The synthesis and characterization of a series of chiral indium complexes bearing a tridentate NNO ligand are reported. The ligand 2-[[[(dimethylamino)cyclohexyl]amino]methyl]- 4,6-bis(tert-butyl) phenol (H₂NNO) was synthesized via a previously published procedure and bound to indium by both a protonolysis and salt metathesis route. A dimethylated indium complex (NNO)InMe₂ (1) was isolated by reaction of InMe₃ with H₂NNO. A one-pot saltmetathesis route was used to produce a unique mixed-bridge dinuclear indium complex [(NNO)InCl] ₂(μ-OEt)(μ-Cl) (3) from a mixture of indium trichloride, potassium ethoxide and the monopotassiated salt of the ligand, KH(NNO). Direct reaction of KH(NNO) and indium trichloride resulted in the formation of (NNO)InCl₂ (4) which was carried forward to 3 by reaction with sodium ethoxide. The complex 3 is active for the ROP of β-butyrolactone ε-caprolactone and lactide and is the first reported indium-based catalyst for lactide or β-butyrolactone ROP. Kinetic studies of 3 for ROP of LA revealed that catalyst was well-behaved, and that the rate was first order with regard to lactide and catalyst. The enthalpy and entropy of activation for the ROP were experimentally determined. Polymer produced by ROP by 3 has narrow molecular weight distribution and a good correlation is seen between the observed moleular weight and monomer loading. A mechanism was proposed for 3 acting as a catalyst for the ROP of lactide; however further experiments are required to confirm this mechanism. Polymer samples isolated from the ROP of rac-lactide by rac-3 show isotactic enrichment. It is postulated that the chiral catalyst 3 is exerting stereocontrol via an enantiomorphic site control mechanism.

The goal of this project was to synthesise potential flavour compounds combinatorially and identify key components for further investigation as flavourants in dairy products. This thesis describes the design and synthesis of libraries of ketones and γ-lactones that will be evaluated for flavour potential. Gas chromatography-mass spectrometry (GCMS), the Fox, and gas chromatography-olfactometry (GC-O) were used throughout this study. Ketones were synthesised individually via a two-step sequence: a Grignard reaction followed by the oxidation of the resulting alcohol in Chapter 2. Some compounds selected from the Fox analysis were assessed by GC-O. The analysis gave promising results for aromatic and cyclopropyl ketones and a library of cyclopropyl ketones was prepared. Individual racemic lactones were synthesised via a two-step sequence: the Linstead modification of the Knoevenagel reaction and subsequent lactonisation in Chapter 3. Libraries of racemic γ-lactones (C8-C12), including α-substituted γ-lactones, were produced combinatorially. Further, synthesis of a library of γ-thionolactones was achieved by treatment of a library of γ-lactones with Lawesson's reagent. The libraries were analysed by GC-O. A (R)-dodecalactone was synthesised from L-glutamic acid and the (S)-enantiomer was synthesised by the same sequence from D-glutamic acid in Chapter 4. Asymmetric syntheses of both enantiomeric series of γ-lactones utilizing the Sharpless asymmetric dihydroxylation reaction was employed to give the libraries in Chapter 5. Libraries of a-substituted and β-substituted γ-lactones were synthesised combinatorially and analysed by GC-O.

Thesis (M.Sc.). / Written for the Dept. of Epidemiology, Biostatistics and Occupational Health. Title from title page of PDF (viewed 2008/07/30). Includes bibliographical references.

