L'obtenció de precursors de lactones i d'alcohols asimètrics té gran valor ensíntesi orgànica ja que són intermediaris clau per a la preparació de moltscompostos bioactius, com medicaments, agroquímics i additius alimentaris. Toti que es disposa d'un gran nombre de reaccions selectives per a moltesnecessitats sintètiques, és encara necessari millorar i trobar nous processos quanes vol disposar de productes amb una estereoquímica definida, a més de trobarnous sistemes més respectuosos amb el medi ambient i la salut humana.En aquesta tesi es presenten diferents aproximacions per a l'obtenció d'alcoholsquirals i de precursors de lactones. Una de les aproximacions consisteix en unmètode quimio-enzimàtic, amb un primer pas de síntesi d'èsters α-funcionalitzats seguit d'una hidròlisi estereoselectiva d'aquests èsters amblipases per a l'obtenció d'halohidrines quirals. Es va estudiar l'aplicabilitat delslíquids iònics, l'ús de reactius poc contaminants i l'ús d'enzims comercials iresting-cells d'origen fúngic. Aquesta aproximació ha permès l'obtenció del S-1-cloro-2-octanol i el S-1-bromo-2-octanol. La segona aproximació consisteixen la utilització d'oxidoreductases per a la biotransformació de cetonesproquirals. Aquestes estan presents en cèl·lules en creixement de noves soquesfúngiques aïllades com a endòfits de plantes. S'ha trobat una soca de Rhizopusoryzae amb activitat biocatalítica per a l'obtenció d'alcohols quirals. / La obtención de precursores de lactonas y de alcoholes asimétricos tiene granvalor en síntesis orgánica ya que son intermedios clave para la preparación demuchos compuestos bioactivos, como medicamentos, agroquímicos y aditivosalimentarios. Aunque se dispone de un gran número de reacciones selectivaspara muchas necesidades sintéticas, aún es necesario mejorar y encontrar nuevosprocesos cuando se quiere disponer de productos con una estereoquímicadefinida, además de encontrar nuevos procesos más respetuosos con el medioambiente y la salud humana.En la presente tesis se describen varias aproximaciones para la obtención dealcoholes quirales y precursores de lactonas. Una de las aproximaciones consisteen un método quimio-enzimático, con una primera etapa de síntesis de ésteres α-funcionalizados seguida de una hidrólisis estereoselectiva de estos ésteres conlipasas para la obtención de halohidrinas quirales. Se estudió la aplicabilidad delos líquidos iónicos, el uso de reactivos poco contaminantes y el uso de enzimascomerciales y resting-cells de origen fúngico. Esta aproximación ha permitido laobtención del S-1-cloro-2-octanol y el S-1-bromo-2-octanol. La segundaaproximación consiste en la utilización de oxidoreductasas para labiotransformación de cetonas proquirales. Dichas enzimas están presentes encélulas en crecimiento de nuevos microorganismos aislados como hongosendófitos de plantas. Se ha encontrado una cepa de Rhizopus oryzae conactividad biocatalítica para la obtención de alcoholes quirales. / Asymmetric lactones and alcohols are valuable building blocks in organicchemistry applicable to the synthesis of many bioactive compounds such asdrugs, agrochemicals and food additives. There are a large range of selectiveorganic reactions available for most synthetic needs, but there is still one weakarea in organic chemical synthesis where stereochemistry is involved. Inaddition, there is a need to develop new syntheses and processes less hazardousto human health and the environment.This thesis reports diverse approaches to prepare chiral alcohols and lactonesprecursors. The first one consists of a chemo-enzymatic method to synthesisechiral halohydrins. This process implies a first step of synthesis of α-functionalesters followed by a stereoselective hydrolysis by lipases. The suitability ofionic liquids as reaction media, the use of less polluting reagents, and theapplication of commercial enzymes and resting-cells from fungus were studied.This methodology permits the preparation of S-1-chloro-2-octanol and S-1-bromo-2-octanol. The second approach consists of the biotransformation ofprochiral ketones by oxidoreductases from new endophytic fungus strainsisolated from diverse plants. One Rhizopus oryzae strain was found to be aputative biocatalyst to provide chiral alcohols.

