La présence conjointe de plusieurs fonctions confère aux allylphosphonates β-éthoxycarbonylés une réactivité particulière. Ces derniers sont considérés comme d’excellents précurseurs pour l’accès à de nouveaux composés organophosphorés. Dans le présent travail, nous avons décrit, dans un premier temps, l’utilisation de ces adduits entant qu’accepteurs de Michael. En effet, nous avons effectué des additions conjuguées d ethiols, d’amines et d’anions énolates dans des conditions réactionnelles douces. Ces allylphosphonates ont été également utilisés pour la préparation d’une nouvelle famille de γ-lactames α,β-instaurés phosphono-méthylés.L’étape clé de cette synthèse est une addition conjuguée de nitroalcanes sur les allylphosphonates suivie d’une réaction de Nef..Les cétoesters ainsi obtenus sont convertis en lactames par action d’amines primaires. Des réactions d’arylations pallado-catalysées sur les allyphosphonates ont permis l’accès à des hétérocycles phosphonatés dérivant de lacoumarine, de la quinoléine et de la benzoxépinone. La synthèse de P-hétérocyclesde différentes tailles à partir des allylphosphonates a été aussi possible par la conversion du groupe phosphonate en phosphorochloridate. La réactivité de ce dernier vis-à-vis de différentes amines, a permis d’isoler une nouvelle famille de N,Phétérocyclesà 5, 7, 8 et 9 chaînons. La synthèse de P-hétérocycles à 6 chainons a été également décrite en réalisant des cyclisations dans les conditions de métathèse cyclisante (RCM) à partir d’un bisallylphosphonate et d’un bisallylphosphoramidate issus des mêmes précurseurs. / Due to the joint presence of several functional groups, β-ethoxycarbonylatedallylphosphonates are considered as excellent precursors for the preparation of neworganophosphorus compounds. In the presentwork, we first described the use of suchphosphonates as Michael acceptors. Indeed, weperformed conjugated additions of thiols,amines and enolate-anion under mild reactionconditions. Allylphosphonates were also usedfor the preparation of a new family of phosphonomethyl α,β-unsaturated γ-lactams.The key step of this sequence is a conjugateaddition of nitroalkanes on allylphosphonates followed by a Nef reaction. Ketoester intermediaites were then convertedinto lactams by reaction with primary amines.Pd-catalyzed arylations on allylphosphonates allowed preparing phosphonated heterocyclesderived from coumarin, quinolinone andbenzoxepinone skeletons. The synthesis of Pheterocyclesof various sizes fromallylphosphonates was explored by theconversion of phosphonate inphosphorochloridate. The reactivity of the latterwith amines, allowed isolation of a new familyof 5-,7-, 8- and 9-membered N,P-heterocycles.The synthesis of 6-membered P-heterocycleshas also been described by performingcyclization under the conditions of a ringclosing metathesis (RCM) starting from bisallylphosphonates and bisallylphosphoramidates.

Ammonium ionenes are polycations that have quaternary nitrogens in their macromolecular backbone and are synthesized via step-growth polymerization technique. They offer interesting coulombic properties, and the synthetic design provides control over charge density. Non-covalent interactions including nucleobase hydrogen bonding and electrostatics were studied in ammonium ionenes. The non-covalent interactions are expected to increase the effective molecular weight of polymeric precursors and induce microphase separation due to intermolecular associations. The influence of non-covalent interactions on structure-property relationships of ammonium ionenes were studied regarding mechanical (tensile, DMA), thermal (DSC, TGA), and morphological (AFM, SAXS) properties. Hydrogen bonding interaction (10-40 kJ/mol) was introduced using DNA nucleobase pairs such as adenine and thymine. Novel adenine and thymine functionalized segmented and non-segmented ammonium ionenes were successfully synthesized using Michael addition chemistry. In non-segmented systems, we investigated the influence of spacer length on homoassociation and heteroassociation of complementary nucleobase-containing ionenes. Based on DSC analyses, complementary non-segmented ionenes made miscible blends. The Tgs of ionene blends with shorter spacer length (4 bonds between the nucleobase and secondary amine in the polymer backbone) followed the Fox equation, which indicated no intermolecular interactions. The longer alkyl spacer (9 bonds between nucleobase and secondary amine in the polymer backbone) provided efficient flexibility for the self-assembly process to occur. Thus, increasing the spacer length from 4-bonds to 9-bonds, the Tgs of the blends deviated from both Fox and Gordon-Taylor equations and demonstrated the presence of hydrogen bonding interactions. In segmented systems, we investigated the association between nucleobase-containing ionenes and their complementary guest molecules. Job's method revealed a 1:1 stoichiometry for the hydrogen-bonded complexes. These association constants for the 1:1 complexes, based on the Benesi-Hildebrand model were 94 and 130 M-1 respectively, which were in agreement with literature values for adenine and thymine nucleobase pairs (10-100 M-1). DSC thermograms