Neste trabalho o metilpluviatolido (1), o matairesinol (7), a hinoquinina (11), a cubebina (17) e seus respectivos derivados, providos de algumas modificações estruturais foram submetidos a testes in vitro para a determinação da atividade citotoxica e tripanocida. As substâncias não apresentaram atividade citotoxica significativa para a linhagem celular utilizada (LLC-MK2). Nos ensaios tripanocida in vitro o dimetoximorelensin (8) e 11 foram as substâncias que determinaram as maiores atividades tripanocida sobre as varias formas e cepas de T. cruzi utilizadas e juntamente com a cubebina foram submetidas os ensaios in vivo. As substâncias determinaram alterações significativas no curso da infecção chagásica experimental. No entanto apenas a 8 apresentou efeito semelhante ao do benzonidazol para ambas as cepas, sendo a cepa BOL em relação a cepa Y mais resistente as substâncias 11 e 17. Algumas rotas metabólicas foram avaliadas como mecanismo de ação das substâncias. As substâncias não apresentaram atividade inibitória sobre a enzima gliceraldeído-3-fosfato desidrogenase (GAPDH) de Trypanosoma cruzi, não induziram a produção de H2O2 e outros peróxidos, bem como não induziram a produção de óxido nítrico, tendo algumas inibindo esta produção. No entanto, apresentaram efeito inibitório sobre a respiração celular e efeito inibitório sobre a enzima ferro superóxido dismutase (Fe-SOD) de Trypanosoma cruzi. Adicionalmente foi demonstrado que em sistema livre de células as substâncias não apresentam atividade scavenger de radicais livres e que o tratamento com a substancia 8, avaliado por microscopia eletrônica, provoca alterações nucleares nas formas epimastigotas do parasita, sugerindo que a atividade tripanocida desta substancia envolva a inibição da síntese de DNA e RNA. Dessa forma, podemos concluir que a atividade tripanocida das varias lignano-lactonas avaliadas é promissora e que a produção de H2O2 e outros peróxidos, atividade inibitória sobre a enzima gliceraldeído-3-fosfato desidrogenase (GAPDH) de Trypanosoma cruzi, bem como a capacidade de indução de óxido nítrico pelos derivados bioativos são mecanismos que parecem não estar envolvidos na atividade tripanocida das substâncias. Além disso, que o efeito inibitório sobre a respiração celular parece contribuir para a atividade tripanocida e pode estar envolvido no mecanismo de citotoxicidade destas substâncias. Ainda, que o efeito inibitório sobre a enzima ferro superóxido dismutase (Fe- SOD) de Trypanosoma cruzi parece ser um dos principais mecanismos envolvidos na atividade tripanocida das substâncias. / In this work the compounds methylpluviatolide (1), matairesinol (7), hinokinin (11), cubebin (17) and its derivatives bearing some structural modifications were submitted to in vitro trypanocidal and citotoxic assays. The compounds do not show significant citotoxicity for the LLC-MK2 cells used. In the in vitro trypanocidal assays, the compounds more active against the different strains and forms of T. cruzi were the dimethoxymorelensin (8) and hinokinin (11). These compounds and cubebin (17) were submitted to in vivo trypanocidal assay. The compounds display significant modifications on the experimental chagasic infection. However, for both strains, Y and BOL, only the 8 displayed similar effect of the benznidazole. The BOL strain was more resistant than Y strain to treatment with 11 and 17. Some metabolic routes were evaluated as compounds action mechanism. The compounds do not showed inhibitory activity under enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Trypanosoma cruzi, they do not induced the production of H2O2 and others peroxides and also do not induced the nitric oxide production, instead some compounds decrease this production. On the other hand, they showed inhibitory effect under the cellular respiration and the enzyme iron superoxide dismutase (Fe-SOD) of Trypanosoma cruzi. In addition, it was demonstrated that on system cells free, the compounds do not showed free radicals scavenger activity and that the treatment with the compound 8, evaluated in electron microscopy, display nuclear alterations on epimastigotes forms, suggesting an inhibitory effect on T. cruzi DNA and RNA biosynthesis. In conclusion, the compounds trypanocidal activity is promising and the production of H2O2 and others peroxides, the activity under enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Trypanosoma cruzi, and the induction of nitric oxide production seem do not be involved in the trypanocidal and citotoxity activity of these group of compounds. The inhibitory effect under cellular respiration seems to be contributing for trypanocidal activity and may be involved on its citotoxic mechanism. Moreover, the inhibitory effect under the enzyme iron superoxide dismutase (Fe-SOD) of Trypanosoma cruzi seems to be the main mechanism involved on trypanocidal activity of these compounds.

