Foram sintetizadas duas novas séries de tensoativos de açúcar derivados da 2-D-glucosamina: os metil 2-acilamido-2-deóxi-6-O-sulfonato-D-glucopiranosídeos de sódio (aniônicos) e os cloretos de metil 2-acilamido-2,6-dideóxi-6-trimetilamônio-D-glucopiranosídeos (catiônicos). Os tensoativos aniônicos foram obtidos pela acilação da 2-D-glucosamina com cloretos de acila (com 8, 12 e 16 carbonos), seguida pela metilação desses derivados com metanol em meio ácido, e posterior sulfatação dos metil glucosídeos com complexo trióxido de enxofre-piridina. Os tensoativos catiônicos foram obtidos pela tosilação dos metil glucosídeos, seguida pela quaternização com trimetilamina e troca do contra-íon tosilato por cloreto com resina de troca-iônica. Esses tensoativos apresentaram c.m.c. similares a de outros tensoativos iônicos de cadeia hidrofóbica de igual comprimento, mas energias livres de transferência do grupo polar para a micela muito mais favoráveis. Esse fato foi atribuído à formação de ligações de hidrogênio entre os grupos polares do tensoativo na micela, e à hidrofobicidade do açúcar. As micelas formadas apresentaram números de agregação maiores que os obtidos para outros tensoativos, provavelmente devido às interações atrativas entre os grupos polares. / Two new sugar-based surfactant series were synthesized from 2-D-glucosamine: sodium methyl 2-acylamido-2-deoxi-6-O-sulfonate-D-glucopyranosides (anionic) and methyl 2-acylamido-2,6-dideoxi-6-trimethylamonium-D-glucopyranoside chlorides (cationic). The anionic surfactants were obtained by the acylation of 2-D-glucosamine with acyl chlorides (with 8, 12 and 16 carbons), followed by the methylation of these derivatives with methanol in acidic media, and the sulfation of the methyl glucosides with sulfur trioxide-pyridine complex. The cationic surfactants were obtained by the tosylation of methyl glucosides followed by the quaternization with trimethylamine and exchange of the tosylate contra-ion with chloride ions on an ion exchange resin. These surfactants showed c.m.c. similar to other ionic surfactants with equal hydrophobic chain lengths, but more favorable free energies of transfer of the polar head to the micelle. This fact is attributed to hydrogen bonding between the head groups of the surfactant in the micelle, and the hydrophobicity of the sugar moiety. The micelles of these surfactants showed aggregation numbers larger than those obtained for other surfactants, problably because of head-group attractive interactions.

The use of dietary supplements occurs in the majority of American adults >20 years old and has been reported to be on the rise by the National Health and Nutrition Examination Survey. People are not only taking more dietary supplements, but taking them without the advice of a health care provider. With the lack of education time and focus on this topic, physicians need to know some evidence regarding the most common supplements used, how to understand dietary supplement labels, and where to find reputable information about dietary supplements. Vitamin D, Omega-3, and Glucosamine/ Chondroitin are reviewed here. Also, a description of the various components of a dietary supplement label is explained. Finally, a brief description of independent companies (Consumerlabs.com®, US Pharmacopedial Convention, Natural Medicine Comprehensive Database, and Natural Standard) as well as the federally run Office of Dietary Supplements are presented.

Clinical Question: Does glucosamine or chondroitin reduce pain, improve functional status, or improve prognosis in patients with osteoarthritis?

Des oligomères de taille définie de chitosane ont été préparés et testés en tant qu'organocatalyseurs dans des réactions d'aldolisation énantiosélectives. Les précurseurs de ces catalyseurs sont obtenus en une seule étape par une réaction d'acétolyse contrôlée de la chitine, second polysaccharide le plus abondant. Une méthodologie reposant sur des réactions de glycosylation sous activation micro-ondes a été développée afin de fonctionnaliser la position anomérique de ces oligomères. Ainsi, le triflate de cuivre(II), utilisé en quantité catalytique, s’est révélé être le promoteur le plus efficace pour l’activation de la glucosamine ou du chitobiose peracétylés de configuration α. La sélectivité α des produits glycosylés résultent d’une isomérisation in situ des produits cinétiques β. Des organocatalyseurs se différenciant par leur partie aglycone et par leur degré de substitution ont été synthétisés en peu d’étapes. Les résultats les plus intéressants ont été obtenus avec un dérivé du chitobiose soluble en milieu aqueux. Nous avons montré, qu’en présence d’un co-catalyseur acide, l’acide 4-nitrobenzoïque, la réaction entre la cyclohexanone et le 4-nitrobenzaldéhyde, conduit à l’adduit anti avec un bon excès énantiomérique (89% ee). De plus, nous avons également montré que ce catalyseur pouvait être réutilisé dans plusieurs cycles catalytiques sans perte de sélectivité. / The catalytic behaviour of size-defined chitosan oligomers has been evaluated for asymmetric aldol reactions. These oligomers were obtained from chitin, which is one of the most abundant naturally occurring polymers, as a renewable starting biomolecule. Thus, controlled depolymerization of chitin was carried out by acetolysis providing per-O-acetylated N-acetyl-α-D-glucosamine oligomers with a polymerization degree from 2 to 4. To investigate the influence of the aglycon moiety, we developed a Lewis acid-promoted glycosylation reactions under microwave irradiation. Thus, a catalytic amount of copper(II) triflate proved to be the most effective promoter for the activation of α-per-O-acetylated glucosamine oligomers, which are considered as poorly reactive substrates, to selectively obtain α-glycosylated compounds. This selectivity results from in situ isomerization of kinetic β products. Chitosan-based catalysts, which differ in the distribution pattern, were synthesized in a few steps. The most promising results were obtained with a chitobiose derivative, which efficiently catalyzed the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde, in the presence of 4-nitrobenzoic acid as a co-catalyst, in water, providing the anti-adduct in high yield with good enantioselectivity (89% ee). In addition, this homogeneous organocatalyst can be reused in several cycles without loss of catalytic activity.

L'industrie cosmétique a un recours croissant aux espèces végétales comme sources de principesactifs naturels. Leur extraction nécessite des supports sélectifs tels que les polymères à empreintesmoléculaires (MIP). Les travaux de cette thèse reposent sur le développement de MIP pourl’extraction sélective de la glucosamine, de la fructosazine et de la 2,5-déoxyfructosazine.Dans une première partie, trois approches ont été développées pour extraire la glucosamine par desMIP : l’approche covalente, semi-covalente et non covalente. Pour chacune, les différents paramètresintervenant dans la synthèse des MIP ont été optimisés. Les meilleurs résultats ont été obtenus avecun MIP synthétisé selon une approche non covalente ionique reposant sur la complexation de laglucosamine par un acide sulfonique. Les performances du MIP se sont avérées supérieures à cellesde supports commerciaux et des extractions à partir de végétaux ont été réalisées. Le potentielindustrialisable du MIP a été validé lors de premiers tests à plus grande échelle.Dans une deuxième partie, l’extraction simultanée de la fructosazine et de la 2,5-déoxyfructosazine aété réalisée suite au développement d’un MIP synthétisé selon une approche covalente reposant surla formation d’esters boroniques. Une méthode de synthèse originale est exposée puisque lestemplates ont été formés in situ lors de la polymérisation. Le MIP obtenu s’est avéré sélectif dechaque composé et a permis de purifier et de séparer la fructosazine et la 2,5-déoxyfructosazine dematrices végétales et alimentaires.Tous ces travaux ont été réalisés dans une démarche éco-responsable s’appuyant sur l’emploi desolvants aqueux lors de la polymérisation et de l’extraction. / The cosmetic industry uses plants as sources of natural active ingredients. The extraction of theseactive ingredients requires selective extraction method such as molecularly imprinted polymers (MIP)technique. This thesis describes the development of MIP for the selective extraction of glucosamine,fructosazine and 2,5-déoxyfructosazine.In the first part, three approaches were developed to extract glucosamine by MIP technique: thecovalent approach, semi-covalent and noncovalent. For each approach, the various parametersinvolved in the synthesis of the MIP were optimized. The best results were obtained with a MIPsynthesized with a non-covalent ionic approach based on the complexation of glucosamine by asulfonic acid. The MIP exhibits higher performance than commercial media and extractions fromplants were performed. The potential for industrialization of the MIP was validated during initial testson a larger scale.In the second part, the simultaneous extraction of fructosazine and 2,5-déoxyfructosazine wasperformed following the development of a MIP synthesized using a covalent approach based on theformation of boronic esters. An original synthesis method is exposed since the templates were formedin situ during the polymerization. The MIP obtained showed good selectivity for each compound andallowed to separate and purify fructosazine and 2,5-déoxyfructosazine from plant and food matrices.All these works were performed according to an eco-friendly approach based on the use of aqueoussolvents as solvents for polymerization and extraction.

