Essen, Univ., Diss., 2001. / Computerdatei im Fernzugriff.

Essen, Univ., Diss., 2001. / Computerdatei im Fernzugriff.

Essen, Universiẗat, Diss., 2001.

Les anti-inflammatoires non stéroïdiens (AINS) représentent une classe thérapeutique largement utilisée. Néanmoins, divers effets secondaires sont classiquement rencontrés lors de leur utilisation chronique. La démonstration que lusage dinhibiteurs sélectifs ou préférentiels de la COX-2 est corrélé avec une meilleure tolérance a ouvert de nouvelles perspectives dans la recherche de molécules anti-inflammatoires. Dans le présent travail, nous avons développé des analogues originaux du nimésulide, un inhibiteur préférentiel de la COX-2, en série pyridinique au départ du composé FJ29 (36), composé préalablement identifié au sein de notre laboratoire comme un puissant inhibiteur de COXs in vitro présentant une légère sélectivité envers la COX-2 et possédant un important potentiel anti-inflammatoire in vivo. Nous avons dabord synthétisé de nouvelles molécules dans le but daccroître le potentiel inhibiteur de cyclooxygénases et/ou le profil COX-2 préférentiel du composé 36. Diverses pharmacomodulations ont été entreprises autour de la fonction sulfonamide (premier pôle de modulation) et du noyau benzénique (second pôle) du composé 36, générant ainsi plus de cinquante molécules originales. Lévaluation pharmacologique du potentiel inhibiteur des cyclooxygénases et le calcul du ratio de sélectivité envers la COX-2 de ces nouveaux composés a été réalisé in vitro. Tous les composés synthétisés ont démontré, à des degrés divers, un profil inhibiteur de COXs (IC50 de lordre de 0,1 micromolaire pour les composés originaux les plus puissants). Parmi ceux-ci, les composés porteurs dune fonction trifluorométhanesulfonamide présentent une activité inhibitrice des COXs supérieure à leurs analogues en série méthanesulfonamide. Dautre part, la substitution du cycle benzénique du composé 36 en position 3 ou 4 par un atome dhalogène (Cl, Br, I) a permis dexacerber la sélectivité envers la COX-2. Finalement, le caractère COX-2 préférentiel a pu être encore augmenté jusquà un ratio de sélectivité de 15 envers la COX-2 en réalisant une double substitution du cycle benzénique par un atome de brome et un groupement méthyle en position 3 et 4, respectivement. Le potentiel anti-inflammatoire dune sélection de nos composés a ensuite été évalué in vivo après administration intra-péritonéale ou orale en utilisant un modèle de pleurésie chez le rat. Tous les composés étudiés ont présenté une activité anti-inflammatoire et certains se sont révélés plus actifs que le nimésulide ou le célécoxib en réduisant, à la dose de 20 mg/kg, jusquà 69 % de linflammation induite. Limpact de nos molécules sur la migration leucocytaire a démontré que certaines dentre-elles présentent une activité inhibitrice similaire au nimésulide. Dautre part, nos composés ont également démontré un effet inhibiteur sur la production dIL-6 au sein de lexsudat pleural tandis quaucun effet sur la biosynthèse dIL-1 na été observé. La détermination de la concentration plasmatique en drogue obtenue au terme des expérimentations in vivo a démontré que nos composés, administrés par voie intra-péritonéale, sont présents dans le plasma à des concentrations drastiquement inférieures (environ 50 fois) à celles observées avec le nimésulide (100 µg/mL après administration intra-péritonéale à la dose de 20 mg/kg). De plus, ces concentrations sont encore significativement diminuées lorsque nos molécules sont administrées par voie orale.

No description available.

