Orientadores: João Ernesto de Carvalho, Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-09-28T18:41:42Z (GMT). No. of bitstreams: 1 Costa_DeboraBarbosaVendramini_D.pdf: 5920460 bytes, checksum: d6638ad4d3d0a96e4bbcdb55823f3254 (MD5) Previous issue date: 2012 / Resumo: A carcinogênese é um processo longo, multi-etapas, onde células normais progressivamente adquirem um fenótipo neoplásico. Sua origem é favorecida por fatores genéticos, exposição à carcinógenos químicos, infecções crônicas e incorporação de mutações em genes envolvidos com a regulação da homeostase celular. O crescente entendimento da biologia tumoral tem fornecido alvos moleculares para a triagem orientada de quimioterápicos e de agentes quimiopreventivos, geralmente de origem natural ou sintetizados com base em produtos naturais. A evolução da química orgânica permitiu que compostos naturais fossem sintetizados de forma econômica e aperfeiçoados quanto às suas propriedades físico-químicas, favorecendo sua disponibilidade. Esse trabalho teve como foco a goniotalamina, uma estiril-lactona naturalmente encontrada na forma enantiomérica (R) em plantas do gênero Goniothalamus (Annonaceae). Foram sintetizadas as formas (R), (S) e racêmica, que em painel de nove linhagens tumorais humanas levaram à inibição de crescimento e morte celular com elevada potência. Apesar da potência sobre a MCF-7 (carcinoma mamário responsivo ao estrógeno), estudos com estimulação estrogênica revelaram que a atividade da goniotalamina é independente da via hormonal. De qualquer maneira, a goniotalamina racêmica inibiu em 65% a proliferação da MCF-7 implantada em fibras semipermeáveis (hollow fiber) em camundongos. A citometria de fluxo revelou que o racemato de goniotalamina induz apoptose na linhagem tumoral de cólon HT-29 em baixa concentração (10 ?g/mL), com participação das caspases 8 e 9, sugerindo ativação das vias extrínseca e intrínseca. Houve também indução de apoptose na linhagem de melanoma humano SK-MEL-2, mas esse efeito diminuiu quando essa linhagem foi transfectada com Bcl-XL, inibidor apoptótico ligado à mitocôndria, sugerindo ativação principalmente da via apoptótica extrínseca, com ativação da via intrínseca para amplificação do sinal. A goniotalamina em suas três formas comprovou in vivo a atividade apresentada in vitro, pela inibição do desenvolvimento tumoral em modelo de tumor sólido e ascítico de Ehrlich, sem sinais de toxicidade nas doses efetivas. Esses resultados, aliados aos bons rendimentos na rota sintética, favoreceram a continuidade dos estudos com a forma racêmica. Considerando que aproximadamente 25% dos tumores estão relacionados com inflamações crônicas, a goniotalamina racêmica foi avaliada em modelos de edema de pata induzido por carragenina e por diversos mediadores (fosfolipase A2, histamina/serotonina, prostaglandina E2 e bradicinina), apresentando atividade anti-edematogênica em todos os modelos. Corroborando com esses resultados, a goniotalamina apresentou efeito antinociceptivo em modelos de algesia induzidos por processos inflamatórios. A goniotalamina inibiu o desenvolvimento de colite induzida por TNBS e o tratamento oral (30 mg/kg, três vezes por semana/três meses) preveniu o desenvolvimento de inflamação e câncer em animais deficientes em interleucina 10, sem apresentar sinais de toxicidade. Tais dados foram revelados após análise de dano macroscópico e microscópico (histologia) do cólon, havendo diminuição da expressão relativa dos genes para TNF? e MMP9, importantes no processo inflamatório e de invasão e metástase. Além disso, a goniotalamina diminuiu a incidência de metástase pulmonar em modelo de melanoma metastático. Os resultados obtidos e o perfil multi-alvos apresentado pela goniotalamina sugerem sua avaliação em terapias combinatórias para tratamento de processos inflamatórios crônicos e de câncer / Abstract: Carcinogenesis is a long process involving several steps, in which normal cells progressively acquire a neoplastic phenotype. Its origin is favored by genetic factors, exposure to chemical carcinogens, chronic