Spiro-γ-lactones are widely distributed among natural products, several of them being well known by their interesting biological activities. We describe herein the synthesis of 1-oxaspiro[4.4]nonan derivatives and (+-)-andirolactone starting from easily available Diels-Alder adducts of 5-methylene-2(5H)-furanome 1 and classical dianes / La química de les espiro-γ-lactones ha despertat un considerable interès principalment degut a què moltes molècules que posseeixen aquesta estructura presenten diverses i significatives activitats biològiques. En aquesta tesi doctoral, prenent com a precursors els adductes de Diels-Alder, s’han investigat noves rutes sintètiques cap a 2(3H)-dihidrofuanones 5.5-disubstituïdes i oxaspiro[4.4]nonans polifuncionalitzats. Es presenten dues noves síntesis de (+-)-andirolactona 2, sesquiterpenoid amb estructura d’espiro-γ-butirolactona, recentment aïllat del Cedrus Libanotica i interessant per les seves propietats medicinals i biològiques potencials

The thesis entitled “Enantioselective synthesis of bio-active bicyclic acetals, cyclic ethers and lactones” demonstrates the utility of chiral pool tartaric acid as the source in the synthesis of natural products. The results are discussed in three chapters; 1) Enantioselective synthesis of bio-active bicyclic acetals, 2) Enantioselective synthesis of bio-active cyclic ethers and 3) Enantioselective synthesis of bio-active lactones. A brief introduction is provided in each chapter to keep the present work in proper perspective. Compounds (in bold) and references (in superscripts) are sequentially numbered differently for each chapter and references are given as foot notes. Experimental procedures are given differently for each chapter and placed at the end of chapter. Scanned 1H and 13C NMR spectras are given with description of signals. Chapter 1 describes the enantioselective synthesis of bicyclic acetal containing insect pheromones. First part of this chapter deals with the enantiodivergent synthesis of both enantiomers of hydroxy-exo-brevicomin and 2-hydroxy-exo-brevicomin starting from a single chiral compound, bis-Weinreb amide derived from L-(+)-tartaric acid. Controlled addition of Grignard reagent to bis-Weinreb amide followed by diastereoselective reduction of the resultant ketone was employed as the key step for the enantiodivergent synthesis of hydroxy-exo-brevicomin and 2-hydroxy-exo-brevicomin. In the second part, enantioselective synthesis of exo-brevicomin, iso-exo-brevicomin and formal synthesis of frontalin comprising similar framework is demonstrated, utilizing á -benzyloxy aldehydes derived from L-(+)-tartaric acid as chiral building block. Second Chapter describes the enantioselective synthesis of bio-active cyclic ethers, disparlure, centrolobine and isolaurepan. Employing á-benzyloxy aldehydes derived from L-(+)-tartaric acid as the chiral building block, synthesis of both enantiomers of insect pheromone disparlure is achieved involving the diastereoselective addition of allyltributyl tin to the á-benzyloxy aldehyde and cross metathesis of the resultant homoallylic alcohol with 4-methyl-1-pentene. Formal synthesis of centrolobine and isolaurepan are accomplished. Pivotal step involved in the synthesis of centrolobine is iron(III) mediated cyclization of 1,5-diol derived from L-(+)-tartaric acid, while Lewis acid mediated reductive cyclization of the hydroxy ketone derived from á-benzyloxy aldehyde is the key step in the synthesis of isolaurepan. Third chapter in the thesis deals with the enantioselective synthesis of bio-active lactones muricatacin, 6-acetoxy-5-hexadecanolide and boronolide. Utilizing á-benzyloxy aldehyde as the building block, synthesis of five and six membered lactones, muricatacin and 6-acetoxy-5-hexadecanolide were accomplished via the diastereoselective addition of 3-butenylmagnesium bromide and allyltributyl tin to á-benzyloxy aldehyde, respectively. Stereoselective formal synthesis of boronolide was described, starting from D-(–)-tartaric acid. Key reaction sequence includes the elaboration of ã-hydroxy amide obtained by a combination of controlled Grignard addition and diastereoselective reduction from bis- Weinreb amide derived from D-(–)-tartaric acid.

