Fluorine as a Probe in Polycyclic Aromatic Hydrocarbon Carcinogenesis Studies

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Many environmentally prevalent polycyclic aromatic hydrocarbons (PAHs) are metabolized in mammalian systems to carcinogens that react with cellular DMA leading to adverse biological and health effects. This occurs by metabolic activation of a PAH to 4 bay region diol epoxides that are DMA alkylants. These metabolites form covalent adducts with the purine bases and it is the DMA damage induced by this process that ultimately results in mutagenesis and tumorigenesis. Introduction of fluorine can substantially alter biological activity of a PAH and its metabolites. For example, increased activity has been shown for 6- fluorobenzo[c]phenanthrene (6-F-BcPh) compared to benzo[c]phenanthrene (BcPh), whereas 6- fluorobenzo[a]pyrene (6-F-BaP) showed substantially decreased activity. In order to better understand the structure-activity relationships on molecular-genetic level, studies using fluorinated PAHs and their metabolites are proposed. For this, it is critical to have sufficient quantities of regiospecifically fluorinated PAHs, and importantly, their fluorinated metabolites. Two lines of investigations are therefore proposed. (A) Development of novel methods for synthesis of regiospecifically fluorinated PAHs, their putative metabolites and physical as well as biological studies with these compounds. The fluorinated PAHs will be used in 2 types of collaborative studies. One involving mechanistic, theoretical and experimental charge distribution studies and the other an evaluation of metabolic activation of the fluoro BcPh as well as dihydrodiols to DMA alkylating agents and comparisons to the studied BcPh. BcPh-DNA adducts have been stated to be elusive to DNA repair accounting for their higher activity. (B) Comparative physical and NMR studies of DNA modified by inactive 6-F-BaP adducts with those modified by the highly active BaP diol epoxides. Data on the latter is already available in the literature. For these studies DNA modified by 6-F-BaP diol epoxides will be synthesized. Beginning from our prior synthesis of 6-F-BaP dihydrodiol, diastereoselective synthesis of 6-F-BaP diol epoxides will be developed (currently unprecedented). Using the synthetic diol epoxides, nucleoside-diol epoxide adducts of 6-F-BaP will be synthesized and incorporated into biologically important DNA sequences via modified solid-phase DNA synthesis. The structures of DNA site-specifically modified by 6-F-BaP diol epoxides will be studied by NMR. This is to probe the influence of the F atom on DNA conformation and for comparison of the structures to the protio analogs. These studies will provide insight into subtle structural differences that lead to markedly different bioresponses.