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    Synthetic Methodology and Application of Enamine [2+2] Cyclisations for Cyclobutane Synthesis. Development of Integrin Antagonists as Anticancer Therapeutics Towards a Total Synthesis of Providencin

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    PhD Thesis (8.554Mb)
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    Publication date
    2015
    Author
    Throup, Adam Eric
    Supervisor
    Sheldrake, Helen M.
    Patterson, Laurence H.
    Keyword
    Cyclobutane; Cyclobutene; Cyclisation; Integrin; Providencin; Cancer; β3; Metastasis; Anticancer therapeutics
    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    Institute of Cancer Therapeutics
    Awarded
    2015
    
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    Abstract
    Cyclobutanes represent an underutilised structural feature in medicinal chemistry, partially due to difficulties in forming them in an easy and controlled manner. Herein is described their application to a drug discovery project and development of the enamine [2+2] cyclisation; a straightforward synthesis of functionalised cyclobutanes. A library of 30 cyclobutane based integrin antagonists have been designed and synthesised to explore the SAR around the hit dual β3 integrin antagonist ICT9055. Several of which were shown to be highly potent antagonists inhibiting cancer cell adhesion, migration and invasion while remaining non-toxic. ICT9072 had comparable β3 activity to hit compound ICT9055 but also had activity against αvβ5 and therefore showed greater inhibition of migration of DLD-1 cells. This showed the ability to modify this scaffold for multi integrin antagonism and potential benefit of this. Synthetic studies towards the marine natural product providencin has led to the development of a previously unknown intramolecular enamine [2+2] cyclisation which has been shown to proceed in a diastereoselective manner. This reaction has been applied to the synthesis of a highly functionalised enatiopure cyclobutene suitable for inclusion into the total synthesis. A model furyl cyclobutane has also been synthesised to exemplify the route from the enantiopure cyclobutene through to the furyl cyclobutane fragment of providencin.
    URI
    http://hdl.handle.net/10454/14411
    Type
    Thesis
    Qualification name
    PhD
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    Theses

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