MSc dissertation School of Chemistry Faculty of Science 0004984F / Many azapolycyclic aromatic ring systems, whether they are naturally occurring or synthetically made, display important biological activities. One important class of naturally occurring azapolycyclic aromatic ring systems are the dibenzopyrrocoline alkaloids, which contain an indole ring fused to an isoquinoline moiety, where they share a common nitrogen. The basic skeleton of these alkaloids is the indolo[2,1-a]isoquinoline nucleus. Both the dibenzopyrrocoline alkaloids and the indolo[2,1-a]isoquinolines have been found to inhibit tubulin polymerization and thus possess antitumour and antileukemic activities. In our laboratories, a variety of indolo[2,1-a]isoquinolines, for example 5,12- dimethyl-6-phenylindolo[2,1-a]isoquinoline, have been synthesized using the Suzuki-Miyaura cross coupling reaction and reaction conditions for the formation of aromatic rings (KOBut in DMF and a light source – developed in our laboratories) as key steps. In this dissertation we discuss the synthesis of (±)-5,6-dihydro-6-phenylindolo[2,1-a]isoquinolin-5-ol and ethyl indolo[2,1- a]isoquinoline-6-carboxylate using these reaction conditions as our key steps. The syntheses commenced with the N-protection of isatin with a benzyl and an ethyl acetate group to afford 1-benzylindoline-2,3-dione and ethyl 2-(2,3- dioxoindolin-1-yl)acetate respectively. The next step was the synthesis of the brominated compounds 1-benzyl-2-bromo-1H-indole and ethyl 2-(2-bromo- 1H-indol-1-yl)acetate by means of a functional group interconversion of the oxygen in the 3-position to two chlorine atoms, followed by hydrodehalogenation, using zinc in AcOH, and then bromination, using POBr3 in CH2Cl2. Having obtained the brominated compounds we went on and coupled them with 2-formylphenylboronic acid using the Suzuki-Miyaura cross coupling reaction to obtain the coupled products 2-(1-benzyl-1H-indol-2- yl)benzaldehyde and ethyl 2-(2-(2-formylphenyl)-1H-indol-1-yl)acetate in 92 and 77% yield, respectively. Aromatisation of ethyl 2-(2-(2-formylphenyl)-1Hindol- 1-yl)acetate to ethyl indolo[2,1-a]isoquinoline-6-carboxylate occurred smoothly in 2 minutes using 10 mol % KOBut in DMF at room temperature. Using the same reaction conditions on 2-(1-benzyl-1H-indol-2- yl)benzaldehyde to form 6-phenylindolo-[2,1-a]isoquino-line resulted in (±)- 5,6-dihydro-6-phenylindolo[2,1-a]iso-quinolin-5-ol being obtained in 75% yield (7:3 ratio of anti:syn). An attempt to dehydrate this compound using p-TSA in CH2Cl2 in the presence of molecular sieves was not successful. Time constraints prevented any further attempts at dehydrating (±)-5,6-dihydro-6- phenylindolo[2,1-a]iso-quinolin-5-ol. In conclusion, we managed to synthesize (±)-5,6-dihydro-6-phenylindolo[2,1- a]isoquinolin-5-ol and ethyl indolo[2,1-a]isoquinoline-6-carboxylate using the Suzuki-Miyaura cross coupling reaction and specific reaction conditions, using the base KOtBu, for the formation of aromatic rings, both as key steps.

Duas abordagens foram estudadas para a síntese enantiosseletiva do (+)-4a-H-eudesman-5a-ol ou (+)-pendulol (128) (esquema 1) . Numa primeira rota sintética (Rota 1), construiu-se enantiosseletivamente a octalona 92 , por urna reação de anelação de Robinson assimétrica via imina quiral. A redução da octalona 92, produziu o f3-álcool 114, que por desoxigenação do carbono C-3, forneceu a octalina 120. Contando com a possibilidade da metila angular induzir estereosseletividade na epoxidação da ligação dupla endocíc1ica na octalina 120, tentou-se a obtenção do a-epóxido 124. Entretanto, este foi obtido em urna mistura equimolecular com seu diastereoisômero, o f3-epóxido 124a. Numa segunda alternativa sintética (Rota 2), foi estudada a redução da octalona 92 L-selectride® de modo a obter-se o a-álcool 115. A complexação da a-hidroxila do substrato com o agente epoxidante, com posterior desoxigenação do carbono C-3, poderia permitir a preparação estereosseletiva do epóxido 124. O resultado desta etapa de redução não forneceu o produto esperado em rendimento apreciável, o que conduziu à utilização da metodologia de inversão da configuração da hidroxila em 114, desenvolvida por Mitsunobu. O a-álcool 115 foi obtido e epoxidado fornecendo o epoxi-álcool135. As tentativas de desoxigenação do carbono C-3via xantato não forneceram o a-epóxido 124. Desta forma optou-se pela abertura do anel oxirano em 135, sendo obtido o dio1137. Este foi submetido à mesilaçãoda hidroxila em C-3 com posterior redução por LiAIH4, o que forneceu urna mistura de prováveis produtos de eliminação, não permitindo a obtenção do (+)-pendulol (128). esquema 1: rotas sintéticas para a sintese enatiosseletiva do (+)-pendulol. / Two approaches were studied to the enantioselective synthesis of (+)-4a-H-eudesman-Sa-ol or (+)-pendulol (128) (scheme 1). On a first synthetic route (route 1), the octalone 92 was prepared by a Robinson annulation reaction via chiral imine. The reduction of compound 92 and deoxigenation on the C-3 carbon of the correspondent p-alcohol 114, led to the octalin 120. We expect that the angular methyl grou p could exerce sterical hindrance on the p-face of the biciclic sistem and thus directec de epoxidation to the opposite side to afford the epoxide 124 estereosselectively. However, the desired epoxide 124 was obtained in an equimolecular mixture with the diastereoisomer 124a. On a second alternative synthetic route (route 2), was studied reduction of octalone 92 L-selectride® to afford the a-alcohol 115. The expected complexation of the a-hidroxyl group to the epoxidizing agent could permit the stereoselective preparation of epoxide 124. the result of this step doens't led to the expected product in good yield. 