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

Abstract

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.

Tetrapodal pentadentate ligands: Single site reactivity and bond activation in iron(II) complexes

“…The dinuclear iron complexes show significantly enhanced double-strand cleavage activity compared to the mononuclear iron complex. 100 The isomeric iron(II) complexes of the bispidine ligands 15 and 16 catalyze the oxidation of cyclooctene with hydrogen peroxide in acetonitrile under aerobic conditions with high selectivity for the epoxide. The active species is likely an Fe IV =O oxoferryl complex, which is formed by homolytic cleavage of the O-O bond of an iron(III) hydroperoxo intermediate.…”

Mononuclear Fe(ii)-N4Py complexes in oxidative DNA cleavage: structure, activity and mechanism

“…A similar pattern was observed with the di-nuclear Fe(II)-N4Py complexes reported previously. 28,29 This constitutes the first examples of mono-nuclear Fe(II) complexes capable of § The first term of the Poisson distribution predicts that the amount of linear DNA will reach a maximum at around 37%; in practice, this means smaller fragments of DNA are produced and as a result, a smear appears in the gel, which precludes quantitative analysis.…”

“…Uncertainties in the values of m and n were calculated by a Monte Carlo simulation as described previously. 28,29 f III = m ¥e -m…”

“…With their corresponding iron complexes, direct double-strand DNA cleavage was achieved oxidatively with iron for the first time, which was attributed to the increased possibility of a simultaneous delivery of two oxidizing equivalents to the DNA helix. 29,30 Our previous studies indicated that the DNA cleavage activity of Fe(II)-N4Py was enhanced by introducing a DNA binding moiety such as 9-aminoacridine or an ammonium group, which was attributed to the increased interaction of Fe(II)-N4Py and DNA because of the binding moiety. 26 Here, we present the results of a study on the structure and activity of a series of monotopic N4Py ligands with covalently attached DNA-binding moieties, i.e.…”

Oxidative DNA cleavage by Cu(II) complexes: Effect of periphery substituent groups

“…Few synthetic nucleases can create both singleand double-strand breaks in duplex DNA [13][14][15][16]. Single-strand DNA (ssDNA) cleavage and double-strand DNA (dsDNA) cleavage represent different pathways.…”