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Development of therapeutics is an extensive process, consuming significant amounts of time and requiring herculean synthetic efforts. A new therapeutic is most often designed from a previously commercialized scaffold, to increase the chance of success. Designing new molecular scaffolds can be extremely high risk and time consuming, yet at the same time the reward can be substantial. Accessing new molecular scaffolds, with efficient and “green” methods, is important in modern medicinal chemistry to diversify chemical space for therapeutic targets. There may be significant quantities of therapeutic candidates that have been over-looked due to synthetic challenges. There is a need for methodologies to synthesize challenging molecular scaffolds that are underexplored in commercialized therapeutics. The work described herein employs two distinct methodologies to access complex molecular scaffolds: 1) by developing a titanium (II) mediated Kulinkovich de-Meijere reaction arrested by Bredt’s rule and a suitable aryl sulfonyl moiety to afford diverse molecular scaffolds with potential for medicinal chemistry applications and 2) utilizing a [4 + 4] photocycloaddition of 2-pyridone-enolynes to access functionally rich cyclooctanoids that are capable of further photochemical transformations into even more complex molecular scaffolds. The titanium (II) mediated Kulinkovich reaction traditionally yields cyclopropylamines and cyclopropanols from amides and esters, respectively. The reaction involves two consecutive carbon-carbon bond forming steps. The bridged tricyclic intermediates would violate Bredt’s Rule and prevent the final carbon-carbon bond formation. This transformation can access a wealth of cyclic amino-ketones from olefin-tethered lactams. In addition, appropriate selection of an electron withdrawing group on nitrogen achieves the same bond sequestration. Interception of the titanafuran intermediate allows for electrophilic trapping of the titanium-carbon bond. The electronically arrested second carbon-carbon bond forming step adds generality to the interrupted Kulinkovich de-Meijere reaction to access the challenging molecular scaffolds of trans-α,α’-disubstituted cyclic ketones. Intramolecular [4 + 4] photoreaction of 2-pyridones with silyl 3-enol-1-ynes yields a highly reactive 1,2,5-cyclooctatriene. In the presence of a silanol proton source the allene is converted into a 1,3-diene. Without the combination of silyl 3-enol-1-ynes and silanol, as previously reported with 1,3-enynes, complex mixture of products is observed. Use of more nucleophilic solvents results in near quantitative yield of the cyclooctadienone through loss of silicon. Further photochemical manipulations of the cyclooctanoids allows for rapid scaffold diversification into bullvalene-like structures through a di-π-methane rearrangement. / Chemistry

2-Pyridones are known to undergo a facile [4+4] photocycloaddition with themselves and other conjugated molecules. These transformations provide an access to complex molecular structures such as highly substituted cyclooctanoid derivatives, which normally represent a significant synthetic challenge. Moreover, the 2-pyridone photoadducts can be further elaborated into various biologically relevant products. The work presented here broadens the horizons of the [4+4] photocycloaddition in two distinct directions: 1) by utilizing [4+4] photocycloaddition in a total synthesis of crinipellin natural products possessing antibiotic and antitumor activity and 2) by developing a novel type of [4+4] photocycloaddition that employs a conjugated enyne as a partner of 2- pyridone. Our approach to the tetraquinane core of the crinipellins features intramolecular [4+4] photocycloaddition of a tethered furan-pyridone molecule followed by a four-step transannular ring closure. The sequence allows for a rapid assembly of a molecular framework by installing 19 of the 20 required carbon atoms and all but two stereogenic centers. The described synthesis represents an interesting new approach to these polycyclic molecules and a way to access crinipellin analogues. The enyne-pyridone [4+4] photocycloaddition led to formation of intriguing 1,2,5-cyclooctatriene-based products. Presence of the allene functionality was used as a lever in exploring the possibilities for derivatization of these photoadducts. Our investigations of enyne-pyridone photocycloaddition have come a long way: from the first proof-of-concept intermolecular trials producing complex mixtures, through the initial investigations of the intramolecular variant that taught us how to direct the reaction to the necessary mode ([2+2] vs. [4+4] photocycloaddition), and eventually to the controlled formation of stable allenic photoadducts and their further transformation into a diverse set of functionalized molecular scaffolds. We found that the inherent kinetic instability of 1,2,5-cyclooctatrienes facilitates several pathways of strain relief: allene-allene [2+2] dimerization, photooxidative decarbonylation when the irradiation is conducted in presence of air, isomerization of the 1,2-diene fragment into a 1,3-diene and the acid-promoted Cope rearrangement. Additionally, enyne-pyridone photoadducts can undergo transannular ring closure when treated with bromine and also be transformed into valuable bicyclo [5.1.0] octane structures that incorporate a rare example of a stable cyclopropanone by a fast and selective epoxidation-rearrangement process. Several important goals were achieved in the described research study. First, strategic incorporation of [4+4] photocycloaddition as one of the key steps in targeted synthesis of natural products has demonstrated the potential of this powerful reaction. Second, an efficient new approach to a tetraquinane skeleton was developed and successfully executed. Third, the fundamental basis for the novel photochemical transformation (enyne-pyridone cycloaddition) was set and major trends for this reaction were established resulting in obtaining stable allenic photoadducts. Finally, chemical properties and reactivity of stabilized amide-bridged 1,2,5-cyclooctatriene photoproducts were investigated breaking the ground for future involvement of these intermediates in synthetic strategies towards biologically active natural products and their analogues. / Chemistry

Macrophages can be activated by a variety of extracellular signals to polarize to either the M1 (inflammatory and antimicrobial) or to the M2 (wound repair and inflammation resolution) phenotype. Expression of arginase 1 in macrophages is a key marker of the M2 phenotype. Arginase 1 expression is induced by interleukin 4 (IL-4), a cytokine secreted by Th2 helper cells. All-trans retinoic acid (ATRA) is a product of metabolism of dietary retinol (vitamin A). In a manner analogous to hormones, ATRA binds to nuclear receptors in cells and influences gene expression and cell physiology. ATRA is important in the resolution of inflammation systemically and on the cellular level, however it has not been linked to M2 activation or arginase 1 expression. Testing the hypothesis that ATRA can induce arginase 1 in macrophages either directly or indirectly, it was found that ATRA alone cannot cause murine bone marrow-derived macrophages (BMDM) to activate in the M2 phenotype (as indicated by arginase 1 expression), however it can dramatically potentiate induction of arginase 1 expression and activity by IL-4. This is the first observation positively linking ATRA to arginase 1. Lipopolysaccharide (LPS), is a conserved structural component of the outer membrane of Gram negative bacteria, and a potent pyrogen. In metabolic endotoxemia, LPS concentration in the blood is slightly elevated, and over the long term this contributes to diverse inflammatory diseases such as atherosclerosis, obesity, and diabetes. LPS promotes the M1 phenotype and suppresses the M2 phenotype, but its contribution at low doses such as those found in metabolic endotoxemia are not well studied. In order to investigate mechanisms of LPS suppression at low doses, mice deficient in IRAK1 and tollip, key mediators or proinflammatory LPS signaling, were used to study IL-4, ATRA, and LPS crosstalk. LPS suppression of arginase 1 was found to be dependent on IRAK1 and tollip, but only at low doses of LPS. / Ph. D.

