Synthetic/Mechanistic Investigations of Antitumor Agents

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DESCRIPTION (provided by applicant): The long term objective of this research program is to use cell-specific cytotoxic natural products as vehicles to advance the fields of complex molecule synthesis and drug discovery. These goals will require an interdisciplinary approach to define the mechanistic basis by which these natural products selectively target cancer cells using the tools of chemical biology, relying primarily upon the power of chemical synthesis. As such, contributions from our laboratory will focus on the development of efficient and stereocontrolled strategies for the synthesis of complex natural products and their respective congeners of interest. Collaborative efforts will allow us to develop SAR profiles that will ultimately lead to identification of the cellular target for the secondary metabolites that we intend to study. Specific Aims for the forthcoming grant period include: (1) Chemical synthesis azido apoptolidinone; (2) Development of procedures for the enzymatic glycosylation of the unnatural aglycones using precursor directed biosynthesis in collaboration with Professor Brian Bachmann (Vanderbilt Institute of Chemical Biology); (3) Stereocontrolled synthesis of ammocidin, a polyketide derived natural product that selectively induces apoptosis in ras-dependent cells; (4) Identification of the cellular target(s) of apoptolidin and hibarimicin E using a chemical proteomics strategy in collaboration with Professors Dan Liebler and Larry Marnett (Vanderbilt Institute of Chemical Biology); (5) Chemical synthesis of hibarimicinone and the hibarimicin shunt metabolite HMP-Y1. Lay language description: One long term objective is to develop methods for the assembly of a group of natural products that have proven to selectively eliminate cancer cells without harming normal cells. A second objective is to use various chemical and biochemical tools to understand, at a molecular level, how these compounds target cancer cells. Advances in this area could have significant impact in the treatment of cancer.