80 one alternative was the invertion of the hidroxyl configuration on carbon C-3 in compound 114, via Mitsunobu methodology. The a-alcohol 115 was obtained and epoxidized to afford the epoxi-alcohol 135. All affords to deoxigenate the C-3 carbon via xantate do not permit the preparation of the epoxide 124. 80, the oppenning of the oxirane ring in compound 135 was done first, ledding to the diol 137. This compound was submitted to mesylation folowed by reduction, ledding to a mixture of probable elimination products, but de (+)-pendulol (128) was not detected. scheme 1: synthetic routes to the enantioselective synthesis of (+)-pendulol.

Submitted by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2016-01-04T16:31:23Z No. of bitstreams: 2 nayara_rayane_cesar.pdf: 2602002 bytes, checksum: c844463923756f76132f0190a6617bd5 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2016-01-04T16:31:46Z (GMT) No. of bitstreams: 2 nayara_rayane_cesar.pdf: 2602002 bytes, checksum: c844463923756f76132f0190a6617bd5 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2016-01-04T16:31:46Z (GMT). No. of bitstreams: 2 nayara_rayane_cesar.pdf: 2602002 bytes, checksum: c844463923756f76132f0190a6617bd5 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015 / Funda??o de Amparo ? Pesquisa do estado de Minas Gerais (FAPEMIG) / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq) / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (Capes) / O padr?o diet?tico ocidental, caracterizado pelo alto consumo de gordura saturada e carboidratos refinados, favorece o ac?mulo de tecido adiposo e o surgimento de v?rias doen?as cardiometab?licas (DCM). Atualmente, tem-se considerado que n?o apenas a quantidade, mas o perfil das gorduras ingeridas pode exercer forte influ?ncia sobre o desenvolvimento dessas doen?as. Nesse contexto, v?rios estudos t?m demonstrado que o consumo de alimentos fontes de ?cidos graxos monoinsaturados (MUFA) est? associado a um menor risco para o desenvolvimento de DCM. Al?m disso, t?m sido tamb?m identificados muitos compostos bioativos presentes nos alimentos vegetais, os quais t?m sido associados a efeitos ben?ficos na redu??o do risco e, ou, no tratamento de DCM. Dentre esses compostos est?o os carotenoides, que apresentam atividade antioxidante. Nessa perspectiva, o ?leo do pequi apresenta-se como um potencial alimento funcional, dado que os MUFA representam aproximadamente 60% dos seus ?cidos graxos, e possui ainda um teor elevado de carotenoides totais. Considerando que o padr?o de consumo alimentar ocidental favorece o desenvolvimento das DCM, e que o ?leo do pequi ? um potencial alimento protetor, mas ainda n?o foi explorado nesse contexto, o objetivo deste estudo foi avaliar os efeitos da substitui??o parcial da banha de porco (rica em ?cidos graxos saturados - SFA) por ?leo de Caryocar brasiliense ? pequi (rico em MUFA e carotenoides) em uma dieta de padr?o ocidental, sobre o metabolismo, a fun??o card?aca e o estado redox celular de ratos. Ap?s uma semana de adapta??o, os animais rec?m-desmamados foram distribu?dos em tr?s grupos (n=12) e tratados durante 12 semanas. Os grupos foram identificados conforme a dieta que receberam: CTRL ? controle, dieta AIN93G; HFS ? dieta alta em gordura e sacarose; HFS-OP ? dieta alta em gordura e sacarose, com substitui??o parcial da banha de porco por ?leo de pequi (27%). O peso corporal e a ingest?o alimentar foram monitorados durante todo o per?odo experimental; a press?o arterial sist?lica (PAS) e a frequ?ncia card?aca (FC) foram aferidas na 3? e 10? semanas; as fezes das ?ltimas 72 horas foram coletadas para avalia??o das concentra??es de colesterol e triglicer?deos (TG) e, ao final do experimento, os animais foram eutanasiados por decapita??o. As cavidades abdominais e tor?cicas foram abertas para coleta de amostras: (A) cora??es: foram retirados imediatamente para avalia??o da fun??o card?aca ex vivo; posteriormente foram avaliados os n?veis de peroxida??o lip?dica e capacidade antioxidante total; (B): tecido adiposo das regi?es epididimal e retroperitoneal, que foi pesado e posteriormente utilizado para avalia??es da adiposidade e histol?gicas; (C) soro: para determina??o das concentra??es de glicose, colesterol e TG; (D) plasma: para determina??o das concentra??es de insulina, leptina e adiponectina, peroxida??o lip?dica e capacidade antioxidante total; (E) f?gados: para avalia??o das concentra??es de colesterol e TG, an?lises histopatol?gicas e peroxida??o lip?dica, capacidade antioxidante total e atividade enzim?tica (super?xido dismutase, catalase e glutationa peroxidase). Observou-se que os pesos corporais dos animais HFS-OP e HFS foram mais elevados que CTRL (p<0,05), no entanto, a deposi??o de gordura na regi?o visceral em resposta ao consumo das dietas ocidentais foi atenuada pela substitui??o da banha de porco por ?leo de pequi (p<0,05). A menor sobrecarga reduziu a deposi??o de TG no tecido hep?tico o que pode estar associado ao retardo do desenvolvimento do diabetes. De um modo geral, a fun??o