The long term objectives of this project are to contribute to the understanding of the molecular mechanisms of chemical carcinogenesis induced by polycyclic aromatic hydrocarbons (PAHs) through the synthesis of biologically significant metabolites of these PAHs, and the study of their chemical and biological properties and reactions with various nucleophiles including DNAs. During the last grant award period, we have firmly established a totally novel, efficient, generally applicable synthetic method towards the diol epoxide and trans-dihydrodiol metabolites of PAHs. With these successful results in hand, we now wish to turn our focus to even more challenging synthetic and bioorganic and biomechanistic aspects of PAH chemical carcinogenesis.
The specific aims for the next grant award period will be: 1) extension of the aryne-3,4-dibenzyloxyfuran cycloaddition method we have developed to the synthesis of optically active bay region syn- and anti- diol epoxides and other metabolites of highly potent carcinogenic PHAs. These PAHs include: benzo[a]pyrene, 7-methyl, and 7,12-dimethylbenz[a]- anthracene, 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 and its desmethyl analog, 3) synthesis of [3-13C]-cyclopenta[cd]pyrene 3,4-oxide and the use of this epoxide and [2-13C]-naphthalene 1,2-oxide in the study of molecular mechanisms in epoxide hydrolase and glutathione transferase (the former only) reactions, 4) reactions of these metabolites with various nucleophiles in order to obtain pertinent information on their chemical reactivity. These include solvolytic reactions in aqueous solutions and in vitro covalent interactions with DNAs, 5) synthesis of DNA oligomers modified by BP bay region diol epoxides at the specific base sites and elucidation of their molecular conformations. All of the synthetic metabolites will be submitted for extensive biological testings to our collaborators.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA025185-15
Application #
3166742
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1979-01-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
15
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Arts and Sciences
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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