Design, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agents
| dc.contributor.advisor | McCarthy, Florence O. | |
| dc.contributor.author | Pierce, Laurence Thomas | |
| dc.contributor.funder | Irish Research Council for Science Engineering and Technology | en |
| dc.date.accessioned | 2011-08-17T09:09:31Z | |
| dc.date.available | 2014-08-17T04:00:05Z | |
| dc.date.issued | 2011-04 | |
| dc.date.submitted | 2011-04-08 | |
| dc.description.abstract | This 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.sponsorship | Irish Research Council for Science Engineering and Technology (Embark initiative) | en |
| dc.description.status | Not peer reviewed | en |
| dc.description.version | Accepted Version | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.citation | Pierce, L.T. 2011. Design, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agents. PhD Thesis, University College Cork. | en |
| dc.identifier.uri | https://hdl.handle.net/10468/382 | |
| dc.language.iso | en | en |
| dc.publisher | University College Cork | en |
| dc.relation.uri | http://library.ucc.ie/record=b2027884~S0 | |
| dc.rights | © 2011, Laurence T. Pierce | en |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | en |
| dc.subject | Indolocarbazole | en |
| dc.subject | Indole | en |
| dc.subject | Carbazole | en |
| dc.subject | Cancer | en |
| dc.subject | Kinase | en |
| dc.subject.lcsh | Indole--Synthesis | en |
| dc.subject.lcsh | Indole--Therapeutic use | en |
| dc.subject.lcsh | Cancer--Chemotherapy | en |
| dc.title | Design, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agents | en |
| dc.type | Doctoral thesis | en |
| dc.type.qualificationlevel | Doctoral | en |
| dc.type.qualificationname | Ph.D. (Pharmaceutical Chemistry) | en |
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