This grant application is divided into three major sections to study the total synthesis and biosynthesis of three unrelated families of natural products: (1) taxol;(2) the paraherquamides, stephacidins, norgeamides, notoamides, malbrancheamides, asperparalines and congeners;and (3) the okaramines. I. Stephacidins, Paraherquamides, norgeamides, notoamides, malbrancheamides &Asperparalines. The goals of this program are to utilize the tools of total synthesis to fully elucidate the biosynthetic pathway from the primary amino acids (isoleucine, proline, and tryptophan) and mevalonate-derived isoprene moieties to the polycyclic indole alkaloids comprising the paraherquamides, stephacidins, avrainvillamide, notoamides, norgeamides, malbrancheamides and asperparalines. Provocative evidence has been elucidated in our laboratory indicating that this class of alkaloids, are constructed by a rare biosynthetic intramolecular [4+2] cycloaddition reaction. Through the use of total chemical synthesis of isotopically labeled intermediate metabolites, key features of the biosynthetic pathways to these complex secondary metabolites will be experimentally elucidated. In collaboration with Prof. David Sherman's laboratory (University of Michigan), we are actively engaged in the identification, isolation, cloning and functional expression of the biosynthetic gene clusters responsible for the biosynthesis of these agents. Stephacidins A, B and the norgeamides A-D represent new structural and mechanistic classes of anticancer agents. Their mechanism of action is unique which holds promise to develop more selective and less toxic chemotherapeutic agents for treating cancer. The recently discovered malbrancheamides display calmodulin inhibitory activity which is an entirely new biological activity for this family of natural products. Our broad synthetic platform has allowed the synthesis of numerous unnatural, structural analogs of these natural products and are continuously being evaluated for cytotoxic activity and calmodulin inhibitory acitivity. II. Taxol. The biosynthesis of taxol from the cyclization of geranylgeranyl pyrophosphate (ggPP) via taxa- 4(5),11(12)-diene, will be studied in collaboration with Prof. Rod Croteau's laboratory at Washington State University. The sequence of hydroxylation reactions from this simple diterpenoid comprising the core A/B/C ring system of taxol shall be elucidated. Taxol is the number one selling anti-cancer drug in the world. Determination of the biosynthetic pathway to taxol holds significant promise in assisting the expected growing demand for this drug because of limitations on its isolation and production which comes from the Yew tree. III. Okaramines. As a natural out-growth of our work on the paraherquamide family of prenylated indole alkaloids, we propose to initiate a new project to study the total synthesis and biosynthesis of the okaramines, which are complex, polycyclic prenylated indole alkaloids that possess insecticidal activity.

Public Health Relevance

The purpose of this application is to utilize the tools of chemical synthesis to study the molecular details of how Nature biosynthesizes anti-cancer drugs. In one sub-project, involving the study of taxol biosynthesis, the goal is to improve the cell-culture yields of production of the drug, which is currently obtained from the Yew tree, the harvest of which, has created a severe supply-demand problem and important environmental consequences. In addition, the chemical technologies being developed, will be applied to the design and synthesis of new anti-cancer drugs.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-B (02))
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Misra, Raj N
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Colorado State University-Fort Collins
Schools of Arts and Sciences
Fort Collins
United States
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