京都大学 / 新制・課程博士 / 博士(人間・環境学) / 甲第23996号 / 人博第1048号 / 新制||人||246(附属図書館) / 2022||人博||1048(吉田南総合図書館) / 京都大学大学院人間・環境学研究科相関環境学専攻 / (主査)教授 内本 喜晴, 教授 高木 紀明, 教授 白井 理, 教授 光島 重徳 / 学位規則第4条第1項該当 / Doctor of Human and Environmental Studies / Kyoto University / DFAM

<p>Possibly the most fascinating biochemical mechanism remaining to be solved is the formation of oxygen from water in photosystem II. This is a critical part of the photosynthetic reaction that makes solar energy accessible to living organisms.</p><p>The present thesis uses quantum chemistry, more specifically the density functional B3LYP, to investigate a mechanism where an oxyl radical bound to manganese is the active species in O-O bond formation. Benchmark calculations on manganese systems confirm that B3LYP can be expected to give accurate results. The effect of the self-interaction error is shown to be limited. Studies of synthetic manganese complexes support the idea of a radical mechanism. A manganese complex with an oxyl radical is active in oxygen formation while manganese-oxo complexes remain inactive. Formation of the O-O bond requires a spin transition but there should be no effect on the rate. Spin transitions are also required in many short-range electron-transfer reactions.</p><p>Investigations of the superproficient enzyme orotidine decarboxylase support a mechanism that involves an invariant network of charged amino acids, acting together with at least two mobile water molecules.</p>

<p>This dissertation was undertaken to study two different subjects both related to molecular decomposition by applying a shock tube and non-thermal plasma to decompose selected hydrocarbons. The first approach to molecular decomposition concerned thermal decomposition and oxidation of highly diluted nitromethane (NM) in a shock tube. Reflected shock tube experiments on NM decomposition, using mixtures of 0.2 to 1.5 vol% NM in nitrogen or argon were performed over the temperature range 850-1550 K and pressure range 190-900 kPa, with 46 experiments diluted in nitrogen and 44 diluted in argon. By residual error analysis of the measured decomposition profiles it was found that NM decomposition (CH₃NO₂ + M -> CH₃ + NO₂ + M, where M = N₂ /Ar) corresponds well to a law of first order. Arrhenius expressions corresponding to NM diluted either in N₂ or in Ar were found as k_N2 = 1017.011×exp(-182.6 kJ/mole / R×T <cm³/mole×s> and k_Ar = 1017.574×exp(-207 kJ/mole / R×T )<cm3^/mole×s>, respectively. A new reaction mechanism was then proposed, based on new experimental data for NM decomposition both in Ar and N₂ and on three previously developed mechanisms. The new mechanism predicts well the decomposition of NM diluted in both N₂ and Ar within the pressure and temperature range covered by the experiments.</p><p>In parallel to, and following the decomposition experiments, oxidative experiments on the ignition delay times of NM/O₂/Ar mixtures were investigated over high temperature and low to high pressure ranges. These experiments were carried out with eight different mixtures of gaseous NM and oxygen diluted in argon, with pressures ranging between 44.3-600 kPa, and temperatures ranging between 842-1378 K.</p><p>The oxidation experiments were divided into different categories according to the type of decomposition signals achieved. For signals with and without emission, the apparent quasi-constant activation energy was found from the correlations, to be 64.574 kJ/mol and 113.544 kJ/mol, respectively. The correlations for the ignition delay for time signals with and without emission were deduced as τemission = 0.3669×10^-2×[NM]^-1.02[O₂]^-1.08×[Ar]^1.42×exp(7767/T) and τno emission = 0.3005×10^-2×[NM]^-0.28[O₂]^0.12×[Ar]^-0.59×exp(13657/T), respectively.</p><p>The second approach to molecular decomposition concerned the application of non-thermal plasma to initiate reactions and decompose/oxidize selected hydrocarbons, methane and propane, in air. Experiments with a gliding arc discharge device were performed at the university of Orléans on the decomposition/reforming of low-to stoichiometric concentration air/CH₄ mixtures. The presented results show that complete reduction of methane could be obtained if the residence time in the reactor was sufficiently long. The products of the methane decomposition were mainly CO₂, CO and H₂O. The CH₄ conversion rate showed to increase with increasing residence time, temperature of the operating gas, and initial concentration of methane. To achieve complete decomposition of CH₄in 1 m³ of a 2 vol% mixture, the energy cost was about 1.5 kWh. However, the formation of both CO and NOx in the present gliding discharge system was found to be significant. The produced amount of both CO (0.4-1 vol%) and NO_x (2000-3500 ppm) were in such high quantities that they would constitute an important pollution threat if this process as of today was to be used in large scale CH₄ decomposition. Further experimental investigations were performed on self-built laboratory scale, single- and double dielectric-barrier discharge devices as a means of removing CH₄ and C₃H_{8 f}rom simulated reactive inlet mixtures. The different discharge reactors were all powered by an arrangement of commercially available Tesla coil units capable of high-voltage high-frequency output. The results from each of the different experiments are limited and sometimes only qualitative, but show a tendency that the both CH₄ and C₃H₈are reduced in a matter of a 3-6 min. retention time. The most plausible mechanism for explaining the current achievements is the decomposition by direct electron impact.</p>

This dissertation was undertaken to study two different subjects both related to molecular decomposition by applying a shock tube and non-thermal plasma to decompose selected hydrocarbons. The first approach to molecular decomposition concerned thermal decomposition and oxidation of highly diluted nitromethane (NM) in a shock tube. Reflected shock tube experiments on NM decomposition, using mixtures of 0.2 to 1.5 vol% NM in nitrogen or argon were performed over the temperature range 850-1550 K and pressure range 190-900 kPa, with 46 experiments diluted in nitrogen and 44 diluted in argon. By residual error analysis of the measured decomposition profiles it was found that NM decomposition (CH3NO2 + M -&gt; CH3 + NO2 + M, where M = N2 /Ar) corresponds well to a law of first order. Arrhenius expressions corresponding to NM diluted either in N2 or in Ar were found as kN2 = 1017.011×exp(-182.6 kJ/mole / R×T &lt;cm3/mole×s&gt; and kAr = 1017.574×exp(-207 kJ/mole / R×T )&lt;cm3/mole×s&gt;, respectively. A new reaction mechanism was then proposed, based on new experimental data for NM decomposition both in Ar and N2 and on three previously developed mechanisms. The new mechanism predicts well the decomposition of NM diluted in both N2 and Ar within the pressure and temperature range covered by the experiments. In parallel to, and following the decomposition experiments, oxidative experiments on the ignition delay times of NM/O2/Ar mixtures were investigated over high temperature and low to high pressure ranges. These experiments were carried out with eight different mixtures of gaseous NM and oxygen diluted in argon, with pressures ranging between 44.3-600 kPa, and temperatures ranging between 842-1378 K. The oxidation experiments were divided into different categories according to the type of decomposition signals achieved. For signals with and without emission, the apparent quasi-constant activation energy was found from the correlations, to be 64.574 kJ/mol and 113.544 kJ/mol, respectively. The correlations for the ignition delay for time signals with and without emission were deduced as τemission = 0.3669×10-2×[NM]-1.02[O2]-1.08×[Ar]1.42×exp(7767/T) and τno emission = 0.3005×10-2×[NM]-0.28[O2]0.12×[Ar]-0.59×exp(13657/T), respectively. The second approach to molecular decomposition concerned the application of non-thermal plasma to initiate reactions and decompose/oxidize selected hydrocarbons, methane and propane, in air. Experiments with a gliding arc discharge device were performed at the university of Orléans on the decomposition/reforming of low-to stoichiometric concentration air/CH4 mixtures. The presented results show that complete reduction of methane could be obtained if the residence time in the reactor was sufficiently long. The products of the methane decomposition were mainly CO2, CO and H2O. The CH4 conversion rate showed to increase with increasing residence time, temperature of the operating gas, and initial concentration of methane. To achieve complete decomposition of CH4 in 1 m3 of a 2 vol% mixture, the energy cost was about 1.5 kWh. However, the formation of both CO and NOx in the present gliding discharge system was found to be significant. The produced amount of both CO (0.4-1 vol%) and NOx (2000-3500 ppm) were in such high quantities that they would constitute an important pollution threat if this process as of today was to be used in large scale CH4 decomposition. Further experimental investigations were performed on self-built laboratory scale, single- and double dielectric-barrier discharge devices as a means of removing CH4 and C3H8 from simulated reactive inlet mixtures. The different discharge reactors were all powered by an arrangement of commercially available Tesla coil units capable of high-voltage high-frequency output. The results from each of the different experiments are limited and sometimes only qualitative, but show a tendency that the both CH4 and C3H8 are reduced in a matter of a 3-6 min. retention time. The most plausible mechanism for explaining the current achievements is the decomposition by direct electron impact.

Possibly the most fascinating biochemical mechanism remaining to be solved is the formation of oxygen from water in photosystem II. This is a critical part of the photosynthetic reaction that makes solar energy accessible to living organisms. The present thesis uses quantum chemistry, more specifically the density functional B3LYP, to investigate a mechanism where an oxyl radical bound to manganese is the active species in O-O bond formation. Benchmark calculations on manganese systems confirm that B3LYP can be expected to give accurate results. The effect of the self-interaction error is shown to be limited. Studies of synthetic manganese complexes support the idea of a radical mechanism. A manganese complex with an oxyl radical is active in oxygen formation while manganese-oxo complexes remain inactive. Formation of the O-O bond requires a spin transition but there should be no effect on the rate. Spin transitions are also required in many short-range electron-transfer reactions. Investigations of the superproficient enzyme orotidine decarboxylase support a mechanism that involves an invariant network of charged amino acids, acting together with at least two mobile water molecules.

Las sales de oro se han convertido en uno de los catalizadores por excelencia en una gran variedad de transformaciones orgánicas mediante la activación selectiva de alquinos, alenos y alquenos. Parte del trabajo de esta tesis doctoral se ha centrado en el estudio de la naturaleza carbénica o carbocatiónica de los intermedios de reacción presentes en las cicloisomerizaciones de 1,5-eninos catalizadas por complejos de oro. De esta forma se han desarrollado distintas metodologías de ciclación dando lugar a diferentes productos tricíclicos a partir de oxo-1,5-eninos o 1,5-bencileninos. Además, se ha podido aplicar estas nuevas metodologías de ciclación en la síntesis de productos naturales como etapa clave de la misma. Por último, nuestro interés se ha centrado en el desarrollo de reacciones intermoleculares de gran utilizad química catalizadas por oro. Por ello hemos desarrollado la síntesis de fenoles substituidos a partir de diferentes acetilenos y furanos. / Gold salts and complexes are the most active catalysts for the activation of alkynes, allenes and alkenes. Part of this Doctoral Thesis is focused on the study of the carbenic or cationic character of the reaction intermediates presents in the cycloisomerizations of 1,5-enynes catalyzed by goldcomplexes. Different methodologies have been developed to synthesize different tryciclic products from oxo-1,5-enynes or 1,5-benzylenynes. Moreover, these methodologies were applied successfully as the key step in the synthesis of natural products. Finally, our interest was focused on the development of intermolecular gold-catalyzed reactions. Therefore, we have developed a general synthesis of trisubstituted phenols from alkynes and furans.

Boron carbide was produced on tungsten substrate in a dual impinging-jet CVD reactor from a gas mixture of BCl3, CH4, and H2. The experimental setup was designed to minimise the effect of mass transfer on reaction kinetics, which, together with the on-line analysis of the reactor effluent by FTIR, allowed a detailed kinetic investigation possible. The phase and morphology studies of the products were made by XPS, XRD,micro hardness and SEM methods. XPS analysis showed the existence of chemical states attributed to the boron carbide phase, together with the existence of oxy-boron carbide species. SEM pictures revealed the formation of 5-fold icosahedral boron carbide crystals up to 30 micron sizes for the samples produced at 1300oC. Microhardness tests showed change of boron carbide hardness with the temperature of tungsten substrate. The hardness values (Vickers Hardness) observed were between 3850 kg/mm2 and 4750 kg/mm2 corresponding to substrate temperatures of 1100 and 1300 C, respectively. The FTIR analysis of the reaction products proved the formation of reaction intermediate BHCl2, which is proposed to occur mainly in the gaseous boundary layer next to the substrate surface. The experimental parameters are the temperature of the substrate, and the molar fractions of methane and borontrichloride at the reactor inlet. The effects of those parameters on the reaction rates, conversions and selectivities were analysed and such analyses were used in mechanism determination studies. An Arrhenius type of a rate expression was obtained for rate of formation of boron carbide with an energy of activation 56.1 kjoule/mol and the exponents of methane and boron trichloride in the reaction rate expression were 0.64 and 0.34, respectively, implying complexity of reaction. In all of the experiments conducted, the rate of formation of boron carbide was less than that of dichloroborane. Among a large number of reaction mechanisms proposed only the ones considering the molecular adsorption of boron trichloride on the substrate surface and formation of dichloroborane in the gaseous phase gave reasonable fits to the experimental data. Multiple non-linear regression analysis was carried out to predict the deposition rate of boron carbide as well as formation rate of dichloroborane simultaneously.

This thesis deals with desulfurization of hot metal using different agents. The aim of this study was to improve the understanding of commonly used desulfurization agents such as fluidized CaO, CaC2, commercial-CaO, Mg, and mixtures of commercial-CaO-Mg. The possibility to use ZnO for desulfurization of hot metal was also investigated. The desulfurization mechanisms and kinetics of these agents were studied. A broad comparison of the desulfurization abilities of the agents was performed under the same experimental conditions. The experimental studies were carried out in a high temperature resistance furnace at 1773 K with good quenching ability and precise control of the oxygen partial pressure. The influence of ZnO in blast furnace slag on the sulfur removal potential was studied. It was found that ZnO does not stay in blast furnace slag under relevant oxygen potentials and consequently has no influence on its sulfur removal capacity. The reaction mechanism of Mg was studied by adding pure Mg into hot metal. It was found that most Mg (about 90 %) escaped as gas in less than two seconds, only providing a little desulfurization. MgS is not formed by homogenous nucleation, but on MgO particles originating from the surface of the added Mg metal. The growth of CaS around CaC2, fluidized CaO and commercial-CaO were measured and compared. The parabolic rate constants were evaluated to be 2.4∙10-7 [cm s-1] for CaC2, and 5∙10-7 [cm s-1] for fluidized CaO particles. The bigger parabolic rate constant of fluidized CaO explains why fluidized CaO achieved a much better desulfurization of hot metal than CaC2 under the same experimental conditions. Commercial-CaO performed less satisfactory in comparison to fluidized CaO powder. This was due to both its less reactive surface and agglomeration of the particles. Agglomerates and large CaO particles lead to 2CaO.SiO2 formation which hindered further utilization of CaO for desulfurization. The 2CaO.SiO2 formation was favored by a high oxygen potential. Since the desulfurization reaction of CaO not only produced CaS but also oxygen, the local oxygen concentration around big CaO particles was higher than around small particles. When small CaO particles were added together with Mg they quickly transformed to CaS. The Mg-gas helped to distribute the CaO particles in the hot metal and improved the kinetic conditions. The desulfurization abilities of some commonly used agents, namely fluidized CaO, CaC2, commercial-CaO, Mg, mixtures of commercial-CaO-Mg, and ZnO were studied and compared under the same experimental conditions. While fluidized CaO showed the best performance, commercial-CaO mixed with 20 mass % Mg achieved the second best desulfurization. Mg-granules performed slightly better than CaC2 and commercial-CaO, but somewhat less satisfactory compared to fluidized CaO and commercial-CaO-Mg mixtures. ZnO does not influence the sulfur concentration of hot metal. / <p>QC 20140404</p>

Despite advances in technology and understanding of biological systems in the past two decades, modern drug discovery is still a lengthy, expensive, difficult and inefficient process with low rate of new therapeutic discovery. The search for new effective drugs remains a somewhat empirical process. There is compelling need for a more fundamental, mechanistic understanding of human cancers and anticancer drugs to design more appropriate drugs. Radiotherapy is still the major therapy of cancer. It uses high-energy ionizing radiation such as x-rays and charged particle beams to destroy cancer cells. DNA is well known to be the principal biological target of radiotherapy, but the molecular mechanism of ionizing radiation induced DNA damage was elusive. The conventional thought of the ???OH radical as the major origin for ionizing radiation induced DNA damage is questionable. Although various strategies and types of compounds have been designed and developed as potential radiosensitizers to enhance the radiosensitizing efficiency of radiotherapy, none of them have been approved for clinical use. The general outcomes of clinical trials have been disappointing. This thesis presents an innovative molecular-mechanism-based drug discovery project to develop novel drugs for effective radiotherapy of cancer through the emerging femtomedicine approach. Its ultimate goal is to develop more effective radiosensitizers, based on our unique molecular understandings of ionizing radiation induced DNA damage and halopyrimidines as a family of potential radiosensitizers. Direct, real-time observation of molecular reactions is of significant importance in diverse fields from chemistry and biology, environmental sciences to medicine. Femtosecond time-resolved laser spectroscopy (fs-TRLS) is a very powerful, direct technique for real-time observation of molecular reactions. Its key strength lies in short duration laser flashes of a time scale at which reactions actually happen - femtoseconds (fs) (1fs = 10???15 second). Since the late 1980s, its application to study chemical and biological systems led to the births of new subfields of science, called femtochemistry and femtobiology. Recently, femtomedicine has been proposed as a new transdisciplinary frontier to integrate ultrafast laser techniques with biomedical methods for advances in fundamental understandings and treatments of major human diseases. This the remarkable opportunity afforded through real-time observation of biochemical reactions at the molecular level. Femtomedicine holds the promise of advances in the radiotherapy of cancer. Several important findings were made in this thesis. First, our results of careful and high-quality fs-TRLS measurements have resolved the long existing controversies about the physical nature and lifetimes of a novel ultrashort-lived electron species (epre???) generated in radiolysis of water. These results have not only resolved the large discrepancies existing in the literature but provided new insights into electron hydration dynamics in bulk water. Such information is important for quantitative understanding and modeling of the role of non-equilibrium epre??? in electron-driven reactions in diverse environmental and biological systems, from radiation chemistry and radiation biology to atmospheric ozone depletion. Second, our fs-TRLS results have unraveled how epre??? plays a crucial role in ionizing radiation induced DNA damage. We found that among DNA bases, only T and especially G are vulnerable to a dissociative electron transfer (DET) reaction with epre??? leading to bond breaks, while the electron can be stably trapped at C and especially A to form stable anions. The results not only challenge the conventional notion that damage to the genome by ionizing radiation is mainly induced by the oxidizing ???OH radical, but provide a deeper fundamental understanding of the molecular mechanism of the DNA damage caused by a reductive agent (epre???). Our findings have led to a new molecular mechanism of reductive DNA damage. Third, halopyrimidines, especially BrdU and IdU, have passed Phase I to II clinical trials as potential hypoxic radiosensitizers, but the outcome of Phase III clinical trials was disappointing. Our results of fs-TRLS studies have provided a new molecular mechanism of action of halopyrimidines (XdUs, X=F, Cl, Br and I) in liquid water under ionizing radiation. We found that it is the ultrashort-lived epre???, rather than the long-lived ehyd???, that is responsible for DET reactions of XdUs. This reaction leads to the formation of the reactive dU??? radical, which then causes DNA strand breaks and cancer cell death. Our results have challenged a long accepted mechanism that long-lived ehyd??? would be responsible for the radical formation from halogenated molecules. Furthermore, we found that the DET reaction efficacy leading to the formation of the reactive dU??? radical is in the order of FdU << CldU < BrdU < IdU. Thus, only BrdU and IdU could be explored as potential radiosensitizers, in agreement with the results of bioactivity tests and clinical trials. Fourth, our fs-TRLS studies have provided a molecular mechanism for the DNA sequence selectivity of BrdU and IdU in radiosensitization. We found the DET reactions of BrdU/ IdU with dAMP*??? and dGMP*??? formed by attachment of epre??? generated by radiolysis of water in aqueous BrdU-dAMP/dGMP and IdU-dAMP/dGMP complexes under ionizing radiation. This new mechanistic insight into the interaction of BrdU and IdU with DNA provides clues to improve the halogen familty as potential radiosensitizers and to develop more effective radiosensitizers for clinical applications. Fifth, based on our molecular mechanistic understandings of DNA damage induced by ionizing radiation and halopyrimidines as potential radiosensitizers, we develop more effective new radisensitizing drug candidates through the femtomedicine approach. We have performed a fs-TRLS study of the DET reaction of a candidate compound (RS-1) with epre???, and found that the DET reaction of epre??? with RS-1 is much stronger than that of IdU (and certainly BrdU and CldU). Moreover, we have tested the radiosensitizing effect of RS-1 against human cervical cancer (HeLa) cells exposed to various doses of x-ray irradiation through DNA damage measurements by gel electrophoresis and cell viability/death assays by MTT. Our results have confirmed that RS-1 can largely enhance the radiosensitivity of treated human cervical cancer (HeLa) cells to x-ray (ionizing) radiation. It is clearly demonstrated that RS-1 has a much better radiosensitizing effect than IdU. Although these are just preliminary results, our results have shown promise of developing more effective radiosensitizers. In summary, our studies have demonstrated the potential of femtomedicine as an exciting new frontier to bring breakthroughs in understanding fundamental biological processes and to provide an efficient and economical strategy for development of new anticancer drugs.

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