The main aim of this thesis was to study the role of the indirect actions of γ-rays and α-particles on the complexity of primary DNA damages and the repair fidelity of major DNA repair pathways: non-homologous end joining (NHEJ), homologous recombination repair (HRR) and base excision repair (BER). The complexity of radiation-induced damages increases and the proximity between damages decreases with increasing LET due to formation of ionization clusters along the particle track. The complexity of damages formed can be modified by the free radical scavenger dimethyl sulfoxide (DMSO). In addition, the effects of low doses of low dose rate γ-radiation on cellular response in terms of differentiation were investigated. Paper I investigates the role of the indirect effect of radiation on repair fidelity of HRR, NHEJ and BER when damages of different complexity were induced by radiation or by potassium bromate. We found that potassium bromate induces complex DNA damages through processing of base modifications and that the indirect effect of radiation has a high impact on the NHEJ pathway. Results in paper II confirmed our conclusions in paper I that the indirect effect from both γ-rays and α-particles has an impact on all three repair pathways studied and NHEJ benefits the most when the indirect effect of radiation is removed. In paper III we investigated the effects of low dose/dose rate γ-radiation on the developmental process of neural cells by using cell models for neurons and astrocytes. Our results suggest that low dose/dose rate γ-radiation attenuates differentiation and down-regulates proteins involved in the differentiation process of neural cells by an epigenetic rather than cytotoxic mechanism. / <p>At the time of doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.</p>

Treatment of 1-(methylsulfinyl)-2-(phenylethynyl)benzene with 10 mol % of mercury dichloride and 1 equivalent of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in refluxing benzene gave benzo[b]thiophene in good yields. This method tolerated various functional groups in phenylethynyl moiety, including electron donating groups and electron withdrawing groups. Useing 1-(benzylsulfinyl)-2-(phenylethynyl)benzene as reaction substrate increased the yields of benzo[b]thiophene derivatives. Isotope effect showed that this cyclization reaction belong to Pummerer type cyclization reaction.

The products of organic synthesis affect countless aspects of our everyday lives, from our medicines to our fuels, plastics and more. The discovery of new methods for organic synthesis is of paramount importance if we are to find greener and more efficient ways to synthesize commodity and fine chemicals, and lower the impact of the chemical industry on our environment. The aim of my doctoral thesis is to discover fundamentally new enantioselective transformations using transition metal catalysis, which can be applied to the synthesis of pharmaceutical agents, natural products or other fine chemicals. Hydroacylation is the atom economical addition of an aldehyde C–H bond across an unsaturated functional group such as an olefin or ketone. Theoretical studies on an intramolecular ketone hydroacylation catalyzed by rhodium were performed. The insights gained from this mechanistic study were then applied to the development of an asymmetric olefin hydroacylation using ethers, sulfides and sulfoxides as directing groups. Motivated by a desire to discover new catalysts with high activity and selectivity in rhodium catalyzed transformations, a chiral tridentate sulfoxide ligand was designed and synthesized. This ligand was found to be highly enantioselective in rhodium catalyzed 1,4-addition reactions. The use of allylic sulfoxides in a dynamic kinetic resolution was then investigated. The sulfoxide was found to direct a rhodium catalyzed olefin hydrogenation with simultaneous substrate racemization through a rhodium π-allyl pathway. Progress was made towards the total synthesis of a complex polyketide natural product, 6-deoxyerythronolide B. The key macrocyclization step was achieved in a model system by ring closing metathesis, and future work will be directed at completing the synthesis of the natural product.

The products of organic synthesis affect countless aspects of our everyday lives, from our medicines to our fuels, plastics and more. The discovery of new methods for organic synthesis is of paramount importance if we are to find greener and more efficient ways to synthesize commodity and fine chemicals, and lower the impact of the chemical industry on our environment. The aim of my doctoral thesis is to discover fundamentally new enantioselective transformations using transition metal catalysis, which can be applied to the synthesis of pharmaceutical agents, natural products or other fine chemicals. Hydroacylation is the atom economical addition of an aldehyde C–H bond across an unsaturated functional group such as an olefin or ketone. Theoretical studies on an intramolecular ketone hydroacylation catalyzed by rhodium were performed. The insights gained from this mechanistic study were then applied to the development of an asymmetric olefin hydroacylation using ethers, sulfides and sulfoxides as directing groups. Motivated by a desire to discover new catalysts with high activity and selectivity in rhodium catalyzed transformations, a chiral tridentate sulfoxide ligand was designed and synthesized. This ligand was found to be highly enantioselective in rhodium catalyzed 1,4-addition reactions. The use of allylic sulfoxides in a dynamic kinetic resolution was then investigated. The sulfoxide was found to direct a rhodium catalyzed olefin hydrogenation with simultaneous substrate racemization through a rhodium π-allyl pathway. Progress was made towards the total synthesis of a complex polyketide natural product, 6-deoxyerythronolide B. The key macrocyclization step was achieved in a model system by ring closing metathesis, and future work will be directed at completing the synthesis of the natural product.

