Background: In the mid 1990s the structurally related, natural products amphidinolide N and caribenolide I were isolated from a marine dinoflagellate. In preliminary biological screening, these natural products displayed levels of activity against certain cancer cell lines rivaling those of the most potent molecules discovered to date. As a result, these molecules have sparked considerable interest in the fields of biology and pharmacology as promising anticancer therapeutic leads. Unfortunately, their limited availability from natural sources has delayed development. Their novel structures not only provide highly potent biological activities, but also a challenge to synthetic organic chemists. Professor Barry Trost has recently made several advancements in the area of complex molecule synthesis. Application of these advances to the synthesis of amphidinolide N and caribenolide I could provide rapid access to these natural products. Objective/Hypothesis: Recent advancements in the field of organometallic chemistry by the Trost group may provide a novel synthetic approach to amphidinolide N and caribenolide I. Therefore, we propose to synthesize these natural products in order to provide the necessary material for further biological evaluation.
Specific Aims : (1) Apply recent advancements in the field of synthetic organic chemistry to a laboratory synthesis of amphindolide N and caribenolide I; (2) confirm the proposed structures of these natural products; (3) provide the necessary quantities of these natural products for further biological evaluation; (4) provide structural analogs of the natural products to elucidate their biological mode of action. Study Design: By applying recently developed catalytic transformations, we will establish a synthesis that generates molecular complexity in an efficient and atom-economical fashion. In particular, we will design a series of ruthenium catalyzed transformations that carefully manipulates the alkyne functional group in a chemo- and stereoselective fashion. This will allow for a rapid synthesis of both amphidinolide N and caribenolide I. This synthesis will then be used to synthesize appreciable quantities of the natural products necessary for biological testing. Finally, the synthetic route will be modified to provide structural analogs of the natural products that will be used to assess their unique biological modes of action. There is a need for new chemotherapeutic agents that interact selectively with biological targets. These studies will provide access to molecules with proven biological activities against lymphoma, carcinoma, and colon cancer cell lines. Additional evaluation of these natural products may reveal novel biological modes of action that could be used in the future design of chemotherapies. ? ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04A-A (20))
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Fabian, Miles
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Stanford University
Schools of Arts and Sciences
United States
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Trost, Barry M; Masters, James T; Taft, Benjamin R et al. (2016) Asymmetric synthesis of chiral ?-alkynyl carbonyl and sulfonyl derivatives via sequential palladium and copper catalysis. Chem Sci 7:6217-6231
Trost, Barry M; Taft, Benjamin R; Masters, James T et al. (2011) A new strategy for the synthesis of chiral ?-alkynyl esters via sequential palladium and copper catalysis. J Am Chem Soc 133:8502-5
Trost, Barry M; Lumb, Jean-Philip; Azzarelli, Joseph M (2011) An atom-economic synthesis of nitrogen heterocycles from alkynes. J Am Chem Soc 133:740-3