Orientador: Alba Regina Monteiro Souza Brito / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-26T17:16:46Z (GMT). No. of bitstreams: 1 Almeida_AnaCristinaAlvesde_D.pdf: 2447485 bytes, checksum: 029d5569d7c4d1eaaffa8f4a530937dd (MD5) Previous issue date: 2015 / Resumo: A Doença Inflamatória Intestinal (DII), que compreende a Doença de Crohn (DC) e a Retocolite Ulcerativa (RCU), é marcada por resposta inflamatória exacerbada a componentes da microbiota, com danos à mucosa do cólon. O tratamento de DII envolve drogas ineficazes para a remissão de todos os parâmetros da doença, com vários efeitos colaterais e custo elevado, o que motiva a busca de novos agentes terapêuticos. Sendo os produtos naturais uma importante fonte para desenvolvimento de medicamentos, buscou-se, nesse trabalho, avaliar o efeito do alcaloide índigo em modelos experimentais de colite. Inicialmente, foi avaliado o tratamento oral com índigo em colite aguda induzida por ácido trinitrobenzeno sulfônico (TNBS) em ratos HanUnib: WH (Wistar), um modelo experimental de DC. O tratamento com índigo resultou em redução da lesão macroscópica, medida através de escore, na dose de 3 mg/kg, e da área de lesão ulcerativa (doses 0,1; 3; 10 e 30 mg/kg). Apenas a administração da maior dose (30 mg/kg) evitou o aumento da razão peso/comprimento do cólon e não houve diminuição da diarreia e aderência do cólon, após tratamento com o alcaloide. Danos histológicos foram minimizados no cólon de animais tratados com índigo (3, 6 e 12 mg/kg). Como a lesão macroscópica por TNBS é bastante severa, a dose de 3 mg/kg, que reduziu tanto o índice (escore) quanto a área de lesão, foi selecionada para as análises posteriores. Nos ratos tratados com índigo (3 mg/kg), houve aumento na atividade da superóxido dismutase (SOD) e redução da atividade da glutationa peroxidase (GPx), redução dos níveis de peroxidação lipídica (LPO) e, parcialmente, de glutationa (GSH), sem alteração significativa na atividade da glutationa redutase (GR) e catalase (CAT). O tratamento com índigo (3 mg/kg) evitou aumento da expressão de ciclooxigenase 2 (COX-2), e não mostrou efeito significativo na expressão de fator nuclear de transcrição ?B (NF-?B) e na concentração de citocina anti-inflamatória interleucina 10 (IL-10). O segundo modelo experimental empregado neste trabalho foi a indução de colite aguda por dextrana sal sódico (DSS), em camundongos Unib: SW (Swiss), que apresenta similaridades com a RCU. A administração de índigo (3 mg/kg) não levou à redução significativa do índice de atividade da doença (DAI), o qual engloba alteração de peso corporal, presença de diarreia e sangue nas fezes; entretanto, foi eficaz em evitar o aumento da razão peso/comprimento do cólon. Em análise histológica, notou-se menor gravidade dos danos causados pelo DSS (aumento da parede do cólon, com infiltração celular na mucosa e submucosa, desorganização do epitélio). No cólon de animais tratados com índigo, observou-se aumento na atividade da SOD, não acompanhada de mudanças nos níveis de GSH e atividade da GPx, GR e CAT. O alcaloide inibiu aumento na concentração cólica da citocina IL-6, mas não da interleucina IL-1?. Em modelo experimental de colite crônica, com recidiva, associada a câncer de cólon por azoximetano e DSS (AOM/DSS) em camundongos Unib: SW (Swiss) machos, a administração de índigo reduziu a mortalidade, minimizou a perda de massa corporal dos animais e evitou o aumento da razão peso/comprimento do cólon. A substância teste, entretanto, não foi capaz de reduzir o DAI, nesse experimento, por não minimizar a perda de consistência e o aparecimento de sangue nas fezes. No modelo de colite crônica por AOM/DSS (9 semanas), animais sadios tratados com salina fisiológica (veículo) ou índigo (3 mg/kg) foram monitorados para análise de sinais de toxicidade do alcaloide, a partir dos parâmetros: mortalidade, evolução de peso corporal, consumo de ração, peso e avaliação macroscópica