Thesis (M.Sc.) - Carleton University, 2002. / Includes bibliographical references (p. 92-95). Also available in electronic format on the Internet.

Techn. Hochsch., Diss., 2001--Aachen.

Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliographical references.

Submitted by PATRICIA BORIM Borim (borim.patricia@gmail.com) on 2016-03-08T17:20:29Z No. of bitstreams: 1 Dissertação Final - Patricia Borim 23.02.pdf: 2290317 bytes, checksum: 7f7a4c24b72b475628d2c6c665f408e7 (MD5) / Rejected by Ana Paula Grisoto (grisotoana@reitoria.unesp.br), reason: Solicitamos que realize uma nova submissão seguindo as orientações abaixo: No campo “Versão a ser disponibilizada online imediatamente” foi informado que seria disponibilizado o texto completo porém no campo “Data para a disponibilização do texto completo” foi informado que o texto completo deverá ser disponibilizado apenas 6 meses após a defesa. Caso opte pela disponibilização do texto completo apenas 6 meses após a defesa selecione no campo “Versão a ser disponibilizada online imediatamente” a opção “Texto parcial”. Esta opção é utilizada caso você tenha planos de publicar seu trabalho em periódicos científicos ou em formato de livro, por exemplo e fará com que apenas as páginas pré-textuais, introdução, considerações e referências sejam disponibilizadas. Se optar por disponibilizar o texto completo de seu trabalho imediatamente selecione no campo “Data para a disponibilização do texto completo” a opção “Não se aplica (texto completo)”. Isso fará com que seu trabalho seja disponibilizado na íntegra no Repositório Institucional UNESP. Por favor, corrija esta informação realizando uma nova submissão. Agradecemos a compreensão. on 2016-03-09T17:20:50Z (GMT) / Submitted by PATRICIA BORIM Borim (borim.patricia@gmail.com) on 2016-03-14T22:35:01Z No. of bitstreams: 1 Dissertação Final - Patricia Borim 23.02.pdf: 2290317 bytes, checksum: 7f7a4c24b72b475628d2c6c665f408e7 (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-03-15T13:43:13Z (GMT) No. of bitstreams: 1 borim_p_me_sjrp.pdf: 2290317 bytes, checksum: 7f7a4c24b72b475628d2c6c665f408e7 (MD5) / Made available in DSpace on 2016-03-15T13:43:13Z (GMT). No. of bitstreams: 1 borim_p_me_sjrp.pdf: 2290317 bytes, checksum: 7f7a4c24b72b475628d2c6c665f408e7 (MD5) Previous issue date: 2016-02-23 / Os complexos [RuCl2(S-dmso)3(O-dmso)] (complexo 1) e [RuCl2(PPh3)(S-dmso)2] (complexo 2) foram sintetizados e caracterizados por RMN, FTIR, voltametria cíclica e análise elementar. A atividade catalítica dos complexos 1 e 2 foi investigada na polimerização por abertura de anel via metátese (ROMP) de norborneno (NBE) e na polimerização radicalar por transferência de átomo (ATRP) de metacrilato de metila (MMA). As sínteses de polinorborneno (poliNBE) via ROMP com [RuCl2(PPh3)(S-dmso)2] como pré-catalisador foram avaliadas sob diferentes condições de reação ([EDA]/[Ru], [NBE]/[Ru], temperatura e tempo de reação). Os melhores rendimentos de poliNBE foram obtidos a 50 °C durante 120 minutos com razão molar [NBE]/[Ru] = 5000, na presença de 5 µL de EDA. A polimerização de MMA via ATRP foi conduzida independentemente usando os complexos 1 ou 2. Os testes catalíticos na ATRP de MMA foram avaliados em função das razões molares [EBiB]/[Ru] e [MMA]/[Ru] e do tempo de reação. Todos os experimentos via ATRP foram conduzidos à 85 °C. As polimerizações realizadas com 2 mostraram que as massas moleculares aumentaram linearmente com a conversão. As massas moleculares obtidas no estudo cinético com 1 também aumentaram com a conversão, mas foram maiores do que as massas moleculares teóricas. Este comportamento pode ser explicado pelo processo redox reversível de 2, como confirmado por voltametria cíclica. O complexo [RuCl2(PPh3)(S-dmso)2] (2) demonstrou menor atividade catalítica do que o complexo [RuCl2(S-dmso)3(O-dmso)] (1), o qual é consistente com o melhor controle na polimerização. / The [RuCl2(S-dmso)3(O-dmso)] (1) and [RuCl2(PPh3)(S-dmso)2] (2) complexes were synthesized and characterized by NMR, FTIR, cyclic voltammetry and elementary analysis. Their catalytic activity was investigated in the ring-opening metathesis polymerization (ROMP) of norbornene (NBE) and in the atom transfer radical polymerization (ATRP) of methyl methacrylate (MMA). Syntheses of polynorbornene (polyNBE) via ROMP with 2 as precatalyst were evaluated under different reaction conditions ([EDA]/[Ru], [NBE]/[Ru], temperature and reaction time; EDA is ethyldiazoacetate). PolyNBE yields were dependent on the EDA volume, monomer concentration, temperature and reaction time. The best yields of polyNBE were obtained at 50 °C for 120 min with [NBE]/[Ru] = 5000 in presence of 5 µL of EDA. MMA polymerization via ATRP was conducted independently using the complexes 1 and 2 as catalysts as a function of time and initiator and monomer concentration. The kinetic data for polymerizations carried out with 2 show that molecular weights increase linearly with conversion. The molecular weights obtained in the kinetic study with 1 also increase with conversion but show a marked deviation above the theoretical molecular weights. This behavior was explained by the reversible redox process of 2 as confirmed by cyclic voltammetry. The complex [RuCl2(S-dmso)2(PPh3)] (2) promotes the polymerization with a rate of polymerization slower than that obtained using the complex [RuCl2(S-dmso)3(O-dmso)] (1); it is consistent with the better control in the polymerization.

