I. Synthetic Studies towards NF00659B1 II. Design, Synthesis, and Characterization of Manassantin Analogues

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2015

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Kwon, Do Yeon

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Hong, Jiyong

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Abstract

Despite natural products play a crucial role in drug discovery and chemical biology, these compounds are often available in limited quantities. Therefore, there is a need for efficient methods that allow access to the natural products as well as analogues for the evaluation of biological activity, investigation of structure activity relationships, and generation of more improved bioactive molecules. This dissertation consists of two parts focused on synthetic studies towards biologically active natural products and their analogues.

Part I: Since bioactive diterpenoid pyrones produced by microbes have limitless potential in pharmaceutical applications, a considerable effort has been devoted to the synthesis of diterpenoid pyrones and the identification of their structure-activity relationships. This chapter describes our synthetic studies towards the first total synthesis of NF00659B1, the 4,5-seco-tricyclic diterpene α-pyrone. Our synthetic efforts are focused on an efficient construction of the key intermediate oxepanol and installation of the α-pyrone moiety by Cu(I)-mediated intermolecular SN2’ reaction. Using efficient synthetic methods, we have been investigating the unknown absolute and relative stereochemistry of NF00659s. In addition, these synthetic strategies will contribute to a more thorough elucidation of their bioactivities. Due to their bioactivities, NF00659s are expected to be promising new anticancer drugs. Part II: Hypoxia-inducible factor 1 (HIF-1) plays a significant role in the adaptation of tumor cells to hypoxia by activating the transcription of genes involved in critical aspects of cancer, making it a leading target for the treatment of cancer. Despite several small molecules have been reported to inhibit the HIF-1 signaling pathway, these compounds exhibit relatively low HIF-1 inhibitory activity. In addition, most of them lack the desired selectivity or toxicity profiles required for a useful therapeutic agent. Therefore, development of potent and selective HIF-1 inhibitors is urgently needed. Manassantin A, a dineolignan isolated from Saururus cernuus L. (Saururaceae) has been shown to be a potent inhibitor of HIF-1α in vitro with minimal cytotoxicity. Previously, we reported a convergent and efficient synthesis of manassantin A, which enables the creation of various analogues. This chapter describes our medicinal chemistry efforts for design, synthesis, and biological evaluation of manassantin analogues to establish structure-activity relationships of the natural product as well as identification of potential lead compounds with reduced structural complexity and improved drug-like properties. In addition, we have developed chemical probes by modifying structure of the natural product to determine the molecular mechanisms of manassantin-mediated HIF-1 inhibition. In conclusion, we expect that these two projects will provide efficient synthetic approaches to the natural products and their analogues as well as invaluable tools to identify the mechanisms of action of the natural products.

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Kwon, Do Yeon (2015). I. Synthetic Studies towards NF00659B1 II. Design, Synthesis, and Characterization of Manassantin Analogues. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/10506.

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