Abstract Dietary xylitol supplementation increases bone calcium and phosphorus concentrations in healthy rats, as well as protects against the decrease of bone minerals and bone density during experimental osteoporosis. This suggests that dietary xylitol might have a favorable effect on the prevention of osteoporosis. However, before any conclusions can be drawn about the usefulness of a compound, studies including structural evaluation and biomechanical testing of bones must first be performed. Thus, the aim of the present study was to clarify whether dietary xylitol affects bone resorption, bone structure, and bone biomechanics in healthy rats, and whether dietary xylitol offers some preventive effects against the increased bone resorption, decreased bone trabeculation, and weakened bone biomechanical properties during experimental osteoporosis. Dietary xylitol reduced bone resorption in 3-mo old healthy male rats, and protected significantly against the increase of bone resorption in 3-mo old ovariectomized rats, as measured by the urinary excretion of 3H following [3H]tetracycline-prelabeling. In addition, increased trabecular bone volume of proximal tibia in 4-mo old healthy male rats was detected after a 1-mo xylitol feeding period, and significant protection against the decrease of trabecular bone volume in 6-mo old ovariectomized rats was observed after a 3-mo xylitol feeding period. Furthermore, dietary xylitol increased the strength properties of long bones in 6-mo old healthy male rats after a 3-mo feeding period, without affecting the bone elastic properties as tested by three-point bending of tibia, torsion of femur, and loading of femoral neck. Accordingly, dietary xylitol protected significantly against the weakening of bone biomechanical properties in 6-mo old ovariectomized rats after a 3-mo feeding period. In conclusion, the above results strongly support the hypothesis that oral administration of xylitol protects effectively against the progression of experimental osteoporosis. Dietary xylitol was effective both in increasing bone mass in healthy rats, and in preventing bone loss in ovariectomized rats, suggesting a favorable effect of xylitol on both main targets in the prevention of osteoporosis. As dietary xylitol was effective also in protecting against the experimental osteoporosis-caused changes in bone structure and weakening of bone biomechanical properties, oral xylitol administration seems to provide interesting possibilities when searching for new physiological choices for the prevention of osteoporosis.

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Os filmes de quitosana/amido são utilizados para preparação de sistemas biocompatíveis de liberação controlada, materiais de revestimento e filmes comestíveis. As propriedades reológicas, térmicas, mecânicas, de taxa de transmissão de vapor de água (WVP) e solubilidade foram avaliadas em função das mudanças estruturais do amido (gelatinizado ou oxidado), da adição de polióis (etilenoglicol, glicerol e sorbitol) e da razão amilose/amilopectina (73% e 100% amilopectina). Os ensaios de reologia mostraram que as blendas formadas por quitosana e amido (100% amilopectina) tiveram interações mais fortes quando comparadas com as blendas de quitosana/amido (73% amilopectina), tanto na forma oxidada quanto na forma gelatinizada. Os polióis causam mudanças nas redes tridimensionais formadas entre a quitosana e o amido, tanto quando se usa amido gelatinizado como quando se usa o amido oxidado. Os valores de G´ encontrados para as blendas preparadas com amido oxidado foram em todos os casos menores em relação às blendas preparadas com amido gelatinizado, indicando diferenças na estrutura do gel formado e também na organização dos seus componentes. Essas mudanças foram resultantes da associação que ocorre entre a quitosana e o amido oxidado que é diferente daquela que ocorre entre quitosana e amido gelatinizado. A oxidação do amido A termogravimetria mostrou que a razão amilose/amilopectina não influencia o perfil de perda de massa e a oxidação amido aumenta a quantidade de água nos filmes e também diminui a estabilidade térmica observada por Tonset. O glicerol é o poliol que provoca maiores mudanças no comportamento de perda de massa dos filmes, pois é observada a decomposição de parte do glicerol que não está interagindo com a quitosana e o amido. O DSC mostrou que a presença de amilose nas blendas provoca uma interação mais forte da água com os polissacarídeos. Para todos os filmes com amido gelatinizado, a adição de polióis aumenta a temperatura de pico endotérmico e esta é quase sempre maior quando o glicerol é adicionado e que a oxidação do amido provoca um aumento nos valores de pico endotérmico, sugerindo que mais água está interagindo com os polímeros. A adição dos polióis aumenta os valores de espessura dos filmes, pelo aumento do volume livre do sistema, tanto nos filmes preparados com amido gelatinizado, quanto no oxidado. A presença de amilose nos filmes aumenta os valores de WVP e de solubilidade, provavelmente porque a presença de amilose auxilia no aumento da difusão de moléculas de água pelo e facilita a entrada de água e sua posterior solubilização. A adição dos polióis diminui os valores de WVP nos filmes de quitosana e amido gelatinizado. A oxidação do amido interfere mais nos valores de WVP para os filmes de quitosana/amido (100% amilopectina), sugerindo maior difusão das moléculas de água pelo filme. A oxidação aumenta os valores de solubilidade, pois as interações ocorrem em menor quantidade entre a quitosana e o amido, o que acaba facilitando o processo de solubilização. A adição dos polióis provoca um aumento na solubilidade de todos os filmes. Os ensaios preliminares de tração por DMA indicaram que os filmes de quitosana/amido gelatinizado e os filmes de quitosana/amido oxidado são rígidos e quebradiços e com a adição dos polióis ocorre um aumento na flexibilidade. Estudos preliminares destes filmes como suportes para liberação controlada de ciprofloxacina mostraram que estes são promissores para esta aplicação. / Chitosan/starch association represents an interesting alternative to the preparation of biocompatible drug delivery systems, packing materials and edible films. Changes in rheological, thermal and mechanical properties, water vapor permeability and solubility of chitosan/starch films were evaluated varying the starch structure form (gelatinized or oxidized), poliol addition (ethyleneglycol, glycerol and sorbitol) and amylose/amylopectin ratio (73% and 100% amylopectin). Rheological measurements showed that chitosan/starch (100% amylopectin) blends had stronger interaction compared to chitosan/starch (73% amylopectin) blends, both in gelatinized and oxidized starch form. Polyols cause changes in chitosan/starch three-dimensional networks due to reduction in polymer-polymer chain bonding that reflect in rheological properties. G´ modulus value decreases with starch oxidation, indicating variation in gel structure and also in organization of polymeric components, due to differences in association between chitosan and gelatinized or oxidized starch. Thermogravimetric curves showed that amylose/amylopectin ratio does not influence the weight loss behavior and starch oxidation increases the amount of water and decrease thermal stability of films, as observed by Tonset. Glycerol causes changes in weight loss behavior due to the presence of glycerol that not interact with chitosan and starch. DSC results suggest that amylose presence promotes a higher water interaction with polysaccharides. Polyol addition shift the endothermic peak associated to free water for higher temperatures, suggesting interaction between biopolymers and polyols. Also, polyol increases thickness values in all films as increase the free volume of the system. Amylose presence increases WVP and solubility values, suggesting the formation of low dense structure, which increases the water molecules diffusion and facilitates the dissolution of films in water. Polyols presence decrease WVP values in chitosan/gelatinized starch films. Starch oxidation affected the WVP values in chitosan/starch (100% amylopectin) films, suggesting low compact structure that allows the water molecule diffusion in the films. Starch oxidation increases solubility values as lower interaction between chitosan and oxidized starch, which facilitates the solubility process. Polyols addition causes an increase in solubility in all films. Preliminary mechanical tests performed by DMA indicated that chitosan/starch (gelatinized or oxidized) films are rigid and brittle and polyol addition increases the flexibility. In vitro ciprofloxacin drug delivery behavior showed that films are promising for this application.

