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Structure-Activity Relationships Analysis of (+)-Discodermolide and the Synthesis of Precursors for Further Analogue Studies

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 (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Short, Amy L.alg112@pitt.eduALG112
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCurran, Dennis P.curran@pitt.eduCURRAN
Committee MemberBrummond, Kay M.kbrummon@pitt.eduKBRUMMON
Committee MemberHorne, W. Sethhorne@pitt.eduHORNE
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


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