Made available in DSpace on 2014-06-11T19:24:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-02-25Bitstream added on 2014-06-13T19:11:19Z : No. of bitstreams: 1 cervezan_tcm_me_botfca.pdf: 497237 bytes, checksum: d6694ebd7c9403db49840bbd8579a450 (MD5) / A espécie Artemisia annua, Asteraceae, nativa da China, tem a artemisinina como seu principal componente ativo, é considerado um potente antimalárico. Com o aumento do valor dos princípios ativos naturais, estudos relacionados à pós-colheita e armazenamento de material vegetal tornam-se importantes para melhor conservação de suas propriedades fitoterápicas. O presente estudo teve como objetivo definir as melhores condições de armazenamento para preservar a qualidade da droga vegetal. Folhas de A. annua secas foram armazenadas por seis meses em sacos de polietileno envolto por papel Kraft e acondicionadas em quatro tratamentos: em condição ambiente e refrigerada a 4º±2C, em embalagem normal e em embalagem sob vácuo. No tempo zero e nos períodos de 30, 90, 120 e 180 dias foram realizados as análises microbiológicas e avaliação do teor de artemisinina. Os resultados dos ensaios microbiológicos não demonstraram contaminação significante, assim como o teor de umidade do material armazenado, que permanecem entre 5% a 10%, mantendo-se dentro do parâmetro aceitável. O tratamento sem vácuo ambiente (SVA) foi o que melhor manteve estabilidade de armazenamento durante os 180 dias, no entanto, foi o sem vácuo refrigerado (SVR) que apresentou maior eficiência para a conservação do teor de artemisinina / Artemisia annua is an Asteracea native to China, its principal active component, artemisinin, is considered a potent antimalarial drug. With the increased interest in natural active principles, studies related to post-harvest and storage of vegetable material become important for better conservation of its phytotherapic properties. Therefore, the present study had as objective define best storage conditions to preserve and keep the quality of phytotherapic Leaves of A. annua dried were stored for six months in polyethylene bags wrapped in Kraft paper and packed in four treatments: at ambient condition, at ambient condition with vacuum packing in refrigerated conditions at 4° ± 2C normal and vacuum packing. At time zero, and the periods of 30, 90, 120 and 180 days were performed microbiological analyzes and evaluation of the level of artemisinin. The results of microbiological tests showed no significant contamination, as well as the moisture content of stored (biological) material, which remain between 5% and 10%, keeping within acceptable parameters. The vacuum environment without treatment (SVA) was the best storage stability maintained during 180 days, however, no vacuum was refrigerated (SVR) showed that greater efficiency to conserve the content of artemisinin, compared to the others

Orientador: Fernando Broetto / Banca: Glyn Mara Figueira / Banca: Filipe Pereira Giardini Bonfin / Resumo: A espécie Artemisia annua, Asteraceae, nativa da China, tem a artemisinina como seu principal componente ativo, é considerado um potente antimalárico. Com o aumento do valor dos princípios ativos naturais, estudos relacionados à pós-colheita e armazenamento de material vegetal tornam-se importantes para melhor conservação de suas propriedades fitoterápicas. O presente estudo teve como objetivo definir as melhores condições de armazenamento para preservar a qualidade da droga vegetal. Folhas de A. annua secas foram armazenadas por seis meses em sacos de polietileno envolto por papel Kraft e acondicionadas em quatro tratamentos: em condição ambiente e refrigerada a 4º±2C, em embalagem normal e em embalagem sob vácuo. No tempo zero e nos períodos de 30, 90, 120 e 180 dias foram realizados as análises microbiológicas e avaliação do teor de artemisinina. Os resultados dos ensaios microbiológicos não demonstraram contaminação significante, assim como o teor de umidade do material armazenado, que permanecem entre 5% a 10%, mantendo-se dentro do parâmetro aceitável. O tratamento sem vácuo ambiente (SVA) foi o que melhor manteve estabilidade de armazenamento durante os 180 dias, no entanto, foi o sem vácuo refrigerado (SVR) que apresentou maior eficiência para a conservação do teor de artemisinina / Abstract: Artemisia