Les signatures histopathologiques de principales maladies neurodégénératives - maladie d'Alzheimer et la maladie de Parkinson - sont les enchevêtrements neurofibrillaires formés par la protéine tau et les corps de Lewy, formés par l'α-synucleine agrégée. Les mécanismes précis du repliement et de l'agrégation de ces protéines, pour la protéine tau comme pour l'α-synucleine, ne sont pas totalement compris à ce jour. Ici, nous nous sommes intéressés à cette question en utilisant des modèles in vitro et in vivo. En étudiant l'agrégation tau in vitro, nous avons mis en évidence un nouvel auto- assemblage réversible de tau, qui dépend de la température et de la présence d’ions zinc, et qui est a priori différent de l'agrégation de tau en présence d'inducteurs d'agrégation tels que l'héparine. Ce processus pourrait néanmoins être impliqué dans les premières étapes de l'agrégation pathologique de tau. Dans une deuxième partie nous avons développé des modèles murin pour étudier les dysfonctionnement de l’α-synucleine. Nous avons montré que l’α-synucleine est directement impliquée dans le développement embryonnaire de régions spécifiques du système nerveux, et qu'elle a des propriétés modulatrices seulement sur les neurones dopaminergiques de la substantia nigra, qui sont touchés dans la maladie de Parkinson.Les résultats obtenus dans nos études de deux protéines qui subissent une agrégation pathogène et forment des inclusions intracellulaires ont contribué à la compréhension des processus moléculaires et cellulaires associés à la dégénérescence neuronale, ce qui fournira de nouvelles pistes pour développer de nouvelles stratégies de thérapies de maladies neurodégénératives. / The histopathological hallmarks of the most common neurodegenerative diseases – Alzheimer’s disease and Parkinson’s disease are neurofibrillary tangles formed by tau protein and Lewy bodies inclusions formed by aggregated α-synuclein. The formation and accumulation of these proteins into inclusions cause functional disruptions of the cytoskeleton and leads to neuronal degeneration. The precise mechanisms of tau and synuclein misfolding and aggregation leading to those cellulare incluses, even though very studied, are not fully understood neither for tau protein nor for α-synuclein.Here we have addressed this question using both in vitro and in vivo models. Investigating tau aggregation in vitro, we have found a reversible self-assembly of tau, which depends on temperature and is induced by zinc ions, which is different from the tau aggregation in the presence of aggregation-inducers such as heparin. This process could be implicated in the first steps of tau pathological aggregation. In a second part, we have developed a mouse model for studying the α-synuclein dysfunction. We have shown that α- synuclein is directly involved in the embryonic development of the specific regions of the nervous system, and that it has modulating effect only on the populations of dopaminergic neurons of substantia nigra, which are affected in Parkinson’s disease.Results obtained in our studies of two proteins that undergo pathogenic aggregation and form intracellular inclusions contributed to understanding of molecular and cellular processes associated with neuronal degeneration, which is important for the development of new disease-modifying therapies of neurodegenerative disorders.

