No / 4-Chloro-2(H)-pyran-2-one undergoes thermal Diels−Alder cycloaddition with electron-deficient dienophiles to afford, without any significant selectivity, 6-endo- and 5-endo-substituted bicyclic lactone cycloadducts. In contrast to 3- and 5-bromo-2(H)-pyran-2-one, 4-chloro-2(H)-pyran-2-one does not undergo thermal cycloadditions with electron-rich dienophiles. The regio- and stereochemical preferences of the cycloadditions of 4-chloro-2(H)-pyran-2-one and other related 2(H)-pyran-2-ones are investigated computationally. Calculations were carried out on the transition states leading to the four possible regio- and stereoisomeric cycloadducts using density functional theory (B3LYP/6-31G*). These studies allow prediction of the regio- and stereoselectivity in these reactions which are in line with experimental observations.

A Terapia Fotodinâmica (TFD) é um tratamento usado principalmente na terapia anticâncer e que depende da retenção de um composto fotossensibilizante nas células tumorais e posterior irradiação dessas células com luz visível. Após ativação, o fármaco pode gerar espécies reativas de oxigênio (EROs), como o oxigênio singlete (1O2) e radicais (O2-, OH), que são capazes de danificar membranas, DNA e outras estruturas celulares, induzindo a apoptose ou necrose das células tumorais. O ácido fólico, por ser super expressado na superfície das células de alguns tipos de cânceres (principalmente os ginecológicos), pode desempenhar o papel de vetorizador, tornando-se um importante aliado aos sistemas de liberação de fármacos. Neste trabalho foi avaliado o uso de ácido fólico como aditivo aos lipossomas contendo ftalocianina de cloro-alumínio como fármaco fotossensibilizante, aplicados em TFD com células MCF7. Os estudos demonstraram que os sistemas lipossomais desenvolvidos apresentam tamanho nanométrico (menor que 200 nm) e possuem biocompatibilidade quando avaliados em cultura celular de monocamada. Além disso, foi possível observar o efeito fototóxico satisfatório das formulações e o aumento da internalização do fármaco, quando utilizado o ácido fólico como vetorizador. / Photodynamic Therapy (PDT) is mainly used in anticancer therapy. The efficiency of this treatment is dependent on retention of photosensitizer compound at the tumor cells and posterior irradiation of these cells with visible light. After activation, the drug may generate reactive oxygen species (ROS) such as singlet oxygen (1O2) and radicals (O2-, OH), which are capable of damaging membranes, DNA and other cell structures, inducing apoptosis or necrosis of tumor cells. Folic acid is super-expressed on the surface of some cancers cells (especially gynecological cancer cells) and can play the role of target system, becoming an important ally for drug delivery systems. This study evaluated the use of folic acid as an additive to liposomes containing chloro-aluminum phthalocyanine as a photosensitizer drug, applied in PDT with MCF7 cells. These studies showed that liposomal systems have nanometer size (less than 200 nm) and have biocompatibility when evaluated in monolayer cell culture. Moreover, it was possible to observe satisfactory phototoxic effect of the formulations and increased internalization of the drug when folic acid is used.

Disinfectants in drinking water can interact with natural organic matter (NOM) to form disinfection by-products (DBPs). Halogenated furanones (including MX and MCA) are a group of emerging DBPs that can account for a significant amount of the total mutagenicity found in drinking water. Source water characteristics and NOM removal capabilities of coagulation can greatly influence the formation of DBPs. This project examines the effects of bench scale coagulation and chlorination tests on NOM removal, DBP formation, and genotoxicity. NOM was characterized using liquid chromatography-organic carbon detection (LC-OCD). Experiments with Ottawa River, Otonabee River, and Lake Simcoe waters show that DBPs decreased with increases in coagulant dosage, due to the removal of NOM during coagulation. DBP formation and speciation was then compared with NOM content to identify specific fractions that contribute to the formation of these DBPs. Genotoxicity was directly linked to MX presence in chlorinated waters.