Os filmes de quitosana/amido são utilizados para preparação de sistemas biocompatíveis de liberação controlada, materiais de revestimento e filmes comestíveis. As propriedades reológicas, térmicas, mecânicas, de taxa de transmissão de vapor de água (WVP) e solubilidade foram avaliadas em função das mudanças estruturais do amido (gelatinizado ou oxidado), da adição de polióis (etilenoglicol, glicerol e sorbitol) e da razão amilose/amilopectina (73% e 100% amilopectina). Os ensaios de reologia mostraram que as blendas formadas por quitosana e amido (100% amilopectina) tiveram interações mais fortes quando comparadas com as blendas de quitosana/amido (73% amilopectina), tanto na forma oxidada quanto na forma gelatinizada. Os polióis causam mudanças nas redes tridimensionais formadas entre a quitosana e o amido, tanto quando se usa amido gelatinizado como quando se usa o amido oxidado. Os valores de G´ encontrados para as blendas preparadas com amido oxidado foram em todos os casos menores em relação às blendas preparadas com amido gelatinizado, indicando diferenças na estrutura do gel formado e também na organização dos seus componentes. Essas mudanças foram resultantes da associação que ocorre entre a quitosana e o amido oxidado que é diferente daquela que ocorre entre quitosana e amido gelatinizado. A oxidação do amido A termogravimetria mostrou que a razão amilose/amilopectina não influencia o perfil de perda de massa e a oxidação amido aumenta a quantidade de água nos filmes e também diminui a estabilidade térmica observada por Tonset. O glicerol é o poliol que provoca maiores mudanças no comportamento de perda de massa dos filmes, pois é observada a decomposição de parte do glicerol que não está interagindo com a quitosana e o amido. O DSC mostrou que a presença de amilose nas blendas provoca uma interação mais forte da água com os polissacarídeos. Para todos os filmes com amido gelatinizado, a adição de polióis aumenta a temperatura de pico endotérmico e esta é quase sempre maior quando o glicerol é adicionado e que a oxidação do amido provoca um aumento nos valores de pico endotérmico, sugerindo que mais água está interagindo com os polímeros. A adição dos polióis aumenta os valores de espessura dos filmes, pelo aumento do volume livre do sistema, tanto nos filmes preparados com amido gelatinizado, quanto no oxidado. A presença de amilose nos filmes aumenta os valores de WVP e de solubilidade, provavelmente porque a presença de amilose auxilia no aumento da difusão de moléculas de água pelo e facilita a entrada de água e sua posterior solubilização. A adição dos polióis diminui os valores de WVP nos filmes de quitosana e amido gelatinizado. A oxidação do amido interfere mais nos valores de WVP para os filmes de quitosana/amido (100% amilopectina), sugerindo maior difusão das moléculas de água pelo filme. A oxidação aumenta os valores de solubilidade, pois as interações ocorrem em menor quantidade entre a quitosana e o amido, o que acaba facilitando o processo de solubilização. A adição dos polióis provoca um aumento na solubilidade de todos os filmes. Os ensaios preliminares de tração por DMA indicaram que os filmes de quitosana/amido gelatinizado e os filmes de quitosana/amido oxidado são rígidos e quebradiços e com a adição dos polióis ocorre um aumento na flexibilidade. Estudos preliminares destes filmes como suportes para liberação controlada de ciprofloxacina mostraram que estes são promissores para esta aplicação. / Chitosan/starch association represents an interesting alternative to the preparation of biocompatible drug delivery systems, packing materials and edible films. Changes in rheological, thermal and mechanical properties, water vapor permeability and solubility of chitosan/starch films were evaluated varying the starch structure form (gelatinized or oxidized), poliol addition (ethyleneglycol, glycerol and sorbitol) and amylose/amylopectin ratio (73% and 100% amylopectin). Rheological measurements showed that chitosan/starch (100% amylopectin) blends had stronger interaction compared to chitosan/starch (73% amylopectin) blends, both in gelatinized and oxidized starch form. Polyols cause changes in chitosan/starch three-dimensional networks due to reduction in polymer-polymer chain bonding that reflect in rheological properties. G´ modulus value decreases with starch oxidation, indicating variation in gel structure and also in organization of polymeric components, due to differences in association between chitosan and gelatinized or oxidized starch. Thermogravimetric curves showed that amylose/amylopectin ratio does not influence the weight loss behavior and starch oxidation increases the amount of water and decrease thermal stability of films, as observed by Tonset. Glycerol causes changes in weight loss behavior due to the presence of glycerol that not interact with chitosan and starch. DSC results suggest that amylose presence promotes a higher water interaction with polysaccharides. Polyol addition shift the endothermic peak associated to free water for higher temperatures, suggesting interaction between biopolymers and polyols. Also, polyol increases thickness values in all films as increase the free volume of the system. Amylose presence increases WVP and solubility values, suggesting the formation of low dense structure, which increases the water molecules diffusion and facilitates the dissolution of films in water. Polyols presence decrease WVP values in chitosan/gelatinized starch films. Starch oxidation affected the WVP values in chitosan/starch (100% amylopectin) films, suggesting low compact structure that allows the water molecule diffusion in the films. Starch oxidation increases solubility values as lower interaction between chitosan and oxidized starch, which facilitates the solubility process. Polyols addition causes an increase in solubility in all films. Preliminary mechanical tests performed by DMA indicated that chitosan/starch (gelatinized or oxidized) films are rigid and brittle and polyol addition increases the flexibility. In vitro ciprofloxacin drug delivery behavior showed that films are promising for this application.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Thesis (Ph. D.)--University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed May 6, 2009). Vita. Includes bibliographical references.