annua is an Asteracea native to China, its principal active component, artemisinin, is considered a potent antimalarial drug. With the increased interest in natural active principles, studies related to post-harvest and storage of vegetable material become important for better conservation of its phytotherapic properties. Therefore, the present study had as objective define best storage conditions to preserve and keep the quality of phytotherapic Leaves of A. annua dried were stored for six months in polyethylene bags wrapped in Kraft paper and packed in four treatments: at ambient condition, at ambient condition with vacuum packing in refrigerated conditions at 4° ± 2C normal and vacuum packing. At time zero, and the periods of 30, 90, 120 and 180 days were performed microbiological analyzes and evaluation of the level of artemisinin. The results of microbiological tests showed no significant contamination, as well as the moisture content of stored (biological) material, which remain between 5% and 10%, keeping within acceptable parameters. The vacuum environment without treatment (SVA) was the best storage stability maintained during 180 days, however, no vacuum was refrigerated (SVR) showed that greater efficiency to conserve the content of artemisinin, compared to the others / Mestre

Plant secondary metabolites (SM) are widely used by humans in many ways (pharmacy, biotechnology etc.). For making their use even more effective, it is important to know the seasonality of these chemicals in plants and what affect those changes. Three Artemisia species (Artemisia annua, A. absinthium, A. vulgaris) were cultivated during one vegetation season (from April to September 2016). Plant growth parameters and the beginning of their generative stages were observed, and leaf samples were collected regularly. Samples of some plants were collected repeatedly. A generalist herbivore (migratory locust), was used as a proxy for studying changes in plant secondary metabolism during the vegetation season. The results proved presence of defence secondary metabolites in plants except A. vulgaris species where the role of SM in defence was not shown. Levels of SM changed nonlinearly during the vegetational season and were time-dependent. Plant size did not influence the levels of SM in plants. Levels of SM were low at the beginning of the experiment followed by rapid increase and remaining on maximal levels. The plants which lost their biomass repetitively grew slowly and bloomed later than the plants which were clipped only once. A delay trend showing seasonality of the plant SM was not proved. In...

Orientador: Anita Jocelyne Marsaioli / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-06T07:10:56Z (GMT). No. of bitstreams: 1 Pomini_ArmandoMateus_M.pdf: 2721194 bytes, checksum: b3d63d99fb0e61f807557af1f715e4ea (MD5) Previous issue date: 2006 / Resumo: Este trabalho abordou dois tópicos relacionados à comunicação química inter e intraespecífica. O primeiro tópico descreveu a produção de sinalizadores químicos da classe das acil-homosserina lactonas (acil-HSLs) por bactérias Gram-negativas fitopatogênicas, em mecanismos comunicativos conhecidos como quorum-sensing. Foram estudadas três espécies: Erwinia psidii RODRIGUES, que causa a principal bacteriose da goiabeira no Brasil;Pantoea ananatis SERRANO, um fitopatógeno de distribuição mundial e que causa perdas em diversas culturas agrícolas e Pantoea agglomerans EWING & FIFE, isolada da doença da ¿pinta branca do milho¿. O estudo propiciou a identificação de diversos metabólitos da classe das acil-HSLs, sendo que os produtos majoritários tiveram suas configurações absolutas estabelecidas. Avaliou-se ainda a atividade biológica de extratos, frações e produtos sintéticos com o biossensor Agrobacterium tumefaciens NTL4(pZLR4), em ensaios de expressão de enzimas ß-galactosidase. Trata-se de um trabalho pioneiro no Instituto de Química da Unicamp. Na segunda linha de pesquisas desenvolvida, o enfoque recaiu sobre alomônios produzidos por opiliões (Arachnida: Opiliones) e utilizados em XII mecanismos de defesa química contra predadores e na defesa territorial. Estudou-se as secreções de defesa das espécies Goniosoma longipes ROEWER e Camarana flavipalpi SOARES, nativas do Estado de São Paulo. Este trabalho