Made available in DSpace on 2014-06-11T19:23:46Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-24Bitstream added on 2014-06-13T18:19:59Z : No. of bitstreams: 1 crivelenti_lz_me_jabo.pdf: 1024671 bytes, checksum: 41f7ae2340e1dfe3960e54cfba80f4a7 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O objetivo do presente trabalho foi avaliar os efeitos do tratamento com DMSO sobre alguns aspectos da função renal, do perfil bioquímico sérico, de parâmetros hematológicos e da condição clínica de cães sadios e de cães com doença renal crônica (DRC). As avaliações foram feitas antes, durante e após a administração de DMSO a 10% na dose de 0,5g/kg, cada 24h, por três dias. Os resultados mostraram que apesar de não ter havido alterações significativas da maioria dos parâmetros analisados, houve diminuição da ingestão de água e ração no grupo de cães sadios durante as primeiras 24 horas pós-tratamento. No grupo DRC, embora tenha havido tendência de diminuição dos valores de hemácias e hematócrito, relacionada ao fator tratamento, o processo foi reversível. O DMSO resultou em alguns efeitos adversos nos cães sadios e também nos cães com DRC, nos quais os efeitos foram mais frequentes e mais graves. A gravidade dos efeitos adversos relacionados ao tratamento com DMSO e possível associação com o óbito em cães com DRC em estágio 4, constituem fatores para contraindicação do fármaco. Considerando que o DMSO pode ser indicado para diversas modalidades terapêuticas, os resultados do presente estudo permitem concluir que no que se refere à função renal, tanto para cães sadios quanto para cães com DRC em estágios 2 e 3, não há contraindicações para o uso do fármaco. O DMSO pode resultar em modificações leves das funções relacionadas aos glomérulos e aos túbulos, mesmo em cães com DRC, que, sabidamente, são limitados quanto à expectativa de melhora da função renal, fato que merece investigação, principalmente em pacientes que já possam estar se beneficiando de tratamento médico de manutenção para a insuficiência renal crônica / The objective of this study was to evaluate the effects of DMSO treatment on some aspects of renal function, serum profile, total blood count parameters and clinical condition of health or chronic kidney disease (CKD) dogs. The evaluations were done before, during and after the administration of DMSO 10% at a dose of 0.5g/kg, each 24h, for three days. The results showed that, although there were no significant changes in the majority of the analyzed parameters, there was decrease of the water and food intake in the health dogs group during the first 24 hours post-treatment. In the CKD group, although there was a tendency toward lower values of red blood cell count and hematocrit, related to the treatment, the process was reversible. DMSO resulted in some adverse effects in both healthy and CKD dogs, however the effects were more frequent and worse in CKD dogs. The severity of adverse effects related to the DMSO and its possible association with death in stage 4 CKD dogs, are contraindications for the drug. Considering that DMSO can be indicated for a variety of therapeutic modalities, the results of this study showed that concerning to the renal function, for both healthy and stages 2 or 3 CKD dogs, there are no contraindications for the drug usage. DMSO can result in some modifications on the functions related to glomeruli and tubules, even in CKD dogs, which are known to be limited on the expectation of renal function improvement, a fact that deserves investigation, especially in patients who are already being benefited from maintenance treatment for chronic renal failure