Advances in analytical chemistry have resulted in a growing body of literature showing measurable concentrations of pharmaceuticals in both drinking and wastewater. Removal of such chemicals is typically inefficient and often poorly characterized. To characterize one such method of removal (micellar enhanced ultrafiltration, (MEUF)), interactions of a cetyl trimethylammonium bromide (CTABr) surfactant and sulfonamide antibiotics were examined by NMR and semi-equilibrium dialysis (SED). The locus and orientation of binding in a micelle was established for seven sulfonamides by 1H NMR, and it was found that hydrophilic sulfonamides showed weak coordination with the micelle, whereas hydrophobic sulfonamides penetrated into the micellar interior with coordination of the SO2NH group to the charged surface layer. Binding constants were determined by 1H NMR and showed apparent order of magnitude differences between nuclei. Several compounds were unable to be characterized in this manner due to low change in chemical shift with addition of CTABr. SED was performed as an alternative method to determine binding constants. Values determined in this manner were higher than those determined by 1H NMR. Binding constants were converted into changes in Gibbs free energy and used to evaluate and, where necessary, modify the orientation and locus proposed by 1H NMR. Attempts are made to correlate binding constants with octanol-water partition coefficients to determine if a free energy relationship can be derived. Characterization of these systems may allow for a predictive methodology to determine the MEUF removal efficiencies of new sulfonamide and surfactant combinations. It is also hoped that this work may be generalized to predict MEUF efficiency for a wide range of contaminants that might be found in wastewater. / Thesis (Master, Chemistry) -- Queen's University, 2011-01-31 09:46:28.248

This thesis documents the development of novel methodologies for access to sulfur-containing compounds, including sulfones, sulfonamides and benzoisothiazoles. <b>Chapter 1</b> provides an overview of the applications and the synthesis of sulfonyl-containing compounds. A comprehensive introduction to the development of sulfur dioxide surrogates and their applications in transition metal-catalysed organic chemistry is given. <b>Chapter 2</b> describes the development of a one-step copper(I)-catalysed sulfonylative Suzuki-Miyaura cross coupling reaction. A wide range of aryl and alkenyl boronic acids are coupled with aryl and alkenyl iodides to give the corresponding sulfones. A two-step one-pot sulfination/derivatisation method was also developed, allowing access to compounds including β-hydroxy sulfones, sulfonamides and sulfonyl fluorides. <b>Chapter 3</b> illustrates a one-step copper(II)-catalysed sulfonamide synthesis using boronic acids, amines and SO2. Various aryl and alkenyl boronic acids as well as amines and anilines are compatible, including active pharmaceutical ingredients such as amoxapine and desloratadine. <b>Chapter 4</b> details an aryne-based selective formation of substituted benzoisothiazoles. Different substitution pattern of the aryne precursor and the thiadiazole are employed, with the target heterocycles being obtained in good to excellent yields. <b>Chapter 5</b> summarises the research and the future work. <b>Chapter 6</b> documents the experimental procedures and data.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-10-30T10:24:52Z No. of bitstreams: 2 Tese - Mirian Rita Carrilho de Castro - 2017.pdf: 7039906 bytes, checksum: 5d352db979557bb35c672dba708ae0e8 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-10-30T10:26:18Z (GMT) No. of bitstreams: 2 Tese - Mirian Rita Carrilho de Castro - 2017.pdf: 7039906 bytes, checksum: 5d352db979557bb35c672dba708ae0e8 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-10-30T10:26:18Z (GMT). No. of bitstreams: 2 Tese - Mirian Rita Carrilho de Castro - 2017.pdf: 7039906 bytes, checksum: 5d352db979557bb35c672dba708ae0e8 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-09-01 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / The chalcones are key intermediates for the biosynthesis of flavonoids and have shown an abundance of pharmacological effects including the antitumor effect. Thus, the synthesis and characterization of several chalcones and derivatives become important to develop a new class of compounds having antitumor activity. In the present work, the synthesis of chalcones, nitrochalcone sulfonamides and quinolinones was performed. By adjusting the reaction time and the sequence of the reactions, hybrids of open-chain chalcone sulfonamide whose molecular hybridization occurred at the ortho position of the benzoyl chalcone group through the Claisen- Schmidt condensation of acetophenone