infections and incorporation of mutations into genes involved in regulation of cellular homeostasis. The increasing understanding of tumor biology has provided molecular targets for screening of targeted chemotherapeutic and chemopreventive agents, usually from natural sources or synthesized based on natural products. The improvement of organic chemistry allowed the synthesis of natural products in an economic and refined way, with improvement on their physicochemical properties and availability. This work focuses on goniothalamin, a styryl-lactone naturally found on its enantiomeric form (R), in plants of Goniothalamus (Annonaceae) genus. The (R), (S) and racemic forms were synthesized and led to growth inhibition and cell death in a panel of nine human tumor cell lines, with high potency. Despite the potency against MCF-7 (breast carcinoma responsive to estrogen), estrogen stimulation studies revealed that the goniothalamin activity is independent of the hormone pathway. Anyway, racemic goniothalamin inhibited on 65% the proliferation of MCF-7 implanted into semi permeable fibers (hollow fiber) in mice. Flow cytometry analysis showed that low concentration of racemic goniothalamin (10 ?g/mL) leads colon tumor cell line (HT-29) to apoptosis with involvement of caspase 8 and 9, suggesting the activation of the extrinsic and intrinsic pathways. Apoptosis was also induced in human melanoma cell line SK-MEL-2, but the activity was decreased in SK-MEL-2 transfected with Bcl-XL, a mitochondrial related apoptotic inhibitor, suggesting mainly activation of the extrinsic apoptotic pathway, with activation of the intrinsic pathway to amplify the signal. Goniothalamin on its three forms comproved in vivo the in vitro activity by inhibiting tumor development in models of Ehrlich solid and ascitic tumor in mice, without signals of toxicity at the effective doses. These results, combined with good yields in the synthetic rout favored the racemic form to continue the in vivo studies. Considering that about 25% of tumors are related to chronic inflammation, racemic goniothalamin was evaluated in models of paw edema induced by carrageenan and various mediators (phospholipase A2, histamine/serotonin, prostaglandin E2 and bradykinin) displaying anti-edematogenic activity in all models. Corroborating these results, goniothalamin showed antinociceptive effect in models of algesia induced by inflammatory processes. It also inhibited the development of TNBS-induced colitis and oral treatment (30mg/kg, three times/week, three months) prevented the development of inflammation and cancer in interleukin-10 deficient mice, without signals of toxicity. These data were revealed after macroscopic and microscopic (histology) colon damage analysis, with decreased expression of TNF? and MMP9, which are important in inflammation, invasion and metastasis process. Furthermore, goniothalamin reduced the incidence of lung metastasis in a metastatic melanoma model. These results and the multitarget profile presented by goniothalamin suggest its evaluation in combinatory therapies for treatment of chronic inflammation and cancer / Doutorado / Biologia Celular / Doutor em Biologia Celular e Estrutural

Neste trabalho o metilpluviatolido (1), o matairesinol (7), a hinoquinina (11), a cubebina (17) e seus respectivos derivados, providos de algumas modificações estruturais foram submetidos a testes in vitro para a determinação da atividade citotoxica e tripanocida. As substâncias não apresentaram atividade citotoxica significativa para a linhagem celular utilizada (LLC-MK2). Nos ensaios tripanocida in vitro o dimetoximorelensin (8) e 11 foram as substâncias que determinaram as maiores atividades tripanocida sobre as varias formas e cepas de T. cruzi utilizadas e juntamente com a cubebina foram submetidas os ensaios in vivo. As substâncias determinaram alterações significativas no curso da infecção chagásica experimental. No entanto apenas a 8 apresentou efeito semelhante ao do benzonidazol para ambas as cepas, sendo a cepa BOL em relação a cepa Y mais resistente as substâncias 11 e 17. Algumas rotas metabólicas foram avaliadas como mecanismo de ação das substâncias. As substâncias não apresentaram atividade inibitória sobre a enzima gliceraldeído-3-fosfato desidrogenase (GAPDH) de Trypanosoma cruzi, não induziram a produção de H2O2 e outros peróxidos, bem como não induziram a produção de óxido nítrico, tendo algumas inibindo esta produção. No entanto, apresentaram efeito inibitório sobre a respiração celular e efeito inibitório sobre a enzima ferro superóxido dismutase (Fe-SOD) de Trypanosoma cruzi. Adicionalmente foi demonstrado que em sistema livre de células as substâncias não apresentam atividade scavenger de radicais livres e que o tratamento com a substancia 8, avaliado por microscopia eletrônica, provoca alterações nucleares nas formas epimastigotas do parasita, sugerindo que a atividade tripanocida desta substancia envolva a inibição da síntese de DNA e RNA. Dessa forma, podemos concluir que a atividade tripanocida das varias lignano-lactonas avaliadas é promissora e que a produção de H2O2 e outros peróxidos, atividade inibitória sobre a enzima gliceraldeído-3-fosfato desidrogenase (GAPDH) de Trypanosoma cruzi, bem como a capacidade de indução de óxido nítrico pelos derivados bioativos são mecanismos que parecem não estar envolvidos na atividade tripanocida das substâncias. Além disso, que o efeito inibitório sobre a respiração celular parece contribuir para a atividade tripanocida e pode estar envolvido no mecanismo de citotoxicidade destas substâncias. Ainda, que o efeito inibitório sobre a enzima ferro superóxido dismutase (Fe- SOD) de Trypanosoma cruzi parece ser um dos principais mecanismos envolvidos na atividade tripanocida das substâncias. / In this work the compounds methylpluviatolide (1), matairesinol (7), hinokinin (11), cubebin (17) and its derivatives bearing some structural modifications were submitted to in vitro trypanocidal and citotoxic assays. The compounds do not show significant citotoxicity for the LLC-MK2 cells used. In the in vitro trypanocidal assays, the compounds more active against the different strains and forms of T. cruzi were the dimethoxymorelensin (8) and hinokinin (11). These compounds and cubebin (17) were submitted to in vivo trypanocidal assay. The compounds display significant modifications on the experimental chagasic infection. However, for both strains, Y and BOL, only the 8 displayed similar effect of the benznidazole. The BOL strain was more resistant than Y strain to treatment with 11 and 17. Some metabolic routes were evaluated as compounds action mechanism. The compounds do not showed inhibitory activity under enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Trypanosoma cruzi, they do not induced the production of H2O2 and others peroxides and also do not induced the nitric oxide production, instead some compounds decrease this production. On the other hand, they showed inhibitory effect under the cellular respiration and the enzyme iron superoxide dismutase (Fe-SOD) of Trypanosoma cruzi. In addition, it was demonstrated that on system cells free, the compounds do not showed free radicals scavenger activity and that the treatment with the compound 8, evaluated in electron microscopy, display nuclear alterations on epimastigotes forms, suggesting an inhibitory effect on T. cruzi DNA and RNA biosynthesis. In conclusion, the compounds trypanocidal activity is promising and the production of H2O2 and others peroxides, the activity under enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Trypanosoma cruzi, and the induction of nitric oxide production seem do not be involved in the trypanocidal and citotoxity activity of these group of compounds. The inhibitory effect under cellular respiration seems to be contributing for trypanocidal activity and may be involved on its citotoxic mechanism. Moreover, the inhibitory effect under the enzyme iron superoxide dismutase (Fe-SOD) of Trypanosoma cruzi seems to be the main mechanism involved on trypanocidal activity of these compounds.