Orientador: Marileda Bonafim Carvalho / Banca: Márcia Mery Kogika / Banca: Áureo Evangelista Santana / Resumo: O objetivo do presente trabalho foi avaliar os efeitos do tratamento com DMSO sobre alguns aspectos da função renal, do perfil bioquímico sérico, de parâmetros hematológicos e da condição clínica de cães sadios e de cães com doença renal crônica (DRC). As avaliações foram feitas antes, durante e após a administração de DMSO a 10% na dose de 0,5g/kg, cada 24h, por três dias. Os resultados mostraram que apesar de não ter havido alterações significativas da maioria dos parâmetros analisados, houve diminuição da ingestão de água e ração no grupo de cães sadios durante as primeiras 24 horas pós-tratamento. No grupo DRC, embora tenha havido tendência de diminuição dos valores de hemácias e hematócrito, relacionada ao fator tratamento, o processo foi reversível. O DMSO resultou em alguns efeitos adversos nos cães sadios e também nos cães com DRC, nos quais os efeitos foram mais frequentes e mais graves. A gravidade dos efeitos adversos relacionados ao tratamento com DMSO e possível associação com o óbito em cães com DRC em estágio 4, constituem fatores para contraindicação do fármaco. Considerando que o DMSO pode ser indicado para diversas modalidades terapêuticas, os resultados do presente estudo permitem concluir que no que se refere à função renal, tanto para cães sadios quanto para cães com DRC em estágios 2 e 3, não há contraindicações para o uso do fármaco. O DMSO pode resultar em modificações leves das funções relacionadas aos glomérulos e aos túbulos, mesmo em cães com DRC, que, sabidamente, são limitados quanto à expectativa de melhora da função renal, fato que merece investigação, principalmente em pacientes que já possam estar se beneficiando de tratamento médico de manutenção para a insuficiência renal crônica / Abstract: The objective of this study was to evaluate the effects of DMSO treatment on some aspects of renal function, serum profile, total blood count parameters and clinical condition of health or chronic kidney disease (CKD) dogs. The evaluations were done before, during and after the administration of DMSO 10% at a dose of 0.5g/kg, each 24h, for three days. The results showed that, although there were no significant changes in the majority of the analyzed parameters, there was decrease of the water and food intake in the health dogs group during the first 24 hours post-treatment. In the CKD group, although there was a tendency toward lower values of red blood cell count and hematocrit, related to the treatment, the process was reversible. DMSO resulted in some adverse effects in both healthy and CKD dogs, however the effects were more frequent and worse in CKD dogs. The severity of adverse effects related to the DMSO and its possible association with death in stage 4 CKD dogs, are contraindications for the drug. Considering that DMSO can be indicated for a variety of therapeutic modalities, the results of this study showed that concerning to the renal function, for both healthy and stages 2 or 3 CKD dogs, there are no contraindications for the drug usage. DMSO can result in some modifications on the functions related to glomeruli and tubules, even in CKD dogs, which are known to be limited on the expectation of renal function improvement, a fact that deserves investigation, especially in patients who are already being benefited from maintenance treatment for chronic renal failure / Mestre