confirmed no macrophase separation for 1:1 [ionene-A/T]:[guest molecule] complexes based on the disappearance of the melting peak of the guest molecule. Morphological studies including atomic force microscopy (AFM) demonstrated a reduced degree of microphase separation for the 1:1 complexes due to the disruption of adenine-adenine or thymine-thymine interactions. Poly(dimethyl siloxane)-based ammonium ionenes having various hard segment contents were synthesized. The charge density or hard segment content was tuned for appropriate application using low molecular weight monomer. The change in hard segment content had a profound effect on thermal, mechanical, rheological, and gas permeability. Microphase separation was confirmed using DSC and DMA in these systems. DMA showed that the rubbery plateau modulus extended to higher temperatures with increasing hard segment content. Tensile analysis demonstrated systematic increase in modulus of PDMS-ionenes with increasing hard segment content. Oxygen transmission rates decreased linearly as the wt% hard segment increased. / Ph. D.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19725号 / 工博第4180号 / 新制||工||1645(附属図書館) / 32761 / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 松原 誠二郎, 教授 中尾 佳亮, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor. Even after patients undergo maximum and safe surgical resection followed by adjuvant chemotherapy and radiation therapy, residual GBM cells form secondary tumors which lead to poor survival times and prognoses for patients. This tumor recurrence can be attributed to the inherent GBM heterogeneity that makes it difficult to eradicate the therapy-resistant and tumorigenic subpopulation of GBM cells with stem cell-like properties, referred to as glioma stem cells (GSCs). Additionally, the migratory nature of GBM/GSCs enable them to invade into the healthy brain parenchyma beyond the resection cavity to generate new tumors. In an effort to address these challenges of GBM recurrence, this research aimed to develop a biomaterials-based approach to attract, capture, and eradicate GBM cells and GSCs with chemical and physical stimuli. Specifically, it is proposed that after surgical removal of the primary GBM tumor mass, an injectable hydrogel can be dispensed into the resection cavity for crosslinking in situ. A combination of chemical and physical cues can then induce the migration of the residual GBM/GSCs into the injectable hydrogel to localize and concentrate the malignant cells prior to non-invasively abating them. In order to develop this proposed treatment, this dissertation focused on 1) characterizing and optimizing the thiol-Michael addition injectable hydrogel, 2) attracting and entrapping GBM/GSCs into the hydrogel with CXCL12-mediated chemotaxis, and 3) assessing the feasibility of utilizing histotripsy to mechanically and non-invasively ablate cells entrapped in the hydrogel. The results revealed that hydrogel formulations comprising 0.175 M NaHCO3(aq) and 50 wt% water content were the most optimal for physical, chemical, and biological compatibility with the GBM microenvironment on the basis of their swelling characteristics, sufficiently crosslinked polymer networks, degradation rates, viscoelastic properties, and interactions with normal human astrocytes. Loading the hydrogel with 5 µg/mL of CXCL12 was optimal for the slow, sustained release of the chemokine payload. A dual layer hydrogel platform demonstrated in vitro that the resulting chemotactic gradient induced the invasion of GBM cells and GSCs from the extracellular matrix and into the synthetic hydrogel with ameboid migration and myosin IIA activation. This injectable hydrogel also demonstrated direct therapeutic benefits by passively eradicating entrapped GBM cells through matrix diffusion limitations as well as decreasing the GBM malignancy and GSC stemness upon cancer cell-hydrogel interactions. Research findings revealed the hydrogels can be synthesized under clinically relevant conditions mimicking GBM resection in vitro, and hydrogels were distinguishable with ultrasound imaging. Furthermore, the synthetic hydrogel was acoustically active to generate a stable cavitation bubble cloud with histotripsy treatment for ablation of entrapped red blood cells with well-defined, uniform lesion areas. Overall, the results from this research demonstrate this injectable hydrogel is a promising platform to attract and entrap malignant GBM/GSCs for subsequent eradication with chemical and physical stimuli. Further development of this platform, such as by integrating electric cues for electrotaxis-directed cell migration, may help to improve the cancer cell trapping capabilities and thereby mitigate GBM tumor recurrences in patients. / Doctor of Philosophy / Glioblastoma multiforme (GBM) is the deadliest type of primary brain cancer. Upon GBM diagnosis, patients first undergo surgery to remove the tumor from the brain. After waiting several weeks for the wound healing process due to surgery, patients are administered chemotherapy with drugs and radiation therapy to eradicate any remaining GBM cells. Even after undergoing these combinatorial treatments, the cancer returns and leads to