<p>The genus <i>Arnica</i> (Asteraceae) was investigated for phylogenetic relationships and sesquiterpene lactone (STL) content with the aims to trace the evolutionary history of the genus and to investigate possible congruencies between DNA sequence data, secondary chemistry, and biological activity. </p><p>Complex evolutionary patterns in <i>Arnica</i> are evident from phylogenetic analyses of chloroplast regions (the <i>rpl16</i> and <i>rps16</i> introns and the <i>psbA–trnH</i>, <i>ycf4–cemA</i>, and <i>trnT–L</i> spacers), nuclear ribosomal regions (the internal and external transcribed spacers) and the nuclear low-copy DNA region coding for the second largest subunit of RNA polymerase II (<i>RPB2</i>) between exons 17 and 23. Polymorphism was detected in nuclear ribosomal and low-copy regions<i>,</i> likely caused by polyploidy and agamospermy. Lineage sorting and/or hybridization is a possible explanation for incongruencies between topologies of the different DNA regions. None of the five subgenera in <i>Arnica</i> constitute a monophyletic group according to any of our analyses. </p><p>Sesquiterpene lactone profiles were compared to nuclear ribosomal DNA data using phylogenetic inference and principal component analysis for 33 accessions of 16 species. Clusters supported by both STL chemistry and ribosomal DNA sequence data consist of multiple accessions of the same species (e.g.<i> A montana </i>and<i> A. longifolia</i>), indicating that these species are well defined both genetically and chemically, based on our sampling. Support for subspecies classification of <i>A. chamissonis</i> and <i>A. parryi</i> was found in chemical data. For the first time STLs are reported from subtribe Madiinae, sister to Arniciinae.</p><p>Anti-inflammatory properties, as measured by inhibition of human neutrophil elastase release from neutrophils and inhibition of the binding of transcription factor NF-κB to DNA, were investigated for extracts of 12 <i>Arnica</i> species. <i>Arnica montana</i>, <i>A. chamissonis</i> and <i>A. longifolia</i> accessions show high inhibitory effects in both bioassays. Generally, species with a more diverse STL chemistry also possess the strongest inhibitory activity in the bioassays.</p>

The genus Arnica (Asteraceae) was investigated for phylogenetic relationships and sesquiterpene lactone (STL) content with the aims to trace the evolutionary history of the genus and to investigate possible congruencies between DNA sequence data, secondary chemistry, and biological activity. Complex evolutionary patterns in Arnica are evident from phylogenetic analyses of chloroplast regions (the rpl16 and rps16 introns and the psbA–trnH, ycf4–cemA, and trnT–L spacers), nuclear ribosomal regions (the internal and external transcribed spacers) and the nuclear low-copy DNA region coding for the second largest subunit of RNA polymerase II (RPB2) between exons 17 and 23. Polymorphism was detected in nuclear ribosomal and low-copy regions, likely caused by polyploidy and agamospermy. Lineage sorting and/or hybridization is a possible explanation for incongruencies between topologies of the different DNA regions. None of the five subgenera in Arnica constitute a monophyletic group according to any of our analyses. Sesquiterpene lactone profiles were compared to nuclear ribosomal DNA data using phylogenetic inference and principal component analysis for 33 accessions of 16 species. Clusters supported by both STL chemistry and ribosomal DNA sequence data consist of multiple accessions of the same species (e.g. A montana and A. longifolia), indicating that these species are well defined both genetically and chemically, based on our sampling. Support for subspecies classification of A. chamissonis and A. parryi was found in chemical data. For the first time STLs are reported from subtribe Madiinae, sister to Arniciinae. Anti-inflammatory properties, as measured by inhibition of human neutrophil elastase release from neutrophils and inhibition of the binding of transcription factor NF-κB to DNA, were investigated for extracts of 12 Arnica species. Arnica montana, A. chamissonis and A. longifolia accessions show high inhibitory effects in both bioassays. Generally, species with a more diverse STL chemistry also possess the strongest inhibitory activity in the bioassays.

The major subject of this thesis is the synthesis of enantiomerically enriched gamma and delta lactones via Ring Closing Metathesis (RCM). Furan and thiophene substituted aldehydes were transformed to the corresponding heteroaryl substituted allylic and homoallylic alcohols by using vinyl and allylmagnesium bromide, respectively and then resultant racemic alcohols were resolved by hydrolase type enzymes (PSC-II, Lipozyme, CAL-B) with high enantiomeric excess values. Since the absolute configuration of alcohols were known, it was possible to determine the configuration of the synthesized compounds. After the enantiomeric enrichment of the alcohols, subsequent acylation with acryloyl and methacryloyl chloride afforded feasible diene system that was subjected to ring closing metathesis reaction 1st and 2nd generation Grubbs&rsquo / catalysts were used. These lactones were used to test their biological activities.

