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SYNTHESIS AND STRUCTURAL OPTIMIZATION OF THE NATURAL PRODUCTS SILVESTROL AND PHYLLANTHUSMIN C

Woodard, John Lewis, IV
http://rave.ohiolink.edu/etdc/view?acc_num=osu1424384284

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Pharmacy.
Historically, natural products have been recognized as an indispensable source of leads for the discovery and development of therapeutic agents. This relationship is partially due to the vast structural diversity possessed by natural products as compared to synthetic compounds, allowing natural products to occupy a larger volume of chemical space and possess a broader distribution of structural and physicochemical properties. Additionally, natural products have been biosynthesized by a host to interact with various proteins, demonstrating an inherent ability to selectively interact with biological targets at a primitive level. Unfortunately, the unmodified natural product is rarely discovered to be the optimal therapeutic agent; rather, natural products often serve as the structural scaffold off of which therapeutic agents are commonly designed. Chemical synthesis is not only utilized to provide material for mechanistic studies, but also to address the pharmacological limitations of natural products through structural manipulation and derivatization. Therefore, this thesis describes the synthesis and structural optimization of two cytotoxic natural products, phyllanthusmin C and silvestrol. Phyllanthusmin C was recently isolated from various plant parts of Vietnamese Phyllanthus poilanei, and was reported to display appreciable antiproliferative activity against a human colorectal carcinoma (HT-29) cell line. The initial series of analogues were synthesized via the late-stage glycosylation of various glycosides onto the diphyllin core and screened for antiproliferative activity. One of the most active analogues, 2”-acetyl-phyllanthusmin D, was selected for in vivo evaluation; unfortunately, this compound was found to be insoluble in aqueous solutions and thus could not be evaluated in vivo. Based upon this observation, methods for introducing polar functionality to combat poor water solubility were explored. This ultimately led to utilizing the glycoside of phyllanthusmin as a linkage point for introducing water solubilizing functionality. When compared to the parent phyllanthusmin, this analogue demonstrated improved biological activity and succeeded as a proof of concept for utilizing the glycoside as a linkage point for the introduction of water solubilizing functionality. Silvestrol is a rocaglamide derivative, possessing an unprecedented dioxanyloxy moiety attached to C6 of its cyclopenta[b]benzofuran core, which has demonstrated selective cytotoxicity toward various cancer cell lines. The synthetic challenges associated with constructing the differentially functionalized cyclopenta[b]benzofuran core of silvestrol along with the remarkable biological activity associated with this molecule spurred our interest in developing a modular and efficient route for the synthesis of the structurally complex core. This dissertation presents the different approaches attempted for generation of the tricyclic scaffold and the discovery of a CAN-mediated oxidative addition/cyclization of 1,3-dicarbonyls into allylic ethers that ultimately furnished the differentially functionalized cyclopenta[b]benzofuran core of silvestrol.
James Fuchs, Ph.D (Advisor)
A. Douglas Kinghorn, Ph.D (Committee Member)
Karl Werbovetz, Ph.D (Committee Member)
336 p.
Chemistry; Organic Chemistry; Pharmacy Sciences
silvestrol; phyllanthusmin; synthesis; natural products

Recommended Citations

Citations

  • Woodard, IV, J. L. (2015). SYNTHESIS AND STRUCTURAL OPTIMIZATION OF THE NATURAL PRODUCTS SILVESTROL AND PHYLLANTHUSMIN C [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1424384284

    APA Style (7th edition)

  • Woodard, IV, John. SYNTHESIS AND STRUCTURAL OPTIMIZATION OF THE NATURAL PRODUCTS SILVESTROL AND PHYLLANTHUSMIN C. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1424384284.

    MLA Style (8th edition)

  • Woodard, IV, John. "SYNTHESIS AND STRUCTURAL OPTIMIZATION OF THE NATURAL PRODUCTS SILVESTROL AND PHYLLANTHUSMIN C." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1424384284

    Chicago Manual of Style (17th edition)

osu1424384284
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© 2015, some rights reserved.Creative Commons License SYNTHESIS AND STRUCTURAL OPTIMIZATION OF THE NATURAL PRODUCTS SILVESTROL AND PHYLLANTHUSMIN C by John Lewis Woodard IV 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.