Design, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agents

dc.contributor.advisorMcCarthy, Florence O.
dc.contributor.authorPierce, Laurence Thomas
dc.contributor.funderIrish Research Council for Science Engineering and Technologyen
dc.date.accessioned2011-08-17T09:09:31Z
dc.date.available2014-08-17T04:00:05Z
dc.date.issued2011-04
dc.date.submitted2011-04-08
dc.description.abstractThis thesis describes work carried out on the design of new routes to a range of bisindolylmaleimide and indolo[2,3-a]carbazole analogs, and investigation of their potential as successful anti-cancer agents. Following initial investigation of classical routes to indolo[2,3-a]pyrrolo[3,4-c]carbazole aglycons, a new strategy employing base-mediated condensation of thiourea and guanidine with a bisindolyl β-ketoester intermediate afforded novel 5,6-bisindolylpyrimidin-4(3H)-ones in moderate yields. Chemical diversity within this H-bonding scaffold was then studied by substitution with a panel of biologically relevant electrophiles, and by reductive desulfurisation. Optimisation of difficult heterogeneous literature conditions for oxidative desulfurisation of thiouracils was also accomplished, enabling a mild route to a novel 5,6-bisindolyluracil pharmacophore to be developed within this work. The oxidative cyclisation of selected acyclic bisindolyl systems to form a new planar class of indolo[2,3-a]pyrimido[5,4-c]carbazoles was also investigated. Successful conditions for this transformation, as well as the limitations currently prevailing for this approach are discussed. Synthesis of 3,4-bisindolyl-5-aminopyrazole as a potential isostere of bisindolylmaleimide agents was encountered, along with a comprehensive derivatisation study, in order to probe the chemical space for potential protein backbone H-bonding interactions. Synthesis of a related 3,4-arylindolyl-5-aminopyrazole series was also undertaken, based on identification of potent kinase inhibition within a closely related heterocyclic template. Following synthesis of approximately 50 novel compounds with a diversity of H-bonding enzyme-interacting potential within these classes, biological studies confirmed that significant topo II inhibition was present for 9 lead compounds, in previously unseen pyrazolo[1,5-a]pyrimidine, indolo[2,3-c]carbazole and branched S,N-disubstituted thiouracil derivative series. NCI-60 cancer cell line growth inhibition data for 6 representative compounds also revealed interesting selectivity differences between each compound class, while a new pyrimido[5,4-c]carbazole agent strongly inhibited cancer cell division at 10 µM, with appreciable cytotoxic activity observed across several tumour types.en
dc.description.sponsorshipIrish Research Council for Science Engineering and Technology (Embark initiative)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationPierce, L.T. 2011. Design, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agents. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/382
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.urihttp://library.ucc.ie/record=b2027884~S0
dc.rights© 2011, Laurence T. Pierceen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectIndolocarbazoleen
dc.subjectIndoleen
dc.subjectCarbazoleen
dc.subjectCanceren
dc.subjectKinaseen
dc.subject.lcshIndole--Synthesisen
dc.subject.lcshIndole--Therapeutic useen
dc.subject.lcshCancer--Chemotherapyen
dc.titleDesign, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agentsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePh.D. (Pharmaceutical Chemistry)en
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