Crystal engineering offers a rational way of analyzing crystal structures and designing new structures with properties. The supramolecular synthon concept was introduced in 1995 and has shown versatility and utility in the design of molecular solids. Chapter 1 gives a general introduction about the development of the concept of supramolecular synthons over the years which has seen a transition from synthesis to structures and dynamics. This thesis focuses on the later phase of the development of the concept of supramolecular synthons. Chapter 2 introduces the idea of structural landscape and describes a structural landscape of a conformationally flexible molecule, orcinol, and explores the synthon preferences of this particular molecule towards cocrystal formation. Chapter 3 explores a combinatorial matrix to show both global and local features of a structural landscape. Chapter 4 takes a component of this landscape namely 4,4'-bipyridine and 4-hydroxybenzoic acid and shows the occurrence of synthon polymorphism in cocrystals which originates from the interplay of geometrical and chemical factors. Chapter 5 introduces a four step method for the identification of multiple synthons by FTIR spectroscopy. Along with, it shows that the rarity of synthon polymorphism is not a case of overlooking of crystals in the process of selecting good looking crystals. Chapter 6 takes a series of dihalogenated phenols and indicates that the Br prefers type II. This chapter also explains elastic bending on the basis of halogen bonds. Chapter 7 attempts to explore the Cl/Br isostructurality in the light of type I and type II contacts and concludes that Cl/Br isostructurality arises from a geometrical model and therefore it is quite similar to Cl/Me isostructurality. Chapter 8 attempts to analyze the class of trichlorophenols and reveals structural modularity in this class of compounds. The modularity of 3,4,5-trichlorophenol is explored in crystal design in chapter 9 in terms of LSAM (Long Range Synthon Aufbau Module) A subsequent study in solution by NMR reveals the presence of LSAM in solution and establishes a hierarchy of the dissociation of its components. The concept of supramolecular synthon has come a long way from being a tool in a crystal engineer’s toolbox to a structural unit responsible for crystallization and therefore offer multiple possibilities both in terms of structures and dynamics. This thesis attempts to explore some of these possibilities based mainly on the concepts of structural landscape and halogen bonds which are blended with the concept of supramolecular synthons.

A Terapia Fotodinâmica (TFD) é um tratamento usado principalmente na terapia anticâncer e que depende da retenção de um composto fotossensibilizante nas células tumorais e posterior irradiação dessas células com luz visível. Após ativação, o fármaco pode gerar espécies reativas de oxigênio (EROs), como o oxigênio singlete (1O2) e radicais (O2-, OH), que são capazes de danificar membranas, DNA e outras estruturas celulares, induzindo a apoptose ou necrose das células tumorais. O ácido fólico, por ser super expressado na superfície das células de alguns tipos de cânceres (principalmente os ginecológicos), pode desempenhar o papel de vetorizador, tornando-se um importante aliado aos sistemas de liberação de fármacos. Neste trabalho foi avaliado o uso de ácido fólico como aditivo aos lipossomas contendo ftalocianina de cloro-alumínio como fármaco fotossensibilizante, aplicados em TFD com células MCF7. Os estudos demonstraram que os sistemas lipossomais desenvolvidos apresentam tamanho nanométrico (menor que 200 nm) e possuem biocompatibilidade quando avaliados em cultura celular de monocamada. Além disso, foi possível observar o efeito fototóxico satisfatório das formulações e o aumento da internalização do fármaco, quando utilizado o ácido fólico como vetorizador. / Photodynamic Therapy (PDT) is mainly used in anticancer therapy. The efficiency of this treatment is dependent on retention of photosensitizer compound at the tumor cells and posterior irradiation of these cells with visible light. After activation, the drug may generate reactive oxygen species (ROS) such as singlet oxygen (1O2) and radicals (O2-, OH), which are capable of damaging membranes, DNA and other cell structures, inducing apoptosis or necrosis of tumor cells. Folic acid is super-expressed on the surface of some cancers cells (especially gynecological cancer cells) and can play the role of target system, becoming an important ally for drug delivery systems. This study evaluated the use of folic acid as an additive to liposomes containing chloro-aluminum phthalocyanine as a photosensitizer drug, applied in PDT with MCF7 cells. These studies showed that liposomal systems have nanometer size (less than 200 nm) and have biocompatibility when evaluated in monolayer cell culture. Moreover, it was possible to observe satisfactory phototoxic effect of the formulations and increased internalization of the drug when folic acid is used.