Au sein du muscle squelettique, le réticulum sarcoplasmique occupe une place essentielle dans la régulation de l’homéostasie calcique et de la contraction musculaire. En particulier, le transporteur calcique SERCA, situé à la membrane du réticulum endoplasmique permet de reconstituer le contenu calcique réticulaire suite à une contraction musculaire. Dans le muscle squelettique, l’activité de SERCA est contrôlée par un peptide inhibiteur spécifique appelé la myoréguline. Nous nous intéressons au rôle du récepteur nucléaire Rev-erb-α, un répresseur de transcription connu pour favoriser la fonction musculaire et dont l’activité peut être modulée par des ligands pharmacologiques. Nos résultats montrent que Rev-erb-α réprime l’expression de la myoréguline en se fixant sur son promoteur, ce qui a pour conséquence l’augmentation de l’activité de SERCA et la hausse du contenu calcique réticulaire. Un traitement avec un agoniste de Rev-erb-α, le SR9009, améliore l’homéostasie calcique et la contractilité musculaire de souris mdx/utr+/-, un modèle de la myopathie de Duchenne. Par ailleurs, le réticulum endoplasmique est le siège de la conformation des protéines de la voie sécrétoire. Des altérations de la conformation protéique provoquent un stress réticulaire et le déclenchement de la réponse aux protéines mal-conformées qui peut conduire jusqu’à l’apoptose. Il est décrit que le stress réticulaire est un phénomène impliqué dans l’activation de la cellule satellite musculaire suite à une blessure. Nous avons établi que Rev-erb-α, en augmentant l’interaction entre le réticulum endoplasmique et la mitochondrie accroit l’activation de la réponse aux protéines mal-conformées et l’apoptose de cellules satellites activées, ce qui pourrait impacter le potentiel de régénération musculaire. En conclusion, nous avons identifié Rev-erb-α comme un modulateur de la fonction du réticulum endoplasmique dans le muscle squelettique. Dans le futur, des thérapies ciblant spécifiquement Rev-erb-α pourraient être développées dans le cadre de pathologies musculaires chez l’Homme. / Within skeletal muscle, the sarcoplasmic reticulum plays an essential role in the regulation of calcium homeostasis and muscle contraction. In particular, the SERCA transporter, located at the membrane of the endoplasmic reticulum, by pumping calcium from cytosol from reticular lumen, allows the reticular calcium content to be reconstituted following muscle contraction. In skeletal muscle, SERCA activity is controlled by a specific inhibitory peptide called myoregulin. We are interested in the role of the nuclear receptor Rev-erb-α, a transcription repressor known to promote muscle function and whose activity can be modulated by pharmacological ligands. Our results show that Rev-erb-α represses the expression of myoregulin by binding to its promoter, which results in an increase in SERCA activity and an increase in reticular calcium content. Treatment with a Rev-erb-α agonist, SR9009, improves calcium homeostasis and muscle contractility in mdx/utr+/- mice, a model of Duchenne myopathy. In addition, the endoplasmic reticulum is the site of protein conformation of the secretory pathway. Alteration in protein conformation causes reticular stress and triggers the unfolded protein response that can lead to apoptosis. It is described that reticular stress is a phenomenon involved in the activation of skeletal muscle satellite cell following an injury. We have established that Rev-erb-α, by increasing the interaction between endoplasmic reticulum and mitochondria enhances the activation of unfolded protein response and apoptosis of activated satellite cells, which could impact the muscle regeneration capacity. In conclusion, we have identified Rev-erb-α as a modulator of endoplasmic reticulum function in skeletal muscle. In the future, specific Rev-erb-α targeting therapies may be developed for human muscle diseases.

Le présent travail rend compte des études phytochimiques et biologiques d'extraits non volatils de quatre plantes utilisées au Bénin dans le traitement du diabète. La première partie passe en revue la bibliographie sur les plantes sujettes à notre étude. Dans cette partie, la systématique, l'importance en pharmacopée ainsi que les travaux déjà effectués sur ces plantes ont été présentés. La deuxième partie présente le mode d'extraction et les études chimiques des extraits et les résultats obtenus. La spectrophotométrie a permis de déterminer quelques grandes familles de composés présents dans les extraits : les polyphénols totaux, les flavonoïdes et les tanins tandis que la GC/MS et la LC/MS ont servi à mettre en exergue la présence de composés volatils et non volatils. La troisième partie décrit les tests biologiques in vitro et ex vitro effectués sur les extraits. Les extraits ont montré de manière générale des activités : inhibitrice de l' α-glucosidase, antioxydantes (DPPH, FRAP, ORAC), antimicrobiennes et l'une (Bridelia ferruginea) une activité cytotoxique sur les cellules cancéreuses (PA1, MCF7, PC3, DU-145), avec une efficacité variable d'une plante à une autre. La quatrième partie discute de manière générale des résultats issus des études phytochimiques et des tests biologiques. Parmi les quatre échantillons de plantes sélectionnées pour notre étude, seul l'extrait semi-éthanolique des racines de Ceiba pentandra a une faible teneur en familles de composés dosés et présente des activités biologiques (ci-dessus citées) faibles comparativement aux extraits de Bridelia ferruginea, de Pseudocedrela kotschyi et de Polygonum senegalensis. L'ensemble des résultats tant sur le plan chimique que biologique met en évidence les potentialités des extraits de plantes étudiées, pour une exploitation à des fins thérapeutiquesfutures. / The present work had reported on the phytochemical and biological studies of non-volatile extracts of four plants used in Benin for diabetes treatment. The first part reviewed the bibliography of investigated plants in our study. In this part, the systematic, the importance in the pharmacopoeia and the previous works done on these plants were presented. The second part has presented the extraction method and chemical studies of the extracts and results obtained. The spectrophotometry has permitted to identify some important families of compounds in the extracts: the total polyphenols, flavonoids and tannins whereas the GC / MS and LC/MS were used to highlight the presence of volatile and non-volatile compounds. The third part described the biological tests in vitro and ex vitro carried out on the extracts. The extracts showed in general activities: α-glucosidase inhibition, antioxidant (DPPH, FRAP, ORAC), antimicrobial, and one of them (Bridelia ferruginea) were cytotoxic on cancer cells (PA1, MCF7, PC3, DU-145), with a variable efficiency from one plant to another. The fourth part had discussed in general about the results obtained from phytochemical studies and biological tests. Among the four plants samples selected for our study, only the semi-alcoholic extract of Ceiba pentandra roots had a low-dosed compounds families and presented of this biological activities (cited below) low comparatively to Bridelia ferruginea, Pseudocedrela kotschyi and Polygonum senegalensis extracts. Both of the chemical and biological results highlight the potential of certain species for future exploitation of their non-volatile extract for therapeutic purposes.

A la suite de la découverte au laboratoire d'une nouvelle réaction entre le méthylglyoxal et un α-aminoazahétérocycle, une nouvelle famille de modulateurs (famille I) de la protéine CFTR (Cystic Fibrosis Transmembrane conductance Regulator) a été mise en évidence. Les dysfonctionnements de cette protéine, qui constitue un canal chlorure transmembranaire, sont responsables de plusieurs pathologies de la mucoviscidose résultant de mutations du gêne correspondant.<br />Nous avons tout d'abord cherché à confirmer la structure du pharmacophore supposé en sélectionnant et évaluant des petites molécules contenant le pharmacophore ou en modifiant les groupements à proximité du pharmacophore. Cette étude a permis l'accès à de nouveaux composés issus de la réaction entre un autre α-oxoaldéhyde (éthylglyoxal) et des α-aminoazahétérocycles et, à deux autres familles de composés dérivés de la première (familles II et III). <br />Par ailleurs, en nous basant sur la structure des deux « chef de files », l'inhibiteur GPinh-5a et le potentiateur/activateur GPact-11a, nous avons développé une pharmacomodulation de la structure de base des composés actifs qui sont des dérivés de purine. Un grand nombre d'analogues ont ainsi été synthétisés.<br />Ces deux approches ont permis la mise en évidence de plusieurs nouveaux inhibiteurs et de deux nouveaux potentiateurs de la protéine CFTR. <br />Au regard des caractéristiques et des propriétés des composés les plus actifs, leur étude biologique doit donc être poursuivie dans le but d'aboutir à une utilisation thérapeutique

