Quantification of thiopurine/UVA-induced singlet oxygen production

Abstract

Thiopurines were examined for their ability to produce singlet oxygen ( 1O 2) with UVA light. The target compounds were three thiopurine prodrugs, azathioprine (Aza), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), and their S-methylated derivatives of 6-methylmercaptopurine (me6-MP) and 6-methylthioguanine (me6-TG). Our results showed that these thiopurines were efficient 1O 2 sensitizers under UVA irradiation but rapidly lost their photoactivities for 1O 2 production over time by a self-sensitized photooxidation of sulfur atoms in the presence of oxygen and UVA light. The initial quantum yields of 1O 2 production were determined to be in the range of 0.3–0.6 in aqueous solutions. Substitution of a hydrogen atom with a nitroimidazole or methyl group at S decreased the efficacy of photosensitized 1O 2 production as found for Aza, me6-MP and me6-TG. 1O 2-induced formation of 8-oxo-7,8-dihydro-2′-dexyguanosine (8-oxodGuo) was assessed by incubation of 6-methylthiopurine/UVA-treated calf thymus DNA with human repair enzyme 8-oxodGuo DNA glycosylase (hOGG1), followed by apurinic (AP) site determination. Because more 8-oxodGuo was formed in Tris D 2O than in Tris H 2O, 1O 2 is implicated as a key species in the reaction. These findings provided quantitative information on the photosensitization efficacy of thiopurines and to some extent revealed the correlations between photoactivity and phototoxicity.