sulfonamide and nitrobenzaldehyde can be obtained at shorter reaction times, whereas quinolinone from cyclization at β carbon can be achieved if the reaction is stopped sequentially later. It is also noted that a novel structure, a chalcone (bis) sulfonamide, was prepared when chalcone was first synthesized and then reacted with benzenesulfonyl chloride. From the sulfonamide chalcones prepared with the m- aminoacetophenone sulfonamide and the o-, m- and p-nitrobenzaldehyde, a single product was formed. Among the 21 compounds prepared, five were ketone sulfonamides and sixteen were hybrid compounds (chalcones, chalcones, sulfonamides and quinolinones), which were purified by extraction, recrystallization and column chromatography and characterized by small molecule crystallography, melting point, Proton Nuclear Magnetic Resonance ( 1 H NMR) and infrared IV (IR). The antitumor activity was evaluated against three cancer cell lines: SF-295 (human glioblastoma), PC-3 (prostate) and HCT-116 (colon). Compounds 39, 40, 42, 43, 45a, 48a, 48b, 48c, 49 and 51 were cytotoxic to the three tumor cell lines tested. However, the quinolinones showed no relevant cytotoxic effect. It is also worth noting that compound 45a with a higher cytotoxic effect than doxorubicin, a drug used today against the three cancer cell lines evaluated, was a promising prototype for a new drug. / As chalconas são compostos intermediários da biossíntese de flavonóides e têm demonstrado uma variedade de efeitos farmacológicos entre eles o efeito antitumoral. Assim a síntese e caracterização de várias chalconas e derivados se tornam importantes para o desenvolvimento de uma nova classe de compostos com atividade antitumoral. No presente trabalho foi realizada a síntese de chalcona, nitro chalconas sulfonamidas e quinolinonas. Ajustando o tempo e a ordem das reações, os híbridos de chalcona sulfonamida de cadeia aberta, cuja hibridação molecularocorreu na posição orto do grupo de chalcona benzoíla através da condensação Claisen-Schmidt da acetofenona sulfonamida e nitrobenzaldeído, podem ser obtidos em tempos de reação mais curtos, enquanto que a quinolinona proveniente da ciclização no carbono β pode ser alcançada se a reação for parada sequencialmente mais tarde. Destaca-se uma nova estrutura, uma chalcona (bis) sulfonamida, foi formada quando se sintetizou a chalcona primeiramente e então reagiu-a com o cloreto de benzenosulfonila. A partir das chalconas sulfonamidas preparadas com a m- aminoacetofenona sulfonamida e o o-, m- e p-nitrobenzaldeído, formou-se apenas um produto. Dos 21 compostos preparados 5 são cetonas-sulfonamidas e 16 compostos híbridos (chalconas, chalconas sulfonamidas e quinolinonas), que foram purificados por extração, recristalização e coluna de separação, e caracterizados por cristalografia de pequenas moléculas, ponto de fusão ressonância magnética de prótons ( 1 H-RMN) e infravermelho (IV). A atividade antitumoral foi avaliada frente a três linhagens de células cancerosas: SF-295 (glioblastoma - humano), PC-3 (próstata) e HCT-116 (colón). Os compostos 39, 40, 42, 43, 45a, 48a, 48b, 48c, 49 e 51, apresentaram citotoxicidade nas três linhagens de células tumorais testadas. Já as quinolinonas não apresentaram efeito citotóxico relevante. Destaca-se ainda que o composto 45a com maior efeito citotóxico do que a doxorrubicina, medicamento utilizado hoje contra as três linhagens celulares de câncer avaliadas, mostra-se como um promissor protótipo a um novo fármaco.

Le développement de composés de coordination biologiquement actifs (antimicrobiens, les anti-inflammatoires, les antifongiques, les anti-oxydants et les anticancéreux) est un domaine de la chimie inorganique en évolution rapide, susceptible d'avoir un impact direct sur l'amélioration de la qualité de la vie. Les complexes métallo-antibiotique tirent parti de l'effet synergique pour aboutir à une activité pharmacologique améliorée. La reconnaissance du rôle des ions métalliques dans les systèmes biologiques et dans le traitement de diverses maladies attire l'attention sur les avantages d'étudier l'interaction des ions métalliques avec les molécules de médicaments organiques. Dans la continuité avec les travaux précédents de l’équipe, nous nous intéressons à la synthèse de nouvelles familles de complexes métaux-antibiotiques associant l’activité antiseptique d’un ion métallique à un ou deux types de molécules bioactives. Leurs actions additives doivent avoir un effet synergique et conduire à des traitements plus efficaces et devraient fortement minimiser les risques d'apparition de bactéries mutantes. Au cours de ce travail, nous avons réussi à synthétiser le premier complexe métal-antibiotique associant deux types d'antibiotiques différents comme ligands du Zn(II). Des études comparatives montrent