Short, Amy L.
(2014)
Structure-Activity Relationships Analysis of (+)-Discodermolide and the Synthesis of Precursors for Further Analogue Studies.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
In 1990, the natural product discodermolide was isolated from a marine sponge and later found to have exceptional antiproliferative activity in cancer cells. Further studies showed discodermolide to stabilize microtubules via the taxoid binding site on beta-tubulin. Unlike paclitaxel, it is not a substrate for P-glycoprotein transport, is potent in paclitaxel-resistant cell lines with beta-tubulin mutations, exhibits better water solubility, and can act synergistically when combined with paclitaxel treatment. For this reason, discodermolide has been the focus of many synthetic and biological studies, culminating in a 60 gram-scale synthesis and Phase I/II clinical trials carried out by Novartis in 2004. Despite the great level of interest from the scientific community, much about this compound’s behavior in vivo is still unknown. An extended analysis of known structure-activity relationships for discodermolide is presented herein. Also reported are the syntheses of a series of discodermolide fragments, which are designed to enable the formation of a novel analogue library via late-stage multicomponent reactions. Fragments to be synthesized prior to coupling are streamlined alternatives to the discodermolide framework that have shown promise in prior analogue and HQSAR studies. Overall, these modifications have been designed to improve the efficiency of synthetic efforts and to represent a wholly unique series of analogues for biological study.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
22 May 2014 |
| Date Type: |
Publication |
| Defense Date: |
16 April 2014 |
| Approval Date: |
22 May 2014 |
| Submission Date: |
5 May 2014 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
183 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
discodermolide; microtubule; microtubule stabilization; structure-activity relationships; chemotherapeutics; natural product synthesis; analogue studies; multicomponent reaction; Ugi reaction; van Leusen reaction; multicomponent reaction; cytotoxicity |
| Date Deposited: |
22 May 2014 20:21 |
| Last Modified: |
15 Nov 2016 14:20 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/21559 |
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