Mechanistic studies on DNA damage by minor groove binding copper-phenanthroline conjugates.
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 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.
Bales
Brian C
BC
G.E. Global Research, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
Kodama
Tetsuya
T
Weledji
Yvonne N
YN
Pitié
Marguerite
M
Meunier
Bernard
B
Greenberg
Marc M
MM
D001665:Binding Sites; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D007700:Kinetics; D008024:Ligands; D009690:Nucleic Acid Conformation; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D013400:Sugar Acids / Q000737:chemistry
D008024:Ligands; D010618:Phenanthrolines; D013400:Sugar Acids; C014741:bis(1,10-phenanthroline)copper(2+) ion; C056405:2,4,5-trihydroxypentanoic acid gamma-lactone; D004247:DNA; C025205:1,10-phenanthroline