Les éthers cycliques et les lactones représentent des cibles de choix pour la chimie des arômes et parfums. Dans ce contexte, l'objectif de ce travail de thèse concerne la mise au point d'un système catalytique permettant la cycloisomérisation d'alcools et d'acides insaturés, respectivement en éthers cycliques et en lactones.<br /><br />L'utilisation de superacides de Lewis de type triflates métalliques (Mn+(OTf)n) a permis l'élaboration d'un système catalytique faisant intervenir le triflate d'aluminium ou d'étain à 5% molaire dans le nitrométhane. <br /><br />Ce système catalytique a ensuite été appliqué à la synthèse de divers squelettes intéressant en chimie des arômes et parfums tels que les éthers spiranniques, les spirodilactones ainsi que les thioéthers cycliques et les thiolactones. Une synthèse originale de l'oxyde de rose et du Doremox® a également été proposée.<br /><br />En parallèle, l'introduction de ligands chiraux pouvant se coordinner au métal en vue de réaliser des cyclisations énantiosélectives a fait l'objet d'une étude qui est actuellement poursuivie au laboratoire.<br /><br />Enfin, une étude mécanistique faisant appel à des calculs théoriques semi-empiriques ainsi qu'à des analyses par RMN a permis de proposer une hypothèse de chemin réactionnel.

The synthesis and characterization of a series of chiral indium complexes bearing a tridentate NNO ligand are reported. The ligand 2-[[[(dimethylamino)cyclohexyl]amino]methyl]- 4,6-bis(tert-butyl) phenol (H₂NNO) was synthesized via a previously published procedure and bound to indium by both a protonolysis and salt metathesis route. A dimethylated indium complex (NNO)InMe₂ (1) was isolated by reaction of InMe₃ with H₂NNO. A one-pot saltmetathesis route was used to produce a unique mixed-bridge dinuclear indium complex [(NNO)InCl] ₂(μ-OEt)(μ-Cl) (3) from a mixture of indium trichloride, potassium ethoxide and the monopotassiated salt of the ligand, KH(NNO). Direct reaction of KH(NNO) and indium trichloride resulted in the formation of (NNO)InCl₂ (4) which was carried forward to 3 by reaction with sodium ethoxide. The complex 3 is active for the ROP of β-butyrolactone ε-caprolactone and lactide and is the first reported indium-based catalyst for lactide or β-butyrolactone ROP. Kinetic studies of 3 for ROP of LA revealed that catalyst was well-behaved, and that the rate was first order with regard to lactide and catalyst. The enthalpy and entropy of activation for the ROP were experimentally determined. Polymer produced by ROP by 3 has narrow molecular weight distribution and a good correlation is seen between the observed moleular weight and monomer loading. A mechanism was proposed for 3 acting as a catalyst for the ROP of lactide; however further experiments are required to confirm this mechanism. Polymer samples isolated from the ROP of rac-lactide by rac-3 show isotactic enrichment. It is postulated that the chiral catalyst 3 is exerting stereocontrol via an enantiomorphic site control mechanism.

