Studies in Chemical Carcinogenesis

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DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAH) are widely prevalent in the environment and they are products of activities of a modern society. Human exposure to these is unavoidable and many of these compounds are implicated in cancer causation. The work proposed is aimed at studying DNA insult by these compounds and the biological results of the insult. The research is aimed at developing novel synthetic methods for site-specific modification of DNA as well as for the synthesis of novel PAH derivatives for studies in chemical carcinogenesis. For goal one, we anticipate the stereo and regioselective synthesis of a PAH amino triol that will be coupled with fluoro nucleosides to yield the carcinogen-nucleoside conjugates. These will be suitably manipulated and incorporated into specific sites of biologically relevant ras DNA sequences. These modified DNA will be used for physical studies such as thermal denaturation and temperature-dependent CD. Duplexes will involve normal complementary strands as well as mismatch incorporated strands. The data will be analyzed for structural information that can be used in concert with the NMR experiments that will be done in order to ascertain unambiguously the structures of the damaged DNA. Subsequently, the modified DNA will be used for structural assessment by NMR and for biochemical experimentation such as DNA excision repair (these will be done collaboratively). It is also anticipated that a new route to angularly fused PAH metabolites will be developed that hinges on a novel metal-mediated cyclization. Overall, it is anticipated that the studies proposed will help in better understanding the basis and steps involved in cellular transformation by an environmentally present carcinogen leading to cancer causation.