This thesis presents results for the extraction, purification and chemical characterisation and quantification of cyclic peptides. The thesis is divided into six chapters including a general introduction, the materials and methods used, in addition to three chapters with detailed experimental results and a chapter on enzyme chemistry. The first part presents data of a chemically synthesized analogue of a natural product myriastramide C which contains its full structural elucidation and comparison of data obtained to that of the natural product reported in literature. The second part discusses enzyme chemistry, chemical characterisation results of natural, new modified heterocyclic peptides produced in vitro and through chemo enzymatic reactions using genetically modified enzymes. Results presented include mass spectroscopic data and NMR structural characterisation for these peptides. The third section presents data for the quantification of heterocyclic peptides using high pressure liquid chromatography coupled in parallel to electrospray mass spectrometer and inductively coupled plasma (HPLC-ICP-MS), their quantification was achieved using their sulfur content without authentic standards. Naturally occurring cyclic peptide were also quantified using proton nuclei magnetic resonance (qNMR) with a non peptidic ERETIC reference material. In conclusion, this work highlights the possibility of multi-disciplinary science in the production of synthetic and semi-synthetic compounds through the use of enzymes. It is possible to produce new analogs of natural products, hence, providing an avenue for increasing the library of new compounds. Accurate quantification of these compounds is also essential for the acquisition of proper pharmacokinetic data for these new compounds so that unambiguous biological data can be obtained.

Cyclic peptides constitute an attractive class of compounds for drug development, however the numerous problems associated with their synthesis have limited their applicability. The cyclisation step itself is particularly problematic, with solution phase cyclisations being required to be conducted under very high dilution to promote cyclisation over unwanted side reactions such as oligomerisation. In addition, epimerisation, leading to the loss of chiral integrity at the terminal residues is a major concern. Attention is now turning to biochemical cyclisation strategies, such as SICLOPPS and sortase mediated ligation, although these also come with their own inherent disadvantages, for example, in the case of sortase mediated ligation, there is significant “scarring” of the target due to the presence of a four amino acid long recognition sequence. Cyclisation using ribosomally synthesised post translationally modified enzymes is also gaining popularity. One such family of enzymes is the patellamides. PatGmac is capable of performing cyclisations on linear peptide substrates with minimal scarring compared to the aforementioned alternatives and, importantly, with no epimerisation and could constitute a greener and more facile route to cyclic peptides. The work herein details some of the investigations designed to define the range of synthetic utility and test the flexibility of the enzymes. This was done qualitatively, by designing a variety of linear peptide analogues of the natural product, homophymine A, featuring unique structural moieties and evaluating their compatibility with the enzyme. It was also done quantitatively, using an LCMS based semi-quantitative strategy, to assess differences between similar, but different, enzymes and to assess whether there were differences in how different substrates are processed by the same enzyme. In addition to this, a variety of these substrates were also assessed for their proclivity to cyclise under standard chemical conditions for comparison. Lastly, with the increasing appearance cyclic peptides and non-peptidic macrocycles in the libraries of compounds being considered for clinical trials, there is now a growing need for computational modelling of these structures. Herein, a 3D v structure for the natural product callipetin N is proposed for the first time, determined using a combination of computational and NMR techniques.

Ce travail de thèse a eu pour thème central la birnessite, un oxyde de manganèse ubiquiste dans le milieu naturel et jouant un rôle fondamental dans la géochimie des sols. La première partie de cette thèse a été consacrée à l’électrodépôt et à la caractérisation de la birnessite par des méthodes électrochimiques couplées à la diffraction des rayons X. La caractérisation DRX in-situ au cours de l’électrodépôt a permis de mettre en évidence, lorsqu’on est en présence du cation électrolytique Na+, la formation d’un précurseur, la busérite, alors qu’en présence du cation électrolytique K+, la synthèse aboutit directement à la birnessite sans formation d’intermédiaire. La réduction électrochimique de la birnessite a également été étudiée en fonction du milieu ([Mn(II)], pH, potentiel). Cette dernière se réduit en hausmannite(Mn3O4), feitknechtite (-MnOOH), ou en composé amorphe de Mn(II), selon les conditions expérimentales. Dans la deuxième partie de cette thèse, les films minces ont été utilisés pour étudier la réactivité de la birnessite vis-à-vis du glyphosate, ainsi que celle de son principal métabolite l’AMPA (acide amino-méthyl-phosphonique). Le glyphosate est dégradé avec formation simultanée d’AMPA, de formaldéhyde, d’ions phosphate, nitrate et ammonium sans modification macroscopique de la birnessite. Les quatre derniers sous-produits sont également obtenus lors de la dégradation de l’AMPA par la birnessite. Les bons rendements de dégradation obtenus au cours des interactions glyphosate/birnessite et AMPA/birnessite laissent envisager une possible application de ces échantillons pour le traitement des eaux usées. / This thesis has been focused on birnessite, a ubiquitous manganese oxide in the environment, which plays a fundamental role in soil geochemistry. The first part of this thesis has been devoted to the electrodeposition and the characterizations of birnessite by electrochemical methods coupled with X-ray diffraction. The in-situ XRD characterization during electrodeposition has shown, in presence of the electrolytic cation Na+, the formation of a precursor, buserite, whereas no precursor is formed in presence of electrolytic cation K+, the synthesis leading directly to birnessite. The electrochemical reduction of birnessite has also been studied in function of the medium ([Mn (II)], pH, potential). Birnessite is reduced into hausmannite (Mn3O4), feitknechtite (-MnOOH), or an amorphous compound of Mn (II), as function of experimental conditions. In the second part of this thesis, the thin films have been used to study the reactivity of birnessite for degrading glyphosate and its metabolite AMPA (amino-methyl phosphonic). Glyphosate is degraded with simultaneous formation of AMPA, formaldehyde, phosphate ion, nitrate ion and ammonium ion, without macroscopic modification of birnessite. The last four by-products are also obtained during the degradation of AMPA by birnessite. The good yields obtained during glyphosate / birnessite and AMPA / birnessite interactions permit to envisage a possible application of these thin films for the treatment of wastewater.