card?aca foi prejudicada pelas dietas ocidentais em compara??o ao CTRL. Nas avalia??es in vivo n?o foram observados efeitos diferenciais da substitui??o parcial da banha de porco por ?leo de pequi, contudo, quando a fun??o card?aca foi avaliada ex vivo, a ingest?o do ?leo atenuou os danos ? fun??o card?aca (p<0,05), sugerindo que, ainda que modestamente, o ?leo do pequi exerceu um efeito protetor sobre as estruturas card?acas intr?nsecas. Al?m disso, foi observada uma atenua??o da peroxida??o lip?dica no tecido hep?tico para HFS-OP em rela??o ? HFS (p<0,05), sugerindo que o ?leo do pequi pode ter favorecido a incorpora??o dos MUFA e de carotenoides nas membranas dos cardiomi?citos, o que exerceu um efeito protetor. Devido ao papel prim?rio do f?gado no controle metab?lico de todo o organismo, esse efeito de prote??o contra a peroxida??o lip?dica n?o p?de ser observado nos hepat?citos. Contudo, a presen?a dos carotenoides na dieta HFS-OP fortaleceu o sistema antioxidante ex?geno, evitando que a atividade das enzimas super?xido dismutase e glutationa peroxidase fosse prejudicada em HFS-OP como observado para HFS (p<0,05). Essas adapta??es sugerem que a substitui??o parcial da banha de porco por ?leo de pequi foi capaz de atenuar alguns efeitos delet?rios da dieta ocidental sobre o metabolismo lip?dico, a fun??o card?aca e o estado redox celular de ratos. / Disserta??o (Mestrado) ? Programa Multic?ntrico de P?s-gradua??o em Ci?ncias Fisiol?gicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2015. / ABSTRACT The Western diet pattern, which means a high saturated fat and refined carbohydrates intake, leads to body fat accumulation and several cardiometabolic diseases (CMD). Currently, it has been considered that, not only the amount, but the fat quality, can exert a strong influence in the development of those diseases. In this context, several studies have shown that consuming foods high in monounsaturated fatty acids (MUFA) is associated with lower risk for CMD. Moreover, it has also been identified many bioactive compounds in plant foods which are associated with beneficial effects in reducing the risk, or treating DCM. Among these compounds are carotenoids, which have strong antioxidant activity. In this perspective, pequi oil is a potential functional food, since MUFA represent approximately 60% of its fatty acids content, and it is also high in several antioxidant carotenoids. So, considering that western diet pattern promotes CMD development, and pequi oil is a potential functional food, but it has not been explored in this context, the aim of this study was to evaluate the effects of a partial replacement of lard (high in SFA) by pequi oil (high in MUFA and carotenoids), into a Western diet model, on metabolism, cardiac function and cellular redox status of rats. The animals were divided into three groups (n = 12) and treated during 12 weeks: CTRL - control, AIN93G diet; HFS ? high in saturated fat and sucrose; HFS-OP - high in saturated fat and sucrose, with partial replcement of lard by pequi oil (27%). Body weight and food intake were monitored throughout the experimental period; systolic blood pressure (SBP) and heart rate (HR) were measured at the 3rd and 10th weeks; faeces from the last 72 hours were collected for evaluation of cholesterol and triglycerides (TG). At the end of the experiment, all animals were killed by decapitation, the abdominal and thoracic cavities were opened for collection of samples: (A) hearts were taken immediately to evaluate the ex vivo cardiac function; levels of lipid peroxidation and total antioxidant capacity; (B): epididymal and retroperitoneal adipose tissues were harversted, weighed and subsequently used for adiposity and histological evaluations; (C) serum: for glucose, cholesterol and TG determination; (D) plasma: for insulin, leptin and adiponectina determinations, lipid peroxidation, total antioxidant capacity; (E) livers: for cholesterol and TG levels, histopathological analyzes, lipid peroxidation, total antioxidant capacity and enzyme activities. Body weights from HFS-OP and HFS animals were equally higher than CTRL (p<0.05); however, visceral fat deposition in response to consumption of the Western diet was attenuated by replacing lard by pequi oil and it also led to less TG deposition in the liver (p<0.05). In general, cardiac function was impaired by Western diet, promoting a higher blood pressure and heart rate in vivo and a lower cardiac contractility and relaxation efficiency ex vivo (p<0,05). However, although there were no differential effects from the partial replacement of lard by pequi oil on blood pressure and heart rate in vivo, this replacement attenuated the damage to cardiac function compared to HFS (p<0.05), suggesting that, eventhough modestly, pequi oil exerted a protective effect on intrinsic cardiac structures. In addition, the partial replacement of lard by pequi oil reduced lipid peroxidation in cardiomyocytes (p<0.05) compared to HFS, which was not observed in hepatocytes. Moreover, in the hepatocytes, there were an increasing in total antioxidant capacity and catalase and glutathione peroxidase activities compared to HFS (p<0.05). These adaptations suggest that the partial replacement of lard by pequi oil mitigated some deleterious effects of the Western diet on lipid metabolism, cardiac function and cellular redox status of rats.

