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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Combining synthesis and biosynthesis to generate novel antibiotics

Abou Fayad, Antoine January 2014 (has links)
This thesis focuses upon pacidamycin, a member of the uridyl peptide antibiotics, a family of antibiotics which exhibit an, as yet, clinically unexploited mode of action, against MraY. The Goss group has previously demonstrated the ease of accessing N and C-termini analogues of pacidamycin utilizing precursor directed biosynthesis. The central diamino acid is key to pacidamycin's activity, yet little work has been carried out, to date, to investigate the SAR around this moiety. Particularly this thesis describes work toward generating pacidamycin analogues using the complementary tools of organic synthesis and biosynthesis. Chapter 1 introduces natural compounds and their importance in clinical use, provides a brief overview of the history of antibiotics and focuses on the urgent need for new antibiotics displaying new chemical architectures and possessing novel modes of action. This chapter also introduces uridyl peptide antibiotics and overviews the SAR studies around these unusual peptides, focusing on pacidamycin in particular. Diaminobutyric acid is central to these structures and a discussion of a selection of published methods to synthesis α, β-diaminobutyric acid (DABA) is also presented. Chapter 2 describes the synthesis of DABA and two analogues, in which the C-methyl moiety has been substituted by an ethyl or a cyclopropyl group. The mutasynthesis approach utilised in the attempt to generate novel pacidamycins and discussion around the results observes is also described. Chapter 3 demonstrates a three step one-pot reaction to access 1,3-disubstituted urea molecules. The chapter starts with a brief overview of previously established methods in the literature to access these useful molecules, and then moves towards a discussion about the reaction optimisation. The chapter also describes a family of analogues generated utilising this novel approach; and exploring the use of these analogues in the mutasynthesis of pacidamycin. In order to access the desired pacidamycin analogues with the modified diamino acid residue, it was determined that it is currently not possible to use a mutasynthesis approach, instead an approach of total synthesis needed to be employed. Chapter 4 describes this total synthesis. The C- terminal urea motif was generated using a novel 1-pot phosphine free route developed during this study. To access the central native (2S, 3S)- DABA, a variation of the route of Merino et al's via Garner's aldehyde was initially utilised. Subsequently, a shorter and more flexible approach from Soloshonok et al via a Ni (II) Schiff base complex of glycine was adopted. Unpublished results from the Goss group have shown that the 2',3'dihydroxy uridine analogues in pacidamycin conferred broader spectra of activity. Work towards the synthesis of these analogues has been conducted. The order of assembly of the peptide and the nucleoside fragments was in alignment with Boojamra et al's approach. If the de-protection chemistry had worked according to plan, this would have resulted with a synthesis that is at least 6 steps shorter and higher yielding then Boojamra's. The introduction in this chapter reports the various methods previously reported in the literature for the total synthesis of pacidamycin. A discussion about the current progress in the total synthesis highlighting the difficulties faced is also shown. Chapter 5 demonstrates utilising semi-synthesis as a useful tool to generate novel pacidamycins by applying a Pictet-Spengler reaction on pacidamycin 4. This chapter starts with an overview of this phosphate mediated Pictet-Spengler reaction. In addition, a discussion about the large-scale fermentation of Streptomyces coeruleorubidus, the wild type producer of pacidamycin, and the generation of pacidamycin analogues utilising a semi-synthesis approach is also presented. Chapter 6 describes the future work following on from this study building upon each of the above chapters.
2

Analyse de la neurotoxine β-méthylamino-L-alanine (BMAA) et ses isomères dans les lacs et les réservoirs pollués par chromatographie liquide couplée à la spectrométrie de masse haute résolution.