dos órgãos coração, pulmões, rins e fígado. Não foram encontrados indícios de toxicidade nos parâmetros avaliados, mas devido à mortalidade de 17 % dos camundongos tratados com índigo, foi realizado teste de toxicidade aguda de dose única. Após 14 dias da administração oral e intraperitoneal de índigo (1000 mg/kg), em camundongos Unib:SW (Swiss) machos e fêmeas, não foram observadas alterações na evolução de peso corporal, consumo de água e ração, peso de órgãos vitais, comportamento e sobrevivência dos animais. Em suma, o alcaloide índigo apresentou efeito anti-inflamatório em modelos de colite por TNBS, DSS e AOM/DSS. A redução do estresse oxidativo deve ter papel central na redução das lesões causadas pelo TNBS, enquanto que na colite por DSS, a regulação da IL-6 parece ser determinante para redução dos danos. Apesar de não minimizar todos os parâmetros de danos causados pela colite, o tratamento com índigo possibilitou que os animais ficassem, em geral, menos debilitados (evidenciado pelo maior peso e consumo de ração) que os animais não tratados / Abstract: Inflammatory Bowel diseases (IBD) are known as na exacerbated imune response within the intestinal tract, mainly the mucosa of the colon. The IBD treatment is rather ineffective, including various side effects and high costs. Thus, the research with active compounds may bring therapeutic alternatives for IBD. Since natural products have been a vast source for pharmacology, we decided to investigate the effect of Indigo alkaloid in experimental models of IBD. The oral administration of Indigo (3 mg/Kg) in trinitrobenzenesulphonic acid (TNBS) -induced colitis showed beneficial results in the macroscopic and microscopic lesions, without significant results in the other evaluated parameters (diarrhea and intestine adhesion). We observed a reduction in the sulfhydryl groups (GSH) and in the activity of Glutathione peroxidase (GPx), an increase in the activity of Superoxide Dismutase (SOD) and Lipid Peroxidation (LPO). The treatment with Indigo (3 mg/Kg) prevented an increase in the LPO levels, and partially, the reduction of GSH levels. Furthermore, Indigo inhibited the increase of Cycloxigenase 2 (COX-2) expression. In the Indigo-treated animals, the expression of the Nuclear Factor kB (NF-kB) and the concentration of interleukin 10 (IL-10) were kept at intermediary levels between the healthy group and the non-treated colitic group (Veículo + TNBS). In the Dextran Sodium Salt (DSS), Indigo showed no effect on the disease associated index (DAI), which includes body weight reduction, consistence and blood in feces. However, the 7-day oral treatment with Indigo was capable of avoiding the weight/length ratio of the colon, which is usually augmented in the intestinal inflammation. In the histological, we observed a thickening of the intestinal wall, with mucosal and submucosal cell infiltration, necrotic areas as well as epithelium disorganization in the DSS-induced inflammation. The treatment with Indigo showed less severe morphological lesions. In the Dss-induced colitis, IL-6 and IL-1? levels were higher in the negative control group (DSS), which was prevented with the treatment with Indigo. In the azoximethane/DSS-cancer associated recidive model of colitis, the administration of Indigo lowered the death rate, minimized the body weight loss and also prevented the increase in the wejght/length ratio of the colon. The test substance, however, was not capable of of reducing DAI in this model, since it didn't minimize the loss of consistence and neither the blood in feces. Animals treated with saline or Indigo for 9 weeks were used for the analyses of Indigo toxicity through the following parameters: body weight evolution, chaw consumption, organ weight and macroscopic evaluation (heart, kidneys, lung and liver). In this analysis, no signs of toxicity were found for this dose of Indigo. Although it did not enhance all the parameters studied in this model of colitis, we observed that the Indigo-treated animals were, in general, less debilitated than the non-treated ones. Other studies and parameters have to be performed for a better understanding of the alkaloid effects in the intestinal inflammation / Doutorado / Fármacos, Medicamentos e Insumos para Saúde / Doutora em Ciências

Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-26T22:32:16Z (GMT). No. of bitstreams: 1 BritoJunior_GilmarAraujo_D.pdf: 17782870 bytes, checksum: 5c94657b3c62d85cdf49bb3535c55ecb (MD5) Previous issue date: 2014 / Resumo: Os alcaloides Estemona são um grupo de cerca de 170 substancias com características estruturais intrínsecas. Dentro desses compostos o alcaloide Parviestemoamida (11a/11b) foi isolado em 1991, mas não teve sua estrutura tridimensional elucidada. Através de estudos prévios no nosso grupo de pesquisa, um possível epímero para a estrutura 11b proposta foi sintetizado, mas a não exatidão das análises espectroscópicas não permitiu a conclusão da elucidação estrutural para esse composto. Diversas metodologias foram testadas visando à preparação da lactama de 10 membros em 48, 52 e 57, mas esses produtos nunca foram obtidos. Mudança no plano sintético foi feito baseado em construir inicialmente o anel de 10 membros e por fim o de 5 membros. Dessa maneira, através da reação de ciclização radicalar foi possível sintetizar o composto 92, já contendo todos os átomos de carbono presentes na estrutura proposta 11a/11b, porém não foi possível a funcionalização da ligação dupla nesse composto, por nenhuma das metodologias testadas. Utilizando-se de ferramentas computacionais e análises comparativas com o produto natural Estemoamida (17), sugerimos que o produto natural isolado por Xu e colaboradores é a própria Estemoamida (17) ou algum isômero. O outro alcaloide, Estemoamida (17) já teve sua estrutura tridimensional elucidada bem como foi objeto de várias sínteses totais. A hidrogenólise seguido de ciclização em cascata do intermediário 51a levou favorecidamente à estrutura tricíclica presente no alcaloide 9a-epi-Estemoamida (96b) com razão de 5:1. Através desses resultados variações nas condições reacionais, como pressão e solvente, buscamos uma condição para que o triciclo presente no produto natural (17) fosse favorecido. A hidrogenólise seguido de ciclização em cascata do intermediário 51b sob 10 atm de pressão de hidrogênio e trifluoretanol como solvente, levou ao isômero desejado 96a com razão de 10:1. Cálculos computacionais foram utilizados buscando uma explicação para essa diferença de seletividade. A conversão dos triciclos 96a e 96b nos alcaloides (±)-Estemoamida e (±)-9a-epi-Estemoamida, já se encontra presente na literatura. Dessa maneira, realizamos uma síntese formal, curta e bastante eficiente para esses alcaloides / Abstract: The Stemona alkaloids are a group of about 170 substances that possess unique structural features. Among those compounds, Parviestemoamide (11a/11b) was isolated in 1991, but its tridimensional structure was not elucidated. Through previous studies in our research group, a possible epimer of the proposed structure 11b was synthetized, but the spectroscopic analysis did not match with the reported data, preventing an unambiguous structural elucidation of this compound. Several synthetic approaches toward the 10 membered lactam in 48, 52 and 57 were tested, but the desired products were never obtained in any condition tested. A alternative synthetic strategy to initially prepare the 10 membered ring and then the 5 membered lactone was planned. In this way, compound 92 was prepared by the radical cyclization reaction, already having all the carbon atoms present in the proposed structure 11a/11b, but unfortunately it was not possible to conduct the double bond functionalization in this bicyclic compound using the tested methodologies. Employing computational tools and by comparative analysis with the