This thesis investigated the phytochemistry and pharmacology of immunomodulatory medicinal plant species used traditionally by the Q’eqchi’ Maya Healers Association (QMHA) of Belize, and the Cree of Eeyou Istchee (CEI) of northern Quebec. Using quantitative ethnobotanical methodology, we identified 107 plant species belonging to 49 families used by Q’eqchi’ healers in the treatment of symptoms from 14 usage categories related to inflammation. Regression analysis revealed that the Piperaceae, Araceae, and Begoniaceae are preferentially selected by the Maya. Healer consensus for plant species was high, with 56 species (52%) being used by all the healers, and consensus for usage categories was also high, as informant consensus factor (FIC) values for each category were greater than 0.4. Fifty-two Belizean species were evaluated for their TNF-α inhibitory activity in an LPS-stimulated THP-1 monocyte model. Twenty-one species (40%) demonstrated significant TNF-α inhibition when assayed at 100 µg/mL, 8 of which had greater than 50% of the activity of the parthenolide positive control (10 µg/mL). Significant regressions were found between the anti-inflammatory activity and total healer frequency of use (Fuse) and the use reports for 3 usage categories, which indicated that ethnobotanical parameters can in part predict the activity of traditionally used species. Five sesquiterpene lactones were isolated from the leaves of Neurolaena lobata, one of the most active species tested, all of which demonstrated anti-inflammatory activity greater than that of parthenolide (IC50 = 4.79 µM), with IC50s ranging from 0.17-2.32 µM. Lobatin B was the most active isolate tested. Ethanolic and water extracts of 17 species used by Cree healers were evaluated for their immunomodulatory activity. In general, the average anti-inflammatory activity of ethanolic extracts was 1.8 times greater than that of water extracts, and the pro-inflammatory activity of water extracts was 3.7 times greater than ethanolic extracts. Picea mariana and Pinus banksiana were the most anti-inflammatory ethanolic and water extracts, while the water extract of Sarracenia purpurea was the most pro-inflammatory. Picea marina cones, the most anti-inflammatory Cree medicine, were subjected to bioassay guided isolation. This led to the isolation of the anti-inflammatory lignan (+)-lariciresinol-9’-p-coumarate, which had an IC50 of 28.4 µM. Together, these results validate the traditional knowledge shared by our Q’eqchi’ and Cree collaborators, and draw attention to the therapeutic potential of subtropical and boreal plants as culturally appropriate complements to modern medicine. - Cette thèse porte sur la phytochimie et la pharmacologie des espèces de plantes médicinales immunomodulatrices utilisées traditionnellement par le Q’eqchi’ Maya Healers Association (QMHA) du Belize, et les Cris d'Eeyou Istchee (CEI) du nord du Québec. En utilisant une méthodologie ethnobotanique quantitative, nous avons identifié 107 espèces végétales appartenant à 49 familles utilisées par les guérisseurs Q'eqchi’ dans le traitement de symptômes appartenant à 14 catégories d'utilisation liées à l'inflammation. Une analyse de régression a révélé que les familles Piperaceae, Araceae, et Begoniaceae sont préférentiellement choisis par les Mayas. Le consensus entre guérisseurs pour les espèces végétales était élevé, avec 56 espèces (52%) étant utilisés par tous les guérisseurs, et le consensus pour les catégories d'utilisation était également élevé, car les valeurs de facteur de consensus des informants (FIC) pour chaque catégorie étaient supérieurs à 0,4. Cinquante-deux espèces du Belize ont été évaluées pour leur activité inhibitrice de TNF-α dans un modèle de THP-1 monocytes stimulés par le LPS. Vingt-et-une espèces (40%) ont montré une inhibition significative de TNF-α lorsque dosés à 100 µg/mL, dont 8 d’entre elles ont démontrées plus de 50% de l'activité du contrôle