RESUME: Le travail de recherche rapporté dans cette thèse concerne lamélioration de traceurs marqués au fluor-18 utilisés en routine clinique : la 2-[18F]fluoro-L-tyrosine et le 2-désoxy-2-[18F]fluoro-D-glucose. Les résultats relatifs à lacide aminé, de valeur confirmative pour les connaissances publiées antérieurement dans la littérature, consistent en une validation chez le rat qui entérine le potentiel de ce traceur pour létude de la vitesse de synthèse des protéines cérébrales in vivo. Les perspectives futures pour ce traceur sont dès lors lextension de son utilité dans le domaine de loncologie et son utilisation pour létude de phénomènes physiologiques neurologiques. Durant ce travail, des techniques décrites dans la littérature, mais non pratiquées au CRC ont fait lobjet dune implémentation et sont maintenant accessibles (modèle du rat vigile, méthodes de synthèse de polymères à empreinte moléculaire). La partie principale du travail concerne la récupération du [18F]fluorure et son utilisation pour le marquage nucléophile sans étape dévaporation. La synthèse du 2-désoxy-2-[18F]fluoro-D-glucose a servi de réaction témoin pour tester lapplicabilité des méthodes développées dans ce cadre. Deux stratégies différentes, lune utilisant des supports ioniques et des solvants protiques, lautre utilisant des supports non ioniques et des solvants non protiques, ont permis datteindre les buts fixés avec des rendements dincorporation du [18F]fluorure de même ordre de grandeur que ceux obtenus en radiochimie usuelle du fluor-18. La méthode utilisant les supports non ioniques a par ailleurs démontré sa grande généralité vis-à-vis de précurseurs divers, aliphatiques et aromatiques, dans des conditions de marquage diverses, notamment à température modérée. Les perspectives de ces méthodes nouvelles pour la fabrication des traceurs TEP tirent parti de la possibilité de les implanter dans un automate miniaturisé (milli- ou micro-réacteur), à visée synthétique ou analytique. Lefficacité et la simplicité des méthodes de récupération sans évaporation mises au point dans ce travail les destinent à être utilisées aussi bien en développement des traceurs quen synthèse de routine. Elles sont applicables aussi bien à léchelle des automates courants quà celle des futures applications microfluidiques. Par ailleurs, nous sommes persuadés de lintérêt des polymères à empreinte moléculaire dans le créneau des méthodes analytiques. Egalement applicables à des systèmes miniaturisés, ils devraient aider à la réalisation danalyses automatisées des produits finis et à une libération accélérée. Le gain de temps et les moindres pertes de principe actif conduiront alors à une meilleure disponibilité des traceurs TEP et à leur participation accrue aux objectifs de la médecine personnalisée. Nous pensons dès lors avoir ouvert quelques pistes de recherche prometteuses pour la mise en application de ses nouvelles technologies au domaine de la tomographie à émission de positon. / SUMMARY: The results reported in this work concern the improvement of 18-fluorine labelled radiopharmaceuticals used in routine clinical applications: 2-[18F]fluoro-L-tyrosine and 2-deoxy-2-[18F]fluoro-D-glucose. The study of the metabolism of non carrier added 2-[18F]fluoro-L-tyrosine in rats confirms that this tracer is rapidly and extensively incorporated into cerebral proteins and is therefore well suited to the assessment of Protein Synthesis Rate (PSR) in vivo by PET. A correction for the appearance of metabolites is advised for quantitative interpretation of the data. An improvement in the radiosynthesis is necessary to make 2-[18F]fluoro-L-tyrosine widely available for its application in oncology and to envisage the extended use of this tracer for the study of the protein synthesis in other physiological or pathological processes. The second chapter deals with use of molecular imprints in the PET radiochemistry. The molecularly imprinted polymers were synthetized, characterized and tested for the production of specific PET tracers and the plasma analysis of the parent metabolites. The third part of the work consisted in