qu'il a une meilleure activité antibactérienne contre E. Coli, E. Aureus, E. Feacalis que les antibiotiques parents et les complexes ne contenant qu'un seul de ces antibiotiques. Cela ouvre un nouveau concept appelé « Assemblage de Biomolécules Multi-actifs, ABM ». De plus, nous décrivons la synthèse et la caractérisation de nouveaux ligands antimicrobiens trifluorométhylés / Development of novel coordination complexes with diverse biological activities (antimicrobial, anti-inflammatory, antifungal, antioxidant and anticancer) is a rapidly evolving field of inorganic chemistry with potential direct impact on quality of life. Metal–drug complexes are of increasing interest in bioinorganic chemistry, leveraging the synergistic effect to lead to compounds with improved pharmacological activity. The recognition of the role of metal ions in biological systems and in treatment of various diseases calls attention to the benefits of studying the interaction of metal ions with organic drug molecules. In continuation with previous works of team, we focus here on the synthesis of new families of metal-antibiotic complexes associating, on one single-molecule, the antiseptic activity of a metal ion with the bioactivity of one or two type of bioactive molecules. Their additive actions have a synergetic effect and lead to more effective and shorter treatments and should strongly minimize the risks for appearance of bacteria mutants. In this work, we succeeded to synthesis the first metal-antibiotic complex associating two types of different antibiotic as ligands with Zn(II). The structure in the solid state of this new complex was established together with the studies of the chemical-physical properties. Comparative studies show it has a better antibacterial activity against (E.Coli, E,Aureus, E.Feacalis ) than parent antibiotics and complexes with only one of the antibiotic. This open a new concept named as Multi-Active Biomolecule Assembly. Moreover, the synthesis and characterisation of new trifluorométhylated antimicrobial ligands are described

Als Hilfsstoffe in der Arzneimittelentwicklung können Cyclodextrine und ihre Derivate aufgrund der Fähigkeit zur Bildung von Wirt-Gast-Komplexen mit organischen Molekülen zu unterschiedlichsten Zwecken verwendet werden. Ein Verständnis aller Einflussfaktoren auf die Komplexbildung wäre von großem Wert, weil man so gegebenenfalls vorab entscheiden könnte, ob ein Einsatz von Cyclodextrinen überhaupt in Betracht käme, und wenn ja, welches Cyclodextrin den beabsichtigten Effekt brächte. In der vorliegenden Arbeit wurden mit Hilfe verschiedener Methoden Informationen zu den Einschlusskomplexen gesammelt, die natürliche Cyclodextrine mit einer Reihe typischer Arzneistoffmoleküle bilden. Als Modellsubstanzen wurden die Sulfonamide Sulfadiazin, Sulfadimidin, Sulfafurazol, Sulfaguanidin, Sulfamerazin, Sulfameter, Sulfamethoxazol, Sulfanilamid und Sulfathiazol gewählt. Aufgrund ihrer Molekülgröße bilden die gewählten Gäste in wässriger Lösung bevorzugt mit dem siebengliedrigen β-Cyclodextrin Komplexe, die Wechselwirkungen sind im Vergleich mit anderen Gastmolekülen jedoch relativ schwach. Im Rahmen von Löslichkeitsstudien wurden verschiedene Einflüsse (pH, Temperatur) auf die Komplexbildung in Lösung untersucht. Mit Hilfe von Van’t Hoff Plots wurden die thermodynamischen Größen der Komplexbildung bestimmt, wo das Phänomen der Enthalpie-Entropie-Kompensation beobachtet werden konnte. Die Stöchiometrie der Komplexe wurde unter anderem in Job’s Plots mit Hilfe der 1H-NMR-Spektroskopie bestimmt. Die Komplexbildung geht im Fall der Sulfonamide meist nicht nur mit einer Löslichkeitssteigerung des Gastes, sondern auch des nur eingeschränkt wasserlöslichen β-Cyclodextrins einher. Dieser Effekt wurde bei verschiedenen pH-Werten quantifiziert und tritt bei allen Gastmolekülen, mit Ausnahme von Sulfathiazol, in vergleichbarem Umfang auf. Unter Ausnutzung dieses Phänomens kann je nach Gast eine Konzentration des Wirtes in Lösung erreicht werden, die ein Vielfaches seiner intrinsischen Löslichkeit beträgt. Sowohl in Lösung als auch im Feststoff wurde die Struktur der Einschlusskomplexe mit spektroskopischen Verfahren untersucht. ROESY-Spektren zeigten, dass die chemisch sehr ähnlichen Gastmoleküle teilweise erheblich von einander abweichende Positionen und Orientierungen in der Kavität des Cyclodextrins einnehmen. FTIR-Spektren fester Komplexzubereitungen unterstützen die detaillierteren NMR-Ergebnisse für die meisten Gäste. Ergänzend wurden mit Hilfe von molekularmechanischen Methoden theoretisch plausible Komplexstrukturen erstellt. Dabei wurde die Flexibilität der Cyclodextrinmoleküle und das mögliche Auftreten eines induced-fit durch die Generierung verschiedenartiger Konformere des β-Cyclodextrins in einer Molekulardynamikstudie