In an effort to more fully understand the chemical basis for carcinogenic/mutagenic activity in several classes of environmentally ubiquitous PAHs, the major thrust of the proposal is to generate their carbocations directly under stable ion conditions and to derive charge delocalization pathways based on NMR studies (at 500 MHz), in order to search for correlations between charge delocalization mode(s) and magnitude of carcinogenic activity. Charge delocalization mapping enables the most likely sites for nucleophile attachment to be identified. Previous studies supported under the AREA program emphasized cyclopenta[a]phenanthrenes, benzo[a]anthracenes, chrysenes, methylene bridged-PAHs and fluoranthene-PAHs, having varied degrees of carcinogenic, mutagenic and tumorigenic activities. In continuation, structure-reactivity studies on a series of strategically substituted benzo[a]anthracenes, a series of alkylated benzo[c]phenanthrenes and their methoxy/hydroxy derivatives, dibenzoanthracenes, their alkyl and dihydrodiols, and several other classes of polyarenes are planned. Parallel DNA-binding studies on representative covalent precursors (alcohols and halides) with MCF-7 cells and mutagenicity studies will be performed to correlate carbocation-based studies with carcinogenic/mutagenic activity. To mimic PAH-DNA adduct formation, quenching experiments with model bases will be performed with the aim to compare product distribution and regio selectitivities with the PAH-DNA adducts obtained from mammalian cell cultures. Other studies focus on heterocations and carbocations derived from aza-PAHs in relation to their dual carcinogenic/anti-cancer functions. Nitro-PAHs will be used to synthesize novel DNA-intercalating agents. A unique feature of this work is that reactive intermediates are examined directly. The results should provide a clearer mechanistic picture, bridging metabolic studies with mechanism and theory as a basis for predictability of cancer induction. DNA binding and mammalian cell mutagenicity studies on the substituted and derivatized-PAHs proposed for stable ion work will enhance the available literature data on structure/reactivity relationships. ? ?
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