a development of new methods for the [18F]fluoride recovery in order to permit the labelling of different precursors through nucleophilic substitution without the evaporation step classically performed in 18-fluorine radiochemistry. The synthesis of 2-deoxy-2-[18F]fluoro-D-glucose has been used as a tool for the evaluation of the developed methods. Two strategies were considered to concentrate and recover the [18F]fluoride. The first one used ionic solid supports and protic solvents. The second one relied on the use of non ionic solid supports and non protic solvents. Both strategies led us to reach [18F]fluoride incorporation yields as high as in classical radiosyntheses with evaporation. Ionic liquids and tertiary alcohols were also evaluated in order to improve the tolerance of the [18F]fluoride nucleophilic substitution to water. The molecularly imprinted polymers and the new methods for the recovery of [18F]fluoride will now be tested for the implementation of PET tracers radiosynthesis and quality control into microchip devices.

No description available.

<p>This thesis presents novel approaches for structural investigation of glucuronides using chemical derivatization in combination with liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MSⁿ).</p><p>Today, LC-ESI-MSⁿ is the dominant technique for quantitative as well as qualitative analyses of metabolites, due to its high sensitivity and selectivity. However, for compounds without an easily ionizable group, e.g., steroids, the sensitivity is limited. In the work presented in this thesis, a derivatization procedure forming a basic oxime significantly increased the detection sensitivity for the altrenogest glucuronide. </p><p>Furthermore, in structural evaluations of glucuronides, the limitation of LC-MSⁿ becomes evident due to the initial neutral loss of 176 u, i.e. monodehydrated glucuronic acid, which often makes it impossible to elucidate the structures of the conjugates. To solve this problem, the main part of the work described in this thesis was devoted to chemical derivatization as a means of facilitating the determination of the site of conjugation. </p><p>For the first time, the isomeric estriol glucuronides were evaluated using a combination of three reagents 2-chloro-1-methylpyridinium iodide (CMPI), 1-ethyl-3-(3-dimethyl- aminopropyl)-carbodiimide (EDC), and 2-picolylamine (PA). Interestingly, the derivatization gave a selective fragmentation pattern leading to differentiation of the isomers. </p><p>Another derivatization reagent, 1,2-dimethylimidazole-4-sulfonyl chloride (DMISC), was also tested for the first time in structural investigations. The isomeric glucuronides of morphine, formoterol, and hydroxypropranolol were evaluated. They can all be conjugated in aliphatic as well as aromatic positions. DMISC was proven to be useful in two ways. Firstly, the morphine and formoterol glucuronides that contained a free phenol could be differentiated from those that were conjugated in the aromatic position based on different reactivity. Secondly, for the aromatic <i>O</i>-glucuronide of 4’-hydroxypropranolol, DMISC was proven to react with the amine. This product gave a different fragmentation pattern compared to the corresponding derivative of the aliphatic glucuronide. </p>

<p>DESCARTES is a light-weight, balloon-borne grab sampler for stratospheric long-lived tracers developed at the University of Cambridge. 33 flights have been performed with two versions of the instrument at northern latitudes by the DESCARTES team at the Swedish Institute of Space Physics (IRF) in Kiruna during the years 1997-2000.</p><p>The general interest in long-lived stratospheric tracers is to study the general global circulation of air in the stratosphere and the exchange between the stratosphere and troposphere. In the study of chemical ozone depletion in the stratosphere, long-lived tracers serve as an important reference to distinguish between the variations in ozone of dynamical and chemical origin.