N-phenylpyridin-2-amine , treated with stochiometric amount of palladium(II) acetate in dichloromethane at 65-70¢J for 4 h, to give high yield palladacycle 53. The reaction of palladacycle 53 with potassium aryltrifluoroborates in 1,4-dioxane at 140¢J for 24 h, could give a variety of N-(2-pyridinyl)carbazoles 55a-55m via sequential C-H bond activation. Carbazole derivative 55a reacted with irdium chloride gave iridium dimer, which followed by addition of picolinic acid via ligand exchange will form iridium complexes, which can further be utilized as OLEDs materials.

Under the conditions of transfer hydrogenation utilizing chromatographically purified ortho-cyclometallated iridium C,O-benzoate precatalysts, enantioselective carbonyl crotylation and methallylation can be performed in the absence of stoichiometric metallic reagents and stoichiometric chiral modifiers. In the case of carbonyl crotylation, use of a preformed precatalyst rather than an in situ generated catalyst results in lower reaction temperatures, providing generally higher diastereoselectivity and yields. By utilizing a more reactive leaving group in chloride over acetate on our methallyl donor, the inherently shorter lifetime of the olefin π-complex is compensated for, giving our group’s first report of reactivity utilizing 1,1-disubstituted allyl donors. / text

Under the conditions of transfer hydrogenation employing ortho-cyclometallated iridium C,O-benzoate catalysts, two protocols of iterative chain elongation of 1,3-diols to furnish 1,3-polyols were developed. First, one-directional chain elongation employing mono-protected 1,3-diols as starting materials was achieved. In all cases, high levels of catalyst-directed enantioselectivity and diastereoselectivity were observed. Then, double asymmetric allylation of 1,n-glycols to deliver C₂-symmetric adducts with exceptional level of enantioselectivity was devised. Iterative two-directional elongation of 1,3-diols to furnish 1,3-polyols with high level of catalyst-directed diastereoselectivity was then achieved. Implementation of this methodology and other hydrogenative C-C bond formations proved to be effective means for the preparation of a known bryostatin A-ring fragment and the total synthesis of bryostatin 7. / text

Esta tesis doctoral se centró en la síntesis y la caracterización de nanopartículas metálicas (Pd, Ni, Pt) estabilizadas por varios tipos de ligandos y el uso de estas nanopartículas en reacciones de formación de nuevos C-C o C-heteroatomo: a) Reacción de substitución alílica catalizadas por Pd; b) Reacción de acoplamiento asimétrico de Suzuki-Miyaura; c) Reacción de acoplamiento de Suzuki-Miyaura; d) reacción de adición 1,4 de ácidos borónicos a cetonas. En cada una de estas reacciones se llevó a cabo la síntesis y caracterización de nanoparticulas metálica y complejos moleculares usando muchos tipos de ligandos en los sistemas moleculares y los sistemas análogos cataliazados por nanopartículas. Excelentes actividades y enatioselectividades fueron obtenidas en la reacción de alquilación y aminación alílica. Además, estos sistemas fueron reciclados usando líquidos iónicos. También, nuevos y selectivas nanoparticulas fueron sintetizadas y caracterizadas. Estas nanopartículas fueron usadas exitosamente en varias reacciones de formación de nuevos enlaces C-C. / This doctoral thesis focuses on the synthesis and characterization of metal nanoparticles (Pd, Ni, Pt) stabilized by several types of ligands and the used of these nanoparticles in new C-C or C-heteroatom bond formation reactions: a) Pd-catalysed asymmetric allylic substitution reactions; b) Pd-catalysed asymmetric Suzuki-Miyaura coupling reactions; c) Ni-catalysed Suzuki-Miyaura coupling reactions; d) Pt-catalysed 1,4-addition of phenylboronic acid to 2-cyclohexen-1-one reaction. For each reaction, the synthesis and characterization of metal nanoparticles and molecular complexes using several types of ligands were performed and both types of catalytic systems were tested in the appropriate reactions. Remarkably, excellent enantioselectivities using Pd/phosphite ligand were obtained in allylic substitution reaction. An efficient recovery of the catalytic system was carried out using ionic liquids as reaction medium. New active and selective nanoparticles were synthesized and characterized. These nanoparticles were applied successfully in various C-C bond formation reactions.

