Synthetic studies towards the cytotoxic marine natural product diazonamide A

The thesis describes synthetic studies towards the marine natural product diazonamide A. This unprecedented compound was recently isolated from a colonial ascidian and displays exceptional levels of cytotoxic activity against human cancer cell lines. The Introduction includes an account of how diazonamide A was isolated and its structure determined. This is followed by a summary of the different natural products which have been isolated from ascidians, and highlights the structural similarities between these compounds and diazonamide A. The Introduction concludes with a review of structurally related natural products which concentrates on compounds containing oxazole rings or biaryl bonds. The Results and Discussion section of the thesis details our general strategy for a synthesis of the macrocyclic aromatic core of diazonamide A. A synthesis of the two key fragments in this strategy, namely the benzofuran oxazole unit and the iodoindole unit, is then described. This is followed by the elaboration of these units towards the target macrocycle. A detailed discussion is presented throughout this section including a review of the Heck and Ullmann reactions, and methods of oxazole formation. This section culminates by describing our initial synthetic efforts on an alternative approach to the macrocyclic core of diazonamide A. The third chapter of the thesis is the Experimental section containing full details of the preparative work completed and listing spectroscopic and analytical data for all new compounds synthesised during the study. The thesis is concluded by a schematic account of the contemporaneous work towards a total synthesis of diazonamide A that has been conducted by four other research groups

Synthetic studies towards the cytotoxic marine natural product diazonamide A

The thesis describes synthetic studies towards the marine natural product diazonamide A. This unprecedented compound was recently isolated from a colonial ascidian and displays exceptional levels of cytotoxic activity against human cancer cell lines. The Introduction includes an account of how diazonamide A was isolated and its structure determined. This is followed by a summary of the different natural products which have been isolated from ascidians, and highlights the structural similarities between these compounds and diazonamide A. The Introduction concludes with a review of structurally related natural products which concentrates on compounds containing oxazole rings or biaryl bonds. The Results and Discussion section of the thesis details our general strategy for a synthesis of the macrocyclic aromatic core of diazonamide A. A synthesis of the two key fragments in this strategy, namely the benzofuran oxazole unit and the iodoindole unit, is then described. This is followed by the elaboration of these units towards the target macrocycle. A detailed discussion is presented throughout this section including a review of the Heck and Ullmann reactions, and methods of oxazole formation. This section culminates by describing our initial synthetic efforts on an alternative approach to the macrocyclic core of diazonamide A. The third chapter of the thesis is the Experimental section containing full details of the preparative work completed and listing spectroscopic and analytical data for all new compounds synthesised during the study. The thesis is concluded by a schematic account of the contemporaneous work towards a total synthesis of diazonamide A that has been conducted by four other research groups

Prenatal factors contribute to the emergence of kwoshiorkor or marasmus in severe undernutrition: evidence for the predictive adaptation model

Severe acute malnutrition in childhood manifests as oedematous (kwashiorkor, marasmic kwashiorkor) and non-oedematous (marasmus) syndromes with very different prognoses. Kwashiorkor differs from marasmus in the patterns of protein, amino acid and lipid metabolism when patients are acutely ill as well as after rehabilitation to ideal weight for height. Metabolic patterns among marasmic patients define them as metabolically thrifty, while kwashiorkor patients function as metabolically profligate. Such differences might underlie syndromic presentation and prognosis. However, no fundamental explanation exists for these differences in metabolism, nor clinical pictures, given similar exposures to undernutrition. We hypothesized that different developmental trajectories underlie these clinical-metabolic phenotypes: if so this would be strong evidence in support of predictive adaptation model of developmental plasticity

Equivalence of arterial and venous blood for [11C]CO2-metabolite analysis following intravenous administration of 1-[11C]acetate and 1-[11C]palmitate

PURPOSE: Sampling of arterial blood for metabolite correction is often required to define a true radiotracer input function in quantitative modeling of PET data. However, arterial puncture for blood sampling is often undesirable. To establish whether venous blood could substitute for arterial blood in metabolite analysis for quantitative PET studies with 1-[(11)C]acetate and 1-[(11)C]palmitate, we compared the results of [(11)C]CO2-metabolite analyses performed on simultaneously collected arterial and venous blood samples. METHODS: Paired arterial and venous blood samples were drawn from anesthetized pigs at 1, 3, 6, 8, 10, 15, 20, 25 and 30min after i.v. administration of 1-[(11)C]acetate and 1-[(11)C]palmitate. Blood radioactivity present as [(11)C]CO2 was determined employing a validated 10-min gas-purge method. Briefly, total blood (11)C radioactivity was counted in base-treated [(11)C]-blood samples, and non-[(11)C]CO2 radioactivity was counted after the [(11)C]-blood was acidified using 6N HCl and bubbled with air for 10min to quantitatively remove [(11)C]CO2. RESULTS: An excellent correlation was found between concurrent arterial and venous [(11)C]CO2 levels. For the [(11)C]acetate study, the regression equation derived to estimate the venous [(11)C]CO2 from the arterial values was: y=0.994x+0.004 (r(2)=0.97), and for the [(11)C]palmitate: y=0.964x-0.001 (r(2)=0.9). Over the 1-30min period, the fraction of total blood (11)C present as [(11)C]CO2 rose from 4% to 64% for acetate, and 0% to 24% for palmitate. The rate of [(11)C]CO2 appearance in venous blood appears similar for the pig model and humans following i.v. [(11)C]-acetate administration. CONCLUSION: Venous blood [(11)C]CO2 values appear suitable as substitutes for arterial blood samples in [(11)C]CO2 metabolite analysis after administration of [(11)C]acetate or [(11)C]palmitate ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Quantitative PET studies employing 1-[(11)C]acetate and 1-[(11)C]palmitate can employ venous blood samples for metabolite correction of an image-derived tracer arterial input function, thereby avoiding the risks of direct arterial blood sampling

Flourishing Youth Provision: The Potential Role of Positive Psychology and Coaching in Enhancing Youth Services

This article discusses how positive psychology and evidence-based coaching can support youth service provision in order to promote cross fertilisation between these different domains of practice. The transition from adolescence to adulthood is difficult for many young people and there is growing recognition that there should be a greater emphasis on the provision of youth services to help young people to achieve physical, emotional and psychological well-being at this key development stage. A literature review was conducted to identify key themes emerging in recent youth work strategies in the United Kingdom and Australia and from the positive psychology and evidence-based coaching research literature. Clear links can be made between the aims and objectives of youth work strategy and positive psychology and evidence-based coaching, and these have potential for use within youth services as a means of enhancing the well-being, resilience and hope of both young people and those who work to support them