Les iminosucres, analogues de sucres dont l'oxygène intracyclique a été remplacé par un azote, constituent une classe importante de mimes de sucres. Introduire une chaîne alkyle sur le carbone pseudo-anomérique donne accès à une classe importante d'iminosucres, les iminosucres C-glycosides, qui peuvent être des inhibiteurs de glycosidases puissants et sélectifs.Le principal défi associé à la synthèse d'iminosucres C-glycosides est la mise au point de voies de synthèse efficaces et applicables à tous types de sucres permettant ainsi d'accéder à une grande diversité de synthons et d'accélérer la découverte de molécules d'intérêt biologique.Ce travail de thèse a consisté dans un premier temps à élaborer une synthèse efficace et convergente d'iminosucres C-glycosides à six et sept chaînons, à partir d'un précurseur commun, le 6-azido-6-désoxy-2,3,4-tri-O-benzyl-D-glucopyranose. Cette nouvelle méthode implique une réaction tandem Staudinger/Aza-Wittig ainsi qu'une isomérisation de cycle d'azépanes stéréocontrolée.La deuxième partie de ce manuscrit traite de l'extension de cette méthodologie à la synthèse de nouveaux D- et L-iminosucres C-glycosides à six chainons mimes de la N-acétyle-D-glucosamine.La dernière partie de ce travail a été consacrée à la synthèse d'iminosucres-aza-couronnes, qui constituent un nouveau type de récepteur moléculaire. L'étude de leur capacité à complexer des métaux a été effectuée par des techniques de RMN ou fluorimétrie et a donné des résultats prometteurs. / Iminosugars, sugar analogs in which the endocyclic oxygen has been replaced by a nitrogen, constitute a major class of sugar mimetics. Introducing an alkyl chain at the pseudoanomeric carbon position leads to another class of important iminosugars, the iminosugars C-glycosides that can be potent and selective glycosidase inhibitors. The main challenge associated with iminosugars C-glycosides synthesis is currently the design of efficient and general routes applicable to any starting sugar and enabling introduction of structural diversity from advanced synthons to accelerate the discovery of biologically relevant molecules.The first part of this work focused on the development of an efficient and convergent synthesis of six and seven membered iminosugars C-glycosides from a common 6-azido-6-deoxy-2,3,4-tri-O-benzyl-D-glucopyranose precursor. This new methodology involves a highly diastereoselective tandem ring enlargement/alkylation and a stereocontrolled ring contraction.The second part of the thesis delt with the extension of the methodology to access six-membered D- and L-iminosugars C-glycosides derived from N-acetyl-D-glucosamine.The third part of this work was devoted to the synthesis of iminosugar-aza-crowns, which constitute a new type of molecular receptors, using the synthetic route developed in the first part. The ability of these compounds to complex metals was studied either by NMR or fluorimetric techniques and showed promising results.

Unsold bread makes up a signification fraction of waste occurring in Swedish supermarkets. This thesis seeks to address the problem of food waste, by cultivating filamentous fungi on bread waste and producing chitinous films and nonwovens from them. Rhizopus delemar was cultivated on bread waste in liquid-state fermentation in order to obtain mycelia biomass. The biomass was processed by alkali or protease treatments to disrupt the fungal cells and remove proteins and fats. Afterwards it was subjected to a bleaching treatment to remove lignin fractions of bread residues. The treated biomass was then subjected to a grinding treatment for a homogeneous dispersion of mycelial fibers, where the dispersion was confirmed by microscopic images. The chemically and mechanically processed biomass was used for the preparation of films and nonwoven composites by employing a wet-laid papermaking process. The films exhibited plastic-like features, due to their brittleness and their smooth upper surface. Films and nonwoven composites were characterized on their tensile properties, surface water contact angle and their surface morphology by scanning electron microscopy. Treating fungal biomass by alkali and then bleaching resulted in films with atensile modulus of 3.38 GPa and an ultimate tensile strength of 71.50 MPa. These are the highest reported tensile properties for mycelia derived films to date. Water contact angle measurements confirmed a hydrophobic quality of mycelial films. Scanning electron microscopy showed a very dense and even surface without an obvious fibrous morphology. Fungal biomass and viscose fibers together form a rigid nonwoven composite, in which fungal biomass takes over the role of a natural eco-friendly binding matrix. Flexural rigidity measurements were out of bounds and need to be confirmed by future studies. Additionally, a second strain of fungi, Fusarium venenatum, was cultivated on bread particles in water suspension in order to determine optimum growth conditions for future scale-up investigations.