High plasma concentrations of Lipoprotein(a) (Lp(a)) have been identified as a risk factor for a variety of atherogenic disorders such as cerebrovascular disease, peripheral vascular disease, and coronary heart disease. Lp(a) consists of a lipoprotein moiety containing apolipoproteinB-100 (apoB-100), as well as apolipoprotein(a) (apo(a)), a unique glycoprotein to which the majority of Lp(a) functions are attributed. Variation in the number of identically repeated kringle IV type 2 (KIV2) motifs of apo(a) forms the molecular basis of Lp(a) isoform size heterogeneity, which is a hallmark of this lipoprotein. There is a general inverse correlation between apo(a) size and plasma Lp(a) concentrations, attributed in part to less efficient secretion of larger apo(a) isoforms from hepatic cells. The present study provides a preliminary investigation into processes involved in apo(a) secretion, with respect to isoform size, to understand this inverse correlation at a molecular level. Pulse-chase experiments were performed in human embryonic kidney (HEK 293) cells and human hepatoma (HepG2) cells, both stably expressing differently-sized recombinant apo(a) isoforms representing the range of apo(a) sizes observed in the population. The folding kinetics for the different apo(a) isoforms were determined by changes in the mobility of the non-reduced radiolabelled species on SDS-PAGE gels. In HEK 293 cells, the rate at which apo(a) is folded correlated well with isoform size. In HepG2 cells, however, folding times were comparable regardless of isoform size. Apo(a) secretion from both cell lines exhibited size-dependency. Preliminary experimentation on endoplasmic reticulum (ER)-resident protein modifications of apo(a) was performed, resulting in the identification of apo(a) interactions with PDI, Erp57, Calnexin, Grp78, Grp94, and EDEM. Preliminary experiments indicate a role for intracellular apo(a) degradation in the amount of apo(a) that is secreted from HepG2 cells, although an isoform size dependency of this degradation process cannot be established with current experimental data. Further experimentation is required to confirm enzyme interactions with differently-sized apo(a) isoforms, to identify other chaperones involved in apo(a) secretion, and to confirm the role of proteasomes in intracellular apo(a) degradation. This may, in turn, provide information regarding the mechanism of how apo(a) secretion from hepatic cells is regulated. / Thesis (Master, Biochemistry) -- Queen's University, 2009-09-20 19:10:09.497

No description available.

Abstract Protein folding of outer membrane and secreted proteins, including receptors, cytokines and antibodies is often linked to disulphide bond formation. Native disulphide bond formation is complex and is usually the rate limiting step in the folding of such proteins. The enzymes which catalyse the slow steps in disulphide bond formation belong to the protein disulphide isomerase (PDI) family. PDI catalyses formation, reduction and isomerization of newly synthesized disulphide bonds. The mechanisms of action of the PDIs are currently poorly understood and this not only inhibits our understanding of the biogenesis of a range of medically important proteins, and hence associated disease states, but also prevents the effective manipulation of the cellular environment by the biotechnology industry for the production of high value therapeutic proteins. Hence, understanding the mechanism of action of these enzymes is vital for a wide range of medically important processes and therapies. In this study the role of a conserved arginine residue in the catalytic activity of PDI was shown. The movement of this residue into and out of the active site locale of PDI was shown to modulate the pKa of the C-terminal active site cysteine of PDI and by that way to allow the enzyme to act efficiently as catalyst both of oxidation and isomerization reactions. The possible role of hydrogen peroxide produced by sulphydryl oxidases during disulphide bond formation was studied in an oxidative protein refolding assay. Analysis showed that hydrogen peroxide can be used productively to make native disulphide bonds in folding proteins with minimal side reactions. In addition, the kinetics of oxidation and reduction of the <b>a</b> domains of PDI and Pdi1p by glutathione was studied in this thesis. The kinetics obtained with stopped-flow and quenched-flow experiments showed the reactions to be more rapid and complex than previously thought. Significant differences exist between the kinetics of PDI and Pdi1p. This implies that the use of yeast systems to predict physiological roles for mammalian PDI family members should be treated cautiously.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20192号 / 理博第4277号 / 新制||理||1615(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 依光 英樹, 教授 丸岡 啓二, 講師 西村 貴洋 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20409号 / 工博第4346号 / 新制||工||1674(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 村上 正浩, 教授 吉田 潤一, 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

京都大学 / 新制・課程博士 / 博士(理学) / 甲第24441号 / 理博第4940号 / 新制||理||1706(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)准教授 齊藤 尚平, 教授 依光 英樹, 教授 畠山 琢次 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM