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京都大学 / 0048 / 新制・課程博士 / 博士(地球環境学) / 甲第20038号 / 地環博第154号 / 新制||地環||31(附属図書館) / 33134 / 京都大学大学院地球環境学舎環境マネジメント専攻 / (主査)教授 梶井 克純, 准教授 真常 仁志, 准教授 田中 周平 / 学位規則第4条第1項該当 / Doctor of Global Environmental Studies / Kyoto University / DFAM

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En industrie chimique, on cherche continuellement des molécules biologiquement actives essentiellement pour les domaines pharmaceutique et agrochimique. De plus en plus les exigences à ces produits deviennent dures. Elles concernent, par exemple, les activités secondaires ou l'écotoxicité. En conséquence, un grand nombre de structures doit être testé pour trouver des composés actifs remplissant les propriétés imposées. En parallèle, les capacités dans l'industrie pour tester un grand nombre de composés différents en peu de temps ont considérablement augmentées. En conséquence, l'industrie cherche des nouvelles méthodes de synthèse pour accéder rapidement à une plus grande variété des structures moléculaires.Dans ce contexte, l'industrie chimique et pharmaceutique s'intéresse fortement aux réactions photochimiques appliquées en synthèse organique. Ces réactions permettent de synthétiser des composés en grande variété structurale inaccessibles par la synthèse organique conventionnelle. Les produits des réactions photochimiques sont une partie de l’espace chimique qui n’a pas encore été complètement exploré pour la recherche des structures avec de l’activité biologique.Dans les travaux de thèse presentés nous nous sommes interessés d’abord à la photocycloaddition [2+2] entre un groupement carbonyl et un alcène, la réaction de Paternò-Büchi. Nous avons utilisé cette reáction pour obtenir des oxétanes qui possèdent des groupements intéressants en agrochimie et au même temps des sites clés qui permettront d’autres transformations lors des étapes ultérieures. Par la suite nous avons exploré la réaction de Paternò-Büchi avec des alcènes fluorés. Les résultats ont été très encourageants. Nous avons découvert une nouvelle famille d’oxétanes fluorés très stables. Au vu de ses propriétés, ces produits peuvent être utilisés comme des <chassis moléculaires> pour l’obtention des composés biologiquement actifs. D’autre côté, une nouvelle reactivité photochimique a été découverte : il s’agit d’une réaction Photo-Wittig analogue. Cette reactivité chimique dépend des substituants sur le carbonyl. Nous pensons que cette réactivité chimique est directement liée à l’état excité du carbonyl. / In life sciences, there is a continuos research for new biological active molecules, this is true for both pharmaceultical industry and agrochemical industry. In the last years regulations have become more and more severe. In recent years, the technology for the test of new chemical compounds in industry has considerably evolved. Nowdays it is possible to test a vast number of compounds for the screening of biological activity in a short time. This means that industry is searching for new methodologies that allow the obtention of diverse chemical structures that can present biological activity.In this context, chemical industry, in particular, pharmaceutical and agrochemical industry are interested in the use of photochemical reactions in organic synthesis. Photochemical reactions allow the obtention of a variety of complex structures that are not easily obtained by classical methods. This chemical space has not been completly explored in the search of biological active compounds.In the works presented in this PhD research we first explored the [2+2] photocycloadtion of a carbonyl compound to an olefin, the called Paternò-Büchi reaction. We succesfully applied this reaction to obtain oxetanes wich posses agro-like substituents and key sites for further functionalization, a requirement demanded in industry. We also explored the use of fluorinated olefins in this photoreaction. The results are very promising: we discovered a new family of stable fluorinated oxetanes. These compounds can be used cas molecular scaffolds for the obtention of biological active compounds. At the same time, we discovered a new photochemical reactivity: a Photo-Wittig like reaction. This new reactivity depends on the substitution pattern of the carbonyl group. We hypothesize that the new reactivity depends on the excited state of the carbonyl compound.

