Oxygen-linked Phenol-DNA Adducts

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DESCRIPTION (provided by applicant): Phenols are ubiquitous components of the human environment. The broad objectives of this research program are to determine the chemical and biochemical processes controlling the balance between their carcinogenic and anticarcinogenic properties. The central hypothesis is that phenolic compounds can form DNA lesions, containing an O-linked aryl group at the C8 position of purine nucleosides, which may contribute to cancer etiology. To develop the chemical tools needed to address these issues, the specific aims of this proposal are: (1) Develop a synthetic approach to phenol-substituted purine nucleoside analogs modified at C8; (2) Synthesize oligonucleotides containing O-linked phenol adducts and determine their stability; and (3) Develop an analytical method for the detection of O-linked phenol adducts and characterize the relationship between phenol activation and adduct formation. The results of this study can be important for evaluating the role of phenols in cancer, developing biomarkers of exposure, generating environmental regulatory guidelines, and establishing concepts important for phenol-based chemoprevention. The candidate will become (July, 2004) an assistant professor of Medicinal Chemistry at the University of Minnesota with an appointment in the Cancer Center. She holds a Ph.D. in Chemistry from MIT, where her research focused on organic synthesis. As an American Cancer Society postdoctoral fellow, the focus shifted to carcinogenesis and chemoprevention. The candidate has been presented with diverse opportunities for professional development through participation in collaborative research, supervising students, grant-writing, departmental service, teaching, and scientific conferences. Immediate career goals include transitioning to an independent faculty position and initiating a research program based on the union of synthetic organic chemistry with the study of carcinogenic mechanisms. The long-term career objective is to foster a rigorously active research group investigating initiation of cancer by environmental agents, diagnostic tools for carcinogen exposure, and prevention methods. The research career development plan is a phased program - a mentored period designed to strengthen the candidate's cancer research skills and professional development, and an independent phase to transition the research to the independent laboratory. The research environment presents faculty expertise and major instrumentation ideally suited for the proposed work.