The general goal of this proposed investigation is to study the synthesis, the chemical and biological properties, and the reactions of the biologically important metabolites of carcinogenic and/or mutagenic polycyclic aromatic hydrocarbons (PAH's). Novel methodologies of general application for the efficient, stereo- and regiochemically controlled synthesis of the optically pure bay-region metabolites of PAH's will be developed. The in vitro binding of several key diol epoxide metabolites to nucleic acids will be extensively studied and the structures of the covalently modified nucleic acids will be elucidated. We would like to continue our studies in the area of the bioorganic mechanisms of the PAH chemical carcinogenesis with the following specific aims: 1) to develop expedient and stereo- and regiochemically controlled synthetic methods for the optically active bay-region metabolites of benzo[c]phenanthrene, 5-methylchrysene, 7-methyl- and 7,12-dimethylbenz[a]anthracene, 3-methyl-cholanthrene and dibenz[a,c]anthracene. The cycloaddition of the arynes with 3,4-dibenzyloxyfuran will be exploited for this purpose; 2) to study the chemical properties of the diol epoxide metabolites of 7,12-dimethylbenz[a]anthracene and 5-methylchrysene and their in vitro reactions with nucleic acids; 3) to synthesize C-13 labeled arene oxides for their use in the regiochemical studies for the enzymatic epoxide ring opening reactions with glutathione transferase and epoxide hydrolase. Throughout these bioorganic studies together with biological testings for the carcinogenic an/or mutagenic activity of synthetic arene oxides and their analogs, pertinent information on the biochemical processes associated with these environmental carcinogens will be obtained, which will allow us to experimentally evaluate the bay-region concept.
| 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 |