positif parthénolide (10 µg/mL). Des régressions significatives ont été observées entre l'activité anti-inflammatoire et la fréquence d'utilisation de guérisseurs totale (Fuse) et les rapports d'utilisation pour 3 catégories d'utilisation, ce qui indique que les paramètres ethnobotaniques peuvent en partie prédire l'activité des espèces traditionnellement utilisées. Cinq lactones sesquiterpéniques ont été isolés à partir des feuilles de Neurolaena lobata, l'une des espèces les plus actives testées, qui a démontré une activité anti-inflammatoire supérieure à celle du parthénolide (CI50 = 4,79 µM), avec des CI50 allant de 0,17 à 2,32 µM. Lobatin B était l’isolât le plus actif testé. Des extraits éthanoliques et aqueux de 17 espèces utilisées par les guérisseurs Cris ont été évalués pour leur activité immunomodulatrice. En général, l'activité anti-inflammatoire moyenne des extraits éthanoliques était 1,8 fois supérieure à celle des extraits d'eau, et l'activité pro-inflammatoire des extraits d'eau était de 3,7 fois supérieure à celle des extraits éthanoliques. Picea mariana et Pinus banksiana étaient les extraits éthanoliques et aqueux avec le plus d’activité anti-inflammatoire, tandis que l'extrait aqueux de Sarracenia purpurea était le plus pro-inflammatoire. Le cône de Picea marina, le médicament traditionnelle Cris le plus anti-inflammatoire, a été soumis à une isolation guidée par essais biologiques. Cela a mené à l'isolement du lignane anti-inflammatoire (+)-lariciresinol-9'-p-coumarate, qui avait une CI50 de 28,4 µM. Ensemble, ces résultats valident les connaissances traditionnelles partagées par nos collaborateurs Q'eqchi' et Cris, et mettent en évidence le potentiel thérapeutique des plantes subtropicales et boréales comme des compléments à la médecine moderne qui sont culturellement appropriées.

For the first time in human history, more people worldwide suffer from obesity than are undernourished. Numerous health complications are associated with obesity including cardiovascular disease, Type 2 Diabetes, cancers of reproductive tissues, stroke, depression, anxiety disorders, and Alzheimer’s disease. A deeper understanding of the anti-adipogenic effects and mechanism of action of sesquiterpene lactones may have pharmacological import in the continuing search for therapeutic modalities to ameliorate the effects of this global obesity epidemic. Dehydroleucodine (DhL), 11,13-dihydro-dehydroleucodine (DH-DhL), and dehydroparashin-B (DhP), sesquiterpene lactones extracted from or derived from compounds extracted from Artemisia douglasiana, were investigated for their anti-adipogenic effects on 3T1-L1 preadipocytes. Dehydroleucodine inhibited the expression of C/EBPa and PPARg, and also strongly blocked the expression of C/EBPβ, an early stage biomarker of early adipogenesis, in a concentration-dependent manner. Dehydroleucodine arrested the cell cycle at the G0/G1 phase, increased p27 and decreased both cyclins A and D and their partners (e.g., CDK2 and CDK4). Furthermore, DhL downregulated expression of histone demethylase JMJD2 as well as repressed the expression of histone methyltransferase MLL4, which in turn diminished the expression of C/EBPb and PPARg, respectively. 11,13-dihydro-dehydroleucodine blocked the accumulation of lipid droplets and inhibited the expression of PPARγ and C/EBPβ. Collectively, the results indicate that the inhibition of early stage preadipocyte differentiation by DH-DhL may be associated with cell cycle arrest at the G0/G1 phase. Dehydroparashin-B significantly decreased the accumulation of lipid content and downregulated the expression of CEBPβ, PPARγ and CEBPα as well as FAS. Interestingly, the addition of DhP inhibited the number as well as the size of the lipid droplets during the differentiation of 3T3-L1 preadipocytes. Taken together, this data suggests that DhP has an important inhibitory effect on cellular pathways regulating adipocyte differentiation.

