Photochemistry of N-isopropoxy-substituted 2(1H)-pyridone and 4-p-tolylthiazole-2(3H)-thione: alkoxyl-radical release (spin-trapping, EPR, and transient spectroscopy) and its significance in the photooxidative induction of DNA strand breaks.
UVA-irradiation of the photo-Fenton reagents N-isopropoxypyridone 2b and N-isopropoxythiazole-2(3H)-thione 3b releases radicals which induce strand breaks. Transient spectroscopy establishes N-O bond scission [Phi(N)(-)(O) = (75 +/- 8)% for 2b and (65 +/- 7)% 3b] as the dominating primary photochemical process to afford the DNA-damaging radicals. Product studies and laser-flash experiments reveal that the thiazolethione 3b leads primarily to the disulfide 5, from which through C-S bond breakage, the bithiazyl 6, the thiazole 7, and the isothiocyanate 8 are derived. Upon irradiation of pyridone 2b (300 nm) in aqueous media, a mixture of isopropoxyl and 2-hydroxyprop-2-yl radicals is formed, as confirmed by trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and EPR spectroscopy. In contrast, the photolysis of the thiazolethione 3b (350 nm) affords exclusively the DMPO adducts of the isopropoxyl radicals. Control experiments disclose that the thiazolethione-derived photoproduct disulfide 5, or the intermediary thiyl radicals B, scavenge the carbon-centered 2-hydroxyprop-2-yl radicals, which are generated from the isopropoxyl radicals by hydrogen shift. With supercoiled pBR 322 DNA in a 60:40 mixture of H(2)O-MeCN, the pyridone 2b and the thiazolethione 3b display moderate strand-break activity (17% open-circular DNA for 2b and 12% for 3b). In pure water, however, the pyridone 2b photoinduces substantially more DNA cleavage (32% open-circular DNA), which is attributed to the peroxyl radicals generated from the 2-hydroxyprop-2-yl radicals by oxygen trapping. The lower strand-break activity of the thiazolethione 3b derives presumably from isopropoxyl radicals, because only these are detected in the photolysis of this photo-Fenton reagent.
Adam
Waldemar
W
Institut für Organische Chemie, Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany. adam@chemie.uni-wuerzburg.de
Hartung
Jens
J
Okamoto
Hideki
H
Marquardt
Stefan
S
Nau
Werner M
WM
Pischel
Uwe
U
Saha-Möller
Chantu R
CR
Spehar
Kristina
K
D004249:DNA Damage; D004578:Electron Spin Resonance Spectroscopy; D017665:Hydroxyl Radical / Q000737:chemistry; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010777:Photochemistry; D010782:Photolysis; D011728:Pyridones / Q000737:chemistry*; D013844:Thiazoles / Q000737:chemistry*; D013871:Thiones / Q000737:chemistry*
D011728:Pyridones; D013844:Thiazoles; D013871:Thiones; D017665:Hydroxyl Radical