Grandes centros urbanos e regiões industriais estão contribuindo para o aumento das emissões antrópicas para a atmosfera. No Brasil, nas ultimas décadas, o interesse por estudos relacionados à poluição urbana tem adquirido muita ênfase; as regiões metropolitanas das principais cidades do país apresentam níveis de concentração elevados de poluentes conforme a resolução do CONAMA, preocupando a população. Modelos numéricos de previsão do tempo e qualidade do ar ganha espaço nas áreas de estudo com o objetivo de prever e avaliar o comportamento dos poluentes com origem antropogênica. Devido a grande complexidade das reações fotoquímicas, que ocorrem entre os poluentes primários após lançados na atmosfera, ferramentas como ReLACS (Regional Lumped Atmospheric Chemical Sheme) são implementados aos modelos químicos facilitando estas analises. Estudos em regiões metropolitanas buscam o melhoramento funcional deste mecanismo para a obtenção de uma boa resposta operacional para cada região. No Rio Grande do Sul, na região metropolitana de Porto Alegre (RMPA), o modelo CCATT-BRAMS (Coupled Aerosol and Tracer Transport model to the Brazilian Developments on the Regigional Atmospheric Modelling System) apresenta bons resultados aos processos de formação e destruição dos principais poluentes que agravam a saúde pública: o Ozônio Troposférico. A implementação do ReLACS auxilia nos mecanismos químicos que compreende as reações entre seus precursores tais como: os óxidos de Nitrogênio (NOx), monóxido de carbono (CO) e hidrocarbonetos (HC). Este estudo teve como objetivo avaliar e observar o melhoramento da resposta operacional do RELACS para a Região Metropolitana de Porto Alegre, com base no comportamento das concentrações de formação e destruição do ozônio em superfície, partindo de reações fotoquímicas entre seus precursores, NOx (NO + NO2) e compostos orgânicos voláteis (COV), através de simulações numéricas realizadas no CCATT-BRAMS. A avaliação final dos resultados é comparada com os dados de razão de mistura obtidos pelas estações de monitoramento de qualidade do ar na RMPA. / Big cities and industrial regions are contributing to the increase of anthropogenic emissions into the atmosphere. In Brazil, in recent decades, interest in studies related to urban pollution has raised; major cities metropolitan areas have high concentration levels of pollutants according to the resolution of CONAMA, preoccupying the population. Numerical models of weather prediction and air quality is gaining ground in the study areas in order to predict and evaluate the behavior of pollutants with anthropogenic origin. Due to the great complexity of photochemical reactions that occur among primary pollutants emitted into the atmosphere after, tools like ReLACS (Regional Lumped Atmospheric Chemical Sheme) are implemented to chemical models making these analyzes easy. Researches in metropolitan areas search for functional improvement of this mechanism to obtain a good operational response for each region. In Rio Grande do Sul, in the metropolitan region of Porto Alegre (MRPA), the CCATT-BRAMS (Coupled Aerosol and Tracer Transport model to the Brazilian Developments on the Regigional Atmospheric Modelling System) model seems to be a good solution to the process of formation and destruction of pollutants that aggravate the public health: Ozone Tropospheric. The implementation of ReLACS assists in chemical mechanisms comprising the reactions among their precursors such as: nitrogen oxides (NOx), carbon monoxide (CO) and hydrocarbons (HC). This research aimed to access and monitor the improvement of ReLACS the operational response to the metropolitan area of Porto Alegre, based on the behavior of the training levels and ozone depletion in surface, from photochemical reactions between their precursors, NOx (NO + NO2) and volatile organic compounds (VOC), through numerical simulations in CCATT-BRAMS. The final evaluation of the results is compared with the mixing ratio of data obtained by the quality monitoring stations air in MRPA.

Grandes centros urbanos e regiões industriais estão contribuindo para o aumento das emissões antrópicas para a atmosfera. No Brasil, nas ultimas décadas, o interesse por estudos relacionados à poluição urbana tem adquirido muita ênfase; as regiões metropolitanas das principais cidades do país apresentam níveis de concentração elevados de poluentes conforme a resolução do CONAMA, preocupando a população. Modelos numéricos de previsão do tempo e qualidade do ar ganha espaço nas áreas de estudo com o objetivo de prever e avaliar o comportamento dos poluentes com origem antropogênica. Devido a grande complexidade das reações fotoquímicas, que ocorrem entre os poluentes primários após lançados na atmosfera, ferramentas como ReLACS (Regional Lumped Atmospheric Chemical Sheme) são implementados aos modelos químicos facilitando estas analises. Estudos em regiões metropolitanas buscam o melhoramento funcional deste mecanismo para a obtenção de uma boa resposta operacional para cada região. No Rio Grande do Sul, na região metropolitana de Porto Alegre (RMPA), o modelo CCATT-BRAMS (Coupled Aerosol and Tracer Transport model to the Brazilian Developments on the Regigional Atmospheric Modelling System) apresenta bons resultados aos processos de formação e destruição dos principais poluentes que agravam a saúde pública: o Ozônio Troposférico. A implementação do ReLACS auxilia nos mecanismos químicos que compreende as reações entre seus precursores tais como: os óxidos de Nitrogênio (NOx), monóxido de carbono (CO) e hidrocarbonetos (HC). Este estudo teve como objetivo avaliar e observar o melhoramento da resposta operacional do RELACS para a Região Metropolitana de Porto Alegre, com base no comportamento das concentrações de formação e destruição do ozônio em superfície, partindo de reações fotoquímicas entre seus precursores, NOx (NO + NO2) e compostos orgânicos voláteis (COV), através de simulações numéricas realizadas no CCATT-BRAMS. A avaliação final dos resultados é comparada com os dados de razão de mistura