A química de produtos naturais sempre foi uma fonte importante de novas substâncias e de substâncias bioativas. No mundo moderno, o homem utiliza os produtos naturais para diversos fins: corantes, edulcorantes, essências, defensivos agrícolas e principalmente medicamentos. Com o desenvolvimento das técnicas de isolamento de substâncias, cresceu a necessidade de organizar as informações obtidas e também a criação de meios para a identificação mais rápida das substâncias isoladas. Esta foi uma das necessidades que fez surgir a Quimioinformática. Quimioinformática é uma disciplina que utiliza os métodos da informática para organizar dados químicos, analisar estes dados e gerar novas informações a partir destes dados. Esta ferramenta tem sido utilizada com sucesso em procura por novas drogas (QSAR/QSPR), elucidação estrutural automatizada de substâncias orgânicas e em cálculos e previsão de propriedades físico-químicas de diversas moléculas. Os objetivos do presente trabalho foram o estudo fitoquímico de espécies dos gêneros Dimerostemma e Ichthyothere com o intuito de isolar novas substâncias e o desenvolvimento de técnicas envolvendo quimioinformática com o intuito de auxiliar a elucidação estrutural de produtos naturais. Realizou-se a técnica de microamstragem de tricomas glandulares de diversas espécies pertencentes a gêneros da tribo Heliantheae (Viguiera, Tithonia, Dimerostemma). Através da microamostragem foi possível identificar diversas substâncias presentes nos tricomas glandulares das espécies analisadas. Das duas espécies de Dimerostemma investigadas (D. brasilianum e D. rotundifolium) foi possível identificar dois germacrolidos e dois eudesmanolidos, enquanto que de Ichthyothere terminalis foi possível a identificação de dois melampolidos, todos eles lactonas sesquiterpênicas. Foram treinadas redes neurais artificiais para a realização da identificação dos esqueletos carbônicos de determinadas substâncias a partir dos dados obtidos através dos espectros de RMN 13C, sendo que os resultados obtidos podem ser considerados satisfatórios. Foi desenvolvido um software para efetuar a identificação automática de substâncias através da comparação com uma biblioteca de padrões que possui dados cromatográficos de 51 lactonas sesquiterpênicas. Esse software, chamado de NAPROSYS, também é capaz de fazer comparação de dados de RMN de amostra com dados de RMN presentes em uma biblioteca de dados, tornando possível a identificação imediata de substâncias presentes na biblioteca e também auxiliar a elucidação estrutural de substâncias que não estão nela presentes. Para testar a eficiência do NAPROSYS, o programa foi utilizado com sucesso para identificar LSTs através da microamostragem de tricomas glandulares. A eficiência do NAPROSYS em identificar dados de RMN de substâncias presentes na biblioteca foi testada com substâncias isoladas do gênero Tithonia e Viguiera que possuem substâncias bem descritas na literatura e já isoladas no nosso laboratório, sendo que os resultados apresentados foram excelentes. Criou-se também dois modelos de redes neurais para prever tempos de retenção de lactonas sesquiterpênicas em cromatografia líquida (QSRR) com o objetivo de melhorar o desempenho do NAPROSYS em análises de dados cromatográficos. Os resultados para este caso, embora coerentes, precisam ser melhorados. Neste trabalho concluimos que o uso das técnicas clássicas juntamente com as novas técnicas de Quimoinformática pode se tornar uma ferramenta muito eficaz para a elucidação estrutural e busca de substâncias com determinadas propriedades químicas ou mesmo na bioprospecção de novas substâncias bioativas. / Natural products chemistry has always been an important source for new andbioactive compounds. In modern world, mankind uses natural products to do many tasks: colouring, as essences, as agricultural defensives and many as medicines. Within the development of compound isolation techniques, the need for information organisation has grown. The need for quickly identification of isolated compounds has also grown. This was one of the necessities that made Chemoinformatics emerge. Chemoinformatics is a discipline that uses informatics as a tool to organise, analise and to generate new knowledge from chemical data. This tool has been used with success in automate structure elucidation, drug development (QSAR/QSPR) and to predict