Many environmentally prevalent polycyclic aromatic hydrocarbons (PAHs) are metabolized in mammaliansystems to carcinogens that react with cellular DMA leading to adverse biological and health effects. Thisoccurs by metabolic activation of a PAH to 4 bay region diol epoxides that are DMA alkylants. Thesemetabolites form covalent adducts with the purine bases and it is the DMA damage induced by this processthat ultimately results in mutagenesis and tumorigenesis. Introduction of fluorine can substantially alterbiological 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 thestructure-activity relationships on molecular-genetic level, studies using fluorinated PAHs and theirmetabolites are proposed. For this, it is critical to have sufficient quantities of regiospecifically fluorinatedPAHs, 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 metabolitesand physical as well as biological studies with these compounds. The fluorinated PAHs will be used in 2types of collaborative studies. One involving mechanistic, theoretical and experimental charge distributionstudies and the other an evaluation of metabolic activation of the fluoro BcPh as well as dihydrodiols to DMAalkylating agents and comparisons to the studied BcPh. BcPh-DNA adducts have been stated to be elusiveto DNA repair accounting for their higher activity. (B) Comparative physical and NMR studies of DNAmodified by inactive 6-F-BaP adducts with those modified by the highly active BaP diol epoxides. Data onthe latter is already available in the literature. For these studies DNA modified by 6-F-BaP diol epoxides willbe synthesized. Beginning from our prior synthesis of 6-F-BaP dihydrodiol, diastereoselective synthesis of6-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 importantDNA sequences via modified solid-phase DNA synthesis. The structures of DNA site-specifically modifiedby 6-F-BaP diol epoxides will be studied by NMR. This is to probe the influence of the F atom on DNAconformation and for comparison of the structures to the protio analogs. These studies will provide insightinto subtle structural differences that lead to markedly different bioresponses.
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