median survival times of only 15 months in 90% of patients. Complete GBM eradication is difficult, since the cancer cells can migrate into healthy brain tissue beyond the original tumor site. Additionally, GBM is highly heterogenous and composed of different cell types that can resist chemotherapy and radiation therapy, which lead to secondary tumors and cancer relapse. To address these challenges, this dissertation aimed to develop a polymer-based material (specifically a hydrogel) that can attract, entrap, and localize the GBM cells into the material to subsequently eradicate them with chemical and physical signals. This hydrogel platform would have important clinical implications, as it can potentially be dispensed into the empty cavity after surgical removal of the tumor in the brain. The hydrogel can then be harnessed to attract residual GBM cells for directed migration into the hydrogel to concentrate and localize the cancer cells for their subsequent destruction with a non-invasive technology. In order to develop this proposed treatment, this dissertation investigated the following three aims: 1) to study and optimize the injectable hydrogel for chemical, physical, and biological compatibility with the GBM therapy; 2) to utilize chemical signals to attract and entrap the GBM cells into the hydrogel; and 3) to apply focused ultrasound with high amplitude, short duration negative pressure pulses to mechanically fractionate and destroy the cells entrapped in the hydrogel. The results revealed that the hydrogel comprising 0.175 M NaHCO3(aq) and 50 wt% water content was the most optimal formulation. CXCL12 chemokine proteins loaded into the hydrogel at 5 µg/mL released slowly from the hydrogel to generate a chemical gradient and thereby attract GBM cells to promote their invasion into the hydrogel matrix. The hydrogel was demonstrated to respond well to focused ultrasound treatment, which was capable of mechanically fractionating and destroying red blood cells in the hydrogel uniformly. Overall, the results from this research provide support that this hydrogel platform can attract, entrap, and eradicate GBM cells with chemical and physical stimuli. Hence, further improvement of this platform and implementation of this novel GBM treatment may in the future help minimize GBM cancer relapse in patients who undergo conventional therapies, thereby extending their survival times.

The work focused on addressing four main objectives. The first objective was to quantify protein and amino acid substitution reactions. Michael addition reactions were used to modify the amino acids and protein. Amino acids alanine, cysteine, and lysine, and protein ovalbumin (OA) were substituted with different concentrations of ethyl vinyl sulfone (EVS). The substituted products were analyzed using Raman spectroscopy and UV-spectroscopy based ninhydrin assay. In case of alanine, Raman and UV results correlated with each other. With cysteine at lower EVS substitutions amine on the main chain was the preferred site while the substitution shifted to thiols at higher substitutions. This could only be discerned using Raman spectroscopy. Lysine has amines on the main chain and side chain while main chain amine was the most reactive site at lower concentrations of EVS while at higher concentrations side chain amines were also substituted. This information could be discerned using Raman spectroscopy only and not UV spectroscopy. In case of protein as observed by Raman and UV spectroscopy the reaction continued at higher concentrations of EVS indicating the participation of glutamine and asparagines at higher substitutions. However, the reaction considerably slowed down at higher EVS substitutions. The second objective of the study was to decrease the glass transition temperature (Tg) of OA through internal plasticization and also study the effects of the substituents on the thermal stability of OA. The hypothesis was by covalently attaching substituents to OA, number of hydrogen bonds can be reduced while increasing the free volume and this would reduce Tg. EVS, acrylic acid (AA), butadiene sulfone (BS) and maleimide (MA) were the four groups used. EVS was the most efficient plasticizer of all the four substituents. The Tg decreased with the increasing concentration of EVS until all of the reactive of groups on OA were used up. Tg decreased slightly with AA and BS while no change was observed with MA. However, the substituents showed exact opposite trend in thermal stability as measured using thermogravimetric analysis (TGA). The thermal stability of MA substituted OA was the highest and that of EVS substituted OA was least. FT-IR spectroscopy results indicated that all four substituents caused structural changes in OA. This implied that there were intermolecular interactions between substituted protein chains in case of AA, BS, and MA. This caused an increase in the thermal stability. EVS on the other hand is a linear chain monomer with a hydrophobic end group and hence could not participate in the intermolecular interactions and hence caused a decrease in Tg. As mentioned above the limitation to this technique is the number of available reactive groups on the