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.

Design, synthesis and evaluation of novel ellipticine derivatives and analogues as anti-cancer agents

This thesis describes work carried out on the synthesis of novel 5- and 11-substituted ellipticines and derivatives of the ellipticine analogues, isoellipticine and deazaellipticine, followed by investigation of their potential as anti-cancer agents. Preparation of the key 5- and 11-substituted ellipticine targets involved the development of regiospecific, sequential alkylation reactions with alkenyllithium and Grignard reagents. Investigation of these novel reactions resulted in a new route towards 5-substituted ellipticines via Grignard reaction with vinylmagnesium bromide. These novel 5-vinylellipticine derivatives were further functionalised in an ozonolysis reaction, followed by oxidation to give a range of novel 5-substituted ellipticines. Less success was encountered in the 11-substituted ellipticine series, however preparation of these derivatives using a previously published route was accomplished, and the resulting 11-formylellipticine was further derivatised to give a panel of novel 9- and 11-substituted ellipticines, incorporating amide, carboxylate, imine and amine functionality. The successful route towards 5-substituted ellipticines was applied to the preparation of a range of novel 11-substituted isoellipticines and 6-substituted deazaellipticines, the first time substantial synthesis has been undertaken with these analogues. In addition to this, the first preparation of isoellipticinium salts is described, and a panel of novel isoellipticinium, 7 formylisoellipticinium and 7-hydroxyisoellipticinium salts were synthesised in good yields. Biological evaluation of a panel of 43 novel ellipticine, isoellipticine and deazaellipticine derivatives was accomplished with a topoisomerase II decatenation assay and submission to the NCI 60-cell line screen. Four novel isoellipticine topoisomerase II inhibitors were identified from the decatenation assay, with strong activity at 10 μM. In addition to this, NCI screening identified five highly cytotoxic ellipticine and isoellipticine compounds with remarkable selectivity profiles for different cancer types. These novel lead compounds represent new templates for further research and synthesis.

A new world a new American foreign policy: the Carter administration, Nicaragua, and the legacy of the Vietnam War, 1977-1981

The impact of the Vietnam War conditioned the Carter administration’s response to the Nicaraguan revolution in ways that reduced US engagement with both sides of the conflict. It made the countries of Latin America counter the US approach and find their own solution to the crisis, and allowed Cuba to play a greater role in guiding the overthrow of Nicaraguan dictator Anastasio Somoza Debayle. This thesis re-evaluates Carter’s policy through the legacy of the Vietnam War, because US executive anxieties about military intervention, Congress’s increasing influence, and US public concerns about the nation’s global responsibilities, shaped the Carter approach to Nicaragua. Following a background chapter, the Carter administration’s policy towards Nicaragua is evaluated, before and after the fall of Somoza in July 1979. The extent of the Vietnam influence on US-Nicaraguan relations is developed by researching government documents on the formation of US policy, including material from the Jimmy Carter Library, the Library of Congress, the National Security Archive, the National Archives and Records Administration, and other government and media sources from the United Nations Archives, New York University, the New York Public Library, the Hoover Institution Archives, Tulane University and the Organization of American States. The thesis establishes that the Vietnam legacy played a key role in the Carter administration’s approach to Nicaragua. Before the overthrow of Somoza, the Carter administration limited their influence in Nicaragua because they felt there was no immediate threat from communism. The US feared that an active role in Nicaragua, without an established threat from Cuba or the Soviet Union, could jeopardise congressional support for other foreign policy goals deemed more important. The Carter administration, as a result, pursued a policy of non-intervention towards the Central American country. After the fall of Somoza, and the establishment of a new government with a left wing element represented by the Sandinistas, the Carter administration emphasised non-intervention in a military sense, but actively engaged with the new Nicaraguan leadership to contain the potential communist influence that could spread across Central America in the wake of the Nicaraguan revolution.

A study of diet and health in the elderly; the gut microbiota as a source of bioactive agents

The global proportion of older persons is increasing rapidly. Diet and the intestinal microbiota independently and jointly contribute to health in the elderly. The habitual dietary patterns and functional microbiota components of elderly subjects were investigated in order to identify specific effector mechanisms. A study of the dietary intake of Irish community-dwelling elderly subjects showed that the consumption of foods high in fat and/or sugar was excessive, while consumption of dairy foods was inadequate. Elderly females typically had a more nutrient- dense diet than males and a considerable proportion of subjects, particularly males, had inadequate intakes of calcium, magnesium, vitamin D, folate, zinc and vitamin C. The association between dietary patterns, glycaemic index and cognitive function was also investigated. Elderly subjects consuming ‘prudent’ dietary patterns had better cognitive function compared to those consuming ‘Western’ dietary patterns. Furthermore, fully-adjusted regression models revealed that a high glycaemic diet was associated with poor cognitive function, demonstrating a new link between nutrition and cognition. An extensive screening study of the elderly faecal-derived microbiota was also undertaken to examine the prevalence of antimicrobial production by intestinal bacteria. A number of previously characterised bacteriocins were isolated (gassericin T, ABP-118, mutacin II, enterocin L-50 and enterocin P) in this study. Interestingly, a Lactobacillus crispatus strain was found to produce a potentially novel antimicrobial compound. Full genome sequencing of this strain revealed the presence of three loci which exhibited varying degrees of homology with the genes responsible for helveticin J production in Lb. helveticus. An additional study comparing the immunomodulatory capacity of ‘viable’ and ‘non-viable’ Bifidobacterium strains found that Bifidobacterium-fermented milks (BFMs) containing ‘non-viable’ cells could stimulate levels of IL-10 and TNF-α in a manner similar to those stimulated by BFMs containing ‘viable’ cells in vitro.