natural product Stemoamide (17), we suggest that the natural product isolated by Xu and coworkers is Stemoamide (17) itself or an isomer of 17. On the other hand, Stemoamide (17) already has had its tridimensional structure elucidated through syntheses by many research groups. The hydrogenolysis followed by cascade cyclization on intermediate 51a led to the core 96b present in 9a-epi-Estemoamida (98) and its 9a epimer in a 5:1 ratio, respectively. Inspired by this result, we sought a condition that could provide the other diastereomer, 96a, present in the natural Stemona alkaloid, Stemoamide (17). Based on this, the intermediate 51b was submitted to a similar condition, with 10 atm of H2 pressure and trifluoroethanol as solvent. In this way, the desired isomer 96a was obtained with 10:1 diastereoisomeric ratio. Computational calculations have been employed to explain this facial selectivity. The conversion of compounds 96a and 96b in the alkaloids (±)-Stemoamide (17) and (±)-9a-epi-Stemoamide (98) is already reported in the literature, so we could perform a short and efficient synthesis of these alkaloids / Doutorado / Quimica Organica / Doutor em Ciências

A cultura popular atribui ao gênero Passiflora várias propriedades medicinais e funcionais. Frutas frescas e secas, cascas, infusões e suco da polpa de maracujás silvestres são consumidos e comercializados para controlar ansiedade, insônia, tremores, diabetes e obesidade, entre outras indicações. Dessa forma, os objetivos deste trabalho foram caracterizar e comparar as folhas e frutos (pericarpo, polpa e sementes) das espécies P. edulis Sims variedades BRS Sol do Cerrado, Ouro Vermelho e Gigante Amarelo, P. alata Curtis, P. setacea DC e P. tenuifila Killip em relação ao seu potencial funcional, avaliando-se conteúdos de compostos fenólicos totais, proantocianidinas, vitamina C, alcaloides, tipos e teores de flavonoides, controle potencial de glicemia pós-prandial (inibição de α-amilase e α-glicosidase in vitro) e capacidade antioxidante in vitro. O principal flavonoide encontrado tanto em folhas como em frutos foi a homoorientina e as maiores concentrações foram encontradas em folhas, seguido de pericarpo. Os maiores teores de alcaloides foram detectados nas polpas dos frutos de P. edulis (0,1-0,2 mg/100 g b.s.). As maiores concentrações de compostos fenólicos foram detectadas nas folhas de P. edulis e P. alata, porém as sementes de P. tenuifila e principalmente P. setacea apresentaram os teores mais elevados em comparação com as outras frações. Em relação às proantocianidinas, este é o primeiro estudo que mostra a presenças destes compostos em Passiflora spp, em concentrações significativamente maiores nas sementes. Além disso, o estilbeno piceatanol (3,4,3\',5\'-tetrahidroxi-trans-estilbeno) também foi encontrado nas sementes de P. edulis variedades BRS Ouro Vermelho (2 mg/100 g b.s.) e Gigante Amarelo (3 mg/100 g b.s.) e P. alata (10 mg/100 g b.s.). Os compostos fenólicos encontrados nas sementes de todas as espécies de Passiflora analisadas se mostraram potentes inibidores das enzimas α-amilase e α-glicosidase. Este trabalho mostrou que os frutos e as folhas de Passiflora spp podem ser considerados boas fontes de compostos bioativos, especialmente com atividade antioxidante, apresentando, portanto, potenciais efeitos benéficos sobre a saúde humana. / Folk culture assigns to the genus Passiflora various medicinal and functional properties. Fresh and dried fruits , barks , teas and wild passion fruit pulp juice are consumed and sold to control anxiety, insomnia , tremor , diabetes and obesity , among other indications .Thus, the aim of this study were to characterize the leaves and fruit (pericarp , pulp and seeds) of the species P. edulis Sims varieties BRS Sol do Cerrado, Ouro Vermelho e Gigante Amarelo, P. alata Curtis, P. setacea DC e P. tenuifila Killip in relation to their functional potential , evaluating content of total