</p><p>This thesis focuses on calibrations and quality assessment of the measurements made with the third version of the DESCARTES instrument based at IRF. Two different general approaches to make calibrations are discussed. Uncertainty estimations for both of these methods are made and the results are tested by laboratory methods and by comparisons to other instruments, including comparisons between two versions of DESCARTES. Analyzed and calibrated flight data for all successful flights are presented.</p><p>The basic principle of the instrument is to chemically adsorb a number of tracers (in practice only CFC-11 is measured) in an adsorption bed of Carboxen in a micro trap through which the sampled air is driven by a pump. After recovery the adsorbed species in the trap is desorbed by electrical heating of the trap and analysed by gas chromatography.</p><p>The resulting estimated mixing ratios from the instrument are directly dependent on the adsorption of the sampled species being quantitative in the traps. Laboratory experiments are described using two traps in series, where the performance of the first is tested by sampling the breakthrough by the second. A model is developed to recreate these tests in order to be able to compensate for breakthrough during flights. The model showed that the adsorption in the traps is not explained by simple chromatographic theory and the results allow us only to give an estimation of the uncertainty due to breakthrough.</p> / <p>DESCARTES är ett lätt ballongburet provtagningsinstrument för stratosfäriska spårgaser. Det är utvecklat vid universitetet i Cambridge. DESCARTES-teamet vid Institutet för rymdfysik (IRF) i Kiruna har under åren 1997-2000 genomfört 33 flygningar med två olika versioner av instrumentet från nordliga latituder.</p><p>Det generella intresset av långlivade stratosfäriska spårgaser är att studera den globala cirkulationen i stratosfären och utbytet av luft mellan stratosfären och troposfären. För studier av den kemiska ozonnedbrytningen i stratosfären spelar långlivade spårgaser en avgörande roll som referens för att skilja mellan variation i ozonkoncentrationen av kemiskt och dynamiskt ursprung.</p><p>Denna avhandling fokuserar på kalibrering och kvalitetssäkring av mätningar gjorda med den tredje versionen av DESCARTES-instrumentet hemmahörande vid IRF. Två i grunden olika kalibreringsförfaranden för instrumentet behandlas. Osäkerhetsuppskattningar är gjorda för båda dessa metoder och resultaten är prövade i laboratorietester. Dessutom jämförs resultaten från två versioner av DESCARTES och andra instrument. Analyserade data från samtliga lyckade flygningar presenteras.</p><p>Den grundläggande principen för instrumentet är att pumpa luftprover genom en fälla som innehåller en bädd av det kemiska adsorptionsmaterialet Carboxen, som adsorberar ett antal spårgaser. När instrumentet hämtats tillbaka efter en flygning gasas de adsorberade ämnena i fällan ut genom att fällan upphettas på elektrisk väg. De utgasade ämnena analyseras med gaskromatografi. I praktiken kan endast CFC-11 analyseras.</p><p>Den slutgiltiga bestämningen av blandningsförhållandet från instrumentet är direkt beroende av att adsorptionen i fällorna för de ämnen man vill undersöka är fullständig. En serie laboratorieexperiment har genomförts där två likadana fällor kopplats efter varandra. På så sätt har tillförlitligheten av den första fällan kunnat studeras genom att uppmäta hur mycket som bryter igenom till den andra fällan. En modell har utvecklats för att förstå resultatet av dessa tester och kunna kompensera för eventuella genombrott vid provtagning under flygningar. Modellen visade att adsorptionen i fällorna inte kan förklaras med enkel kromatografisk teori. Resultaten ger endast möjlighet att bedöma osäkerheten i mätningarna till följd av risken för genombrott.</p>