Duas abordagens foram estudadas para a síntese enantiosseletiva do (+)-4a-H-eudesman-5a-ol ou (+)-pendulol (128) (esquema 1) . Numa primeira rota sintética (Rota 1), construiu-se enantiosseletivamente a octalona 92 , por urna reação de anelação de Robinson assimétrica via imina quiral. A redução da octalona 92, produziu o f3-álcool 114, que por desoxigenação do carbono C-3, forneceu a octalina 120. Contando com a possibilidade da metila angular induzir estereosseletividade na epoxidação da ligação dupla endocíc1ica na octalina 120, tentou-se a obtenção do a-epóxido 124. Entretanto, este foi obtido em urna mistura equimolecular com seu diastereoisômero, o f3-epóxido 124a. Numa segunda alternativa sintética (Rota 2), foi estudada a redução da octalona 92 L-selectride® de modo a obter-se o a-álcool 115. A complexação da a-hidroxila do substrato com o agente epoxidante, com posterior desoxigenação do carbono C-3, poderia permitir a preparação estereosseletiva do epóxido 124. O resultado desta etapa de redução não forneceu o produto esperado em rendimento apreciável, o que conduziu à utilização da metodologia de inversão da configuração da hidroxila em 114, desenvolvida por Mitsunobu. O a-álcool 115 foi obtido e epoxidado fornecendo o epoxi-álcool135. As tentativas de desoxigenação do carbono C-3via xantato não forneceram o a-epóxido 124. Desta forma optou-se pela abertura do anel oxirano em 135, sendo obtido o dio1137. Este foi submetido à mesilaçãoda hidroxila em C-3 com posterior redução por LiAIH4, o que forneceu urna mistura de prováveis produtos de eliminação, não permitindo a obtenção do (+)-pendulol (128). esquema 1: rotas sintéticas para a sintese enatiosseletiva do (+)-pendulol. / Two approaches were studied to the enantioselective synthesis of (+)-4a-H-eudesman-Sa-ol or (+)-pendulol (128) (scheme 1). On a first synthetic route (route 1), the octalone 92 was prepared by a Robinson annulation reaction via chiral imine. The reduction of compound 92 and deoxigenation on the C-3 carbon of the correspondent p-alcohol 114, led to the octalin 120. We expect that the angular methyl grou p could exerce sterical hindrance on the p-face of the biciclic sistem and thus directec de epoxidation to the opposite side to afford the epoxide 124 estereosselectively. However, the desired epoxide 124 was obtained in an equimolecular mixture with the diastereoisomer 124a. On a second alternative synthetic route (route 2), was studied reduction of octalone 92 L-selectride® to afford the a-alcohol 115. The expected complexation of the a-hidroxyl group to the epoxidizing agent could permit the stereoselective preparation of epoxide 124. the result of this step doens't led to the expected product in good yield. 80 one alternative was the invertion of the hidroxyl configuration on carbon C-3 in compound 114, via Mitsunobu methodology. The a-alcohol 115 was obtained and epoxidized to afford the epoxi-alcohol 135. All affords to deoxigenate the C-3 carbon via xantate do not permit the preparation of the epoxide 124. 80, the oppenning of the oxirane ring in compound 135 was done first, ledding to the diol 137. This compound was submitted to mesylation folowed by reduction, ledding to a mixture of probable elimination products, but de (+)-pendulol (128) was not detected. scheme 1: synthetic routes to the enantioselective synthesis of (+)-pendulol.

