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

AbstractCopper-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 beta-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.
AuthorsBrian C Bales, Tetsuya Kodama, Yvonne N Weledji, Marguerite Pitié, Bernard Meunier, Marc M Greenberg (Affiliation: G.E. Global Research, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.)
JournalNucleic acids research (Nucleic Acids Res) Vol. 33 Issue 16 Pg. 5371-9 ( 2005) ISSN: 1362-4962 England
PMID16186134 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Ligands
  • Phenanthrolines
  • Sugar Acids
  • bis(1,10-phenanthroline)copper(2+) ion
  • 2,4,5-trihydroxypentanoic acid gamma-lactone
  • 1,10-phenanthroline
  • DNA
Topics
  • Binding Sites
  • DNA (chemistry)
  • DNA Damage
  • Kinetics
  • Ligands
  • Nucleic Acid Conformation
  • Oxidation-Reduction
  • Phenanthrolines (chemical synthesis, chemistry, toxicity)
  • Sugar Acids (chemistry)