El polímers termoestables són materials de gran interès i amb una amplia versatilitat en el món industrial degut a les seves excel·lents propietats. El treball que es presenta, s'emmarca en aquest camp i es dirigeix cap a l'obtenció de nous materials epoxídics, que puguin ésser utilitzats com a recobriments de components electrònics. Els objectius que es van plantejar van ser: obtenir materials que 1) durant el procés de curat, experimentessin una baixa contracció, 2) permetessin una degradació tèrmica de forma controlada un cop ha finalitzat la vida útil dels components i 3) milloressin les propietats mecàniques respecte als materials epoxídics convencionals. La contracció de la xarxa polimèrica durant el procés de curat produeix tensions mecàniques internes i conseqüentment pot conduir a l'aparició d'esquerdes. Els espiroortoesters (SOEs) són monòmers considerats expansibles, que experimenten expansió durant el procés de polimerització. La síntesi dels SOEs es pot portar a terme per reacció d'epòxids amb lactones en presència d'un catalitzador àcid de Lewis. L'expansió en volum d'aquests monòmers es deguda a que en la polimerització per obertura d'anell es produeix un canvi de distancies covalents en la forma cíclica a distancies de Van der Waals en la forma oberta. La copolimerització de reïnes epoxi amb lactones en presència d'un àcid de Lewis porta a la formació "in situ" d'espiroortoesters. Un cop formats, polimeritzen i donen lloc a unitats de poli(èter-ester) a la xarxa tridimensional. Al polimeritzar generen expansió en l'última etapa del curat, precisament quan el material no té mobilitat, evitant així l'aparició de tensions internes.D'altra banda, l'estructura típica d'un termoestable implica que aquests materials, una vegada aplicats sobre un component electrònic, no poden ser eliminats ni mitjançant dissolvents ni per escalfament. La introducció de grups ester a la xarxa, especialment si son terciaris, permet disminuir la temperatura de degradació tèrmica en comparació a la dels materials epoxídics convencionals. Sotmesos els materials a un procés tèrmic, la xarxa termoestable sofreix una degradació parcial. Aquesta és suficient perquè es puguin eliminar per dissolució o mitjançant fricció mecànica. Així, el material electrònic pot ésser reparat o reciclat.Finalment, la introducció de restes alifàtiques a la xarxa termoestable redueix la densitat d'entrecreuament i amb ella la fragilitat dels materials, fent-los més flexibles.S'ha utilitzat una reïna comercial, el diglicidil èter del bisfenol A (DGEBA). Com a lactones el 2,2-dimetil-4,6-dioxo-1,3-dioxà o àcid de Meldrum (MA) i tres dels seus derivats amb la posició 5 disubstituïda. L'estructura d'aquests compostos permet introduir grups ester terciaris i cadenes alifàtiques a la xarxa epoxídica.S'ha sintetitzat una nova reïna epoxi: la 5,5-bis(2,3-epoxipropil)-2,2-dimetil-4,6-dioxo-1,3-dioxà (DGMA), on es conjuga en un mateix compost l'anell de bislactona i els grups glicidílics. Aquesta reïna s'ha homopolimeritzat i copolimeritzat amb la reïna epoxi de diglicidil èter de bisfenol A.Com a àcids de Lewis s'han estudiat els triflats de terres rares. Aquests permeten dur a terme el curat en condicions atmosfèriques. Els materials obtinguts amb els triflats de terres rares s'han comparat amb els obtinguts amb trifluorur de bor complexat, que és un iniciador catiònic convencional.A més, s'han obtingut materials a partir dels mateixos monòmers utilitzant un iniciador aniònic. En aquest cas, el mecanisme de curat no implica la generació de grups espiroortoester, però igualment porta a xarxes amb estructura de poli(èter-ester).Les etapes seguides en el present treball són:1. Síntesi i caracterització estructural dels derivats de l'àcid de Meldrum.2. Estudi del mecanisme de les reaccions de copolimerització catiònica i aniònica de la reïna epoxi amb l'àcid de Meldrum i derivats emprant els triflats de lantànid i el BF3·MEA i la DMAP, mitjançant calorimetria i FTIR/ATR.3. S'ha estudiat la cinètica dels processos de curat per calorimetria.4. Caracterització estructural dels diferents materials obtinguts.5. Avaluació de les propietats tèrmiques i mecàniques dels materials i del grau de contracció que experimenten en curar.6. Estudi dels processos de degradació dels materials termoestables obtinguts, així com les condicions que es produeix. De l'estudi realitzat s'ha pogut concloure que s'ha assolit una reducció global de l'encongiment al curar, s'han obtingut materials que inicien la degradació a temperatures inferiors a les de les reïnes epoxi convencionals i que van resultar ser més flexibles.ENGLISH / Thermosetting polymers are interesting materials widely versatilities in the electronics industry because of their good characteristics. The present work is included in this field and it is focused in obtaining new epoxydic thermosets that may be useful as coatings for electronic devices. The objectives posed in this work were to obtain materials that: 1) undergo low shrinkage during curing process, 2) allow to be thermally degraded in a controlled way once their service life is over and 3) improve the mechanical properties with respect to the conventional epoxy materials. The shrinkage of the polymeric network during curing process produces internal mechanical stress and consequently it can lead to the appearance of microvoids and microcracks. Spiroorthoesters (SOEs) are considered to be expandable monomers, which experience expansion during polymerization process. SOEs can be synthesized by reaction of epoxides with lactones in the presence of a Lewis acid as catalyst. The