chemical-physical data of many molecules. The aims of the present work were the phytochemical study of species of the genera Dimerostemma and Ichthyothere to isolate new compounds, and the development of chemoinformatics techniques to aid natural products structure elucidation. The glandular trichome microsampling was made for diverse species of genera from the tribe Heliantheae (Viguiera, Tithonia, Dimerostemma). Many compounds were identified through glandular trichome microsampling. Two germacrolides and two eudesmanolides were identified from Dimerostemma species (D. brasilianum and D. episcopale), while from Ichthyothere terminalis two melampolides were identified, all of them being sesquiterpene lactones. Artificial Neural Networks were trained to make skeleton identification from data obtained from 13C NMR and the obtained results can be considered satisfactory. A software was developed to make automatic compound identification through the comparation with a compound library that possesses data from 51 STLs. This software is called NAPROSYS is also able to compare the NMR data of the sample with the NMR data stored into a compound library, making the imediate identification of compounds present into library possible and also help the structure elucidation of unknown compounds. To test NAPROSYS\' efficience to identify NMR data of compunds sored into the library was made with compounds isolated from species of Tithonia and Viguiera genera, because these genera has well describe compounds in the literature and that has been isolated in our laboratory, and the obtained results are excellent. Two Artificial Neural Network models were created to predict the retention time of sesquiterpene lactones in liquid cromatography (QSRR) with the aim of improve NAPROSYS performance in cromatographic data analysis. The results for this case, although coherent, can be improved. The conclusion of this work is that the use of classical techniques with the new techniques of chemoinformatics can be a very efficient tool to make structure elucidation, search for compounds with certain chemical properties and even the search for new bioactive compounds.

O presente trabalho mostra a utilização de métodos computacionais e os resultados obtidos na determinação estrutural de produtos naturais, neste caso sesquiterpenos lactonizados. Nosso grupo de pesquisa tem desenvolvido nos últimos anos o projeto denominado SISTEMAT para a determinação estrutural de produtos naturais. Este sistema é composto de programas utilizados para a construção de bancos de dados capazes de armazenar qualquer tipo de informação referente a substâncias orgânicas, e programas que permitem a recuperação e análise das informações contidas nos bancos de dados (programas aplicativos). Foi também construído um programa para a previsão de espectros de RMN 13C utilizando modelos tridimensionais para a representação das moléculas. O programa considera cada carbono e sua vizinhança química em três dimensões como uma subestrutura. Para encontrar o deslocamento químico equivalente a uma nova subestrutura, ele procura no banco de dados um carbono com uma vizinhança equivalente. O banco de dados criado para o SISTEMAT contém 1300 espectros de RMN 13C de sesquiterpenos lactonizados, enquanto que o utilizado para o programa simulador de espectros de RMN 13C possui 1600 substâncias codificadas. / This work shows the use of computational methods and the results obtained in the structure determination of sesquiterpene lactones. Our research group have developed in the last years the expert system named SISTEMAT, to structure determination of natural products. This system have programs used to construct a database able to store any kind of information about the compounds and programs used to retrieve and analyse informations obtained in the database. It was also planned a program to make predictions of 13C NMR spectra of sesquiterpene lactones. It uses a codification working with tridimensional substructures. The program treats each carbon atom and its neighbouring as a substructure. It can scan all the database for other equal or similar chemical shift values that can be used to predict the 13C NMR spectrum for a new compound. The current database contains about 1300 13C NMR spectra of sesquiterpene lactones. The other database used in the program for 13C NMR prediction has 1600 compounds.

