Design, synthesis and evaluation of novel ellipticine derivatives and analogues as anti-cancer agents

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dc.check.infoThis thesis has been partially restricted until 23 February 2016. Chapter 2 (pp.43 - 98), Chapters 4 - 7 and Appendices (pp. 107 - 350)are currently unavailable.en
dc.contributor.advisorMcCarthy, Florence O.
dc.contributor.authorMiller, Charlotte M.
dc.contributor.funderHigher Education Authorityen
dc.date.accessioned2012-02-23T16:51:21Z
dc.date.available2016-02-24T05:00:08Z
dc.date.issued2011-12
dc.date.submitted2012-02-20
dc.description.abstractThis thesis describes work carried out on the synthesis of novel 5- and 11-substituted ellipticines and derivatives of the ellipticine analogues, isoellipticine and deazaellipticine, followed by investigation of their potential as anti-cancer agents. Preparation of the key 5- and 11-substituted ellipticine targets involved the development of regiospecific, sequential alkylation reactions with alkenyllithium and Grignard reagents. Investigation of these novel reactions resulted in a new route towards 5-substituted ellipticines via Grignard reaction with vinylmagnesium bromide. These novel 5-vinylellipticine derivatives were further functionalised in an ozonolysis reaction, followed by oxidation to give a range of novel 5-substituted ellipticines. Less success was encountered in the 11-substituted ellipticine series, however preparation of these derivatives using a previously published route was accomplished, and the resulting 11-formylellipticine was further derivatised to give a panel of novel 9- and 11-substituted ellipticines, incorporating amide, carboxylate, imine and amine functionality. The successful route towards 5-substituted ellipticines was applied to the preparation of a range of novel 11-substituted isoellipticines and 6-substituted deazaellipticines, the first time substantial synthesis has been undertaken with these analogues. In addition to this, the first preparation of isoellipticinium salts is described, and a panel of novel isoellipticinium, 7 formylisoellipticinium and 7-hydroxyisoellipticinium salts were synthesised in good yields. Biological evaluation of a panel of 43 novel ellipticine, isoellipticine and deazaellipticine derivatives was accomplished with a topoisomerase II decatenation assay and submission to the NCI 60-cell line screen. Four novel isoellipticine topoisomerase II inhibitors were identified from the decatenation assay, with strong activity at 10 μM. In addition to this, NCI screening identified five highly cytotoxic ellipticine and isoellipticine compounds with remarkable selectivity profiles for different cancer types. These novel lead compounds represent new templates for further research and synthesis.en
dc.description.sponsorshipHigher Education Authority (PRTLI cycle 4, Biopharmaceutical & Pharmacological Sciences Program)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMiller, C. M., 2011. Design, Synthesis and Evaluation of Novel Ellipticine Derivatives and Analogues as Anti-Cancer Agents. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/534
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2011, Charlotte Milleren
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectEllipticineen
dc.subjectAnti-canceren
dc.subjectTopoisomerase inhibitoren
dc.subjectOrganic synthesisen
dc.subject.lcshAntineoplastic agents--Developmenten
dc.subject.lcshEnzyme inhibitorsen
dc.subject.lcshDrugs--Designen
dc.subject.lcshCancer--Chemotherapyen
dc.subject.lcshOrganic compounds--Synthesisen
dc.titleDesign, synthesis and evaluation of novel ellipticine derivatives and analogues as anti-cancer agentsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Chemistry)en
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