expansion in volume of these monomers is due to the ring-opening polymerization process. It produces a change in atomic distances from the cyclic form (covalent distance) to the open one (Van der Waals distance). The copolymerization of epoxy resins with lactones in the presence of a Lewis acid leads to "in situ" formation of spiroorthoesters. Once it is formed, it polymerizes yielding poly(ether-ester) unities into the three-dimensional network. On polymerizing expansion is produced, just when the material has no mobility and therefore avoiding internal stress. The typical structure of a thermoset implies that once it is applied over an electronic device neither solvents nor heat can remove it. The introduction of ester groups into the network, especially if are tertiary, allows diminishing the temperature of thermal degradation in comparison to that of conventional epoxy materials. When these new materials are subjected to a thermal process, the thermoset network undergoes a partial degradation. This is enough to remove it by dissolution or mechanical friction. Therefore, the electronic device can be repaired or recycled. Finally, the introduction of aliphatic moieties into the thermoset network reduces the cross-linking density and the fragility of materials, giving more flexibility to the material. In the present work, a commercial epoxy resin, diglycidyl ether of bisphenol A (DGEBA) was used. As lactones 2,2-dimethyl-4,6-dioxo-1,3-dioxane or Meldrum acid (MA) and three of its derivatives with the five position disubstituted. The structure of these compounds allows incorporating tertiary ester groups and aliphatic chains into the epoxydic network. A new epoxy resin was synthesized: 5,5-bis(diglycidyl)-2,2-dimethyl-4,6-dioxo-1,3-dioxane (DGMA), which present both a bislactone ring and glicydilyc groups. This resin was homopolymerized and copolymerized with the epoxy resin of diglycidyl ether of bisphenol A. As Lewis acids triflates of rare earths were studied. These allow curing in atmospheric conditions. The materials obtained with triflates of rare earths were compared to the materials obtained with boron trifluoride complex, which is a conventional cationic initiator. Furthermore, materials from the same monomers were obtained by using an anionic initiator. In this case, the curing mechanism does not imply the generation of spiroorthoester groups, but equally it leads to networks with a poly (ether-ester) structure. The followed steps in the present work are:1. Synthesis and structural characterization of Meldrum acid derivatives. 2. Study of the mechanism of cationic and anionic copolymerization reactions of the epoxy resin with Meldrum acid and its derivatives using lanthanide triflats, BF3·MEA and DMAP, by differential scanning calorimetry and FTIR-ATR. 3. The kinetics of the curing process was studied by differential scanning calorimetry.4. Structural characterization of the materials obtained.5. Evaluation of the thermal and mechanical properties of materials and the degree of shrinkage experimented in the curing. 6. Study of the degradation process of thermosetting materials obtained and the conditions in which it is produced. From the study carried out it can be concluded that a global reduction in the shrinkage on curing was achieved. Also, materials that start the degradation at lower temperatures than conventional epoxy resins were obtained. These materials come to be more flexible

Aquest treball s'emmarca en el camp dels materials termoestables amb aplicacions en recobriments o encapsulants per microelectrònica i pretén l'obtenció de materials amb millor durabilitat i que després del temps d'ús puguin ser degradats i permetin la recuperació del material electrònic, el que constitueix una gran avantatja des del punt de vista mediambiental. L'estratègia escollida ha estat la copolimerització de diglicidilèter de bisfenol A (DGEBA) amb mono-&#61543;-lactones i bis-&#61543;-lactones utilitzant diversos triflats de terres rares i el BF3·MEA com iniciadors catiònics i varies amines terciàries com iniciadors aniònics. Aquesta estratègia permet la introducció de grups ester, tèrmica i químicament làbils i alhora reduir l'encongiment que es produeix durant el curat. La incorporació de cadenes alifàtiques, provinents de les lactones, entre punts d'entrecreuament augmenta la flexibilitat de la xarxa polimèrica i disminueix la fragilitat del material. La millora de les propietats mecàniques també va ser estudiada addicionant montmorillonites laminars. / This work focuses on the thermosetting materials area with applications in coatings or encapsulates for microelectronic devices and it seeks to obtain materials with better durability that after their working life, could be degraded and let the recuperation of the electronic material, which means a great advantage for the environment. The strategy followed has been the copolymerization of diglycidylether of bisphenol A (DGEBA) with mono-&#61543;-lactones and condensed bis-&#61543;-lactones using several rare earth triflates and BF3·MEA as cationic initiators and several tertiary amines as anionic iniciators. This strategy lets the introduction of ester linkages, thermal and chemically cleavable and at the same time the reduction of the shrinkage which is produced during the curing process. The incorporation of aliphatic chains, that come from lactones, between cross-linking points increases the flexibility of the polymeric network and decreases the fragility of the material. The improvement of the mechanical properties also was studied adding layered montmorillonites.