This thesis investigated the phytochemistry and pharmacology of immunomodulatory medicinal plant species used traditionally by the Q’eqchi’ Maya Healers Association (QMHA) of Belize, and the Cree of Eeyou Istchee (CEI) of northern Quebec. Using quantitative ethnobotanical methodology, we identified 107 plant species belonging to 49 families used by Q’eqchi’ healers in the treatment of symptoms from 14 usage categories related to inflammation. Regression analysis revealed that the Piperaceae, Araceae, and Begoniaceae are preferentially selected by the Maya. Healer consensus for plant species was high, with 56 species (52%) being used by all the healers, and consensus for usage categories was also high, as informant consensus factor (FIC) values for each category were greater than 0.4. Fifty-two Belizean species were evaluated for their TNF-α inhibitory activity in an LPS-stimulated THP-1 monocyte model. Twenty-one species (40%) demonstrated significant TNF-α inhibition when assayed at 100 µg/mL, 8 of which had greater than 50% of the activity of the parthenolide positive control (10 µg/mL). Significant regressions were found between the anti-inflammatory activity and total healer frequency of use (Fuse) and the use reports for 3 usage categories, which indicated that ethnobotanical parameters can in part predict the activity of traditionally used species. Five sesquiterpene lactones were isolated from the leaves of Neurolaena lobata, one of the most active species tested, all of which demonstrated anti-inflammatory activity greater than that of parthenolide (IC50 = 4.79 µM), with IC50s ranging from 0.17-2.32 µM. Lobatin B was the most active isolate tested. Ethanolic and water extracts of 17 species used by Cree healers were evaluated for their immunomodulatory activity. In general, the average anti-inflammatory activity of ethanolic extracts was 1.8 times greater than that of water extracts, and the pro-inflammatory activity of water extracts was 3.7 times greater than ethanolic extracts. Picea mariana and Pinus banksiana were the most anti-inflammatory ethanolic and water extracts, while the water extract of Sarracenia purpurea was the most pro-inflammatory. Picea marina cones, the most anti-inflammatory Cree medicine, were subjected to bioassay guided isolation. This led to the isolation of the anti-inflammatory lignan (+)-lariciresinol-9’-p-coumarate, which had an IC50 of 28.4 µM. Together, these results validate the traditional knowledge shared by our Q’eqchi’ and Cree collaborators, and draw attention to the therapeutic potential of subtropical and boreal plants as culturally appropriate complements to modern medicine. - Cette thèse porte sur la phytochimie et la pharmacologie des espèces de plantes médicinales immunomodulatrices utilisées traditionnellement par le Q’eqchi’ Maya Healers Association (QMHA) du Belize, et les Cris d'Eeyou Istchee (CEI) du nord du Québec. En utilisant une méthodologie ethnobotanique quantitative, nous avons identifié 107 espèces végétales appartenant à 49 familles utilisées par les guérisseurs Q'eqchi’ dans le traitement de symptômes appartenant à 14 catégories d'utilisation liées à l'inflammation. Une analyse de régression a révélé que les familles Piperaceae, Araceae, et Begoniaceae sont préférentiellement choisis par les Mayas. Le consensus entre guérisseurs pour les espèces végétales était élevé, avec 56 espèces (52%) étant utilisés par tous les guérisseurs, et le consensus pour les catégories d'utilisation était également élevé, car les valeurs de facteur de consensus des informants (FIC) pour chaque catégorie étaient supérieurs à 0,4. Cinquante-deux espèces du Belize ont été évaluées pour leur activité inhibitrice de TNF-α dans un modèle de THP-1 monocytes stimulés par le LPS. Vingt-et-une espèces (40%) ont montré une inhibition significative de TNF-α lorsque dosés