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dc.contributor.advisorPors, Klaus
dc.contributor.advisorPatterson, Laurence H.
dc.contributor.advisorSheldrake, Helen M.
dc.contributor.authorNeves dos Santos, Ana Rita*
dc.date.accessioned2014-05-06T12:31:25Z
dc.date.available2014-05-06T12:31:25Z
dc.date.issued2014-05-06
dc.identifier.urihttp://hdl.handle.net/10454/6311
dc.description.abstractThe generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA.en
dc.description.sponsorshipFundação Para a Ciência e a Tecnologia (FCT)en_US
dc.language.isoenen_US
dc.rights<a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>.eng
dc.subject[2+2+2] cyclotrimerisationen_US
dc.subjectAlkynesen_US
dc.subjectBiological probeen_US
dc.subjectDiversity-oriented synthesis; DOSen_US
dc.subjectTetrahydroisoquinolineen_US
dc.subjectTransition-metal chemistryen_US
dc.subjectOrganometallic chemistryen_US
dc.subjectMicrowave chemistryen_US
dc.subjectTetrahydronaphthyridineen_US
dc.subjectDihydropyrrolopyridineen_US
dc.titleExploration of [2+2+2] cyclotrimerisation reactions of alkynes. A new methodology for the synthesis of small molecules to probe biological systemsen_US
dc.type.qualificationleveldoctoralen_US
dc.publisher.institutionUniversity of Bradfordeng
dc.publisher.departmentInstitute of Cancer Therapeuticsen_US
dc.typeThesiseng
dc.type.qualificationnamePhDen_US
dc.date.awarded2013


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