Duas abordagens foram estudadas para a síntese enantiosseletiva do (+)-4a-H-eudesman-5a-ol ou (+)-pendulol (128) (esquema 1) . Numa primeira rota sintética (Rota 1), construiu-se enantiosseletivamente a octalona 92 , por urna reação de anelação de Robinson assimétrica via imina quiral. A redução da octalona 92, produziu o f3-álcool 114, que por desoxigenação do carbono C-3, forneceu a octalina 120. Contando com a possibilidade da metila angular induzir estereosseletividade na epoxidação da ligação dupla endocíc1ica na octalina 120, tentou-se a obtenção do a-epóxido 124. Entretanto, este foi obtido em urna mistura equimolecular com seu diastereoisômero, o f3-epóxido 124a. Numa segunda alternativa sintética (Rota 2), foi estudada a redução da octalona 92 L-selectride® de modo a obter-se o a-álcool 115. A complexação da a-hidroxila do substrato com o agente epoxidante, com posterior desoxigenação do carbono C-3, poderia permitir a preparação estereosseletiva do epóxido 124. O resultado desta etapa de redução não forneceu o produto esperado em rendimento apreciável, o que conduziu à utilização da metodologia de inversão da configuração da hidroxila em 114, desenvolvida por Mitsunobu. O a-álcool 115 foi obtido e epoxidado fornecendo o epoxi-álcool135. As tentativas de desoxigenação do carbono C-3via xantato não forneceram o a-epóxido 124. Desta forma optou-se pela abertura do anel oxirano em 135, sendo obtido o dio1137. Este foi submetido à mesilaçãoda hidroxila em C-3 com posterior redução por LiAIH4, o que forneceu urna mistura de prováveis produtos de eliminação, não permitindo a obtenção do (+)-pendulol (128). esquema 1: rotas sintéticas para a sintese enatiosseletiva do (+)-pendulol. / Two approaches were studied to the enantioselective synthesis of (+)-4a-H-eudesman-Sa-ol or (+)-pendulol (128) (scheme 1). On a first synthetic route (route 1), the octalone 92 was prepared by a Robinson annulation reaction via chiral imine. The reduction of compound 92 and deoxigenation on the C-3 carbon of the correspondent p-alcohol 114, led to the octalin 120. We expect that the angular methyl grou p could exerce sterical hindrance on the p-face of the biciclic sistem and thus directec de epoxidation to the opposite side to afford the epoxide 124 estereosselectively. However, the desired epoxide 124 was obtained in an equimolecular mixture with the diastereoisomer 124a. On a second alternative synthetic route (route 2), was studied reduction of octalone 92 L-selectride® to afford the a-alcohol 115. The expected complexation of the a-hidroxyl group to the epoxidizing agent could permit the stereoselective preparation of epoxide 124. the result of this step doens't led to the expected product in good yield. 80 one alternative was the invertion of the hidroxyl configuration on carbon C-3 in compound 114, via Mitsunobu methodology. The a-alcohol 115 was obtained and epoxidized to afford the epoxi-alcohol 135. All affords to deoxigenate the C-3 carbon via xantate do not permit the preparation of the epoxide 124. 80, the oppenning of the oxirane ring in compound 135 was done first, ledding to the diol 137. This compound was submitted to mesylation folowed by reduction, ledding to a mixture of probable elimination products, but de (+)-pendulol (128) was not detected. scheme 1: synthetic routes to the enantioselective synthesis of (+)-pendulol.

Made available in DSpace on 2014-06-11T19:28:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-04-08Bitstream added on 2014-06-13T18:57:11Z : No. of bitstreams: 1 maccari_flr_me_arafcf.pdf: 1400540 bytes, checksum: 7bc406a11537837c7f75cdf60b68c782 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / O terpinen-4-ol é o principal componente da M. alternifólia, apresenta atividade antiinflamatória, antibacteriana e antifúngica; em estudos recentes in vitro a atividade antineoplásica para linhagens celulares de melanoma (M14) foi demonstrada. O objetivo específico deste trabalho foi verificar a atividade farmacológica in vitro dos isômeros óticos (-) terpinen-4-ol e (+) terpinen-4-ol e do óleo de Melaleuca alternifolia em nove linhagens diferentes de células tumorais, incluindo a célula UACC-62 do melanoma que ainda não havia sido estudada, e a concentração eficaz para o desenvolvimento de formulação que possa ter ação contra o melanoma. Após realização dos ensaios farmacológicos in vitro verificou-se que o (-)terpinen-4-ol apresentou melhor atividade nas linhagens celulares de melanoma, sendo o princípio ativo de escolha para as duas formulações que foram desenvolvidas, testadas e comprovadas a qualidade e estabilidade. Para caracterização das formulações foram efetuados os ensaios reológicos, sendo comprovado que as emulsões desenvolvidas são adequadas para o uso tópico no que diz respeito às suas características reológicas, sendo que as duas apresentaram comportamento de fluxo semelhante, diferindo apenas na área de histerese. Posteriormente foram feitos testes de permeação e retenção cutânea in vitro, para verificar qual formulação permite que o princípio ativo atinja em maior concentração a camada de interesse para atividade contra o melanoma. O método proposto para quantificação do (-)-terpinen-4-ol foi validado e utilizado nos ensaios de estabilidade acelerada, liberação, permeação e retenção cutânea in vitro. Os ensaios de liberação demonstraram