The general, long term objectives of this project is to study the synthesis, the chemical and biological properties, and the reactions of biologically significant metabolites of carcinogenic and/or mutagenic polycyclic aromatic hydrocarbons (PAH's). During the last grant award period, we have endeavored to establish a totally novel, efficient, and generally applicable synthetic method towards the diol epoxide and other PAH metabolites. In light of the success we have achieved, and considering the recent progress of other groups, we would like to propose continuation of our study in the area of the mechanisms of PAH chemical carcinogenesis with the following specific aims: 1) application of the aryne-3,4-dibenzyloxyfuran cycloaddition method to the synthesis of the optically active syn- and anti-bay- region diol epoxide and other metabolites of the significant highly potent carcinogenic PAH's. These PAH's include: 1,4- dimethylphenanthrene, 7-methyl- and 7,12- dimethylbenz(a)anthracenes, and 3-methylcholanthrene. 2) synthesis of the optically active bay-region diol epoxide and other metabolites of the potent carcinogen 15,16-dihydro-11- methylcyclopenta (a)phenanthren-17-one. 3) study of the metabolism of the carcinogen azuleno(1,2,3- cd)phenalene to examine the possible loss of CO upon in vitro incubation with oxidizing enzyme systems; synthesis of the putative active forms, azuleno(1,2,3-cd)phenalene 1,2- and 4,5- oxides and examination of their chemical reactivity toward nucleophiles. 4) synthesis of 2-13C-naphthalene 1,2-oxide and 3-13C- cyclopenta(cd)pyrene 3,4-oxide and their use in the study of molecular mechanisms in epoxide hydrolase and glutathione transferase reactions. 5) covalent binding studies of the synthetic diol epoxide metabolites with nucleic acids and elucidation of their in vitro reaction products. C-13 nmr analysis for the presence of phosphotriester upon in vitro reaction of DNA with 10-13C-benzo (a)pyrene anti-diol epoxide as possible mechanism for DNA strand scission. All of the synthetic metabolites will be submitted for extensive biological testing to our collaborators.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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Sinsheimer, J E; Giri, A K; Hooberman, B H et al. (1991) Mutagenicity in Salmonella and sister chromatid exchange in mice for 1,4-, 1,3-, 2,4-, and 3,4-dimethylphenanthrenes. Environ Mol Mutagen 17:93-7
Sinsheimer, J E; Giri, A K; Messerly, E A et al. (1989) Mutagenicity in Salmonella and sister chromatid exchange in mice for the bay-region syn- and anti-diol epoxides of 1,4-dimethylphenanthrene. Carcinogenesis 10:1123-6
Frantz, S W; van den Eeckhout, E; Sinsheimer, J E et al. (1985) Mutagenicity in Salmonella assays of cyclohexane epoxide derivatives. Toxicol Lett 25:265-71