Diazoparaquinone Natural Products Chemistry

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Funding from the Chemical Synthesis Program of the Chemistry Division of the National Science Foundation will enable Dr. Ken Feldman of the Chemistry Department at the Pennsylvania State University to pursue the chemistry of diazoparaquinone natural products. Naturally occurring molecules that feature a diazoparaquinone function are quite rare and are among the few examples of organic species that feature a molecule of nitrogen gas as a covalent substituent. Several of these diazoparaquinone-containing species exhibit very potent activity against a range of human cancers, and moreover appear to display a cytotoxicity profile distinct from any other class of anticancer natural products. These observations suggest a unique mechanism-of-action based upon the unusual diazoparaquinone function. The total chemical syntheses of two structurally complex and biologically potent members of this class of compounds are planned. In addition, the design and synthesis of rationally designed analogues of the natural products will be pursued. Together, the natural products and the derived analogues will serve as probes to help elucidate the details of the cytotoxicity mechanism-of-action. Preliminary results implicate both a DNA-damaging sp2 radical and a DNA alkylating orthoquinonemethide electrophile as plausible candidates for the lethal chemical functionality. Successful prosecution of these research objectives may lead to new drug leads, which in turn will impact favorably on the pharmaceutical enterprise in the United States. In addition, this project will provide training for undergraduate and graduate students, including historically underrepresented groups in the sciences, such that these students will be ready to contribute to the scientific enterprise in the United States.