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Nucleic Acids Research 2005 33(16):5371-5379; doi:10.1093/nar/gki856
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Published online 26 September 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Mechanistic studies on DNA damage by minor groove binding copper–phenanthroline conjugates

Brian C. Bales, Tetsuya Kodama1, Yvonne N. Weledji1, Marguerite Pitié2, Bernard Meunier2 and Marc M. Greenberg1,*

G.E. Global Research, Johns Hopkins University 3400 North Charles Street, Baltimore, MD 21218, USA 1Department of Chemistry, Johns Hopkins University 3400 North Charles Street, Baltimore, MD 21218, USA 2Laboratoire de Chimie de Coordination du CNRS 205 route de Narbonne, 31 077 Toulouse Cedex 4, France

*To whom correspondence should be addressed. Tel: +33 410 516 8095; Fax: +33 410 616 7044; Email: mgreenberg{at}jhu.edu

Received August 2, 2005. Revised September 6, 2005. Accepted September 6, 2005.

Copper–phenanthroline complexes oxidatively damage and cleave nucleic acids. Copper bis-phenanthroline and copper complexes of mono- and bis-phenanthroline conjugates are used as research tools for studying nucleic acid structure and binding interactions. The mechanism of DNA oxidation and cleavage by these complexes was examined using two copper–phenanthroline conjugates of the sequence-specific binding molecule, distamycin. The complexes contained either one or two phenanthroline units that were bonded to the DNA-binding domain through a linker via the 3-position of the copper ligand. A duplex containing independently generated 2-deoxyribonolactone facilitated kinetic analysis of DNA cleavage. Oxidation rate constants were highly dependent upon the ligand environment but rate constants describing elimination of the alkali-labile 2-deoxyribonolactone intermediate were not. Rate constants describing DNA cleavage induced by each molecule were 11–54 times larger than the respective oxidation rate constants. The experiments indicate that DNA cleavage resulting from ß-elimination of 2-deoxyribonolactone by copper–phenanthroline complexes is a general mechanism utilized by this family of molecules. In addition, the experiments confirm that DNA damage mediated by mono- and bis-phenanthroline copper complexes proceeds through distinct species, albeit with similar outcomes.


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