The enzyme α-isopropylmalate synthase (IPMS) catalyses the reaction between acetyl coenzyme A (AcCoA) and α-ketoisovalerate (KIV) to produce free coenzyme A and α isopropylmalate (IPM). This reaction is a key control point in the biosynthesis of a leucine, a pathway absent in animals but present in plants, fungi and bacteria. As a result, IPMS is a antibiotic and herbicidal target that has been validated by knockout studies for M. tuberculosis, the causative agent of tuberculosis. Engineered IPMSs have also been used in the fermentative production of long chain alcohols for use as fuels. IPMS belongs to a family of related enzymes called α-ketoacid: AcCoA re-aldolases (KARAs), with each subfamily differing in the specific α-ketoacid that AcCoA is reacted with. The known KARA subfamilies are IPMS, citramalate synthases (CMSs), homocitrate synthases (HCSs), methylthioalkylmalate synthases (MAMSs) and re-citrate synthases (RCSs), respectively involved in the biosynthesis of isoleucine, lysine, glucosinolates and TCA cycle intermediates. This thesis describes work aimed at improving understanding of both specific subfamilies of KARA enzymes and also the genetic and functional relationships between the subfamilies. A particular emphasis is placed on relating primary structure to function, allowing the inference of function from a very small subset of residues. IPMSs are divided into two classes, the Mtu-like IPMSs and the much less studied Eco-like IPMSs. Chapter 2 details the expression and characterisation of the Eco like IPMS from N. meningitidis (NmeIPMS). Overall NmeIPMS showed similar properties to MtuIPMS, but unlike that enzyme NmeIPMS is inhibited by high divalent metal ion concentrations, does not require monovalent metal ions, and shows some activity with the α-ketoacid 3-methyl α ketovalerate. Several previous results showing inhibitory activity of Zn2+, Cd2+ and bromopyruvate were also found to be the results of interference with the assay system and all three were found to be much weaker inhibitors than previously determined.   Phylogenetic analysis of the different KARA subfamilies revealed certain specific positions that were believed to control substrate specificity. Chapter 3 details mutagenesis experiments on MtuIPMS that probe the function of these residues. Once the importance of the residues had been established, substitutions were made in which IPMS residues were replaced with their equivalents from HCSs and CMSs in order to change substrate specificity. The most successful result was the Y169L substitution based on HCS, which decreased the specificity constant with KIV by four orders of magnitude while improving other activities, successfully shifting the best activity to the unbranched α-ketoacid α-ketobutyrate. Chapter 4 of this thesis details the purification and functional testing of the RCS from C. saccharolyticus (CscRCS), the first thermophilic RCS characterised. CscRCS was found to have an extremely low Km for its substrate oxaloacetate (1.7 µM), believed to be an adaptation to the instability of oxaloacetate at the temperatures CscRCS operates at in vivo. The enzyme also showed competitive affinity by α-ketoglutarate, the end product of the pathway. Unlike other characterised RCSs, CscRCS showed no oxygen sensitivity. The phylogenetic analysis conducted for this thesis identified a subfamily of KARAs dubbed pseudo-IPMSs (PIPMSs) that showed no substantial homology to any studied subfamily. In Chapter 5 the PIPMS from T. thermophilus (TthPIPMS) was expressed and characterised. TthPIPMS showed many features of a CMS, being most active with the same substrate (pyruvate) and sensitive to the same inhibitor (isoleucine). Unlike the previously studied CMS subfamilies, TthPIPMS possesses a nanomolar IC50 for its inhibitor, and also shows substantial activity as an RCS. The results of these chapters are then drawn together in Chapter 6 to create a picture of the relationships between the KARA enzymes, in terms of their functional characteristics as well as the sequence and evolutionary relationships between them that have bought about their diverse functions.