phenolic compounds , proanthocyanidins , vitamin C , alkaloids , types and levels of flavonoids, potential control of postprandial glycemia (inhibition of α-amylase and α-glucosidase in vitro) and in vitro antioxidant capacity. The main flavonoid found in both leaves and fruits was homoorientina and the highest concentrations were found in leaves, followed by pericarp . The highest levels of alkaloids were detected in the pulp of the fruits of P. edulis ( 0.1-0.2 mg/100 g b.s. ) . The highest concentrations of phenolic compounds were identified in the leaves of P. edulis and P. alata, but the seeds of P. tenuifila and especially P. setacea showed higher levels compared with the other fractions . With respect to proanthocyanidin, this is the first study to show the presence of these compounds in Passiflora spp at concentrations significantly increased in seeds. Furthermore, piceatannol stilbene ( 3,4,3\',5\'- tetrahydroxy -trans- stilbene ) was also found in the seeds of P. edulis varieties BRS Ouro Vermelho (2 mg/100 g d.w.) and Gigante Amarelo (3 mg/100 g d.w.) and P. alata (10 mg/100 g d.w.). Phenolic compounds found in the seeds of all species analyzed are good inhibitors of α-amylase and α-glicosidase. This work showed that the fruit and leaves of Passiflora spp. can be considered good sources of bioactive compounds, especially with antioxidant activity, thus presenting potential beneficial effects on human health.

Orientador: Gisela Ferreira / Resumo: Além das formas clássicas de identificação de espécies e variedades realizadas por meio da diferenciação morfológica de órgãos das plantas, como as folhas, flores e frutos, contamos com diferentes técnicas de estudo que analisam aspectos moleculares e químicos. A junção de mais de uma técnica de análise taxonômica é utilizada quando apenas a diferenciação morfológica não é capaz de identificar e classificar uma espécie. A quimiossistemática, recentemente nomeada quimiofenética utiliza dados químicos, provenientes do metabolismo especializado das plantas, para auxiliar na classificação de diferentes famílias, gêneros, espécies e variedades. A espécie Annona emarginata (Schltdl.) H. Rainer, conhecida por seu valor econômico e ecológico, é popularmente chamada como araticum de terra-fria e como araticum mirim, observações de campo e diversos estudos demonstram diferenças fisiológicas e morfológicas entre os araticuns. Sendo assim, o objetivo desse trabalho foi utilizar caracteres morfológicos e químicos provenientes do metabolismo especializado para esclarecer se os araticuns (araticum de terra-fria e araticum mirim) podem ser tratados como variedades de Annona emarginata (Schltdl.) H. Rainer. Para tanto, foram realizadas análises morfométricas do limbo foliar e da coloração das flores e, análises do metabolismo especializado dos araticuns, considerando a) o perfil químico de alcaloides da raiz, expressado como abundância e perfil químico de alcaloides totais, e abundância de um... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: In addition to the classical forms of identification of species made through the morphological differentiation of plant organs, such as leaves, flowers and fruits, we have different study techniques that analyze molecular and chemical aspects. The addition of more than one taxonomic analysis technique is used when only morphological differentiation is not able to identify and classify a species. The chemosystematics, recently named chemophenetic, uses chemical data from specialized plant metabolism to aid in the classification of different families, genera, species and varieties. The species Annona emarginata (Schltdl.) H. Rainer, known for its economic and ecological value, is popularly called araticum de terra-fria and araticum mirim. Field observations and several studies demonstrate physiological and morphological differences between them. Therefore, the purpose of this work is to use morphological and