protein. However, we successfully demonstrated the feasibility of this method in decreasing Tg of protein. The third objective was to create hydrogels by crosslinking OA with divinyl sulfone (DVS). Protein hydrogels due to their biocompatible nature find applications in drug delivery and tissue engineering. For tissue engineering applications the hydrogels need to be mechanically stable. In this study the protein was substituted with EVS or AA and then crosslinked with DVS. The swelling ratio was measured as a function of pH. All the hydrogels showed the same trend and swelled the least at pH 4.5 which is the isoelectric point of the protein. At basic pH conditions EVS substituted hydrogels swelled the most while AA substituted hydrogels showed least swelling. The static and dynamic moduli of the hydrogels were determined using tensile tester and rheometer respectively. The static modulus values were three times the dynamic modulus. The modulus of the control which is crosslinked OA was least and that of AA substituted OA was highest. The stress relaxation test also showed similar results in which AA substituted OA relaxed the most and the control relaxed the least. FT-IR of the dry hydrogels showed that the amount of hydrogen bonding increased with AA substitution. The hydrophilic AA end groups interacted with each other forming hydrogen bonds. These hydrogen bonds served as additional crosslinks there by increasing the modulus of the hydrogels. EVS on the other hand was incapable of interactions due to the lack of hydrophilic end groups. We were successfully able to create protein hydrogels and control the swelling and mechanical properties by varying the amount of substituted group. The final objective of the study was to create and characterize microstructures from substituted alanine and lysine. Alanine and lysine were substituted with different concentrations of EVS. Bars and fibers were observed for alanine at moderate substitutions while at higher concentrations random structures were observed using scanning electron microscopy (SEM). Lysine formed tubes at moderate EVS substitutions and rosettes at high concentrations of EVS as evidenced by SEM. FT-IR results suggested that instead of carbonyl one of sulfonyl bonded to the available amine in modified amino acids. And only in this case fibers, tubes and rosettes were observed. X-ray diffraction (XRD) results supported this observation. Using these results we hypothesized that the self assembled structures very much depended on the amount of EVS present in the substituted product and sulfonyl forming β-sheet analogs with amine. / Ph. D.

Polymer functional groups have critical impacts upon physical, chemical and mechanical properties, and thus affect the specific applications of the polymer. Functionalization of cellulose esters and ethers has been under extensive investigation for applications including drug delivery, cosmetics, food ingredients, and automobile coating. In oral delivery of poorly water-soluble drugs, amorphous solid dispersion (ASD) formulations have been used, prepared by forming miscible blends of polymers and drugs to inhibit crystallization and enhance bioavailability of the drug. The Edgar and Taylor groups have revealed that some cellulose omega-carboxyalkanoates were highly effective as ASD polymers, with the pendant carboxylic acid groups providing both specific polymer-drug interactions and pH-triggered release through swelling of the ionized polymer matrix. While a variety of functional groups such as hydroxyl and amide groups are also of interest, cellulose functionalization has relied heavily on classical methods such as esterification and etherification for appending functional groups. These methods, although they have been very useful, are limited in two respects. First, they typically employ harsh reaction conditions. Secondly, each synthetic pathway is only applicable for one or a narrow group of functionalities due to restrictions imposed by the required reaction conditions. To this end, there is a great impetus to identify novel reactions in cellulose modification that are mild, efficient and ideally modular. In the initial effort to design and synthesize cellulose esters for oral drug delivery, we developed several new methods in cellulose functionalization, which can overcome drawbacks of conventional synthetic pathways, provide novel cellulose derivatives that are otherwise inaccessible, and present a platform for structure-property relationship study. Cellulose omega-hydroxyalkanoates were previously difficult to access as the hydroxyl groups, if not protected, react with carboxylic acid/carbonyl during a typical esterification reaction or ring opening of lactones, producing cellulose-g-polyester and homopolyester. We demonstrated the viability of chemoselective olefin hydroboration-oxidation in the synthesis of cellulose omega]-hydroxyesters in the presence of ester groups. Cellulose esters with terminally olefinic side chains were transformed to the target products by two-step, one-pot hydroboration-oxidation reactions, using 9-borabicyclo[3.3.1]nonane (9-BBN) as hydroboration agent, followed by oxidizing the organoborane intermediate to a