DIOL EPOXIDE AND OTHER DERIVATIVES OF PAH AND AZA-PAH

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Polycyclic aromatic hydrocarbons (PAH) are ubiquitous components of the environment, produced by the combustion of organic matter. PAH exhibit widely varying carcinogenicities, and elucidation of the basis for that variation has been a research goal for over fifty years. Within the past ten years, evidence has been accumulating that metabolism to diol epoxides is the key event in activation of the PAH to ultimate carcinogenic, and mutagenic, forms. Among the most potent carcinogens are those in which a bay region diol epoxide would be sterically hindered at the epoxide moiety, either by a benzo ring (fjord region) or by a methyl group. In this research, diol epoxide and other derivatives of the carcinogen benzo[g]chrysene will be synthesized. This hydrocarbon, with both bay and fjord regions, provides a good test of the apparent structure-activity relation-ships for less structurally complex unsubstituted PAH diol epoxides that have been obtained from previous work. Methyl substitution on PAH is also common, and methylated PAH are among the most carcinogenic. Through the preparation of dihydro derivatives and tetrahydroepoxide derivatives on the angular ring of various methylated benz[a]anthracenes, it will be possible to probe the electronic effect of the methyl group when it is remote from the epoxide, and the steric effect when it is proximate to the epoxide. Compounds synthesized in this work will be tested for mutagenicity and tumorigenicity through collaborative arrangements.