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.
Members of the naturally occurring diazoparaquinone-containing family of secondary metabolites have demonstrated significant anticancer activity in various screening assays. That these species feature the very uncommon and chemically unusual diazoparaquinone functionality begs the question, "How does this potentially reactive chemical unit contribute to the potent cytoxicity of some of these species towards cancer cells?" We have developed a model that attempts to account for how the chemistry of diazoparaquinones might lead to cellular death. Our approach to test this hypothesis involved developing a synthesis scheme to prepare the naturally occurring material as well as designed analogues as probes molecules. Our synthesis approach focused on one class of the diazoparaquinones, the lomaiviticins. These structures are dimeric, consisting of two equal diazoparaquinone units linked together by a very sterically congested carbon-carbon bond. Thus, any synthesis endeavor targeted these species must solve the very daunting challenge of forging this key connection between the halves with complete control of regiochemistry and stereochemistry. Our approach was to develop a two-directional, divergent strategy to the stereochemically rich dimeric core, and build outward. We designed and executed a novel double Claisen rearrangement-based approach to securing both the key carbon-carbon bond and the correct relative stereochemistry at the joining site as well as adjacent stereocenters. The net result was an enantioselective construction of the bicyclic lomaiviticin core over 11 steps. Extending the core outward in two directions has yet to be achieved. The intellectual merit of the research lies in the development of a new strategy for the synthesis of the dimeric lomaiviticin core structure, and the demonstration of a diastereoselective double, divergent Claisen rearrangement sequence. The broader impacts lie in the area of introducing new strategy-level thinking into the organic synthesis enterprise, which in turn can impact on how pharmaceutical agents are prepared.
