Antitumour imidazotetrazines: probes for the major groove of DNA

The antitumour imidazotetrazinones are believed to act as prodrugs for the triazene series of alkylating agents, showing a marked pteference for the alkylation of the middle guanine residue in a run of three or more contiguous guanines. However, the. exact nature of the interactions of imidazotetrazinones within the micro~environment of DNA are; as yet unknown. In order to examine such interactions a three pronged approach involving molecular modelling, synthetic chemistry and biological analysis has been undertaken during the course of this project. . Molecular modelling studies have shown that for the 8-carboxamido substituted imidazotetrazinones antitumour activity is dependent upon the. presence of a free NH group which can be involved in the formation of both intramolecular and intermolecular hydrogen bonds, and the presence of a non-bulky substituent with a small negative potential . volume. Modelling studies involving the docking of .mitozolomide into the major groove of DNA in the region of a triguanine sequence has shown that a number of hydrogen bonding interactions are feasible. A series of 8-substituted carboxamide derivatives of mitozolomide have been synthesised via the 8-acid chloride and 8-carboxylic acid derivatives including a number of peptide analogues. The peptide derivatives were based upon the key structural features of the helix-turn-helix motif of DNA-binding proteins with a view to developing agents that are capable of binding to DNA with greater selectivity. An examination of the importance of intramolecular hydrogen bonding in influencing the antitumour activity:of :the imidazotetrazinones has led to the synthesis of the novel pyrimido[4',5' :4,3]pyrazolo[5,1-d]-1,2,3,5-tetrazine ring system. In general, in vitro cytotoxicity assays showed that the new derivatives were less active against the TLX5 lymphoma cell line. than the parent compound mitozolomide despite an increased potential for hydrogen bonding interactions. Due to the high reactivity of the: tetrazinone ring system it is difficult to study the interactions between the imidazotetrazinones and DNA. Consequently a number of structural analogues that are stable under physiological conditions have been. prepared based upon the 1,2,3 triazin-4(3H)-one ring system fused with both benzene and pyrazole rings. Although the 3-methylbenzotriazinones failed to antagonise the cytotoxic activity of temozolomide encouraging results with a 3-methylpyrazolotriazinone may suggest the existence of an imidazotetrazinone receptor site within DNA. The potential of guanine rich sequences to promote the alkylating selectivity of imidazotetrazinones by acting as a catalyst for ring cleavage and thereby generation of the alkylating agent was examined. Experiments involving the monitoring: of the rate of breakdown of mitozolomide incubated in the presence of synthetic oIigonucleotides did not reveal any catalytic effect resulting from the DNA. However, it was noted that the breakdown of mitozolomide was dependent upon the type of buffer used in the incubations and this may indeed mask any catalysis by the oligonucleotides.

Design, synthesis and evaluation of dipeptides as probes for studies of gastrointestinal tract dipeptide transport system

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Design, synthesis and evaluation of dipeptides as probes for studies of gastro-intestinal tract dipeptide transport

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

The United Kingdom between Mars and Venus:bridge or Bermuda triangle?

The concept of the United Kingdom acting as a bridge between Europe and the United States has been a key element in British foreign policy for six decades. Under the second Blair Premiership it reached both its apogee and its nadir. This paper analyses these developments focusing both on the transatlantic and European ends. Particular attention is paid to the failure of the Blair government either to establish a secure place for Britain as a co-leader or to make the British people more comfortable in their European skins. This failure occurred at a period when the EU is characterised by leadership transition and confusion. New leaderships will emerge in the EU over the next two years but it seems unlikely that Britain, characterised by a continuing disconnect between a Euro-sceptic public discourse and deep involvement at a governmental level will develop a European policy narrative that is regarded as convincing at either the EU or domestic level. This weakness is compounded by a failure to develop new thinking about the rise of new powers such as China and India.

Practitioners are from Mars; academics are from Venus? An investigation of the research-practice gap in management accounting

Purpose: The aim of this paper is to identify and gain insights into the significance of barriers contributing to the purported "gap" between academic management accounting research and practice. Design/methodology/approach: Drawing on diffusion of innovations theory, this study collects and analyses data from a questionnaire survey and follow-up interviews with 19 representatives of the four principal professional accounting bodies in Australia. Findings: Professional accounting bodies perceive the gap between academic research and practice in management accounting to be of limited concern to practitioners. The two most significant barriers to research utilisation by practitioners are identified as: difficulties in understanding academic research papers; and limited access to research findings. In acting as a conduit between the worlds of academia and practice, professional bodies have an important role to play by demonstrating the mutual value to both academics and practitioners resulting from a closer engagement between MA research and practice. Research limitations/implications: As one of the few empirically-based, theoretically informed investigations exploring the research-practice gap in management accounting, this study provides insights rather than "answers". Its findings therefore serve as a foundational basis for further empirical and theoretical enquiry. Originality/value: This study contributes to the conversation about the "research-practice gap" in management accounting by adopting a distinct theoretical vantage point to organize, analyse and interpret empirical evidence obtained from Australian professional accounting bodies about management accounting practice. © Emerald Group Publishing Limited.