The organic chemical investigations and the synthetic chemistry in the Project together provide a platform for the structural and biological research studies described by other members of the program. As in the past, one of the principle objectives is the synthesis of DNA oligomers that contain modified 2'-deoxynucleotides, located site-specifically, and which represent damage caused by genotoxic environmental agents. Many of these modified deoxynucleotides are known only from their biological origin and have never been synthesized in the quantities that make extensive biological work feasible. A specific area of synthesis that has been particularly barren is that of the carcinogenic amines, especially the food mutagens. Now having solved the synthetic problem of the simpler N 2-dG aminoaryl adducts, a significant effort will be made to general methods for the C8-dG food mutagen adducts. A second area of investigation will be to apply the known alkylating lexitropsins to oligomeric DNA so as to generate N3-alkylating forms of deoxyadenosine and carba-deoxyadenosine in a """"""""post-synthetic"""""""" process. These adducts pre instability and the previous lack of any method to generate them in a controlled manner. Structural studies using NMR spectroscopy and computational methods will be carried out on oligomers containing carcinogenic amine adducts and separately, on oligomers containing N3-alkylated carba dA residues. These studies will establish the degree of local dislocation of DNA by this study of adduct and allow a correlation with mutagenesis and DNA-repair processes. A third area of investigation concerns the chemically reactive sites in DNA (hot-spots) and their relationship to agents that cause damage. This study will attempt to clarify why specific nucleoside sequences in DNA are more reactive than others. Finally, because of the universal presence of bisphenol-A in the environment, any nucleoside adducts that form from its metabolites will be synthesized and incorporated into DNA for biological studies.
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