title: UV-Induced DNA Interstrand Cross-Linking and Direct Strand Breaks from a New Type of Binitroimidazole Analogue.
abstract: Four novel photoactivated binitroimidazole prodrugs were synthesized. These agents produced DNA interstrand cross-links (ICLs) and direct strand breaks (DSB) upon UV irradiation, whereas no or very few DNA ICLs and DSBs were observed without UV treatment. Although these four molecules (1-4) contain the same binitroimidazole moiety, they bear four different leaving groups, which resulted in their producing different yields of DNA damage. Compound 4, with nitrogen mustard as a leaving group, showed the highest ICL yield. Surprisingly, compounds 1-3, without any alkylating functional group, also induced DNA ICL formation, although they did so with lower yields, which suggested that the binitroimidazole moiety released from UV irradiation of 1-3 is capable of cross-linking DNA. The DNA cross-linked products induced by these compounds were completely destroyed upon 1.0 M piperidine treatment at 90 °C (leading to cleavage at dG sites), which revealed that DNA cross-linking mainly occurred via alkylation of dGs. We proposed a possible mechanism by which alkylating agents were released from these compounds. HRMS and NMR analysis confirmed that free nitrogen mustards were generated by UV irradiation of 4. Suppression of DNA ICL and DSB formation by a radical trap, TEMPO, indicated the involvement of free radicals in the photo reactions of 3 and 4 with DNA. On the basis of these data, we propose that UV irradiation of compounds 1-4 generated a binitroimidazole intermediate that cross-links DNA. The higher ICL yield observed with 4 resulted from the amine effector nitrogen mustard released from UV irradiation.
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, United States.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, United States.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, United States.
authors.forename: Yunyan
authors.initials: Y
authors.lastname: Kuang
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, United States.
authors.forename: Huabing
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, United States.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Peng
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000235:genetics*; D053960:DNA Breaks / Q000187:drug effects* / Q000528:radiation effects*; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D009588:Nitrogen Mustard Compounds / Q000737:chemistry / Q000494:pharmacology; D009593:Nitroimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D009690:Nucleic Acid Conformation / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D007364:Intercalating Agents; D009588:Nitrogen Mustard Compounds; D009593:Nitroimidazoles; D004247:DNA