α-Isopropylmalate synthase (α-IPMS) catalyses the first committed step in leucine biosynthesis in bacteria, including Neisseria meningitidis and Mycobacterium tuberculosis. It catalyses the condensation of α-ketoisovalerate (α-KIV) and acetyl coenzyme A (AcCoA) to form α-isopropylmalate (α-IPM). Like many key enzymes in biosynthesis, α-IPMS is inhibited by the end-product of the biosynthetic pathway, in this case leucine. α-IPMS is homodimeric, with monomers consisting of a (β/α)8-barrel catalytic domain, two subdomains and a C-terminal regulatory domain, responsible for binding leucine and providing feedback inhibition for leucine biosynthesis. The exact mechanism of feedback inhibition in this enzyme is unknown, despite the elucidation of crystal structures with and without leucine bound. This thesis explores the nature of allosteric regulation in α-IPMS, including the effects of the regulatory domain and the importance of structural asymmetry on catalytic activity. Chapter 2 details the characterisation of wild-type α-IPMS from N. meningitidis (NmeIPMS). This protein was successfully cloned, expressed and purified by metal-affinity and size-exclusion chromatography. NmeIPMS has similar characteristics to previously characterised α-IPMSs, being a dimer and demonstrating substrate binding affinities in the micromolar range. This enzyme has a turnover number of 13s⁻¹ and is sensitive to mixed, non-competitive inhibition by the amino acid leucine. Small angle X-ray scattering experiments reveal that the solution-phase structure of this protein is likely similar to existing crystal structures of other α-IPMSs. In Chapter 3, substitutions of residues potentially involved in the binding and transmission of the leucine regulatory mechanism are described. Most of these amino acid substituted variants reduce enzyme sensitivity to leucine, and one variant is almost entirely insensitive to this inhibitor. Another of these variants demonstrates an unexpected decrease in substrate affinity, despite the substituted residue being located far from the active site. The independence of α-IPMS domains is investigated in Chapter 4. The catalytic domains were isolated from NmeIPMS and the α-IPMS from M. tuberculosis (MtuIPMS), and found to be unable to catalyse the condensation of substrates, despite maintaining the wild-type structural fold. Complementation studies with Escherichia coli cells lacking the gene for α-IPMS show that the truncated variants are unable to rescue growth in these cells. Binding of α-KIV in the truncated NmeIPMS variant is much stronger than in the wild-type, and this may be the reason for lack of competent catalysis. A crystal structure was solved for the truncated variant of NmeIPMS and indicates that the regulatory domain is required for proper positioning of large regions of the protein. Two isolated regulatory domains from NmeIPMS were cloned, but with limited success in characterisation. Finally, Chapter 5 describes substitutions made in MtuIPMS to affect relative domain orientations within the protein. Dimer asymmetry is investigated by substituting residues at the domain interfaces. These substitutions did have some effect on catalysis and inhibition, but did not show any change in average solution-phase structure. These results are drawn together in the greater context of allostery in general in Chapter 6, along with ideas for future research in this field. This chapter reviews the insights gained into protein structure from this thesis, particularly the importance of residues at protein domain interfaces. The asymmetry in the α-IPMS structure is discussed, along with small-molecule binding regulatory domains.

Die vorliegende Untersuchung hatte zur Zielsetzung, bei Kühen die Unterschiede zwischen hypokalzämischen und normokalzämischen Festliegern zu analysieren. Es sollte geklärt werden, welche klinischen und labordiagnostischen Veränderungen, außer der Kalzium- (Ca) Konzentration, dem normokalzämische Festliegen zugrunde liegen. Des Weiteren wurden die TNF-α-, Haptoglobin- (Hp-) und TEAC-Konzentrationen in Beziehung zum Festliegen, den Mineralstoffkonzentrationen sowie hinsichtlich diagnostischer Information geprüft. Außerdem wurden die Festlieger mit Nachgeburtsverhaltung (Ret. sec.) und die Kühe mit Exitus letalis labordiagnostisch genauer analysiert.