Multinuclear non-heme iron complexes for double-strand DNA cleavage.
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.
Megens
Rik P
RP
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
van den Berg
Tieme A
TA
de Bruijn
A Dowine
AD
Feringa
Ben L
BL
Roelfes
Gerard
G
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D010084:Oxidation-Reduction
D000970:Antineoplastic Agents; D008024:Ligands; D007501:Iron