obtidos pelas estações de monitoramento de qualidade do ar na RMPA. / Big cities and industrial regions are contributing to the increase of anthropogenic emissions into the atmosphere. In Brazil, in recent decades, interest in studies related to urban pollution has raised; major cities metropolitan areas have high concentration levels of pollutants according to the resolution of CONAMA, preoccupying the population. Numerical models of weather prediction and air quality is gaining ground in the study areas in order to predict and evaluate the behavior of pollutants with anthropogenic origin. Due to the great complexity of photochemical reactions that occur among primary pollutants emitted into the atmosphere after, tools like ReLACS (Regional Lumped Atmospheric Chemical Sheme) are implemented to chemical models making these analyzes easy. Researches in metropolitan areas search for functional improvement of this mechanism to obtain a good operational response for each region. In Rio Grande do Sul, in the metropolitan region of Porto Alegre (MRPA), the CCATT-BRAMS (Coupled Aerosol and Tracer Transport model to the Brazilian Developments on the Regigional Atmospheric Modelling System) model seems to be a good solution to the process of formation and destruction of pollutants that aggravate the public health: Ozone Tropospheric. The implementation of ReLACS assists in chemical mechanisms comprising the reactions among their precursors such as: nitrogen oxides (NOx), carbon monoxide (CO) and hydrocarbons (HC). This research aimed to access and monitor the improvement of ReLACS the operational response to the metropolitan area of Porto Alegre, based on the behavior of the training levels and ozone depletion in surface, from photochemical reactions between their precursors, NOx (NO + NO2) and volatile organic compounds (VOC), through numerical simulations in CCATT-BRAMS. The final evaluation of the results is compared with the mixing ratio of data obtained by the quality monitoring stations air in MRPA.

Grandes centros urbanos e regiões industriais estão contribuindo para o aumento das emissões antrópicas para a atmosfera. No Brasil, nas ultimas décadas, o interesse por estudos relacionados à poluição urbana tem adquirido muita ênfase; as regiões metropolitanas das principais cidades do país apresentam níveis de concentração elevados de poluentes conforme a resolução do CONAMA, preocupando a população. Modelos numéricos de previsão do tempo e qualidade do ar ganha espaço nas áreas de estudo com o objetivo de prever e avaliar o comportamento dos poluentes com origem antropogênica. Devido a grande complexidade das reações fotoquímicas, que ocorrem entre os poluentes primários após lançados na atmosfera, ferramentas como ReLACS (Regional Lumped Atmospheric Chemical Sheme) são implementados aos modelos químicos facilitando estas analises. Estudos em regiões metropolitanas buscam o melhoramento funcional deste mecanismo para a obtenção de uma boa resposta operacional para cada região. No Rio Grande do Sul, na região metropolitana de Porto Alegre (RMPA), o modelo CCATT-BRAMS (Coupled Aerosol and Tracer Transport model to the Brazilian Developments on the Regigional Atmospheric Modelling System) apresenta bons resultados aos processos de formação e destruição dos principais poluentes que agravam a saúde pública: o Ozônio Troposférico. A implementação do ReLACS auxilia nos mecanismos químicos que compreende as reações entre seus precursores tais como: os óxidos de Nitrogênio (NOx), monóxido de carbono (CO) e hidrocarbonetos (HC). Este estudo teve como objetivo avaliar e observar o melhoramento da resposta operacional do RELACS para a Região Metropolitana de Porto Alegre, com base no comportamento das concentrações de formação e destruição do ozônio em superfície, partindo de reações fotoquímicas entre seus precursores, NOx (NO + NO2) e compostos orgânicos voláteis (COV), através de simulações numéricas realizadas no CCATT-BRAMS. A avaliação final dos resultados é comparada com os dados de razão de mistura obtidos pelas estações de monitoramento de qualidade do ar na RMPA. / Big cities and industrial regions are contributing to the increase of anthropogenic emissions into the atmosphere. In Brazil, in recent decades, interest in studies related to urban pollution has raised; major cities metropolitan areas have high concentration levels of pollutants according to the resolution of CONAMA, preoccupying the population. Numerical models of weather prediction and air quality is gaining ground in the study areas in order to predict and evaluate the behavior of pollutants with anthropogenic origin. Due to the great complexity of photochemical reactions that occur among primary pollutants emitted into the atmosphere after, tools like ReLACS (Regional Lumped Atmospheric Chemical Sheme) are implemented to chemical models making these analyzes easy. Researches in metropolitan areas search for functional improvement of this mechanism to obtain a good operational response for each region. In Rio Grande do Sul, in the metropolitan region of Porto Alegre (MRPA), the CCATT-BRAMS (Coupled Aerosol and Tracer Transport model to the Brazilian Developments on the Regigional Atmospheric Modelling System) model seems to be a good solution to the process of formation and destruction of pollutants that aggravate the public health: Ozone Tropospheric. The implementation of ReLACS assists in chemical mechanisms comprising the reactions among their precursors such as: nitrogen oxides (NOx), carbon monoxide (CO) and hydrocarbons (HC). This research aimed to access and monitor the improvement of ReLACS the operational response to the metropolitan area of Porto Alegre, based on the behavior of the training levels and ozone depletion in surface, from photochemical reactions between their precursors, NOx (NO + NO2) and volatile organic compounds (VOC), through numerical simulations in CCATT-BRAMS. The final evaluation of the results is compared with the mixing ratio of data obtained by the quality monitoring stations air in MRPA.