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-09-19T12:33:33Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação de Mestrado com Ficha Catalográfica - Leonilda (6).pdf: 1607291 bytes, checksum: 83e1d52bc2be1f64f2a2a27dc1f58889 (MD5) / Made available in DSpace on 2016-09-19T12:33:33Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação de Mestrado com Ficha Catalográfica - Leonilda (6).pdf: 1607291 bytes, checksum: 83e1d52bc2be1f64f2a2a27dc1f58889 (MD5) Previous issue date: 2016-02-18 / A infecção pelo Vírus da Imunodeficiência Humana 1 (HIV-1) tem como característica clássica a depleção de linfócitos T (LT) CD4+, que quando não tratada culmina na Síndrome da Imunodeficiência Adquirida (AIDS). Com o surgimento terapia antirretroviral (TARV), na década de 80, ocorreu uma verdadeira revolução. A TARV, apesar de não eliminar o vírus, consegue manter a carga viral em níveis indetectáveis, melhorando a qualidade de vida dos portadores. No entanto, entre 15-30% dos indivíduos em uso regular de TARV e com carga viral indetectável não consegue recuperar os níveis de LT CD4+ (Recuperação Imunológica). Estudos apontam que a apoptose pode estar envolvida na diminuição dos LT CD4+ e que variações genéticas como polimorfismos de base única (SNPs) em moléculas envolvidas nas vias da apoptose podem levar a diferentes respostas imunológicas do indivíduo à infecção. Neste sentido, o presente estudo se propôs a investigar o papel de SNPs (rs1800692, rs767455, rs2270926, rs8904, rs1800629) em genes codificadores de proteínas que ativam a via extrínseca da apoptose através do TNF-α/TNFR1, e sua relação com a recuperação imunológica de pacientes com uso regular de TARV. Foram estudados 113 pacientes HIV positivos, atendidos e tratados no Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), em uso de TARV por um ano e com carga viral indetectável, os quais foram divididos em dois grupos: sucesso imunológico (controle) e falha imunológica (caso). Não foram observadas associações entre os polimorfismos dos genes estudados com o sucesso ou falha imunológica apresentada pelos indivíduos fazendo uso regular da TARV. Também não foi observada nenhuma associação entre a falha imunológica e as variáveis clínicas: peso, etnia, idade, gênero e esquema terapêutico. Apesar da ausência de associações dos SNPs estudados com a falha imunológica, alguns fatores limitantes do estudo devem ser considerados (pequeno número amostral, não inclusão de outras moléculas da via estudada), se fazendo necessário novos estudos de réplica em outras populações. / Infection by Human Immunodeficiency Virus 1 (HIV-1) has as a classic feature the depletion of T lymphocytes (TL) CD4 + that, when untreated, culminates in Acquired Immunodeficiency Syndrome (AIDS). With the advent of HAART (Highly Active Antiretroviral Therapy), in the 80s, there was a real revolution. The ART, although it doesn't eliminate the virus, it can keep the viral load in undetectable levels, improving the quality in patient's' lifes. However, 15-30% of individuals regularly using HAART and with undetectable viral load, cannot recover CD4 + LT levels (Immune Recovery). Studies have shown that apoptosis may be involved in CD4 + depletion and genetic variations, such as single nucleotide polymorphisms (SNPs), in molecules involved in apoptosis pathways can lead to different immune responses from the individuals to the infection. Therefore, the present study aims to investigate the role of SNPs (rs1800692, rs767455, rs2270926, rs8904, rs1800629) in genes encoding proteins that activate the extrinsic pathway of apoptosis, by TNF-α / TNFR1, and its relationship with immune recovery of patients in regular use of HAART. We studied 113 HIV-positive patients assisted and treated by the Institute of Integrative Medicine Professor Fernando Figueira (IMIP), who were under HAART for at least one year and with undetectable viral load, which we divided into two groups: immunological success (control) and immunological failure (case). There were no associations between the polymorphisms of the studied genes with the immune failure presented by individuals making regular use of HAART. Also, it has been observed no associations between the immunologic failure with the clinical variables: weight, ethnicity, age, gender and treatment regimen. Despite the absence of associations of SNPs studied with immunological failure, some limitations of the study should be considered (small sample size, no inclusion of other molecules of the studied pathway), thus new replica studies in other populations are necessary.