linear DNA and shows remarkable cytotoxicity in comparison with related complexes. As 2b is more cytotoxic than HL1, the dicopper core is kept in the cell. A boron dipyrromethene (Bodipy)-modified complex of the p-cresol-2,6-bis(dpa) amide-tether ligand having a Bodipy pendant (HL2), [Cu 2 (μ-OAc) 2 (L2)](OAc) (3), was synthesized to visualize intracellular behavior, suggesting that 2b attacks the nucleolus and mitochondria. A comet assay clearly shows that 2b does not cleave nuclear DNA. The apoptotic cell death is evidenced from flow cytometry.

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.