Ce travail, sur la dépollution de l’eau par OVHC sur charbon actif (CA), étudie l'interaction oxydation - adsorption : comment l'oxydation sur charbon de produits aromatiques modifie ses propriétés et en particulier sa capacité d'adsorption et d'oxydation (désactivation). Divers charbons commerciaux, mais aussi issus de boues activées, ont été caractérisés avant et après oxydation : propriétés texturales, composition élémentaire (CHNSO), fonctions de surface, pH au point de charge nulle et allure des courbes ATG. Seule leur teneur en cendres semble différer notablement. Les charbons actifs de boues ont une surface spécifique bien moindre (de 90 à 265 m².g-1) et un taux de cendres supérieur à 50% qui en font de moins bons adsorbants. Cependant la présence de métal, notamment le fer, a un effet positif sur l'oxydation catalytique. L'étude comparative en oxydation catalytique de 4 CA commerciaux en grains montre une désactivation intense (qui augmente avec la concentration de polluant) sur les 3-4 premières utilisations, puis une stabilisation. Le charbon résultant est nettement moins adsorbant. Les CA S23 et F22 ainsi stabilisés ont ensuite été utilisés pour déterminer la cinétique d'oxydation catalytique apparente et intrinsèque du phénol, grâce à un modèle incluant la diffusion. La comparaison de l'OVHC de 4 polluants aromatiques seuls et en divers mélanges synthétiques met en évidence des effets de mélange significatifs: les polluants les plus réfractaires en oxydation catalytique se dégradent beaucoup plus vite en mélange (ex 4NP) et inversement, les polluants les plus oxydés, lorsqu'ils sont seuls en solution, voient leur cinétique diminuer lorsqu'ils sont mélangés aux autres polluants (ex phénol, 4chlorophénol). Le mélange tend donc à uniformiser les comportements particuliers. Enfin, les essais de faisabilité du procédé de régénération oxydante AD-OX ont été effectués sur des effluents industriels. La régénération du charbon actif comme adsorbant est moins limitée qu'avec des mélanges de phénols substitués. / This work, on water treatment by catalytic Wet Air Oxidation (CWAO) using activated carbon (AC), aimed to study the interaction between oxidation-adsorption phenomena: how the oxidation of aromatic compounds on AC can modify its properties and specially its adsorption and oxidation characteristics (deactivation). Various commercials AC, and AC produced from activated sludge, have been characterized before and after oxidation by according methods such as textural characterization, elemental analysis (CHNSO), functional groups on carbon surfaces analysis, pH of the point of zero charge (pHpzc) analysis and thermogravimetric analysis (TGA); however, only their ash level was significantly different. In addition, the sludge based AC (SBAC) have a specific surface range of 90 to 265 m².g-1, which is lower than commercial AC, and with an ash level over 50%. Consequently they are less good adsorbents. However, the presence of metal, e.g. iron, has a positive affect on catalytic oxidation. The comparative study of catalytic oxidation with 4 commercial AC, show a severe deactivation (which increase with the pollutant concentration) on the first 3-4 utilizations before stabilization. The residual AC is clearly poor adsorbent. After stabilization, 2 commercials AC, only S23 and F22 CA, were studied on catalytic oxidation of phenol in term of apparent and intrinsic kinetics with including the diffusion effect in the model. The CWAO of 4 pure aromatic pollutants, and their various synthetic mixtures, showed mixing effects significantly: the most oxidation catalytic refractory pollutants were degraded rapidly when they mixed (e.g. 4-nitrophenol) but the kinetic was slow down for the pure pollutant whereas, the most oxidised pollutants, for pure solution, have an oxidation kinetic slower than when they mixed with others pollutants (e.g. Phenol, 4-chlorophenol). Therefore, the mixture tends to standardize from the individual behaviour. In conclude, the feasibility study of the oxidative regeneration process (AD-OX) was performed on industrial waste water. The regeneration AC as adsorbent is less limited than with mixtures of substituted phenols.

