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

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.

Bottom-up modelling of energy demand and technical energy savings potential in the Irish residential sector

The International Energy Agency has repeatedly identified increased end-use energy efficiency as the quickest, least costly method of green house gas mitigation, most recently in the 2012 World Energy Outlook, and urges all governing bodies to increase efforts to promote energy efficiency policies and technologies. The residential sector is recognised as a major potential source of cost effective energy efficiency gains. Within the EU this relative importance can be seen from a review of the National Energy Efficiency Action Plans (NEEAP) submitted by member states, which in all cases place a large emphasis on the residential sector. This is particularly true for Ireland whose residential sector has historically had higher energy consumption and CO2 emissions than the EU average and whose first NEEAP targeted 44% of the energy savings to be achieved in 2020 from this sector. This thesis develops a bottom-up engineering archetype modelling approach to analyse the Irish residential sector and to estimate the technical energy savings potential of a number of policy measures. First, a model of space and water heating energy demand for new dwellings is built and used to estimate the technical energy savings potential due to the introduction of the 2008 and 2010 changes to part L of the building regulations governing energy efficiency in new dwellings. Next, the author makes use of a valuable new dataset of Building Energy Rating (BER) survey results to first characterise the highly heterogeneous stock of existing dwellings, and then to estimate the technical energy savings potential of an ambitious national retrofit programme targeting up to 1 million residential dwellings. This thesis also presents work carried out by the author as part of a collaboration to produce a bottom-up, multi-sector LEAP model for Ireland. Overall this work highlights the challenges faced in successfully implementing both sets of policy measures. It points to the wide potential range of final savings possible from particular policy measures and the resulting high degree of uncertainty as to whether particular targets will be met and identifies the key factors on which the success of these policies will depend. It makes recommendations on further modelling work and on the improvements necessary in the data available to researchers and policy makers alike in order to develop increasingly sophisticated residential energy demand models and better inform policy.