que as duas formulações apresentam cinética de zero ordem, com fluxo de 14,62 µg/cm2 /h para formulação 1 e de 6,70 µg/cm2 /h para formulação F2. Na retenção cutânea... / The terpinen-4-ol is the major component of M. alternifolia, has anti-inflammatory, antibacterial and antifungal, in recent studies in vitro anticancer activity for melanoma cell lines (M14) was demonstrated. The specific objective of this study was to assess the in vitro pharmacological activity of optical isomers (-) terpinen-4-ol and (+) terpinen-4-ol and oil of Melaleuca alternifolia in nine different tumor cell lines, including cell UACC -62 melanoma that had not yet been studied, and effective concentration for the formulation development that may have action against melanoma. After performing the in vitro pharmacological tests showed that the (-) terpinen-4-ol showed better activity in melanoma cell lines, with the active ingredient of choice for the two formulations were developed, tested and proven quality and stability. For characterization of the formulations were made the rheological tests and confirmed that the developed emulsions are suitable for topical use in relation to their rheological characteristics, and the two had similar flow behavior, differing only in the area of hysteresis. Subsequent tests were performed permeation and skin retention in vitro, to determine which formulation allows the active ingredient reaches higher concentration in the layer of interest for activity against melanoma. The proposed method for quantification of (-)-terpinen-4-ol was validated and used in accelerated stability testing, release, skin permeation and retention in vitro. The release assays demonstrated that both formulations have zero order kinetics at a rate of 14.62 g/cm2/h for formulation 1 and 6.70 g/cm2/h for formulation F2. In vitro skin retention was found that the F1 showed retention of terpinen-4-ol smaller in the stratum corneum, compared to F2. Conversely, the retention in the epidermis over the dermis of terpinen-4-ol was higher in F1. It was found that formulation F1 ... (Complete abstract click electronic access below)

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-01-16T18:03:33Z No. of bitstreams: 1 YguatyaraDeLunaMachado_TESE.pdf: 3932579 bytes, checksum: ff6076d950bb4fc98594b19efe56ff78 (MD5) / Approved for entry into archive by Elisangela Moura (lilaalves@gmail.com) on 2017-01-16T18:14:01Z (GMT) No. of bitstreams: 1 YguatyaraDeLunaMachado_TESE.pdf: 3932579 bytes, checksum: ff6076d950bb4fc98594b19efe56ff78 (MD5) / Made available in DSpace on 2017-01-16T18:14:01Z (GMT). No. of bitstreams: 1 YguatyaraDeLunaMachado_TESE.pdf: 3932579 bytes, checksum: ff6076d950bb4fc98594b19efe56ff78 (MD5) Previous issue date: 2014-07-02 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / A Ag?ncia Nacional de Petr?leo, G?s Natural e Biocombust?veis tem como principal miss?o regulamentar e especificar toda a produ??o e comercializa??o do biodiesel produzido em territ?rio nacional. Para a sua comercializa??o ? necess?rio que o biodiesel passe por um controle r?gido de qualidade, bem como esteja devidamente especificado pelas principais normas. A estabilidade oxidativa que ? um dos par?metros incluso pela norma europ?ia EN 14214 vem adquirindo cada vez mais espa?o em pesquisas por estar intrinsecamente relacionada ? qualidade do biodiesel. Biodiesel ? uma mistura de ?steres alqu?licos de ?cidos graxos obtido, convencionalmente, atrav?s da rea??o de transesterifica??o de um ?leo vegetal ou gordura animal. No entanto, a natureza da mat?ria-prima a qual lhe dar? origem ? um dos fatores determinantes em seu grau de estabilidade, visto que por apresentarem insatura??es em n?mero e em distintas posi??es os tornam suscept?veis ao ataque do oxig?nio atmosf?rico e a condi??es de elevadas temperaturas proporcionando, assim, a sua degrada??o. Uma das principais problem?ticas enfrentadas, atualmente, pela ind?stria de biodiesel prov?m da sua baixa estabilidade levando a uma diminui??o de sua qualidade por longos per?odos de armazenamento sendo necess?ria a aplica??o de antioxidantes. Nesta tese, um estudo cin?tico experimental baseado no consumo de diferentes antioxidantes sint?ticos adicionados em distintas concentra??es foi realizado com amostras de ?leos vegetais de moringa (Moringa oleifera) e de maracuj? (Passiflora edulis), ?cido ol?ico estocado (AO) durante seis e dezoito meses e biodiesel de soja (Glycine max L.) e girassol (Helianthus annuus) em diferentes temperaturas, a uma press?o de oxig?nio puro a 700 kPa, utilizando a metodologia ASTM D7545 (PetroOXY). O modelo de primeira ordem obtido para o ?leo de moringa, amostras de ?cido ol?ico estocado (AO) e biodiesel de soja permitiu obter informa??es a respeito de par?metros, tais como: concentra??o cr?tica e concentra??o de antioxidante natural inerente ? amostra avaliada , informando que o ?ltimo n?o exerceu influ?ncia, a n?o ser inicialmente, no processo oxidativo das mesmas. Enquanto, o par?metro determinado para o modelo de ordem zero para as amostras de ?leo de maracuj? e girassol relacionou-se a diferentes reatividades da mat?ria-prima. A estabilidade das amostras determinadas pela entalpia de ativa??o (?HA) deu-se na seguinte ordem: ?HA (?leo de moringa) > ?HA (?leo de maracuj?); ?HA (AO 6 meses) ?HA (AO 18 meses) e ?HA (biodiesel de