The explosive 2,4,6-trinitrotoluene (TNT) is currently a main ingredient in munitions; however the compound has failed to meet the new sensitivity requirements. The replacement compound being tested is 2,4-dinitroanisole (DNAN). DNAN is less sensitive to shock, high temperatures, and has good detonation characteristics. However, DNAN is more soluble than TNT, which can influence transport and fate behavior and thus bio-availability and human exposure potential. The objective of this study was to investigate the environmental fate and transport of DNAN in soil, with specific focus on sorption processes. Batch and column experiments were conducted using soils collected from military installations located across the United States. The soils were characterized for pH, electrical conductivity, specific surface area, cation exchange capacity, and organic carbon content. In the batch rate studies, change in DNAN concentration with time was evaluated using the first order equation, while adsorption isotherms were fitted using linear and Freundlich equations. Solution mass-loss rate coefficients ranged between 0.0002 h(-1) and 0.0068 h(-1). DNAN was strongly adsorbed by soils with linear adsorption coefficients ranging between 0.6 and 6.3 L g(-1), and Freundlich coefficients between 1.3 and 34 mg(1-n) L-n kg(-1). Both linear and Freundlich adsorption coefficients were positively correlated with the amount of organic carbon and cation exchange capacity of the soil, indicating that similar to TNT, organic matter and clay minerals may influence adsorption of DNAN. The results of the miscible-displacement column experiments confirmed the impact of sorption on retardation of DNAN during transport. It was also shown that under flow conditions DNAN transforms readily with formation of amino transformation products, 2-ANAN and 4-ANAN. The magnitudes of retardation and transformation observed in this study result in significant attenuation potential for DNAN, which would be anticipated to contribute to a reduced risk for contamination of ground water from soil residues.

This thesis looks at child development based on membership in 4-H clubs.

Submitted by Renorbio (renorbioba@ufba.br) on 2018-04-26T15:58:23Z No. of bitstreams: 1 TESE DE DOUTORADO_GLÁUCIO BARROS SALDANHA.pdf: 4782886 bytes, checksum: 5487ab253c7be5687d66ef5f9581108e (MD5) / Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2018-05-04T14:06:18Z (GMT) No. of bitstreams: 1 TESE DE DOUTORADO_GLÁUCIO BARROS SALDANHA.pdf: 4782886 bytes, checksum: 5487ab253c7be5687d66ef5f9581108e (MD5) / Made available in DSpace on 2018-05-04T14:06:18Z (GMT). No. of bitstreams: 1 TESE DE DOUTORADO_GLÁUCIO BARROS SALDANHA.pdf: 4782886 bytes, checksum: 5487ab253c7be5687d66ef5f9581108e (MD5) / Os neoflavonoides compreendem compostos que possuem um esqueleto básico de carbono (C6-C3-C6) e que podem ser sintetizados ou ser encontrado naturalmente em plantas superiores como das famílias Clusiaceae, Leguminosae, Rubiaceae e Rutaceae. Os neoflavonoides têm atraído grande interesse devido às suas propriedades farmacológicas e bioquímicas apresentadas em estudos in vitro e in vivo. Em relação às doenças tropicais negligenciadas (DTNs), os neoflavonoides demonstraram ser promissoras moléculas bioativas no tratamento da leishimaniose, tripanossomose americana e malária. Sendo assim, estudos adicionais são necessários para dar uma maior ênfase a sua ação farmacológica em outras doenças negligenciadas como a causada por vermes do gênero Schistosoma. Neste contexto farmacológico, o objetivo do presente trabalho foi avaliar o potencial quimioterapêutico do composto 7-acetoxi-4-aril-3,4-di-hidrocumarina, classificado como neoflavonoide, em um modelo experimental contra o Schistosoma mansoni. Além do estudo do potencial antiprotozoário, estudos não clínicos de segurança farmacológica foram realizados pela avaliação da toxicidade em dose única (14 dias) e em doses repetidas (28 dias) em camundongos Swiss fêmeas. O perfil de toxicidade aguda (300 e 2000 mg/kg) e em doses repetidas (250, 500 e 1000 mg/kg) foram realizados em camundongos Swiss fêmeas de acordo com a diretriz 