Photochemistry of <i>N</i>-Isopropoxy-Substituted 2(1<i>H</i>)-Pyridone and 4-<i>p</i>-Tolylthiazole-2(3<i>H</i>)-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 <i>N</i>-isopropoxypyridone <b>2b</b> and <i>N</i>-isopropoxythiazole-2(3<i>H</i>)-thione <b>3b</b> releases radicals which induce strand breaks. Transient spectroscopy establishes N−O bond scission [Φ<sub>N</sub><sub>-</sub><sub>O</sub> = (75 ± 8)% for <b>2b</b> and (65 ± 7)% <b>3b</b>] as the dominating primary photochemical process to afford the DNA-damaging radicals. Product studies and laser-flash experiments reveal that the thiazolethione <b>3b</b> leads primarily to the disulfide <b>5</b>, from which through C−S bond breakage, the bithiazyl <b>6</b>, the thiazole <b>7</b>, and the isothiocyanate <b>8</b> are derived. Upon irradiation of pyridone <b>2b</b> (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 <i>N</i>-oxide (DMPO) and EPR spectroscopy. In contrast, the photolysis of the thiazolethione <b>3b</b> (350 nm) affords exclusively the DMPO adducts of the isopropoxyl radicals. Control experiments disclose that the thiazolethione-derived photoproduct disulfide <b>5</b>, or the intermediary thiyl radicals <b>B</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<sub>2</sub>O−MeCN, the pyridone <b>2b</b> and the thiazolethione <b>3b</b> display moderate strand-break activity (17% open-circular DNA for <b>2b</b> and 12% for <b>3b</b>). In pure water, however, the pyridone <b>2b</b> 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 <b>3b</b> derives presumably from isopropoxyl radicals, because only these are detected in the photolysis of this photo-Fenton reagent.