L’ostéoarthrose (OA) est une maladie articulaire dont l’incidence augmente avec le vieillissement de la population. Elle se caractérise par une détérioration progressive du cartilage articulaire accompagnée du remodelage de l’os sous-chondral et du changement des tissus mous de l’articulation. La douleur et le dysfonctionnement de l’articulation affectée sont généralement attribués à l’inflammation et l’épanchement de la synovie. Plusieurs évidences indiquent que l’inflammation de la membrane synoviale contribue grandement à la pathogenèse de l’OA. En effet, la synthèse et l’expression des enzymes protéolytiques qui dégradent la matrice cartilagineuse sont régulées par de nombreuses cytokines retrouvées au sein de ce foyer inflammatoire. Deux d’entre elles, l’interleukine-1 beta (IL-1β) et le «tumor necrosis factor » alpha (TNF-α), jouent un rôle majeur dans le déclenchement de l’inflammation associée à l’OA. Ces cytokines pro-inflammatoires agissent notamment sur les synoviocytes et les chondrocytes en activant NF-κB qui, à son tour, active les gènes de cytokines. Cette boucle de régulation positive amplifie et perpétue la réponse inflammatoire. Récemment, il a été rapporté que l’activation de NF-κB par TNF-α peut être potentialisée par EXTL3, un récepteur transmembranaire ; mais le mécanisme sous-jacent de cet effet demeure inconnu. Toutefois, les niveaux important d’EXTL3 et de son ligand Reg1B chez les patients arthrosiques, laissent croire que ces protéines jouent un rôle dans le développement de l’OA. Notre objectif était d’étudier le mécanisme par lequel EXTL3 amplifie l’activation de NF-κB par TNF-α et d’examiner si ce phénomène se produit aussi avec l’IL-1β. Nous avons utilisé les cellules C28/I2, une lignée cellulaire de chondrocytes, comme modèle d’étude. Les transfections transitoires avec un vecteur d’expression, les techniques d’immunofluorescence (IF), d’immunoprécipitation (IP) et d’immunobuvardage de type Western (IB); ont été utilisées dans le cadre de diverses approches expérimentales. Les résultats obtenus par transfection ont révélé que la protéine EXTL3 potentialisait l’activation de NF-κB aussi bien par IL-1β que par TNF-α. Ce résultat signifie que la potentialisation de l’activité NF-κB par EXTL3 n’est pas spécifique à TNF-α. D’autre part, l’IP avec TNFRI et TRAF2 a révélé la présence d’EXTL3 dans le complexe TNF-α/TNFRI/TRAF2 qui se forme au niveau de la membrane plasmique. De plus, ceci a été confirmé in vivo par microscopie confocale montrant la co-localisation de TNFRI-TRAF2-EXTL3 dans la membrane nucléaire, suggérant ainsi la formation d’un complexe identique au niveau des membranes plasmique et nucléaires. Toutefois, la présence du ligand Reg1B et/ou de la glucosamine inhibait la formation de ce complexe au niveau de la membrane plasmique, tout comme ils abolissaient la potentialisation de l’activité NF-κB par EXTL3. Ces résultats suggèrent non seulement que le recrutement d’EXTL3 libre dans le complexe TNF-α/TNFR1 est requis pour amplifier l’activation de NF-κB par TNF-α, mais aussi la capacité du ligand Reg1B et de la glucosamine à moduler cette activation à travers la baisse ou l’inhibition de l’interaction EXTL3-TNFR1. Les données de cette étude constituent une avancée majeure dans la compréhension des événements moléculaires qui contrôlent l’activation de NF-κB par les cytokines pro-inflammatoires. Ces résultats pourraient conduire au développement de nouvelles approches thérapeutiques pour le traitement de l’inflammation associée à l’OA et impliquant une activation incessante de NF-κB. / Osteoarthritis (OA) is an articular disease with a particularly high incidence in the elderly. This disease is characterized by the progressive degeneration of the cartilage followed by subchondral bone remodelling and a change in the soft tissues of the joint. Local chronic pain and joint malfunction are generally attributed to the inflammation of the synovial membrane, which in itself has been shown to significantly contribute to the pathogenesis of OA. In fact, the synthesis and expression of many proteolytic enzymes which degrade cartilage matrix are regulated by numerous cytokines originating from these inflammation sites. Two pro-inflammatory cytokines, the