soja) > ?HA (biodiesel de girassol). Fatores de estabiliza??o desempenharam diferentes pap?is na estabiliza??o dos sistemas estudados. Concentra??o de antioxidante e temperatura mostraram distintas influ?ncias, no processo oxidativo, para as amostras de ?leos vegetais e ?cido ol?ico estocadas (AO) acompanhadas pelos seus ?ndices de acidez. / Oxidative stability is a parameter included in the European standard EN 14214 and is closely associated with the quality of biodiesel. The biodiesel is usually obtained in a transterification reaction vegetable oil or animal fat. However, the composition of the raw resources biodiesel is obtained from influences the stability degree of the latter, particularly when biodiesel is stored for long periods of time, causing its degradation, thereby reducing biodiesel quality and making it inadequate for trade. In this thesis, an experimental kinetic study based on the consumption of several synthetic antioxidants added in various concentrations to vegetable oils of moringa (Moringa oleifera), passion fruit (Passiflora edulis) and oleic acid (AO) stored for six and eighteen months at the temperatures 110 ?C, 120 ?C, 130 ?C and 140 ?C, as well as biodiesel from soybean (Glycine max L.) and sunflower (Helianthus annuus) oils at the temperatures 130 ?C, 135 ?C, 140 ?C and 145 ?C at a 700 kPa pure oxygen pressure, using the ASTM D7545 Method (PetroOXY). It has been obtained a first order reaction kinetic model for oleic acid, soybean biodiesel and moringa oil samples, while for passion fruit oil and sunflower biodiesel samples a zero order reaction kinetic model has been obtained. Parameter 0,CICCCC??? determined for the zero order model was related to distinct composition variations of the raw resources. The stability order of samples established using activation enthalpy (?HA) was the following: ?HA (moringa oil) > ?HA (Passion fruit oil); ?HA (oleic acid stored for six months) ? ?HA (oleic acid stored for eighteen months) and ?HA (soybean biodiesel) > ?HA (sunflower biodiesel). In all evaluated temperatures except for 140?C, acid numbers for passion fruit oil with antioxidants added have increased after storage, while for the moringa oil a random behavior has been observed.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-03-21T18:51:09Z No. of bitstreams: 1 MychelleKytchiaRodriguesNunesDuarte_DISSERT.pdf: 2556724 bytes, checksum: 7d5fee1d4fe61eba6aa3c5ddd4fa6747 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-03-28T00:32:58Z (GMT) No. of bitstreams: 1 MychelleKytchiaRodriguesNunesDuarte_DISSERT.pdf: 2556724 bytes, checksum: 7d5fee1d4fe61eba6aa3c5ddd4fa6747 (MD5) / Made available in DSpace on 2017-03-28T00:32:58Z (GMT). No. of bitstreams: 1 MychelleKytchiaRodriguesNunesDuarte_DISSERT.pdf: 2556724 bytes, checksum: 7d5fee1d4fe61eba6aa3c5ddd4fa6747 (MD5) Previous issue date: 2016-12-06 / A doen?a arterial coronarina ? uma das principais causa de ?bitos em todo o mundo e pode ser desencadeada por altera??es no perfil s?rico de ?cidos graxos, nos padr?es de express?o g?nica, no consumo alimentar e diet?tico e por desequil?brios antropom?tricos e/ou de composi??o corporal. O diagn?stico precoce desta doen?a ? um desafio na medicina translacional, visto que os m?todos utilizados s?o onerosos e/ou invasivos. O trabalho ent?o teve como objetivo identificar biomarcadores para o diagn?stico precoce da aterosclerose por meio do perfil serico de ?cidos graxos, express?o do RNAm da enoil-coA-hidratase (ECDHC3) e de fatores nutricionais em pacientes sem les?es e com diferentes extens?es da les?o ateroscler?tica. Realizou-se um estudo observacional, com a amostragem coletada por conveni?ncia, formada por pacientes que iriam realizar pela primeira vez a cinecoronariogradia no setor de Hemodin?mica do Hospital Universit?rio Onofre Lopes. Na primeira casu?stica participam 59 pacientes (n1, 2011-2013) e na segunda 41 (n2, 2014-2015), ambos com idade entre 30-74 anos. Determinou-se a extens?o das les?es por meio do ?ndice de Friesinger, o perfil bioqu?mico (glic?mico,lipid?mico) por espectrometria semiautomatizado; concentra??o s?rica de ?cidos graxos pela cromatografia gasosa; express?o do RNAm do ECHDC3 pela rea??o de cadeia de prolimerase (PCR) em tempo real; consumo alimentar e diet?tico por dois recordat?rios de 24h, par?metros antropom?tricos e composi??o corporal pela balan?a com bioimped?ncia el?trica, fita m?trica e estadiometro. Os pacientes foram classificados em grupos: sem les?o (n1=18/n2 =8), poucas les?es (n1=17/n2=6), intermedi?rias (n1=17/n2=15) e graves (n1=7/n2=12). Na primeira casu?stica foi encontrado elevadas concentra??es s?ricas de ?cido ol?ico e de ?cidos graxos monoinsaturados nos pacientes com poucas les?es e intermedi?rias, quando comparado com pacientes sem les?o (p<0,05). A express?o do ECHDC3 foi 1,2 vezes mais alta em pacientes com poucas les?es que em pacientes sem les?o (p=0,023), e 1,8 vezes mais baixa em pacientes com les?o grave que em pacientes sem les?o (p=0,020). Na segunda casu?stica, a express?o do ECHDC3 foi 1,93 mais alta em pacientes com les?o intermedi?ria do que com poucas les?es (p = 0.011) e 1,91 vezes mais alta em pacientes com les?o grave que em poucas les?es (p = 0.013). A an?lise de Spearman mostrou uma correla??o entre os grupos de Friesinger com a express?o do ECHDC3 (r = 0.327, p =0.037) , e deste