berücksichtigt. In Dockingstudien (Autodock 3.0) wurde nach dem Bindungsmodus gesucht. Unter den Versuchsbedingungen dominieren Orientierungen, bei denen die aromatische Aminogruppe und die schwefelgebundenen Sauerstoffatome mit den Hydroxylgruppen des Wirtes Wasserstoffbrückenbindungen aufbauen können. Die resultierende Störung der intra- und intermolekularen Wechselwirkungen des Cyclodextrins stellt eine mögliche Erklärung der synergistischen Löslichkeitseffekte zwischen Wirt und Gast dar. Die gewonnenen Daten stellen eine Grundlage zur Charakterisierung der Komplexbildung von Sulfonamiden mit natürlichen Cyclodextrinen dar. Alle Modellsubstanzen wurden mit denselben Methoden untersucht, was eine vergleichende Betrachtung ermöglicht. Insgesamt wurde durch die Betrachtung einer so großen Gruppe an Modellsubstanzen ähnlicher chemischer Eigenschaften und Molekülstruktur ein Eindruck gewonnen, wie stark die Vorgänge bei der Komplexbildung mit Cyclodextrinen schon innerhalb einer relativ homogenen Gruppe variieren können. Aus den Ergebnissen der vorliegenden Arbeit ist zu folgern, dass Vorhersagen zur Komplexbildung mit Cyclodextrinen anhand von Untersuchungen mit vergleichbaren Modellsubstanzen nicht endgültig zu treffen sind, sondern immer von einem vom Gastmolekül abhängigen Einzelfall auszugehen ist. / Cyclodextrins and their derivatives with their ability to form host-guest-complexes with organic molecules can be applied for various purposes in drug development. Understanding all effects on complex formation one could be able to predict if the use of cyclodextrins is indicated and which cyclodextrin is appropriate. In this thesis various methods were applied to gather information about complexes formed by natural cyclodextrins and a set of typical drug molecules. Sulfa drugs - sulfadiazine, sulfadimidine, sulfafurazole, sulfaguanidine, sulfamerazine, sulfameter, sulfamethoxazole, sulfanilamide and sulfathiazole - were chosen as model substances. Owing to their molecular size these guests form complexes preferably with β-cyclodextrin in aqueous solution. The interactions are relatively weak compared with other guest molecules. Phase solubility analysis was used to investigate several effects (pH, temperature) on complexation in solution. The thermodynamic parameters for the complexation were derived from linear van’t Hoff plots which indicate the presence of the enthalpy-entropy-compensation phenomenon. The complex stoichiometry was derived amongst others from Job’s plots employing 1H-NMR-spectroscopy. For most sulfa drugs complexation not only results in a solubility enhancement of the guest, but also increases the low intrinsic solubility of β-cyclodextrin itself. This effect was quantified at several pH values. It is of comparable extent for all guest molecules with exception of sulfathiazole. Making use of the described phenomenon one can achieve β-cyclodextrin concentrations many times higher than its intrinsic solubility in solution. The structure of the inclusion complexes was examined in solution and in the solid state using the means of spectroscopy. ROESY spectra of some model substances show that the chemically related molecules occupy considerably different positions and orientations inside the cyclodextrin’s cavity. FTIR spectra of solid complex formulations support the more detailed NMR-results in most cases. In addition, theoretical structures for the inclusion complexes were created by molecular mechanics. Cyclodextrin flexibility and a possible ‘induced-fit’ were simulated by generating multiple conformations of β-cyclodextrin by molecular dynamics. Docking experiments were carried out in order to characterize the inclusion mode of the sulfonamides. Under the experimental conditions we observed those orientations to be predominant where the aromatic amino group and the oxygen atoms of the sulfonamide are able to establish H-bonds to the host’s hydroxyl groups. The resulting disturbance of the intermolecular and intramolecular H-bonds of β-cyclodextrin is one possible explanation for the synergistic solubility effects between host and guest. The data obtained forms a foundation for the characterization of the complexation process of sulfonamides and natural cyclodextrins. All model substances were investigated applying the same methods allowing a comparative interpretation. Overall, studying a larger group of model substances of similar chemical properties und molecular structure showed the variations of the inclusion process even in such a homogenous group of guests. The results of this thesis make it obvious that predictions concerning complex formation with cyclodextrins are not possible by considering investigations of related model substances. Instead, complex formation should always be regarded as an individual case.