tumor necrosis factor alpha (TNF-α) and the interleukine-1β (Il-1β), play a major role in triggering inflammation associated with OA. These cytokines act on synoviocytes and chondrocytes by activating the transcription factor NF-κB, which in turn activates the cytokines’ genes. This positive regulating loop amplifies and maintains inflammatory responses. Recently, studies have shown that the over-expression of the REG receptor/EXTL3, a transmembranous receptor, enhances the activity of cytokine TNF-α in the activation of NF-κB. Unfortunately the mechanism involved in this process is still unknown. In addition, levels of EXTL3 and its ligand REG1B observed in OA patients suggest their possible involvement in the development of OA. Our goal was to study and elucidated the mechanisms used by EXTL3 to amplify NF-κB activation by TNF-α, as well as to examine whether the same phenomenon is occurring with IL-β. A human chondrocytes cell line called C28/I2 as experimental model. The techniques used for the current study were transfection assays, immunoflorescence (IF), immunoprecipitation (IP), and Western blotting (WB). Our transfection data have shown that EXTL3 was able to enhance NF-κB activity induced by TNF-α as well as by IL-1β. This result suggests that the enhanced NF-κB activity by EXTL3 is not specific to TNF-α. The IP experiments with TNFR1 and TRAF2 revealed the presence of EXTL3 in TNF-α/TNFR1 complex which is formed in the plasma membrane. Also, IF assay in combination with confocal microscopy allowed us to detect TNFR1/TRAF2/EXTL3 co-localisation on the nuclear membrane, suggesting the formation of TNF-α/TNFR1 complex on both the nuclear and plasma membranes. Somehow, REG1B, an EXTL3 ligand, and glucosamine were able to inhibit the formation of this complex at the plasma membrane. They were also able to abolish NF-κB activity enhanced by EXTL3. These results suggest that not only EXTL3 recruitment in the TNF-α/TNFR1 complex is required to amplify NF-κB activation by TNF-α, but also that REG1B ligand and glucosamine have the ability to modulate this activation by reducing or inhibiting EXTL3 and TNFR1 interactions. This study’s data represents a major advance in the understanding of molecular events controlling NF-κB activation by pro-inflammatory cytokines. These results could lead to the development of new therapeutics targets, in the treatment of disorders associated to OA and involving recurrent activation of NF-κB.

Low molecular weight gelators (LMWGs) are small molecules that are capable of entrapping solvents to form a gel in organic solvents or aqueous solution. These compounds rely solely on noncovalent forces to form the fibrous networks necessary to entrap a variety of solvents. The organogels and hydrogels thus formed could have applications in a variety of fields from environmental to biological to medicinal. Carbohydrates are ideal starting materials to synthesize LMWGs, because of their natural abundance, dense chirality, and biocompatibility. D-Glucose is the most common monosaccharide and D-glucosamine is isolated from natural sources, such as crab shells. Several series of compounds were synthesized using compounds 1-3 as the starting materials. These include esters, carbamates, amides, and ureas. The structure and gelation relationship was analyzed to obtain guidelines for designing new LMWGs. Compound 1 is a simple derivative of D-glucose and its terminal alkynyl esters and saturated carbamates are effective gelators. Compound 2 is a simple derivative of D-glucosamine and its amide and urea derivatives are also effective gelators. Compound 3 is formed from the deoxygenation of D-glucose. 1OOHOOCH3OHOPh2OOHOOCH3NH2OPh3OOHOOHOPh The design, synthesis and gelation properties of several classes of sugar based low molecular organo/hydrogelators will be discussed in this thesis in chapters 2, 3, and 4. After obtaining highly effective organo/hydrogelators, potential applications of these novel molecular systems can be explored. Some preliminary study on using one of the gelator in enzyme assay has shown that it is possible to utilize the hydrogels to immobilize enzymes. However, future research can explore further on the applications of these gelators.

