Efficient DNA Cleavage with an Iron Complex without Added Reductant

The zinc(II) complexes reported here have been synthesised from the ligand 4‐methyl‐2‐N‐(2‐pyridylmethyl)aminophenol (Hpyramol) with chloride or acetate counterions. All the five complexes have been structurally characterised, and the crystal structures reveal that the ligand Hpyramol gradually undergoes an oxidative dehydrogenation to form the ligand 4‐methyl‐2‐N‐(2‐pyridylmethylene)aminophenol (Hpyrimol), upon coordination to ZnII. All the five complexes cleave the ϕX174 phage DNA oxidatively and the complexes with fully dehydrogenated pyrimol ligands were found to be more efficient than the complexes with non‐dehydrogenated Hpyramol ligands. The DNA cleavage is suggested to be ligand‐based, whereas the pure ligands alone do not cleave DNA. The DNA cleavage is strongly suggested to be oxidative, possibly due to the involvement of a non‐diffusible phenoxyl radical mechanism. The enzymatic religation experiments and DNA cleavage in the presence of different radical scavengers further support the oxidative DNA cleavage by the zinc(II) complexes.

Section: Introductionmentioning

confidence: 99%

Unique Ligand‐Based Oxidative DNA Cleavage by Zinc(II) Complexes of Hpyramol and Hpyrimol

Maheswari

Barends

Özalp-Yaman

et al. 2007

“…The final step involved coupling of the free amines with 9-chloroacridine. [24] The resulting ditopic ligands 5 and 6 were isolated as their HCl salts in quantitative yields. After treatment with aqueous NaOH the free base was obtained, which was used for characterization.…”

Section: Resultsmentioning

confidence: 99%

“…[23] In our group, the pentadentate ligand N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine (N4Py, 1; Figure 1) has been designed as a mimic of the metal-binding domain of BLM. [24][25][26] Its acridine-tethered derivative has proven to be an efficient DNA-cleaving agent when using O 2 as terminal oxidant, without requiring addition of a sacrificial reductant. [24] However, as with other synthetic BLM mimics, only single-strand DNA cleavage was achieved.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Multinuclear Non‐Heme Iron Complexes for Double‐Strand DNA Cleavage

Megens

Berg

Bruijn

et al. 2009

Self Cite

The cytotoxicity of the anti-tumor drug BLM is believed to be related to the ability of the corresponding iron complex (Fe-BLM) to engage in oxidative double-strand DNA cleavage. The iron complex of the ligand N4Py (Fe-N4Py; N4Py = N,N-bis(2-pyridyl)-N-bis(2-pyridyl)methylamine) has proven to be a particularly valuable spectroscopic and functional model for Fe-BLM. It is also a very active oxidative DNA-cleaving agent. However, like all other synthetic Fe-BLM mimics, it gives only single-strand DNA cleavage. Since double-strand DNA cleavage requires the delivery of two oxidizing equivalents to the DNA, it was envisaged that multinuclear iron complexes might be capable of effecting double-strand cleavage. For this purpose, a series of ditopic and tritopic N4Py-derived ligands has been synthesized and the corresponding iron complexes have been evaluated for their efficacy in the oxidative cleavage of supercoiled pUC18 plasmid DNA. The dinuclear iron complexes showed significantly enhanced double-strand cleavage activity compared to mononuclear Fe-N4Py, which was relatively independent of the structure of the linking moiety. Covalent attachment of a 9-aminoacridine intercalator to a dinuclear complex did not give rise to improved double-strand DNA cleavage. The most efficient oxidative double-strand cleavage agents proved to be the trinuclear iron complexes. This is presumably the result of increased probability of the simultaneous delivery of two oxidizing equivalents to the DNA.

“…Syntheses: (1-Methyl-1H-imidazol-4-yl)methanol hydrochloride, [27] 2-(aminomethyl)-1-methyl-1H-imidazole dihydrochloride (8), [28] 6-(chloromethyl)nicotinic acid methyl ester hydrochloride (10), [29] [Cu(OH)TME-DA] 2 Cl 2 [13] and [Cu [30] were prepared by literature procedures. The preparation of (2- …”

Section: Reactions Ofmentioning

confidence: 99%

Synthetic Models of the Active Site of Cytochrome c Oxidase: Influence of Tridentate or Tetradentate Copper Chelates Bearing a HisTyr Linkage Mimic on Dioxygen Adduct Formation by Heme/Cu Complexes

Liu

Naruta

Tani

2007

Two synthetic models of the active site of cytochrome c oxidase--[(LN4-OH)CuI-FeII(TMP)]+ (1 a) and [(LN3-OH)CuI-FeII(TMP)]+ (2 a)-have been designed and synthesized. These models each contain a heme and a covalently attached copper moiety supported either by a tetradentate N4-copper chelate or by a tridentate N3-copper chelate including a moiety that acts as a mimic of the crosslinked His-Tyr component of cytochrome c oxidase. Low-temperature oxygenation reactions of these models have been investigated by spectroscopic methods including UV/Vis, resonance Raman, ESI-MS, and EPR spectroscopy. Oxygenation of the tetradentate model 1 a in MeCN and in other solvents produces a low-temperature-stable dioxygen-bridged peroxide [(LN4-OH)CuII-O2-FeIII(TMP)]+ {nuO--O=799 (16O2)/752 cm(-1) (18O2)}, while a heme superoxide species [(TMP)FeIII(O2-)CuIILN3-OH] {nuFe--O2: 576 (16O2)/551 cm(-1) (18O2)} is generated when the tridentate model 2 a is oxygenated in EtCN solution under similar experimental conditions. The coexistence of a heme superoxide species [(TMP)FeIII(O2-)CuIILN3-OH] and a bridged peroxide [(LN3-OH)CuII-O2-FeIII(TMP)]+ species in equal amounts is observed when the oxygenation reaction of 2 a is performed in CH2Cl(2)/7 % EtCN, while the percentage of the peroxide (approximately 70 %) in relation to superoxide (approximately 30 %) increases further when the crosslinked phenol moiety in 2 a is deprotonated to produce the bridged peroxide [(LN3-OH)CuII-O2-FeIII(TMP)]+ {nuO--O: 812 (16O2)/765 cm(-1) (18O2)} as the main dioxygen intermediate. The weak reducibility and decreased O2 reactivity of the tricoordinated CuI site in 2 a are responsible for the solvent-dependent formation of dioxygen adducts. The initial binding of dioxygen to the copper site en route to the formation of a bridged heme-O2-Cu intermediate by model 2 a is suggested and the deprotonated crosslinked His-Tyr moiety might contribute to enhancement of the O2 affinity of the CuI site at an early stage of the dioxygen-binding process.