rendeu a identificação de benzoquinonas substituídas e um fenol, inclusive com a caracterização de um produto natural inédito (2-etil-3-metil-1,4- benzoquinona) / Abstract: This work encompasses two different topics, both related to the intra and interspecific chemical communication. The first part concerns to the production of acyl-homoserine lactones (acyl-HSLs), which are signalling substances of Gram-negative, plant pathogenic bacteria. These substances are responsible for their chemical communication, in a process known as quorumsensing. Three species were studied: Erwinia psidii RODRIGUES, which causes the most important bacteriosis in Brazilian guava crops; Pantoea ananatis SERRANO, a worldwide-spread phytopathogen, which causes crop losses in different plant species and Pantoea agglomerans EWING & FIFE, isolated from the ¿white spot disease¿ of maize in Brazil. This study allowed the identification of four acyl-HSLs, and the absolute configurations of the most abundant substances were established. The activities of the extracts, fractions and synthetic products were evaluated using the bioreporter Agrobacterium tumefaciens NTL4(pZLR4), in ß-galactosidase expression assays. This is a pioneer work at the Chemistry Institute at Unicamp. The second research topic was on the opilionids allomones (Arachnida: Opiliones), employed in chemical defense mechanisms against predators and in territorial defense. The exudates of Goniosoma longipes ROEWER and Camarana flavipalpi SOARES, both native from São Paulo State (Brazil), were chemically characterized, allowing the identification of a known substituted XIV benzoquinone and a phenol, including a new natural product (2-ethyl-3- methyl-1,4-benzoquinone) / Mestrado / Quimica Organica / Mestre em Química

Orientador: Lucia Helena Brito Baptistella / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-08T22:53:36Z (GMT). No. of bitstreams: 1 Jorge_AndredeCarvalho_M.pdf: 8483799 bytes, checksum: cbe192b8fe9d903f29cd3c2171475ffc (MD5) Previous issue date: 2006 / Resumo: O ácido quínico 1 é um metabólico de planta de ampla ocorrência natural que teve seu uso limitado no passado como precursor quiral em síntese de múltiplas etapas. Essa aplicação mudou em anos mais recentes quando várias publicações demonstraram toda a potencialidade sintética do seu esqueleto quiral altamente funcionalizado. O objetivo deste trabalho é a utilização de 1 para a síntese de biciclos furanofurona saturados e/ou insaturados com substituintes na junção dos anéis. O interesse nesses esqueletos bicíclicos se deve ao enorme potencial de atividade biológica que eles possuem, já que são idênticos àqueles encontrados em alguns compostos naturais isolados de plantas da família Annonaceae. Esses compostos são pertencentes a um grupo de moléculas conhecido como estiril lactonas, cujos membros, em sua grande maioria, apresentam significantes atividades citotóxicas em relação a células tumorais humanas. A seqüência proposta pode abrir novas alternativas para a preparação de análogos inéditos na serie das estiril lactonas, explorando a possibilidade de um aumento de cadeia através de uma reação de Wittig em carbonila de lactona. Estes novos análogos devem também ser submetidos a teste antiproliferativos, visando a análise de suas possíveis atividades farmacológicas. Os estudos efetuados permitem afirmar que a transformação do sistema ácido quínico em furanofuronas saturadas é bastante viável. A partir de 1 não foi possível a preparação do biciclo furanofurona insaturado 2, mas a rota proposta para os derivados furanofurona saturados 3, 4 e 5 se mostrou bastante versátil, abrindo possibilidades para a preparação de outros tipos de derivados. / Abstract: Quinic acid 1 is a plant metabolite widespread in nature that had in the past a limited use as a chiral precursor on organic synthesis. This application changed in recent years, and now several publications has shown the enormous synthetic potential of its highly functionalized skeleton. The purpose of this work is the use of 1 for the synthesis of furanefurone saturated and/or unsaturated bicycles with substitutes in the ring junction. The interest in these bicyclic skeletons is due to their enormous potential for biological activity, since they are identical to those found in some