京都大学 / 新制・課程博士 / 博士(工学) / 甲第23910号 / 工博第4997号 / 新制||工||1780(附属図書館) / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 中尾 佳亮, 教授 松原 誠二郎, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

<p> Nitroarenes are the nitro-functionalized derivatives of polycyclic aromatic hydrocarbons (PAH) which are found in a variety of environmental matrices, and are potential human carcinogens. The 1997 discovery of a potent mutagen, 3-nitrobenzanthrone, in diesel exhaust has renewed interest in these compounds. Theoretically- and experimentally-determined characteristics of nitroarenes have been explored as predictors of their mutagenic potencies in the Ames reversion assay. In this multifaceted project, the relationships of these parameters and rates of nitroarene metabolism to the mutagenic potencies of 11 nitroarenes in Salmonella typhimurium strain YG1021 were explored.</p> <p> Ab initio calculations at the HF/3-21G level were performed for these molecules. Calculated NO2 dihedral angles and εLUMO values were smaller in magnitude than those previously determined by lower quality semi-empirical and STO-3G ab initio calculations, and showed poor correlations with nitroarene mutagenicity. Molecular negative electrostatic potential surfaces for the nitroarenes studied possessed two regions which, when placed in a common orientation in 3-dimensional space, suggested specific binding contacts within the active site of the nitroarene-activating enzyme nitroreductase.</p> <p> An efficient GC-MS method was developed for the analysis of organic extracts from Salmonella incubations with nitroarenes in the determination of relative rates of metabolism, and employed a two-stage solid phase extraction sample clean-up scheme. The rates of nitroarene metabolism for six nitroarenes, whose mutagenic potencies ranged over two orders of magnitude, ranged from 450 to 3600 pmol/hr/mL Salmonella culture at 25°C and showed a good correlation with mutagenicity.</p> <p> The results of this work suggest that mutagenic potency is a direct result of intermediate accumulation, and cast serious doubts on the reported correlations between nitroarene physicochemical properties and mutagenic potencies. This study underscores the need for the in-depth examination of the characteristics of nitroarene intermediates as an explanation of nitroarene mutagenic potencies.</p> / Thesis / Master of Science (MSc)

Project I 2-Deoxystreptamine (2-DOS), the most conserved central scaffold of aminoglycosides, is known to specifically recognize the 5'-GU-'3 sequence step through highly conserved hydrogen bonds and electrostatic interactions within and without the context of aminoglycosides (Figure 1a). We proposed that a novel monomeric unnatural amino acid building block using 2-DOS as a template would allow us to develop RNA binding molecules with higher affinity and selectivity than those currently available. Conjugating two or more of the monomeric building blocks by an amide bond would introduce extra hydrogen bonding donors and acceptors that are absent in natural aminoglycosides and increase specificity of binding to a target RNA through a network of hydrogen bonds. In addition, the amide conjugation between the monomeric building blocks places two GU-base recognizing amines at 5 Å… distance, which is equal to the distance of neighboring base stacks in dsRNAs We hypothesized that targeting dsRNAs containing multiple consecutive 5'-GU-'3 sequence steps would become possible by connecting two or more of the monomeric building blocks by amide bonds. According to the proposed hypothesis, we designed three dimeric 2-DOS compounds connected by an amide bond. These three targets include the dimeric 2-DOS substrate connected by an amide bond, the dimeric 2-DOS containing the sugar moiety from Neamine, and a dimeric 2-DOS connected by a urea linker. These compounds were then tested for sequence specific binding against 8 different RNA strands, and for antibacterial activity against E. coli, actinobacter baumannii and klebsiella. Project II A dual optimization approach was used for to enhance the catalytic activity and chemoselectivity for nitro reduction. In this approach the composition of the nanoparticles and electronics effects of the polymer were studied towards nitro reduction. Bimetallic Ruthenium-Cobalt nanoparticles showed exceptional catalytic activity and chemoselectivity compared to monometallic Ruthenium nanoparticles. The electronic effects of the polymer also had a significant effect on the catalytic activity of the bimetallic nanoparticles. The electron-deficient poly(4-trifluoromethylstyrene) supported bimetallic nanoparticles undergo nitro reduction in 20 minutes at room temperature, whereas electron-rich poly(4-methylstyrene) and poly(4-methoxystyrene) supported bimetallic nanoparticles to longer reaction times to go to completion. Electronics of the polymers also effects the change in mechanism of nitroreduction. Polystyrene bimetallic Ruthenium-Cobalt nanoparticles showed excellent yields and chemoselectivity towards nitro functional group in the presence of easily reducible functional groups like alkenes, alkynes, allyl ethers, propargyl ethers. Monometallic ruthenium nanoparticles also showed excellent reactivity and chemoselectivity towards azide reduction in the presence of easily reducible functional groups. Interestingly monometallic ruthenium nanoparticles showed regioselective reduction of primary azides in the presence of secondary and benzylic azides, also aromatic azides can be selectively reduced in the presence of secondary azides. These polystyrene supported nanoparticles are heterogeneous and are easily separated from the reaction mixture and reused multiple times without significant of catalytic activity.