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-04-20T11:29:02Z No. of bitstreams: 2 Dissertação - Diêgo de Melo - 2017.pdf: 12963482 bytes, checksum: 14979af9bcf3df3d1a038ba4bc54e354 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-04-20T12:38:31Z (GMT) No. of bitstreams: 2 Dissertação - Diêgo de Melo - 2017.pdf: 12963482 bytes, checksum: 14979af9bcf3df3d1a038ba4bc54e354 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-04-20T12:38:31Z (GMT). No. of bitstreams: 2 Dissertação - Diêgo de Melo - 2017.pdf: 12963482 bytes, checksum: 14979af9bcf3df3d1a038ba4bc54e354 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-03-07 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This work describes a practical method for intramolecular heterocyclization of the (-)-α-bisabolol to obtain cyclic arylselenoethers and arylthioethers. The electrophilic cyclization addition is promoted by arylselenenyl bromide (ArSeBr) and arylsulfenyl chloride (ArSCl) through electrophilic addition across the terminally disubstituted double bond of the alfa-bisabolol. The cyclization reaction preceeded cleanly and smoothly under mild reaction conditions and provided the cyclic arylselenoethers and arylthioethers with 71% and 47% of yield respectively, employing pyridine as addictive under inert atmosphere. The methodology showed to be highly regioselective since the tetrahydrofuranes were obtained as unique products, presumably because of electronic and conformational factors. It is well known that cyclic ethers are present in the skeletons of several groups of natural compounds exhibiting important biological activities. / Este trabalho descreve um método simples para a heterociclização Intramolecular do (-)-α-bisabolol para obtenção de ariltioeteres e arilselenoeteres cíclicos. A ciclização eletrofílica é promovida por brometo de arilselenenila (ArSeBr) e cloreto de arilsulfenila (ArSCl) através da adição eletrofílica na dupla ligação terminal dissubstituída do (-)-α-bisabolol A reação de ciclização procedeu-se sob condições brandas fornecendo arilselenoeteres e ariltioeteres cíclicos com 71% e 47% de rendimento respectivamente, empregando piridina como aditivo, em atmosfera inerte. A metodologia mostrou-se altamente regiosseletiva, uma vez que se obteve como produto principal somente tetrahidrofuranos organocalcogeno funcionalizados em consequência de fatores eletrônicos e conformacionais. Adicionalmente, sabe-se que, os éteres cíclicos estão presentes nos esqueletos de vários grupos de compostos naturais, apresentando importantes atividades biológicas.

Abstract The synthesis of α-hydroxy aldehydes and hydroxymethyl ketones as well as their interconversion to each other are discussed in this thesis. The literature survey of the monograph reviews the synthetic methods for the preparation of 1,2-bifunctionalized hydroxy aldehydes and ketones. The keto-aldehyde isomerisation reaction catalyzed by Triosephosphate isomerase enzyme (TIM) and organic compounds that interact with the TIM are also introduced. In addition, the microwave heating techniques in organic syntheses are reviewed. The practical work consists of two entities: The synthesis of new substrate candidates and transition state analogues for a mutated monomeric TIM. These compounds are model compounds for the catalytic activity and the structural studies of the mutated monomeric TIM. The synthesis of the sulphonyl α-hydroxy ketone-based substrate candidates consists of four successive syntheses. The microwave-activation was utilized in the preparation of a carbon-sulphur bond and the synthesis of hydroxymethyl ketones. The improved synthesis of the terminal α-hydroxy ketone functionality with microwave activation is presented. The formation of charged compounds was utilized to improve the absorption of microwave energy of reaction mixtures. The design and the synthetic work were carried out in accordance to principles of green chemistry. The second part of the practical work is the development of an organocatalytic α-oxybenzoylation reaction of aldehydes with high enantiomeric selectivity. This novel method generated enantiomerically pure α-hydroxy aldehydes in the stable benzoate-protected form from achiral starting materials under mild conditions at the presence of air and moisture.