com o percentual de gordura visceral (r = 0.416, p =0.009). O ?ndice de Friesinger tamb?m mostrou uma correla??o com o consumo de carboidrato (r = 0.754, p = 0.002), vitamina B1 (r = 0.507, p = 0.001), vitamina B2 (r = 0.388, p = 0.012), folato (r = 0.599, p = 0.000) e magn?sio (r = 0.528, p = 0.003). Verificou-se que o aumento de ?cido ol?ico s?rico, da express?o do ECHDC3 e da gordura visceral podem contribuir para a progress?o da aterosclerose, uma vez que estes podem favorecer a ? ? oxida??o, rea??o que favorece a forma??o de esp?cies reativas de oxig?nio, desencadeando inflama??o, um dos principais gatilhos para a aterosclerose. Tamb?m foi visto que o consumo de carboidratos e alguns micronutrientes podem favorecer a progress?o da aterosclerose, j? que o aumento da ingest?o destes nutrientes pode propiciar a defici?ncia na absor??o ou estresse oxidativo, que implica diretamente na etiologia desta doen?a. / Coronary arterial disease is a at leading cause of death worldwide and can be triggered by alterations in the serum profile of fatty acids, by patterns of gene expression, changes in dietary intake, and alteration anthropometric. The early diagnosis of this pathophysiology is a challenge in translational medicine, since the methods used are expensive and / or invasive. The aim in the study was to identify biomarkers for the early diagnosis of atherosclerosis through the relationship of serum fatty acid profile, enoyl-coA hydratase (ECDHC3) mRNA expression and nutritional factors in patients without lesions and with different extensions of the atherosclerotic lesion. The study was observational, with the sample collected for convenience in two casuistry in the Hemodynamics sector of the Onofre Lopes University Hospital (HUOL). In the first series, 59 patients partipated (n1, 2011-2013) and in the second 41 individuals ( n2, 2014-2015), both aged 30-74 years and who were undergoing coronariography for the first time. The extent of atherosclerotic lesions was determined by Friesinger index, the biochemical profile by semi-automated spectrometry; the concentration of fatty acids by gas chromatography; gene expression of ECHDC3 mRNA by real-time PCR; food consumption and dietary intake for two 24-hour dietary intake recalls, anthropometric parameters and corporal composition by the electric bioimpedance, measuring tape and stadiometer scale.Patients were classified into groups: no lesion (n1 = 18 / n2 = 8), low lesions (n1 = 17 / n2 = 6), intermediate lesions (n1 = 17 / n2 = 15) and major lesion (n1= 7 / n2 = 12). In n1 was observed high serum concentrations of oleic acid and monounsaturated fatty acids in patients with low lesions and intermediate when compared to patients without lesions (p <0.05). ECHDC3 expression was 1.2 fold-higher in patients with low lesions than in patients without lesions (p = 0.023), and 1.8 fold- lower in patients with major lesions than in patients without lesions (p = 0.020). In the second casuistry, the expression of ECHDC3 was 1.93 fold-higher in patients with intermediate lesions than in low lesions (p = 0.011) and 1.91 fold-higher in patients with severe lesions than in low lesions (p = 0.013). Spearman's analysis showed a positive correlation showed a between ECHDC3 mRNA expression and Friesinger index (r = 0.327, p = 0.037), between the gene and visceral fat (r = 0.416, p = 0.009). The Friesinger index also showed a correlation with the consumption of carbohydrate (r = 0.754, p = 0.002), vitamin B1 (r = 0.507, p = 0.001), vitamin B2 (r = 0.388, p = 0.012), folate (r = 0.599, p = 0.000), magnesium (r = 0.528, p = 0.003). It was verified that oleic acid, ECHDC3 expression, percentage of visceral fat could favors ?-oxidation, trigger for inflammation and CVD; while the greater consumption of carbohydrate and some micronutrients, also could be associated with the CVD development, since the excess or decreased absorption can favors the oxidative stress, that favors the atherosclerosis.

Perfluorinated compounds are organic compounds in which all hydrogen atoms in a carbon chain are substituted with fluorine atoms. These compounds are highly stable, persistent and bioaccumulative. They are purely anthropogenic compounds contained in biota and abiota. Partition coefficient between n-octanol and water is the essential toxicological parameter of a compound. This parameter helps us to assess behaviour of compound in the environment as well as in the living organisms. The shake flask method and the RP-HPLC method were employed to measure the Kow of nine perfluorinated acids. Using the shake flask method, the surface activity of compounds and the acid dissociation caused false results of the measurement. But behaviour of these compounds in the environment can be assess. Accurate and precise results were measured by the RP-HPLC method using an acetate buffer. Log Kow of perfluoro- carboxylic acids, with the carbon chain length of 5-14, were found out, their final value ranging between 1.66 and 5.10. Log Kow of acid with 12 carbons was estimated based on the linear regression of dependence of log Kow on the number of carbons. There were significant differences in the results obtained by various software. Thus, the results cannot be considered relevant. These software are not suitable for...

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