specialized chemical characters to clarify whether both araticuns (araticum de terra-fria and araticum mirim) are varieties of Annona emarginata (Schltdl.) H. Rainer. For this purpose, morphometric analysis of leaf blade and flower color analysis were performed, analysis of the specialized metabolism of araticuns were performed, considering a) chemical alkaloid profile of the root, expressed as abundance and chemical profile of total alkaloids, and abundance of an alkaloid considered a chemotaxonomic marker (liriodenine) of the Annonaceae family, b) profile of leaf volatile... (Complete abstract click electronic access below) / Mestre

La tubuline est une protéine essentielle de la cellule. En polymérisant sous forme de microtubules, elle crée notamment le fuseau mitotique le long duquel migrent les chromosomes pendant la mitose. Les médicaments qui inhibent la polymérisation et/ou la dépolymérisation de la tubuline sont des composés majeurs de la thérapie anticancéreuse. Les vinca-alcaloïdes en sont des représentants importants. Ils induisent la mort des cellules par apoptose, en inhibant la dynamique des microtubules. D’autres molécules d’origine naturelle, comme la phomopsine A, se fixent sur la tubuline à proximité ou dans le même site de fixation que celui des vinca-alcaloïdes. C’est la raison pour laquelle nous avons envisagé d’élaborer des composés antimitotiques hybrides entre la vinblastine et la phomopsine A. Dans ce contexte, deux séries de composés ont été conçues. La première série d’hybrides correspondant à des dérivés de l’anhydrovinblastine fonctionnalisés en position 7’. Cependant, aucune des trois stratégies étudiées n’a permis d’accéder à ces composés. La deuxième série d’hybrides, dérivés de la 7’-homo-anhydrovinblastine a pu être synthétisée grâce à une réaction originale d’insertion d’acétylènes activés au niveau du pont gramine de la vinorelbine, suivie d’une réduction avec un contrôle totale de la régio- et stéréoselectivité. Dans un premier temps, les réactions d’insertion et de réduction ont été mise au point. Ensuite, deux familles d’hybrides portant la chaîne latérale de l’octahydrophomopsine en position 8’ ou 7’ ont été synthétisés. La plupart des composés ainsi obtenus possédent une excellente activité sur la tubuline et sont très cytotoxique. / Tubulin plays a key role in many cellular functions, like cell division. Microtubules, resulting from its polymerisation, form the mitotic spindle along which chromosomes migrate during mitosis. Tubulin-binding molecules are one of the most important classes of anti-cancer agents with major drugs already on the market and many promising compounds in clinical trials. Vinca-alkaloids are one of these antimitotic drugs inhibiting microtubules dynamics. It was shown that the vinca binding site partially overlaps with that of others natural products, like phomopsin A. In order to explore the vinca domain and to elaborate new acute derivatives, we have elaborated antimitotic vinblastine-phomopsin hybrids. We were interested in the synthesis of two series of hybrids. The first, corresponding to 7’-anhydrovinblastine derivatives could not be obtained. None of the three studied strategies lead to desired compounds. The second series of hybrids, corresponding to functionnalized 7’-homo-anhydrovinblastine derivatives, could be synthetised by an original and regioselective insertion reaction, followed by a stereoselective reduction. Firstly, the isertion reaction was studied using different activated acetylenes. Then, two different families of hybrids were obtained, thanks to the selective insertion of the octahydrophomopsin lateral chain in position 8’ or 7’. Almost all the compounds were highly active on tubulin and very cytotoxic.

We describe an efficient synthesis of the methylene-bridged biscarbazole alkaloids bismurrayafoline-A, bismurrayafolinol and chrestifoline B–D using an Ullmann-type coupling at the benzylic position.