423 e 407 da Organização para a Cooperação e Desenvolvimento Econômico (OECD), respectivamente, pelos parâmetros relacionados às alterações do peso corporal, consumo de alimento e água, parâmetros hematológicos e bioquímicos. Na avaliação farmacológica do 7-acetoxi-4-aril-3,4-di-hidrocumarina (6,25, 12,5, 25, 50 e 100 μg/mL) contra o S. mansoni, os parâmetros analisados foram a taxa de mortalidade, redução na atividade motora, número de ovos e alterações tegumentares. De acordo com experimentos realizados, foi demonstrado que o 7-acetoxi-4-aril-3,4-di-hidrocumarina a partir da concentração de 12.5 μg/mL induziu a mortalidade dos vermes S. mansoni, redução na atividade motora, mudanças na morfologia tegumentar e inibição na produção de ovos pela separação de todos os casais de vermes adultos tratados. A capacidade do 7-acetoxi-4-aril-3,4- di-hidrocumarina de manter os vermes adultos machos e fêmeas separados demonstra ser a principal justificativa para elevada redução na oviposição de S. mansoni. Além da atividade quimioterapêutico, os resultados da toxicidade aguda e em doses repetidas de 7-acetoxi-4-aril- 3,4-di-hidrocumarina demonstraram ausência de sinais clínicos adversos (contorções abdominais, reflexo de endireitamento, irritabilidade, piloereção), mortalidade, alterações significativas no peso corporal e dos órgãos internos, consumo de alimento e água. Os parâmetros hematológicos (eritrócitos, plaquetas e leucócitos) e bioquímicos (glicose, ureia, creatinina, ácido úrico, alanina aminotrasaminase, aspartato aminotrasaminase, colesterol, triglicerídeos) também não apresentaram alterações significativas quando comparado com os grupos controles dos estudos de toxicidade em dose única (aguda) e em doses repetidas. Em conclusão, os resultados do presente estudo demonstraram atividade anti-helmíntica do 7- acetoxi-4-aril-3,4-di-hidrocumarina e fornecem uma importante compreensão do perfil de toxicidade deste neoflavonoide, no qual pode ser considerado como sendo um composto com toxicidade superior a 2000 mg/kg em camundongos Swiss fêmeas. / The neoflavonoid group comprise compounds that have a basic carbon skeleton (C6-C3-C6) and that can be synthesized or be naturally found in families of higher plants such as the Clusiaceae, Leguminosae, Rubiaceae and Rutaceae families. Neoflavonoids have attracted great interest because of their pharmacological and biochemical properties presented in the in vitro and in vivo studies. In relation to neglected tropical diseases (NTDs), the neoflavonoids have been shown to be promising bioactive molecules in the treatment of leishmaniasis, American trypanosomiasis and malaria. Thus, additional studies are needed to give greater emphasis to their pharmacological action in other neglected diseases such as that caused by worms of Schistosoma genus. In this pharmacological context, the objective of the present study was to evaluate the chemotherapeutic potential of the 7-acetoxy-4-aryl-3,4- dihydrocoumarin, classified as neoflavonoid, using an experimental model against Schistosoma mansoni. In addition to study the antiprotozoal potential, non-clinical pharmacological safety studies were performed by evaluating single dose (14 days) and repeated doses (28 days) toxicity in female Swiss mice. The acute toxicity profile (300 and 2000 mg/kg) and repeated doses (250, 500 and 1000 mg / kg) were performed in female Swiss mice according to guidelines 423 and 407 of the Organisation for Economic Cooperation and Development (OECD), respectively, by the parameters related to changes in body weight, food and water consumption, as well as hematological and biochemical parameters. In the pharmacological evaluation of 7-acetoxy-4-aryl-3,4-dihydrocoumarin (6.25, 12.5, 25, 50 and 100 μg/ml) against S. mansoni, the parameters analyzed were the mortality rate, reduction in motor activity, number of eggs and tegumentary changes. According to experiments performed, it was demonstrated that the 7-acetoxy-4-aryl-3,4- dihydrocoumarin from the concentration of 12.5 μg/mL induced the mortality of S. mansoni worms, the reduction in motor activity and, changes in tegumentary