Tyrimo tikslas buvo išanalizuoti maisto produktų užterštumą kai kuriomis A grupės farmakologiškai aktyviomis medžiagomis Lietuvoje. Darbo metu atlikta A grupės farmakologiškai aktyvių medžiagų patekimo į organizmą jų sukeliamą žalą bei kiekius maisto produktuose liečiančią mokslinę literatūrą. Aptartas farmakologiškai aktyvių medžiagų teisinis reglamentavimas LR bei ES, išanalizuoti 1998-2006 metų literatūroje rasti farmakologiškai aktyvių medžiagų monitoringo duomenys, bei 1998-1999 ir 2004-2006 metais sukauptų visų farmakologiškai aktyvių A grupės medžiagų stebėsenos rezultatai pagal maisto žaliavų grupes. Informacija ir tyrimų medžiaga gauti iš Nacionalinės veterinarijos laboratorijos ir atlikta jų statistinė analizė SPSS statistiniu paketu (SPSS Inc, 1995-2007). Analizuojant 1998-2006 metų A grupės farmakologiškai aktyvių medžiagų stebėsenos aprašomosios statistikos rezultatus nustatyta, kad daugiausiai mėginių ištirta ieškant chloramfenikolio likučių maisto produktuose (1271). Daugiausiai maisto produktų tyrimų nustatant A grupės medžiagas atlikta 2003 metais (1476). Per analizuojamą laikotarpį daugiausiai ištirta galvijienos (3024) ir kiaulienos (1069) mėginių, mažiausiai – medaus, avienos, triušienos, žvėrienos ir vandens mėginių. Daugumos A grupės medžiagų - stilbeno ir stilbeno produktų, antitiroidinių agentų, steroidų (išskyrus estradiolį ir testosteroną), rezorcilo rūgšties laktinų, beta-antagonistų zeranolio, farmakologiškai aktyvių junginių (chloramfenikolio... [toliau žr. visą tekstą] / The purpose of research was to analyze the contamination of food products with some pharmacologically active substances of group A in Lithuania. The work analyzed the getting of pharmacologically active substances of group A into the organism, the damage that they cause, and the scientific literature related to their amounts in the food products. The legal regulation of pharmacologically active substances in Lithuania and the EU was discussed, the monitoring data on the pharmacologically active substances found in the literature of the years 1998-2006 was analyzed together with the monitoring results of pharmacologically active substances of group A accumulated in 2004-2006, according to the groups of raw food materials. The information and research’s material was received from the National Laboratory of Veterinary and its statistical analysis was done with the help of SPSS statistical package (SPSS Inc, 1995-2007). While analyzing the results of the descriptive statistics of the monitoring of pharmacologically active substances of group A in the years 1998-2006, it was determined that the majority of samples were analyzed in search for the remains of chloramphenicol in the food products (1271). The majority of tests with food products determining the substances of group A was done in 2003 (1476). During the analyzed period the number of samples of cattle meat (3024) and pork (1069) was the biggest, while that of honey, lamb, rabbit, game and water was the smallest. The... [to full text]