<p>Electrospray ionization-tandem mass spectrometry (ESI-MS/MS) has been established as a powerful tool for qualitative and quantitative analysis of biomolecules. However, mass spectrometric analysis of biomolecules is often limited by poor ionization efficiency of analyte for sensitive detection and limited fragmentation for structural characterization. Over the years, various solution phase as well as gas-phase derivatization techniques, have been coupled with MS to increase the ionization efficiency and facilitate the formation of structural informative fragment ions. The research presented in this dissertation falls into two major parts; focusing on method development and application of radical chemistry for enhanced biomolecule analysis on an ESI-MS/MS platform. In the first part, a method of rapid charge tagging of neutral lipids (e.g. sterols, glycerides) with a thiol radical-based charge tag is developed, followed by comprehensive analysis via ESI-MS/MS without the use of a chromatographic separation (shotgun lipidomics). This charge tagging is performed in an easily constructible fused silica capillary-based microflow photo-reactor which is relatively low in cost and requires no instrument modifications. This method significantly enhances the ionization efficiency of the neutral lipids for sensitive MS detection (pM range). This method can be applied to the small volume of biological complex samples (e.g. 1 µL plasma) and doesn’t require extensive sample pretreatment procedure (analysis time of 2 min vs. traditional >60 min on GC-MS and HPLC-MS systems). Furthermore, the derivatized neutral lipids can also be fragmented via soft collision-induced dissociation to obtain fatty acyl chain composition of the neutral lipids (sterol esters, diacylglycerols, triacylglycerols, etc.) for structural characterization. This can especially be useful for determination for fatty acyl compositional isomers in neutral lipids for analysis related to biomarker detection. The characteristic fragmentation pattern of tagged neutral lipids has also been utilized for quantitation of lipids from biological mixture samples. Initial application of this method has shown alteration in the concentration of diacylglycerol lipid species in clinical samples of Type 2 Diabetes Mellitus patients, suggesting the potential of understanding the biological roles of such lipids in insulin resistance. </p> <p>In the second part, a unique approach of radical-induced disulfide bond cleavage in peptides and proteins is demonstrated. Using 254 nm UV emission, acetone was used as a photoinitiator to initiate secondary radical formation i.e. hydroxyalkyl radical, from alcohol co-solvents used for electrospray. These radicals can then be used to efficiently cleave the disulfide bonds (R-S-S-R) in peptide/proteins to give reduced reaction products (RSH) at the cleavage site. Upon soft collision-induced dissociation, the reduced product gave abundant <i>b-</i> and <i>y-</i> type fragment ions for complete or enhanced sequence coverage as compared to intact disulfide-linked peptides and proteins. With the use of a simple microflow photo-reactor, this radical based approach can also be coupled with infusion ESI-MS/MS for a rapid online-based peptide and protein analysis. The yield for disulfide bond reduction was almost 100% within less than 5 s of UV irradiation. Furthermore, by adjusting the UV irradiance time, different degrees of partial reduction could be achieved, which greatly facilitated the disulfide linkage mapping in peptides and proteins with multiple disulfide bonds. This method has been incorporated with both bottom-up and top-down approach for protein analysis for unraveling the molecular complexity, quantifying and deep sequencing of disulfide-linked proteins.</p>

19 Dec 2004. / Published through the Information Bridge: DOE Scientific and Technical Information. "IS-T 1930" Heather Marie Netzloff. 12/19/2004. Report is also available in paper and microfiche from NTIS.