morphology and inhibition in egg production by separation of all couples of adult worms treated. The capacity of 7-acetoxy-4-aryl-3,4-dihydrocoumarin to maintain separate male and female adult worms is shown to be the main justification for high reduction in S. mansoni oviposition. In addition to chemotherapeutic activity, the results of acute toxicity and repeated doses of 7-acetoxy-4- aryl-3,4-dihydrocoumarin demonstrated no clinical adverse symptoms (abdominal contortions, righting reflex, irritability, piloerection), mortality, significant changes in body weight and internal organs, food and water consumption. The hematological parameters (analysis of erythrocyte, platelets and leukocytes) and biochemical parameters (glucose, urea, creatinine, uric acid, aspartate aminotransferase, alanine aminotransferase, cholesterol, and triglycerides) also showed no significant changes when compared to the control groups. In conclusion, the results of the present study demonstrated in vitro anthelmintic activity of 7- acetoxy-4-aryl-3,4-dihydrocoumarin and provide an important understanding of the toxicity profile of this neoflavonoid, in which it can be considered as a compound with toxicity greater than 2000 mg/kg in female Swiss mice.

Made available in DSpace on 2014-07-29T16:11:50Z (GMT). No. of bitstreams: 1 Dissertacao Laura Maia Mairink Nassau.pdf: 2613768 bytes, checksum: d2e4321ca6a3e7930e1a7f57b3099a11 (MD5) Previous issue date: 2010-09-15 / Thromboembolic disorders produce the majority of diseases affecting the heart, and are the third leading cause of death worldwide. Venous thromboembolism is a thromboembolic disorder that occurs in the venous circulation, is a disease of high prevalence and remains a major cause of morbidity and mortality in hospitalized patients undergoing major surgery, the fact that affect patients from the very young, disease free prior to the more elderly mean that it is a problem with major socioeconomic burden by as much as by absenteeism in hospital patients in productive age. This describes the planning and synthesis of intermediates for the collection of new derivatives guanidine drawn from the infestina-4, protein extracted from the stomach Barber Triatoma infestans, with potent inhibitory activity of factor XII. Factor XII acts of direct and indirect enzymatic cascades in four of our body and has an important contribution to the formation of pathological vascular thrombi. The previous study of molecular modeling justified based planning in the structural and the electrostatic infestin. Thus it is concluded that the synthesis of intermediates 25-28, were getting adequate yields of 88.0 and 92.0% for compounds 25 and 26 and 71.4 and 65.0% for compounds 27 and 28 respectively. / As desordens tromboembólicas geram a maioria das doenças que acometem o coração, e são a terceira causa de morte mundial. O tromboembolismo venoso é uma desordem tromboembólica que ocorre na circulação venosa, é uma enfermidade de alta prevalência e continua sendo uma causa importante de morbimortalidade em pacientes hospitalizados e submetidos a cirurgias de grande porte, o fato de afetar pacientes desde os mais jovens, sem doenças prévias, até os mais idosos fazem com que ela constitua um problema sócio-econômico com grandes ônus tanto pelas internações quanto pelo absenteísmo em pacientes em idade produtiva. Este trabalho descreve o planejamento e a síntese de intermediários para obtenção de novos derivados guanidínicos desenhados a partir da infestina-4, proteína extraída do estômago do barbeiro Triatoma infestans, com potente atividade inibitória do fator XII. O fator XII atua de forma direta e indireta em quatro cascatas enzimáticas do nosso organismo e possui importante contribuição na formação patológica de trombos vasculares. O estudo prévio de modelagem molecular justificou o planejamento baseado nas características estruturais e eletrostáticas da infestina. Desta forma, conclui-se que a síntese dos intermediários 25-28 foram adequadas obtendo rendimentos de 88,0 e 92,0% para os compostos 25 e 26 e de 71,4 e 65,0% para os compostos 27 e 28, respectivamente.