In this thesis a series of diphenol phenanthroline (Dpp) peptide conjugates were synthesized and then coupled to ferrocene to give the corresponding organometallic conjugates. The first step of the synthesis was achieved by esterification of peptides with the phenol group of the Dpp. The next step was the removal of the protecting Boc group and the addition of ferrocene acid chloride at high dilutions to give the desired macrocycles of the type Dpp-(peptide)2 Fc. (peptide = Leu-Leu (3), Leu-Leu-Leu (5) ). However, the syntheses proceeded in low yields where only small quantities of the desired products were obtained. A suitable crystal of compound 3 was grown from CHCl3 which shows a number of intra and intermolecular hydrogen bonding interactions between peptides strands.In addition, the system [Dpp-Fc]2 (1) was syntheised by refluxing Dpp and Fc[COCl]2 in dichloromethane. A suitable crystal was grown which has ð-ð interactions between intramolecular Dpp units as well as a number of CH-ð interactions which determine the crystal packing. The electrochemical experiments on compound 1 show a cathodic shift upon addition of Zn2+ to a solution of 1. This observation is believed to occur because of a conformational change in 1. The last area of synthesis that was done was the attempt at â-sheet formation using Fc as a scaffold to align peptide strands. Two systems were studied in this thesis [Fc(n-AA-OMe)(1-AA)]2-1,4butyl diamine. (AA =Ala (8), Gly (9)). Both were studied by 1H NMR to evaluate the presence of hydrogen bonding interactions. The results indicate the presence of intramolecular H-bonding, which is believed to form â-sheet like structures in solution.

In this thesis a series of diphenol phenanthroline (Dpp) peptide conjugates were synthesized and then coupled to ferrocene to give the corresponding organometallic conjugates. The first step of the synthesis was achieved by esterification of peptides with the phenol group of the Dpp. The next step was the removal of the protecting Boc group and the addition of ferrocene acid chloride at high dilutions to give the desired macrocycles of the type Dpp-(peptide)2 Fc. (peptide = Leu-Leu (3), Leu-Leu-Leu (5) ). However, the syntheses proceeded in low yields where only small quantities of the desired products were obtained. A suitable crystal of compound 3 was grown from CHCl3 which shows a number of intra and intermolecular hydrogen bonding interactions between peptides strands.In addition, the system [Dpp-Fc]2 (1) was syntheised by refluxing Dpp and Fc[COCl]2 in dichloromethane. A suitable crystal was grown which has ð-ð interactions between intramolecular Dpp units as well as a number of CH-ð interactions which determine the crystal packing. The electrochemical experiments on compound 1 show a cathodic shift upon addition of Zn2+ to a solution of 1. This observation is believed to occur because of a conformational change in 1. The last area of synthesis that was done was the attempt at â-sheet formation using Fc as a scaffold to align peptide strands. Two systems were studied in this thesis [Fc(n-AA-OMe)(1-AA)]2-1,4butyl diamine. (AA =Ala (8), Gly (9)). Both were studied by 1H NMR to evaluate the presence of hydrogen bonding interactions. The results indicate the presence of intramolecular H-bonding, which is believed to form â-sheet like structures in solution.

In this research,we used the electrochemical (cyclic voltammetry) method to synthesize (polyaniline) PANI thin film on the top of ITO substrate which applied extensively on polymer organic light emitting diodes based on ITO (170nm) / PANI (55nm ) / PFG(60 nm )/LiF(1nm)/Ca(10nm) / Al (200nm) . The PANI thin films have excellent optical and electric properties. According to the measurement results of ultraviolet visible spectrophotometry, the PANI thin films with different aniline monomer concentrations display the absorption peak at the range of 500nm to 600nm and have high light transmission near 90%. The conductivity of PANI thin film (2.02x10-2(s/cm)) is higher than that of PEDOT:PSS thin film (1.28x10-2(s/cm)). The highest occupied molecular orbital value of PANI thin film is about 5.0 eV that close to PEDOT:PSS thin film. Therefore, it is suitable act as hole transporting layer. In this study, we can control the surface morphology of PANI thin film by exchanging synthesized parameters. Finally, we have fabricated a PLED device with PANI as a hole transporting layer by electrochemical synthesis with at the aniline monomer concentration of 0.3M and the scan rate of 0.0.1 V/s. The device exhibits a maximum luminance of 10500 cd/m2 at 15 V and power efficiency of 0.25 lm/W at 10V.

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references (leaves 266-280). Available also in a digital version from Dissertation Abstracts.

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