à 100 µg/mL, dont 8 d’entre elles ont démontrées plus de 50% de l'activité du contrôle positif parthénolide (10 µg/mL). Des régressions significatives ont été observées entre l'activité anti-inflammatoire et la fréquence d'utilisation de guérisseurs totale (Fuse) et les rapports d'utilisation pour 3 catégories d'utilisation, ce qui indique que les paramètres ethnobotaniques peuvent en partie prédire l'activité des espèces traditionnellement utilisées. Cinq lactones sesquiterpéniques ont été isolés à partir des feuilles de Neurolaena lobata, l'une des espèces les plus actives testées, qui a démontré une activité anti-inflammatoire supérieure à celle du parthénolide (CI50 = 4,79 µM), avec des CI50 allant de 0,17 à 2,32 µM. Lobatin B était l’isolât le plus actif testé. Des extraits éthanoliques et aqueux de 17 espèces utilisées par les guérisseurs Cris ont été évalués pour leur activité immunomodulatrice. En général, l'activité anti-inflammatoire moyenne des extraits éthanoliques était 1,8 fois supérieure à celle des extraits d'eau, et l'activité pro-inflammatoire des extraits d'eau était de 3,7 fois supérieure à celle des extraits éthanoliques. Picea mariana et Pinus banksiana étaient les extraits éthanoliques et aqueux avec le plus d’activité anti-inflammatoire, tandis que l'extrait aqueux de Sarracenia purpurea était le plus pro-inflammatoire. Le cône de Picea marina, le médicament traditionnelle Cris le plus anti-inflammatoire, a été soumis à une isolation guidée par essais biologiques. Cela a mené à l'isolement du lignane anti-inflammatoire (+)-lariciresinol-9'-p-coumarate, qui avait une CI50 de 28,4 µM. Ensemble, ces résultats valident les connaissances traditionnelles partagées par nos collaborateurs Q'eqchi' et Cris, et mettent en évidence le potentiel thérapeutique des plantes subtropicales et boréales comme des compléments à la médecine moderne qui sont culturellement appropriées.

<p>U ovom radu prikazana je sinteza 11 tiazolnih izostera goniofufurona (1-11),<br />4 konformaciono kruta analoga goniofufurona (12-15) i jednog butadiolnog<br />derivata&nbsp; tiazofurina&nbsp; (16).&nbsp; Takođe,&nbsp; izvr&scaron;eno&nbsp; je&nbsp; ispitivanje&nbsp; i&nbsp; poređenje<br />biolo&scaron;kih&nbsp; aktivnosti&nbsp; sintetisanih&nbsp; analoga&nbsp; sa&nbsp; sa&nbsp; aktivno&scaron;ću&nbsp; i&nbsp; selektivno&scaron;ću<br />kako GF i TF tako i doksorubicina, jedinjenja &scaron;irokog spektra dejstva (DOX).<br />Hiralni&nbsp; prekursor&nbsp; novosintetisanih&nbsp; jedinjenja&nbsp; 1-15&nbsp; bila&nbsp; je&nbsp; D-glukoza,&nbsp; a<br />jedinjenja 16 D-arabinoza.</p> / <p>A multistep synthesis of 11 novel thiazole isosteres of goniofufurone (1-11), 4 novel conformationally constrained isosteres of goniofufurone (12-15), as well as&nbsp; one&nbsp; butanediole&nbsp; derivative&nbsp; of&nbsp; tiazofurin&nbsp; (16)&nbsp; has&nbsp; been&nbsp; achieved.&nbsp; In&nbsp; vitro cytotoxicity of newly synthetized derivatives has been evaluated and compared with the cytotoxicities of goniofufurone, tiazofurin and doxorubicin.</p>

No / This review summarises the recent developments in the synthesis and applications of polymers derived from malic acid. There has been an increased interest in the design of sustainable and biodegradable polymers as a result of the drive to use renewable feedstocks as an alternative to petrochemicals in addition to their significant potential in biomedical applications. Synthetic strategies to access polymers from malic acid based on both condensation and ring-opening polymerization, across a broad range of conditions, are reviewed along with their advantages and limits. The role that such materials are studied for in biomedical applications is discussed, and their environmental impact based on the biodegradability of the malic polymer backbone is outlined. / The Royal Society, EPSRC, BBSRC