isolated natural compounds found in Annonaceae family plants. These compounds belong to a group of molecules known as styryl lactones, whose members, in its great majority, present significant cytotoxicity against human tumor cells. The proposed sequence can open new alternatives for the preparation of unknown analogous of this series, always exploring the possibility of carbon chain extention through a Wittig reaction in the lactone carbonyl group. These new analogues must also be submitted to some antiproliferative essays. The present studies allow confirming that the transformation quinic acid to furanefurone saturated systems is feasible. From 1, it was not possible the preparation of the unsaturated furanefurone 2, but the proposed sequence for 3, 4 and 5 has shown new possibilities for the synthesis of other derivatives. / Mestrado / Quimica Organica / Mestre em Química

A busca por moléculas de origem natural que ocupem um espaço químico diferente daquelas já existentes tornou-se uma necessidade para atender às novas demandas das indústrias farmacêuticas. A pesquisa envolvendo transformações microbianas de metabólitos secundários de origem vegetal pode ser utilizada como uma nova ferramenta na biosíntese destas novas substâncias, favorecendo a criação de bibliotecas ricas em estruturas com o emprego em diversos alvos biológicos. A tagitinina C é uma lactona sesquiterpênica isolada da Tithonia diversifolia (Asteraceae). Essa substância possui diversas atividades biológicas descritas na literatura. Contudo, há certa ressalva no uso de lactonas sesquiterpênicas para fins terapêuticos devido à elevada toxicidade apresentada por essas substâncias. A biotransformação de substâncias naturais de elevado interesse farmacológico pode ser utilizada com o intuito de diminuir seus efeitos tóxicos ou ampliar sua capacidade terapêutica. Assim, esse trabalho teve como objetivo a utilização de fungos para a biotranformação da tagitinina C. Os resultados obtidos mostraram que os fungos de solo Aspergillus terreus e Mucor rouxii possuem a capacidade de biotransformar tagitinina C. O fungo Aspergillus terreus levou a formação de um produto biotransformado através de uma reação não usual de epoxidação entres os C4-C5 e ainda metoxilação do C1, formando então 1-metóxi-3-hidróxi-3,10-4,5-diepóxi-8-isobutiroilóxi-germacra-11(13)-en-6,12-olido. Os resultados obtidos nesse trabalho demostram que é possível a utilização de fungos na biotransformação da tagitinina C, levando a alterações na molécula que podem influenciar no seu potencial tóxico ou terapêutico. / The search for molecules of natural origin that place a chemical space which is different from the already existing has become that a need in process of discovery new chemical entities with pharmacological interest that support the demand of the pharmaceutical industries. Research involving microbial transformations the secondary metabolites from plants can be used as an alternative for the biosynthesis of such new compounds, thus facilitating the creation of libraries which are rich in structures to be screened against diverse biological targets. Tagitin C is a sesquiterpene lactone isolated from Tithonia diversifolia (Asteraceae) that displays several biological activities already described in the literature. Howeever, due to several reports describing toxic effects of sesquiterpenes lactones, there is a concern in its oral use. Thus, the biotransformation of pharmacologically interesting substances can be carried out with the aim to decrease their toxic effects or amplify their therapeutic properties. Therefore, this work aimed at using of fungi to perform biotransformations of tagitin C. The results showed that the soil fungi Aspergillus terreus and Mucor rouxii have the ability to carry out biological transformations of tagitinin C. The fungus A. terreus led to the formation of a different product through an unusual reaction of epoxidation between C4-C5 and metoxilation of C1 of tagitinin C, the derivative 1-methoxy-3-hydroxy-3,10-4,5-diepoxy-8-isobutiroyloxygermacr- 11 (13)-en-6 ,12-olide. The results of this work show that it is possible to use soil fungi in the biotransformation of tagitinin C, leading to changes in the chemical structure that may influence its toxic or therapeutic potential.