Total synthesis of furospongolide and related furanolipid analogues as potential anti-tumour agents

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dc.contributor.advisor Collins, Stuart en Harrold, Donal P. 2016-04-06T10:18:10Z 2013 2013
dc.identifier.citation Harrold, D.P. 2013. Total synthesis of furospongolide and related furanolipid analogues as potential anti-tumour agents. PhD Thesis, University College Cork. en
dc.identifier.endpage 450 en
dc.description.abstract This thesis details the design, development and execution of innovative methodology in the total synthesis of the terpene-derived marine natural product, furospongolide. It also outlines the synthetic routes used to prepare a novel range of furanolipids derivatives and subsequent evaluation of their potential as antitumour agents. The first chapter is a review of the literature describing efforts undertaken towards the synthesis of biologically active furanosesterterpenoid marine natural products. A brief discussion on the sources and biological activity exhibited by furan natural products is also provided. In addition, a concise account of the role of hypoxia in cancer, and the increasing interest in HIF-1 inhibition as a target for chemotherapeutics is examined. The second chapter discusses the concise synthesis of the marine HIF-1 inhibitor furospongolide, which was achieved in five linear steps from (E,E)-farnesyl acetate. The synthetic strategy features a selective oxidation reaction, a Schlosser sp3-sp3 cross-coupling, a Wittig cross-coupling and an elaborate one-pot selective reduction, lactonisation and isomerization reaction to install the butenolide ring. The structure-activity relationship of furospongolide was also investigated. This involved the design and synthesis of a library of structurally modified analogues sharing the same C1-C13 subunit. This was achieved by exploiting the brevity and high level of convergence of our synthetic route together with the readily amenable structure of our target molecule. Exploiting the Schlosser cross-coupling allowed for replacement of furan with other heterocycles in the preparation of various furanolipid and thiophenolipid derivatives. The employment of reductive amination and Wittig chemistry further added to our novel library of structural derivatives. The third chapter discusses the results obtained from the NCI from biological evaluation From a collection of 28 novel compounds evaluated against the NCI-60 cancer cell array, six drug candidates were successfully selected for further biological evaluation on the basis of antitumour activity. COMPARE analysis revealed a strong correlation between some of our design analogues and the blockbuster anticancer agent tamoxifen, further supporting the potential of furanolipids in the treatment of breast cancer. The fourth chapter, details the full experimental procedures, including spectroscopic and analytical data for all the compounds prepared during this research. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Donal P. Harrold. en
dc.rights.uri en
dc.subject Furospongolide en
dc.subject Hypoxia en
dc.subject Chemotherapeutic agent en
dc.subject Furanolipid en
dc.subject Sesterterpenoid en
dc.subject Total synthesis en
dc.subject Natural product synthesis en
dc.subject Hypoxia inducible factor-1 en
dc.subject Anti-tumour agent en
dc.title Total synthesis of furospongolide and related furanolipid analogues as potential anti-tumour agents en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text not available en Please note that Chapters 2-4 (pp.65-450) are currently unavailable due to a restriction requested by the author. en 2021-04-05T10:18:10Z
dc.description.version Accepted Version
dc.contributor.funder Irish Research Council for Science Engineering and Technology en
dc.description.status Not peer reviewed en Chemistry en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.chapterOfThesis Chapters of thesis - 2, 3 and 4
dc.check.embargoformat Both hard copy thesis and e-thesis en
dc.internal.conferring Spring 2015 en

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© 2013, Donal P. Harrold. Except where otherwise noted, this item's license is described as © 2013, Donal P. Harrold.
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