primary alcohol using mildly alkaline H2O2. The use of 9-BBN as hydroboration agent and sodium acetate as base catalyst in oxidation successfully avoided cleavage of ester linkages by borane reduction and base catalyzed hydrolysis. With the impetus of modular and efficient synthesis, we introduced olefin cross-metathesis (CM) in polysaccharide functionalization. Using Grubbs type catalyst, cellulose esters with terminally olefinic side chains were reacted with various CM partners including acrylic acid, acrylates and acrylamides to afford families of functionalized cellulose esters. Molar excesses of CM partners were used in order to suppress potential crosslinking caused by self-metathesis between terminally olefinic side chains. Amide CM partners can chelate with the ruthenium catalyst and cause low conversions in conventional solvents such as THF. While the inherent reactivity toward CM and tendency of acrylamides to chelate Ru is influenced by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides. We observed that the CM products are prone to crosslinking during storage, and found that the crosslinking is likely caused by free radical abstraction of gamma-hydrogen of the alpha, beta-unsaturation and subsequent recombination. We further demonstrated successful hydrogenation of these alpha, beta-unsaturated acids, esters, and amides, thereby eliminating the potential for radical-induced crosslinking during storage. The alpha, beta-unsaturation on CM products can cause crosslinking due to gamma-H abstraction and recombination if not reduced immediately after reaction. Instead of eliminating the double bond by hydrogenation, we described a method to make use of these reactive conjugated olefins by post-CM thiol-Michael addition. Under amine catalysis, different CM products and thiols were combined and reacted. Using proper thiols and catalyst, complete conversion can be achieved under mild reaction conditions. The combination of the two modular reactions creates versatile access to multi-functionalized cellulose derivatives. Compared with conventional reactions, these reactions enable click or click-like conjugation of functional groups onto cellulose backbone. The modular profile of the reactions enables clean and informative structure-property relationship studies for ASD. These approaches also provide opportunities for the synthesis of chemically and architecturally diverse cellulosic polymers that are otherwise difficult to access, opening doors for many other applications such as antimicrobial, antifouling, in vivo drug delivery, and bioconjugation. We believe that the cellulose functionalization approaches we pioneered can be expanded to the modification of other polysaccharides and polymers, and that these reactions will become useful tools in the toolbox of polymer/polysaccharide chemists. / Ph. D.

Chemical modification of naturally occurring cellulose into ester and ether derivatives has been of growing interest due to inexhaustible cellulose resources, and to excellent properties and extremely broad applications of these derivatives. However, traditional esterification and etherification involve relatively harsh conditions (strongly acidic or strongly alkaline), greatly limiting the content and range of functional groups that may be installed onto the cellulose backbone. Amorphous solid dispersion (ASD) is an effective method to promote oral delivery of poorly-soluble drugs by dispersing crystalline drugs in a polymer matrix, creating drug supersaturation upon release. Cellulose 𝜔-carboxyesters have been proven to be effective ASD matrices for many different drugs; however, synthesis of such polymers involves protecting-deprotecting chemistry and one synthetic route only leads to one structure. Developing a new generation of cellulosic polymers for oral drug delivery such as ASD matrices requires new synthetic techniques and powerful tools. Olefin cross-metathesis (CM) is a mild, efficient and modular chemistry with extensive applications in organic, polymer, and polysaccharide chemistry. Successful CM can be achieved by appending olefin “handles” from cellulose esters and reacting with electron-deficient olefins like acrylic acid. Cellulose ethers have much better hydrolytic stability compared to esters and are also commercially very important. The overarching theme of this dissertation is to investigate modification of cellulose ether derivatives, and to design and synthesize effective ASD polymers by olefin CM. We first validated the strategy of performing CM by appending metathesis “handles” through etherification and then subjected these terminal olefins to various partners (acrylic acid and different acrylates). After demonstration of the concept, we applied different starting materials (e.g. ethyl cellulose, methyl cellulose, microcrystalline cellulose, and hydroxypropyl cellulose) with distinctive hydrophobicity/hydrophilicity balance. Furthermore, α,β-unsaturated CM products tended to undergo radical crosslinking through abstraction of 𝛾-protons and recombination of polymer radicals. In order to resolve this issue, we first applied post-CM hydrogenation and then explored a thiol-Michael addition to the