4-tert-butylperoxymethyl-9-methoxypsoralen as intercalating photochemical alkoxyl-radical source for oxidative DNA damage.
We describe the synthesis of a novel psoralen peroxide 1 that generates on irradiation (350 nm) alkoxyl radicals, namely tert-butoxyl radicals, as confirmed by electron spin resonance studies with the spin trap 5,5-dimethyl-pyrroline-N-oxide. The radical source intercalates into the DNA, which has been demonstrated by linear-flow-dichroism measurements. Thus, the alkoxyl radicals are formed advantageously directly in the DNA matrix. In supercoiled pBR322 DNA, the generation of strand breaks by the photochemically or metal-catalyzed generated alkoxyl radicals is demonstrated. Photosensitization by the psoralen chromophore was excluded because similar substances that do not release radicals caused no DNA damage, nor were the photoproducts of the peroxide 1 active. With calf thymus DNA, 8-oxoGua and small amounts of guanidine-releasing products, e.g. oxazolone, were observed. However, in these reactions the photoproduct also displayed some DNA-oxidizing capacity.
Adam
W
W
Institute of Organic Chemistry, University of Würzburg, Germany. adam@chemic.uni-wuerzburg.de
Arnold
M A
MA
Grimm
G N
GN
Saha-Möller
C R
CR
Dall'Acqua
F
F
Miolo
G
G
Vedaldi
D
D
D003497:Cyclic N-Oxides; D004249:DNA Damage; D004278:DNA, Superhelical / Q000737:chemistry / Q000187:drug effects / Q000528:radiation effects*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology; D008730:Methoxsalen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009691:Nucleic Acid Denaturation; D010782:Photolysis; D010957:Plasmids / Q000737:chemistry / Q000187:drug effects / Q000528:radiation effects*; D013113:Spin Labels; D014466:Ultraviolet Rays
C115510:4-tert-butylperoxymethyl-9-methoxypsoralen; D003497:Cyclic N-Oxides; D004278:DNA, Superhelical; D005609:Free Radicals; D007364:Intercalating Agents; D013113:Spin Labels; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D008730:Methoxsalen