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

• Published in: Dalton transactions : an international journal of inorganic chemistry 2010-09, Vol.39 (34), p.8012-8021
• Main Authors: Li, Qian, van den Berg, Tieme A, Feringa, Ben L, Roelfes, Gerard
• Format: Article
• Language: English
• Subjects: Aminacrine - chemistry; Aminacrine - metabolism; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - metabolism; Bleomycin - chemistry; Bleomycin - metabolism; Catalysis; Dimethyl Sulfoxide - chemistry; Dimethyl Sulfoxide - metabolism; DNA - chemistry; DNA - metabolism; DNA Cleavage; Ferric Compounds - chemistry; Ferric Compounds - metabolism; Ferrous Compounds - chemistry; Ferrous Compounds - metabolism; Iron - chemistry; Iron - metabolism; Ligands; Methylamines - chemistry; Methylamines - metabolism; Models, Molecular; Molecular Structure; Oxidation-Reduction; Oxides - chemistry; Oxides - metabolism; Pyridines - chemistry; Pyridines - metabolism; Reactive Oxygen Species - chemistry; Reactive Oxygen Species - metabolism; Superoxide Dismutase - chemistry; Superoxide Dismutase - metabolism
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/b927145g

A series of monotopic N4Py (N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine, 1) derived ligands have been prepared and evaluated in the iron catalyzed oxidative cleavage of pUC18 DNA, in the presence and absence of external reducing agent DTT. The mononuclear iron(II) complexes induce efficient DNA cleavage in air with a low catalyst loading. It was demonstrated that covalent attachment of 9-aminoacridine, ammonium group or 1,8-naphthalimide leads to increased DNA cleavage activity in the presence of a reductant. Also some complexes displayed a small degree of double-strand DNA cleavage activity. In contrast, in the absence of reducing agent, no beneficial effect of the covalently attached DNA binding moieties was observed, which was attributed to the reduction from Fe(III) to Fe(II), which is required for oxygen activation, becoming rate limiting. Mechanistic investigations revealed an important role for superoxide radicals. A proposed mechanism involves the formation of an Fe(III)-OOH intermediate as the active species or precursor.