Galactitol and cis,cis,cis-1,3,5-cyclohexanetriol are polyols that are ideal examples of model compounds for ligands with lanthanide ions as they have their hydroxyl groups in favourable steric arrangement. Several complexes were synthesised with both lanthanide chloride and lanthanide nitrate salts with galactitol, and a variety of structures, both polymeric and monomeric, were observed. In all these complexes, galactitol acted as a bridging molecule between the lanthanide ions. A notable difference was the lanthanum chloride–galactitol complex that showed both chloride and galactitol bridging. The lanthanide nitrate salts formed only polymeric complexes with galactitol. Not all of the complexes showed nitrate ions coordinated to the metal centre, and in the neodymium nitrate– galactitol complex, which shows both monodentate and bidentate coordination of the nitrate groups. The coordination of the nitrate ions was confirmed using both XRD and IR analysis. Two complexes with lanthanide chloride salts and cis,cis,cis-1,3,5-cyclohexanetriol were synthesised and analysed. Lanthanum chloride formed a polymeric complex, which showed extensive chloride bridging between the metal centres. Praseodymium chloride formed a dimeric complex. All complexes were analysed with single-crystal X-ray diffraction, 1H NMR, 13C NMR and IR spectroscopy.

Les motifs 1,3-polyols sont fréquemment rencontrés dans de nombreuses molécules naturelles biologiquement actives. Cependant, à ce jour, il n'existe que peu de méthodes générales et efficaces permettant d'accéder à ces motifs de manière stéréocontrôlée. Nous nous sommes particulièrement intéressés à la synthèse de 1,3,5,7-tétraols et une méthode a été mise au point pour former ces composés en utilisant deux cyclisations de Prins successives suivies d'une coupure réductrice du bis-tétrahydropyrane obtenu. Cette méthode permet d'accéder à tous les diastéréoisomères des tétraols efficacement et elle a été appliquée avec succès à la synthèse du (+)-cryptocaryol A, un composé polyhydroxylé stabilisant PdCd4, qui est une protéine inhibant le développement cellulaire. Par ailleurs, nous avons développé une approche synthétique de la filipine III, un macrolide naturel possédant des propriétés antibiotiques et antifongiques, et comportant un fragment 1,3-polyol et un fragment pentaénique. Plusieurs stratégies ont été envisagées afin d'accéder à ces deux fragments, qui ont été synthétisés de manière convergente. Leur assemblage a été réalisé grâce à une réaction d'aldolisation diastéréosélective et nous avons pu accéder au squelette carboné complet de la filipine III. / 1,3-Polyols are present in a large variety of biologically active natural products. However, right now only a few general and efficient methods have been described to access these compounds in a stereocontrolled manner. We were particularly interested in the synthesis of 1,3,5,7-tetraols and a method has been developed to prepare these compounds, using two successive Prins cyclizations followed by a reductive cleavage of the resulting bis-tetrahydropyran. This efficient method allows the access to all the diastereomers of these tetraols and has successfully been applied to the synthesis of (+)-cryptocaryol A, a polyhydroxylated compound which stabilizes PdCd4, a protein inhibiting the cellular growth. We have also developed a synthetic approach toward filipin III, an antibiotic and antifungal macrolide, which possesses a 1,3-polyol part and a pentaenic part. Several strategies have been envisaged to construct these fragments, which have been synthesized in a convergent manner. These fragments were then coupled using a diastereoselective aldolisation and we were able to access the complete carbon skeleton of filipin III.