Abbes, Safa 07 1900 (has links)
La neurotoxine β-N-méthyl-amino-l-alanine (BMAA) et ses isomères, notamment la N-(2- aminoéthyl glycine) (AEG), la β-amino-N-méthyl alanine (BAMA) et l'acide 2,4- diaminobutyrique (DAB), ont été détectés précédemment dans des échantillons de cyanobactéries. Cependant, il existe des rapports contradictoires concernant leur présence dans les eaux de surface. Dans cette étude, nous avons évalué l'impact de l'acide trichloracétique (TCA 0,1M) sur la détection des isomères de BMAA, par rapport aux protocoles préexistants. Une méthode instrumentale sensible a été utilisée pour l'étude, avec des limites de détection de l'ordre de 5-10 ng L-1. Des meilleures limites de détection plus élevés et des niveaux significativement plus importants (test des rangs signés de Wilcoxon appariés, p < 0,001) d'isomères de BMAA ont été observés dans les échantillons traités par le TCA, avec des augmentations relatives allant jusqu'à +725 % pour l'AEG et +1450 % pour le DAB, et des augmentations de concentration absolue allant jusqu'à +15 000 ng L-1 pour l'AEG et +650 ng L-1 pour le DAB. Nous avons également documenté les tendances de la présence des isomères de BMAA dans plusieurs lacs de différents pays tels que le Brésil, le Canada, la France, le Mexique et le Royaume-Uni. Les données obtenues au cours de cette étude (n = 390 provenant de 45 sites d'échantillonnage) indiquent des détections fréquentes des isomères AEG et DAB, avec des taux de détection de 30 % et 43 % et des niveaux maximums de 19 000 ng L-1 et 1 100 ng L-1, respectivement. En revanche, le BAMA a été trouvé dans moins de 8 % des échantillons d'eau, et la BMAA n'a été trouvée dans aucun échantillon. Ces résultats appuient les analyses des cyanobactéries libres, dans lesquelles la BMAA a souvent été détectée avec des concentrations inférieures de 2 à 4 ordres de grandeur à celles de l'AEG et du DAB. Les mesures saisonnières effectuées dans deux lacs impactés par des efflorescences ont indiqué des corrélations limitées entre les isomères de la BMAA et les microcystines totales ou la chlorophylle-a, ce qui mériterait une étude plus approfondie. / The neurotoxic alkaloid β-N-methyl-amino-l-alanine (BMAA) and related isomers, including N-(2-aminoethyl glycine) (AEG), β-amino-N-methyl alanine (BAMA) and 2,4-diaminobutyric acid (DAB), have been reported previously in cyanobacterial samples. However, there are conflicting reports regarding their occurrence in surface waters. In this study, we evaluated the impact of amending lake water samples with trichloroacetic acid (0.1M TCA) on the detection of BMAA isomers, compared with pre-existing protocols. A sensitive instrumental method was enlisted for the survey, with limits of detection in the range of 5-10 ng L-1. Higher detection limits ans significantly greater levels (paired Wilcoxon’s signed-rank tests, p < 0.001) of BMAA isomers were observed TCA-amended samples (method B) compared to samples without TCA (method A). The overall range of B/A ratios was 0.67-8.25 for AEG (up to +725 %) and 0.69-15.5 for DAB (up to +1450 %), with absolute concentration increases TCA-amended samples up to +15,000 ng L-1 for AEG and +650 ng L-1 for DAB. We also documented the trends in the occurrence of BMAA isomers for a large breadth of field-collected lakes from Brazil, Canada, France, Mexico, and the United Kingdom. Data gathered during this overarching campaign (overall n = 390 within 45 lake sampling sites) indicate frequent detections of AEG and DAB isomers, with detection rates of 30 % and 43 % and maximum levels of 19,000 ng L-1 and 1,100 ng L- 1, respectively. In contrast, BAMA was found in less than 8 % of the water samples, and BMAA not found in any sample. These results support analyses of free-living cyanobacteria, wherein BMAA was often reported at concentrations 2-4 orders of magnitude lower than AEG and DAB. Seasonal measurements conducted at two bloom-impacted lakes indicated limited correlations of BMAA isomers with total microcystins or chlorophyll-a, which deserves further investigation.

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