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McCarthy, Florence O. Pierce, Laurence Thomas Irish Research Council for Science Engineering and Technology 2011-08-17T09:09:31Z 2014-08-17T04:00:05Z 2011-04 2011-04-08 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. Irish Research Council for Science Engineering and Technology (Embark initiative) Not peer reviewed Accepted Version application/pdf Pierce, L.T. 2011. Design, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agents. PhD Thesis, University College Cork. https://hdl.handle.net/10468/382 en University College Cork http://library.ucc.ie/record=b2027884~S0 © 2011, Laurence T. Pierce http://creativecommons.org/licenses/by-nc-nd/3.0/ Indolocarbazole Indole Carbazole Cancer Kinase Indole--Synthesis Indole--Therapeutic use Cancer--Chemotherapy Design, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agents Doctoral thesis Doctoral Ph.D. (Pharmaceutical Chemistry)info:eu-repo/semantics/openAccess