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The Synthesis and Optimization of Bioactive Natural Products as Anticancer and Antileishmanial Agents

Schwartz, Eric Brandon
http://rave.ohiolink.edu/etdc/view?acc_num=osu1436964192

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Pharmacy.
Natural products continue to play a key role in the discovery and development of therapeutic agents. These naturally occurring compounds frequently serve as drug leads due to their high degree of structural and functional diversity, biochemical specificity for a myriad of targets, and inherent drug-like-properties. This dissertation describes the synthesis and development of two natural products, curcumin and dihydroneridienone, and their structurally related analogues. The primary focus of this dissertation is on part I, which deals with the structural optimization of curcumin as an inhibitor of the JAK/STAT pathway in cancer. This pathway is frequently upregulated in both blood cancers and solid tumors as compared to normal cells, and inhibitors of the pathway are considered attractive targets for the prevention and therapy of cancer. Curcumin been shown to inhibit both JAK2 and STAT3, while displaying little toxicity in vivo. As a drug, however, curcumin is severely limited due to poor bioavailability, rapid metabolism, and poor target selectivity. With this in mind, approaches designed to address these limitations and improve the properties of curcumin through structural manipulation are presented. Including aspects of structure based drug design, synthetic/medicinal chemistry, in vitro and in vivo biological assays, and pharmacokinetic evaluation, this project has been very collaborative and interdisciplinary. Although this section of the thesis attempts to highlight all of these contributions, the focus will lie heavily on the structural analysis of curcumin, the design of key analogues, the development of synthetic methodology for analogue preparation, and ultimately the optimization of the curcumin scaffold for improved drug-like properties. Part II of this dissertation, a very different project in contrast to part I, involves the synthesis of a specific sterol subtype that has been identified during a natural product isolation and screening effort to identify potential antileishmanial compounds. Leishmaniasis is a parasitic disease transmitted by the sand fly vector that currently affects over 12 million people. Approved antileishmanial drugs suffer from many shortcomings, such as high toxicity, high cost, parenteral administration routes, and more recently, the emergence of drug resistant strains. Therefore, novel drugs are needed. The molecules in part II were identified from the Mexican plant Pentalinon andrieuxii, a plant used in traditional medicine to treat the disease. These compounds are more structurally complex than those seen in part I and have therefore required exploration of more diverse synthetic chemistry and have presented significant challenges associated with multi-step synthesis. Because the supply of these natural compounds are severely limited, the synthetic routes presented in this section are critical to the continued biological study of this class of natural product and potential future development.
James R. Fuchs (Advisor)
Karl A. Werbovetz (Committee Member)
Chenglong Li (Committee Member)
317 p.
Chemistry; Pharmacy Sciences

Recommended Citations

Citations

  • Schwartz, E. B. (2015). The Synthesis and Optimization of Bioactive Natural Products as Anticancer and Antileishmanial Agents [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1436964192

    APA Style (7th edition)

  • Schwartz, Eric. The Synthesis and Optimization of Bioactive Natural Products as Anticancer and Antileishmanial Agents. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1436964192.

    MLA Style (8th edition)

  • Schwartz, Eric. "The Synthesis and Optimization of Bioactive Natural Products as Anticancer and Antileishmanial Agents." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1436964192

    Chicago Manual of Style (17th edition)

osu1436964192
463
© 2015, some rights reserved.Creative Commons License The Synthesis and Optimization of Bioactive Natural Products as Anticancer and Antileishmanial Agents by Eric Brandon Schwartz is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.