α,β-unsaturation, which also incorporates an extra functional group through the thioether. We have successfully prepared a collection of cellulose 𝜔-carboxyether derivatives through the above-mentioned method and preliminary drug induction experiments also revealed that these derivatives hold high promise for ASD application. We also explored the possibility of conducting CM in a reverse order: i.e. appending electron-deficient acrylate groups to the polymer, then subjecting it to electron-rich small molecule terminal olefins. The failure of this metathesis approach was speculated to be due mainly to low acrylate reactivity on an already crowded polymer backbone and the high reactivity of rapidly diffusing, small molecule terminal olefins. Last but not least, we further utilized olefin CM to conjugate bile salt derivatives (e.g. lithocholic acid and deoxycholic acid) to a cellulose backbone by converting bile salts into acrylate substrates. Successful CM of bile salt acrylates to cellulose olefin “handles” further demonstrated the great versatility, excellent tolerance, and very broad applicability of this strategy. Overall, we have founded the strategy for performing successful olefin CM in many cellulose ether derivatives with acrylic acid and a variety of different acrylates. Post-CM hydrogenation efficiently removes the α,β-unsaturation and provides stable and effective cellulose 𝜔-carboxyether derivatives for ASD application. Tandem CM/thiol-Michael addition not only eliminates the crosslinking tendency but also enables an even broader library of polymer structures and architectures for structure-property investigations. We anticipate these methods can be readily adapted by polysaccharide chemists and applied with numerous complex structures, which would greatly broaden the range of cellulose and other polysaccharide derivatives for applications including ASDs, P-glycoprotein inhibition, antimicrobial, coating, and other biomedical applications. / Ph. D.

No description available.

Lignocellulosic biomass is believed to serve a prominent role in tomorrow’s sustainable energy and material development. Among the polysaccharide fractions of lignocellulosic biomass, the potential of hemicelluloses as a valuable material resource is increasingly recognized. Thanks to their hydrophilic structure, hemicelluloses are suitable substrates for hydrogel design. The work summarized in this thesis aims to develop feasible strategies for the conversion of O-acetyl galactoglucomannan (AcGGM), an ample hemicellulose in softwood, into hydrogels. Within this framework, four synthetic pathways targeting the formation of crosslinked hydrogel networks from pure or unrefined AcGGM fractions were developed.   Aqueous AcGGM-rich and lignin-containing side-stream process liquors of forest industry, known as softwood hydrolysates (SWHs) were formulated into highly swellable hydrogels by: i) allyl-functionalization of AcGGM chains of crude SWH to obtain a viable precursor for hydrogel synthesis via free-radical crosslinking, ii) directly incorporating unmodified SWH fractions into semi-interpenetrating polymer networks (semi-IPNs). SWH hydrogels and semi-IPNs were characterized with appreciable maximum swelling ratios of Qeq = 170 and Qeq = 225, respectively.   Rapid crosslinking of AcGGM through thiol-click chemistry was addressed by first imparting thiol functionality onto pure AcGGM chains in a one-pot procedure. The thiolated AcGGM proved to be a suitable substrate for the synthesis of hemicellulose hydrogels via thiol-ene and thiol Michael addition reactions. Finally, sequential full IPNs were developed by subjecting single network hydrogels of pure AcGGM to a second network formation. IPNs obtained through either free radical crosslinking or thiol-ene crosslinking exhibited higher shear storage moduli than their single network counterparts. / <p>QC 20161102</p>

Morphine alkaloids and their derivatives are pharmaceutically important substances. Huge production and consumption of these compounds predetermines them to be significant pollutants in the environment. Some of them have been detected in surface waters. The aim of this study was to characterize effects of morphine alkaloids on the physiology of three model organisms: Agrobacterium sp. R89-1, Escherichia coli XL-1 (Blue), and Raoultella sp. kDF8, and elucidation of the mechanisms leading to toxicity. The biotransformation potential and utilization ability were characterized for model organisms. It was demonstrated that the microorganism Agrobacterium sp. R89-1 is capable of rapid biotransformation of codeine to its 14-OH derivatives. The manifestation of morphine compounds toxic effects for the strain R89-1 is the highest. In contrast, microorganism Raoultella sp. KDF8 is able to utilize codeine as a carbon and energy source. The accumulation of 14-OH-derivatives was not observed. Escherichia coli XL-1 (Blue) is not able to biotransform or utilize codeine. Α, β-unsaturated ketones (morphinone, codeinone, 14-OH-morphinone and 14-OH-codeinone) were found as a most toxic intermediates of codeine metabolism. Bacterial cell growth (strains R89-1 and KDF8) in the presence of codeine is characteristic with...