ABSTRACT BACKGROUND: Arthritis is increasingly becoming a public health concern as it is the leading cause of disability. Glucosamine and chondroitin, which are alternative dietary supplements, are commonly marketed for persons with joint pain. The purpose of this study is to examine if self-reported 12-month and past 30-day use of glucosamine and/or chondroitin among persons with any arthritis, unspecified arthritis, and rheumatoid arthritis is associated with reports of past 12-month improved health and reports of past 30-day joint pain, aching, and stiffness, respectively. METHODS: The 2012 National Health Interview Survey (NHIS), a nationally representative cross-sectional household interview survey, was used for this study. The adult sample consisted of 34,525. Subgroup analyses were conducted on 7,654 respondents with any arthritis, 6,016 with unspecified arthritis, and 898 with rheumatoid arthritis. The independent variables were defined as the use of glucosamine only, chondroitin only, or glucosamine and chondroitin one or more times in the past 12 months and past 30 days. The dependent variables were defined as self-reported past 12 month improved health and past 30 day joint pain, aching, and stiffness. Descriptive, bivariate, and multivariate analyses were conducted using SAS 9.4 accounting for the complex survey design, computing missing values as missing completely at random for variance estimation. All multivariate logistic regression models included sociodemographics, use of other observed alternative therapies, and other chronic conditions. RESULTS: Approximately 21.8% of U.S adults had any arthritis, 17.0% had unspecified arthritis and 2.5% had rheumatoid arthritis. Among persons with any arthritis, approximately 3.7% used glucosamine, 0.4% used chondroitin, and 3.4% used both glucosamine and chondroitin within the past 12 months while approximately 5.1% used glucosamine, 0.6% used chondroitin, and 0.4% used both glucosamine and chondroitin within the past 30 days. Among persons with unspecified arthritis, approximately 3.7% used glucosamine, 0.5% used chondroitin, and 3.8% used both glucosamine and chondroitin within the past 12 months while 5.5% used glucosamine, 0.5% used chondroitin, and 0.4% used both glucosamine and chondroitin within the past 30 days. Among persons with rheumatoid arthritis, approximately 2.4% used glucosamine, 0.3% used chondroitin, and 2.1% used both glucosamine and chondroitin within the past 12 months while approximately 2.9% used glucosamine, 0.7% used chondroitin, and 0.5% used both glucosamine and chondroitin within the past 30 days. Women used more of all supplements (past 12 months and past 30 days) except past 12 month use of chondroitin among persons with any arthritis. Persons 56 to 70 years old had the highest proportion of past 12 month and 30 day supplement use among persons with unspecified arthritis. After adjusting for sex, age, race, BMI, poverty level, other health conditions, and other CAM therapies (acupuncture, energy, mind-body, and chiropractic/osteopathic therapies), the use of chondroitin only (adjusted OR= 0.6; p= <0.01) and the use of both glucosamine and chondroitin (adjusted OR= 5.7; p= <0.01) during the past 30 days was associated with self-reported past 30 day joint pain, aching, and stiffness among persons with any arthritis. After adjusting for age, BMI, poverty level, region, other health conditions, and other CAM therapies (acupuncture, energy, mind-body, and chiropractic/osteopathic therapies), the use of chondroitin only was also associated with past 30 day joint pain, aching, and stiffness among persons with unspecified arthritis (adjusted OR= 0.5; p= 0.02). CONCLUSION: Chondroitin alone was associated reports of past 30 day joint pain, aching, and stiffness among persons with any arthritis and unspecified arthritis highlighting a potential effective role and use for this supplement. In addition, the use of both glucosamine and chondroitin were associated with reports of past 30 day joint pain, aching, and stiffness among persons with any arthritis. Marketing may play a role in these relationships and should be further examined.