Bulky DNA adducts formed from chemical carcinogens dictate structure, reactivity, and mechanism of chemical-biological reactions; therefore, their identification is central to evaluating and mitigating cancer risk. Natural food components, or others associated with certain food preparations or metabolic conversions, initiate potentially damaging genetic mutations after forming DNA adducts, which contribute critically to carcinogenesis, despite the fact that they are typically repaired biochemically and they are formed at extremely low levels. This situation places significant limitations on our ability to understand the role of formation, repair, and mutagenesis on the basis of the complex DNA reactivity profiles of food components. The long-term goals of this research are to contribute basic knowledge and advanced experimental tools required to understand, on the basis of chemical structure, the contributions of chronic, potentially adverse, dietary chemical carcinogen exposure to cancer development. It is proposed that a new class of synthetic nucleosides, devised on the basis of preliminary discoveries made in the independent laboratory of the applicant, will serve as molecular probes for bulky DNA adducts and can be effectively used to study and AMPlify, i.e. as a sensitive diagnostic tool, low levels of chemically-specific modes of DNA damage. The proposed research is a chemical biology-based approach to the study of carcinogenesis. Experiments involve chemical synthesis, thermodynamic and kinetic characterization DNA-DNA and enzyme-DNA interactions, and nanoparticle-based molecular probes. The proposal describes a potentially ground-breaking approach for profiling the biological reactivities of chemical carcinogens, and we expect to gain fundamental knowledge and chemical tools that can contribute to the prevention of diseases influenced by gene-environment interactions.