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

Harrold, Donal P.

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

dc.check.opt-out	Not applicable	en
dc.check.reason	This thesis is due for publication or the author is actively seeking to publish this material	en
dc.contributor.advisor	Collins, Stuart	en
dc.contributor.author	Harrold, Donal P.
dc.contributor.funder	Irish Research Council for Science Engineering and Technology	en
dc.date.accessioned	2016-04-06T10:18:10Z
dc.date.issued	2013
dc.date.submitted	2013
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.description.status	Not peer reviewed	en
dc.description.version	Accepted Version
dc.format.mimetype	application/pdf	en
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.identifier.uri	https://hdl.handle.net/10468/2440
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.rights	© 2013, Donal P. Harrold.	en
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/	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.thesis.opt-out	false
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
ucc.workflow.supervisor	stuart.collins@ucc.ie