Les huiles végétales et leurs dérivés ont conduit à de nouveaux précurseurs agro-ressourcés utilisés pour la synthèse de polymères. Grâce au couplage thiol-ène, des polyols ont été obtenus par greffage du mercaptoéthanol directement sur les triglycérides insaturés. De la même manière, les esters méthyliques des huiles végétales ont permis la synthèse d'esters et d'amides diols pseudo-téléchéliques. Des polyols ont également été obtenus grâce à la réaction d'ouverture des cycles oxirane présents sur des huiles végétales époxydées. Différents acides carboxyliques ont permis d'introduire des fonctions hydroxyle sur les triglycérides. Ces différents synthons ont conduit à l'élaboration d'une large gamme de matériaux polyuréthanes, présentant des Tg variant de -10 °C à 100 °C. Le carbonate de glycérol, issu du glycérol agro-ressourcé, a également été utilisé pour l'élaboration de dicyclocarbonates, soit par estérification/trans-estérification à partir de diacides obtenus par greffage de l'acide thioglycolique sur plusieurs acides gras, soit par dimérisation à partir d'un dithiol commercial. Des polyuréthanes sans isocyanate ont ainsi été formulés à partir de ces nouveaux dicyclocarbonates, ouvrant la voie vers des polyhydroxyuréthanes totalement agro-ressourcés. Les précurseurs, ainsi que les matériaux qui en découlent, ont été caractérisés et certains ont fait l'objet de tests à l'échelle pré-industrielle. / Vegetable oils and their derivatives were used to synthesize new precursors suitable for polymer synthesis. Mercaptoethanol was grafted onto unsaturated triglycerides by thiol-ene coupling to yield polyols. This functionalization was also applied to vegetable oil methyl esters, yielding ester and amide containing pseudo-telechelic diols. The second synthetic strategy used ring opening of epoxydized vegetable oils. The reaction between vegetable oil oxiranes and several carboxylic acids afforded a range of polyester polyols. Thus, the synthesized intermediates allowed to formulate various polyurethanes, which exhibited glass transition temperatures ranging from -10 °C to 100 °C. Moreover, either esterification/trans-esterification with fatty acid based diacids, synthesized by thioglycolic acid addition onto different fatty acids, or thiol-ene coupling with a commercial dithiol, were performed on glycerin carbonate, leading to new dicyclocarbonates. Isocyanate free polyurethanes were then obtained from those dicyclocarbonates, opening the way for fully biobased polyhydroxyurethanes. The new precursor, and the polymers therefrom, were deeply characterized and some of them were tested at a pilot scale.

Dans un contexte de valorisation de molécules issues de la biomasse, de nouvelles architectures moléculaires et polyols ont été développé à partir du sorbitol et divers synthons biosourcés en se basant autant que possible sur les principes de la chimie verte. A partir de réactions d’estérifications contrôlées plusieurs polyols polyesters ont été synthétisés, en l’absence de solvant. Grace à l’utilisation de diols de différentes tailles (C2 à C12) comme monomères, la viscosité et la teneur en fonctions hydroxyles des polyols finaux ont pu être adaptée jusqu’à obtention de propriétés satisfaisantes à l’élaboration de mousses polyuréthanes. Ainsi, des mousses polyuréthanes semi-flexible et des mousses polyisocyanurate rigides ont pu être formulés avec des profils cinétiques de moussage rapide (inférieur à 3 min). Les mousses polyisocyanurates rigides présentent d’excellente propriétés mécaniques et thermiques pouvant pleinement satisfaire à la l’isolation thermique de bâtiment. D’autre part, une voie de transestérification entre le sorbitol et diméthyle carbonate a été étudié afin d’élaborer une nouvelle molécule plateforme bi-fonctionnelle : un bis-cyclocarbonate. A partir de cette molécule plateforme des réactions de polymérisation par ouverture de cycles et d’aminolyses ont été mise en place pour la synthèse de diols, polyéthers réticulés, et de polyuréthanes sans isocyanate (NIPU). Les synthèses de NIPU réalisées à partir de diamines courtes ou longues (issus de dimer d’acide gras) a permis d’étudier les relations existantes entre le choix des monomères et les températures de transitions vitreuses des matériaux polymères résultant. / In a context of renewable molecules valorization, new molecular architectures and polyols have been developed from sorbitol and various biobased building-blocks with respect to the green chemistry principles. Several polyesters polyol have been synthesized from controlled esterification reactions in bulk conditions. Thanks to the used of variable size diols (C2 to C12) monomers, polyols final viscosity and hydroxyls values were tuned until the obtaining of suitable properties for polyurethanes foams elaborations. Thus, semi-flexible polyurethane foams and rigid polyisocyanurate foams were formulated with fast foaming kinetic profiles (less than 3 min). Rigids polyisocyanurates foams exhibit excellent mechanical and thermal properties, in great agreement with building insulating application requirement. Otherwise, transesterifications reaction involving sorbitol and dimethyl carbonate were studied in order to develop a new bi-functional chemical platform, a bis-cyclocarbonate. Ring opening polymerization and aminolysis reactions were investigated from this chemical platform to the elaboration of cross-linked polyether and non-isocyanate polyurethanes (NIPU). NIPU syntheses were performed with short and long diamines in order to study the relationships between monomers choice and the resulting polymer material temperature of glass transition.