DESCARTES is a light-weight, balloon-borne grab sampler for stratospheric long-lived tracers developed at the University of Cambridge. 33 flights have been performed with two versions of the instrument at northern latitudes by the DESCARTES team at the Swedish Institute of Space Physics (IRF) in Kiruna during the years 1997-2000. The general interest in long-lived stratospheric tracers is to study the general global circulation of air in the stratosphere and the exchange between the stratosphere and troposphere. In the study of chemical ozone depletion in the stratosphere, long-lived tracers serve as an important reference to distinguish between the variations in ozone of dynamical and chemical origin. This thesis focuses on calibrations and quality assessment of the measurements made with the third version of the DESCARTES instrument based at IRF. Two different general approaches to make calibrations are discussed. Uncertainty estimations for both of these methods are made and the results are tested by laboratory methods and by comparisons to other instruments, including comparisons between two versions of DESCARTES. Analyzed and calibrated flight data for all successful flights are presented. The basic principle of the instrument is to chemically adsorb a number of tracers (in practice only CFC-11 is measured) in an adsorption bed of Carboxen in a micro trap through which the sampled air is driven by a pump. After recovery the adsorbed species in the trap is desorbed by electrical heating of the trap and analysed by gas chromatography. The resulting estimated mixing ratios from the instrument are directly dependent on the adsorption of the sampled species being quantitative in the traps. Laboratory experiments are described using two traps in series, where the performance of the first is tested by sampling the breakthrough by the second. A model is developed to recreate these tests in order to be able to compensate for breakthrough during flights. The model showed that the adsorption in the traps is not explained by simple chromatographic theory and the results allow us only to give an estimation of the uncertainty due to breakthrough. / DESCARTES är ett lätt ballongburet provtagningsinstrument för stratosfäriska spårgaser. Det är utvecklat vid universitetet i Cambridge. DESCARTES-teamet vid Institutet för rymdfysik (IRF) i Kiruna har under åren 1997-2000 genomfört 33 flygningar med två olika versioner av instrumentet från nordliga latituder. Det generella intresset av långlivade stratosfäriska spårgaser är att studera den globala cirkulationen i stratosfären och utbytet av luft mellan stratosfären och troposfären. För studier av den kemiska ozonnedbrytningen i stratosfären spelar långlivade spårgaser en avgörande roll som referens för att skilja mellan variation i ozonkoncentrationen av kemiskt och dynamiskt ursprung. Denna avhandling fokuserar på kalibrering och kvalitetssäkring av mätningar gjorda med den tredje versionen av DESCARTES-instrumentet hemmahörande vid IRF. Två i grunden olika kalibreringsförfaranden för instrumentet behandlas. Osäkerhetsuppskattningar är gjorda för båda dessa metoder och resultaten är prövade i laboratorietester. Dessutom jämförs resultaten från två versioner av DESCARTES och andra instrument. Analyserade data från samtliga lyckade flygningar presenteras. Den grundläggande principen för instrumentet är att pumpa luftprover genom en fälla som innehåller en bädd av det kemiska adsorptionsmaterialet Carboxen, som adsorberar ett antal spårgaser. När instrumentet hämtats tillbaka efter en flygning gasas de adsorberade ämnena i fällan ut genom att fällan upphettas på elektrisk väg. De utgasade ämnena analyseras med gaskromatografi. I praktiken kan endast CFC-11 analyseras. Den slutgiltiga bestämningen av blandningsförhållandet från instrumentet är direkt beroende av att adsorptionen i fällorna för de ämnen man vill undersöka är fullständig. En serie laboratorieexperiment har genomförts där två likadana fällor kopplats efter varandra. På så sätt har tillförlitligheten av den första fällan kunnat studeras genom att uppmäta hur mycket som bryter igenom till den andra fällan. En modell har utvecklats för att förstå resultatet av dessa tester och kunna kompensera för eventuella genombrott vid provtagning under flygningar. Modellen visade att adsorptionen i fällorna inte kan förklaras med enkel kromatografisk teori. Resultaten ger endast möjlighet att bedöma osäkerheten i mätningarna till följd av risken för genombrott.