Literatur verstehen und inszenieren: Foreign language literature through drama, a research project

Based on the experience that today's students find it more difficult than students of previous decades to relate to literature and appreciate its high cultural value, this paper argues that too little is known about the actual teaching and learning processes which take place in literature courses and that, in order to ensure the survival of literary studies in German curricula, future research needs to elucidate for students, the wider public and, most importantly, educational policy makers, why the study of literature should continue to have an important place in modern language curricula. Contending that students' willingness to engage with literature will, in the future, depend to a great extent on the use of imaginative methodology on the part of the teacher, we give a detailed account of an action research project carried out at University College Cork from October to December 2002 which set out to explore the potential of a drama in education approach to the teaching and learning of foreign language literature. We give concrete examples of how this approach works in practice, situate our approach within the subject debate surrounding Drama and the Language Arts and evaluate in detail the learning processes which are typical of performance-based literature learning. Based on converging evidence from different data sources and overall very positive feedback from students, we conclude by recommending that modern language departments introduce courses which offer a hands-on experience of literature that is different from that encountered in lectures and teacher-directed seminars.

Synthesis and evaluation of novel quinolines and quinazolinediones as potential anti-cancer agents

This thesis outlines the design and effectuation of novel chemical routes towards a nascent class of functionalised quinoline-5,8-diones and the expansion of a series of contemporary quinazolinediones towards an innovative family of pyridinoquinazolinetetrone derivatives. This fragment based approach is envisaged to lead to advancements in the three scaffolds, expanding the SAR pool of both quinolines and quinazolinediones with subsequent evaluation of chemotherapeutic potential as well as furnishing a new class of tricycle for biological investigation. Development of novel quinoline-5,8-diones is provided for by expanding on existing methodology. Using a variety of nucleophiles on a critical intermediate, a broad range of novel compounds was afforded allowing chemotherapeutic potential to be assessed, while also serving as intermediates for accomplishing novel pyridinoquinazolinetetrone congeners. In order to incorporate functionality into our quinazolinedione template, an efficient synthetic strategy was constructed which provided a robust route to effectuate a highly derivatised pyrimidinedione ring. As derivatisation of this template is unreported our chief priority was to synthesise a range of diverse quinazolinediones. The application of annulation methodology using functionalised precursors provided a library of N-3 derivatised quinazolinedione analogues. These, along with their N-1 functionalised derivatives provide a wide scope from which to construct a series of pyridinoquinazolinetetrone derivatives while also serving as a unique class of molecules whose biological potential is uncharted. Although the actualisation of the pyridinoquinazolinetetrone was ultimately unsuccessful, our work has led to the development of novel quinoline-5,8-diones which were found to possess excellent anti-cancer activity when assessed by the NCI screen. Of the quinazolinediones synthesised eight compounds were accepted for screening by the NCI. Results from the single-dose tests however indicated that these compounds possessed little cytotoxic activity at 10 μM. The development of this novel template in conjunction with the highly active quinolinediones serves as an excellent rostrum for future synthetic endeavours.

Ford, Carter and Cambodia: US foreign policy and the Khmer Rouge

This thesis is an investigation into the US response to the Khmer Rouge regime in Cambodia between 1974 and 1981. It argues that the US experience in the Vietnam War acted as a causal factor in the formulation of its Cambodian policy during the presidencies of Gerald Ford and Jimmy Carter. From taking power in April 1975 to their removal by the Vietnamese in January 1979, the Khmer Rouge initiated a revolution unrivalled in the 20th Century for its brutality and for the total eradication of modern society. This thesis demonstrates that the Ford administration viewed Cambodia only as it pertained to their strategy in Vietnam and, following US disengagement from Indochina all but ignored the atrocities occurring there as they instead pursued informal relations with the Khmer Rouge as a means of punishing the Vietnamese. The Carter administration formulated a foreign policy based on human rights yet failed to adequately address the genocide that occurred in Cambodia due to its temporal and regional proximity to Vietnam. Instead, this collective reluctance to reengage with the region and the resulting anti-Vietnamese attitude reinforced Brzezinski’s broader global strategy that allied the US with China in support of an independent Cambodia to further isolate Hanoi. Thus this thesis argues that the distorting impact of the Vietnam War, as well as global Cold War calculations, undermined any appreciation of the Cambodian conflict and caused both administrations to pursue policies in Cambodia that ultimately supported the Khmer Rouge regime. This project incorporates declassified material from the Ford and Carter Presidential Libraries, supplemented by the material from the National Archives and Library of Congress, and relevant newspapers and periodicals. It demonstrates that the limitations placed upon US foreign policy by their experience in the Vietnam War may be used to reveal unexplored elements in US-Cambodian relations.