<div> Carbon monoxide is a useful carbon linchpin to construct complex molecules of natural products by stitching different pieces of target molecules together. Recently, our group reported a novel and efficient palladium-catalyzed spirolactonization by Dr. Dexter Davis to construct oxaspirolacones from esters or lactones. As an essential motif, oxaspirolactone structures in natural products exhibit diverse and exciting structures and biological activities. The first part of this thesis mainly describes the total synthesis of stemoamide alkaloids in the stemona family and the application of our palladium-catalyzed spirolactonization, which was developed by our group to complete total synthesis of bisdehydroneostemoninine and bisdehydrostemoninine with Prof. Kaiqing Ma. The total synthesis features a one-pot ring-closing cross-metathesis, Lewis acid-mediated Friedel-Crafts reaction and lactonization, and accomplished bisdehydrostemonine in 15 steps. The total synthesis of stemoamide, tuberostemoamide, and sessilifoliamide A were finished, and the critical step features an mCPBA oxidation to convert pyrrole to lactam in one step without destructing other functional groups. </div><div> In the second part of this thesis, we developed a novel and efficient palladium-catalyzed cascade amino-carbonylative lactonization to streamline the synthesis of dihydropyrrole-fused furanones in collaboration with Prof. Seleem’s lab for biological activities. Using this method, we quickly expanded this method to construct different ring structures, such as β-lactone and dihydropyrrole-fused pyrrolone. This method was applied to the total synthesis study towards stemofoline alkaloids. Our palladium-catalyzed spirolactonizaiton was also used in this total synthesis study for target molecules. </div><div><br></div>

Cryogenine's immunosuppressive activity was first evaluated by Kosersky, et al. (21) who, impressed by the drug's ability to inhibit both the irritant- and immune- mediated phases of adjuvant-induced polyarthritis (11), quantitatively confirmed this activity and clearly differentiated the action of cryogenine from that displayed by 6-mercaptopurine. A definitive study by Watson and Malone (22) confirmed cryogenine's lack of immunosuppressive capacity at effective anti-inflammatory dose levels. The molecular complexity of the lythraceae alkaloids suggests that several active centers may account for their unique pharmacological profile. To assess these potentially active sites, two standard models of acute inflammation were selected for use in this present study -- the carrageenan-induced rat pedal edema assay and the croton oil-induced mouse ear edema assay. While the oral anti-inflammatory capacity of several of the lythraceae alkaloids has been well documented, their topical antiphlogistic capacity has not been evaluated. Moreover, the specific function or functions of the molecule which account for this anti-inflammatory capacity remain a mystery. The present study was undertaken: (i) to asses the topical anti-inflammatory potential of cryogenine, lythrine and two selected lythraceae intermediates and (ii) to investigate the possible molecular compounds which produce this established, yet enigmatic anti-inflammatory effect.

The aim of this diploma thesis is the assay of total alkaloids in different tobacco types. To measure the content of total alkaloids are utilized types of tobacco used for preparation of tobacco blends and consecutive production of cigarettes. The samples of analyzed tobacco include various countries of cultivation and different crop years. There is described tobacco as a plant, in it contained alkaloids and the utilization of tobacco in the theoretical part. In more detail it deals with the production and construction of cigarettes which is closely related to the content monitoring of total alkaloids in tobacco. The contents of total alkaloids are determined by the continuous flow analyzer- SKALAR. On this spectrophotometer are set the contens of reducing sugars as well. The comparison of total alkaloids contents and reducing sugars from the perspective of single tobacco types, countries of cultivation and crop years is clearly summarized in the experimental part of the thesis that was performed in the company Philip Morris ČR, a.s.

Une étude synthétique de la koumine par une stratégie basée sur une étape de désymétrisation a permis de développer, par un résultat inattendu, une fragmentation de 1,3-cyclohexanediones en lactones. Suite à ce résultat, une étude méthodologique a été réalisée en partant de différentes dicétones substituées pour synthétiser des lactones indoliques, ainsi que déterminer la régiosélectivité et la diastéréosélectivité. Finalement, la synthèse totale de la goniomitine a été éffectuée en utilisant cette méthode de fragmentation. / A synthetic study of koumine by a strategy based on a desymmetrization step led, through an unexpected result, to the development of a fragmentation of 1,3-cyclohexanediones into lactones. Following this result, a methodological study was carried out starting from different substituted diketones to synthesize indolic lactones, as well as to determine regioselectivity and diastereoselectivity. Finally, the total synthesis of goniomitine was performed using this fragmentation method.