Thesis (Ph.D.)--McMaster University (Canada), 1992. / Source: Dissertation Abstracts International, Volume: 54-08, Section: B, page: 4182. Adviser: J. E. Greedan.

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This research has focused on the development of novel substrate mimics as potential DXR inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), an essential enzyme in the mevalonate-independent pathway for the biosynthesis of isoprenoids in Plasmodium falciparum. DXR mediates the isomerisation and reduction of 1-deoxy-D-xylulose-5-phosphate (DOXP) into 2C-methyl-D-erithrytol 4-phosphate (MEP) and has been validated as an attractive target for the development of novel anti-malarial chemotherapeutic agents. Reaction of various amines with specially prepared 4-phosphonated crotonic acid in the presence of the peptide coupling reagent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), has afforded a series of amido-phosphonate esters in moderate to good yields (48% - 73%) which, using a RuCl₃/CeCl₃/NaIO₄ catalyst system, have been dihydroxylated to furnish the dihydroxy-amido phosphonate ester pro-drugs; subsequent hydrolysis under microwave irradiation has afforded the corresponding phosphonic acids. A second series of potential inhibitors viz., 3-substituted aniline-derived phosphonate esters, their corresponding phosphonic acids and mono-sodium salts, have also been successfully synthesised. In these compounds, the essential functional groups are separated by one, two, three or four methylene groups, Deprotonation of the 3-substituted aniline substrates, followed by reaction with the appropriate ω-chloroalkanoyl chloride produced the ω-chloroamide intermediates, which were subjected to the Michaelis-Arbuzov reaction to afford the diethyl phosphonate esters in moderate to good yields (48% - 74%). Microwave-assisted TMSBrmediated cleavage of the phosphonate esters furnished the phosphonic acids, neutralisation of which afforded the mono-sodium salts. Furan-derived phosphate esters and phosphonic acids have been prepared as conformationally-restricted DOXP analogues. Functionalization at C-5 of the trityl-protected furan was achieved using the Vilsmeier-Haack formylation and Friedel-Crafts acylation reactions and, following de-tritylation, phosphorylation and oximation, using hydroxylamine hydrochloride, the novel oxime derivatives have been isolated as a third series of potential DXR inhibitors in very good yields (87% - 96%). Finally, in order to exploit an additional binding pocket in the PƒDXR active site, a series of N-benzylated phosphoramidic derivatives were obtained in seven steps from the starting material, diethyl phosphoramidate. The known inhibitors, fosmidomycin and its acetyl derivative FR900098, were also successfully synthesised as standards for STD-NMR binding and inhibition assays. In all, over 200 compounds (136 novel) have been prepared and appropriately characterised using 1-and 2-D NMR and IR spectroscopic analysis and, where necessary, HRMS or combustion analysis. Saturation Transfer Difference (STD) protein-NMR experiments, undertaken using selected compounds, have revealed binding of most of the ligands examined to EcDXR. Computersimulated docking studies have also been used to explore the preferred ligand-binding conformations and interactions between the ligands and essential DXR active-site residues, while DXR-enzyme inhibition assays of selected synthesised ligands have revealed certain patterns of inhibitory activity.

No description available.

It was the purpose of this investigation to study the effect of varying the direct to reverse time ratio of periodically reversed direct current from 1.0 to 20.0 on the electrolytic production of lead chromate at an average anode current density of 0.0059 amperes per square centimeter, and to study the effect of 60 and 502.3 ± 7.7 cycles per second from 0.00113 to 0.01546 amperes per square centimeter of peak superimposed alternating current on direct current on the yield of lead chromate prepared by the electrolysis of a bath containing potassium chromate and sodium nitrate between lead electrodes. Electrolysis of a bath containing 3.60 grams of potassium chromate, 11.62 grams of sodium nitrate, end 1000 grams of water with simple direct current yielded 6.07 grams of lead chromate per ampere-hour, the purity being 92.7 percent lead chromate. The anode current density was 0.0049 amperes per square centimeter, and the current efficiency was 98.1 percent. During the electrolysis, by maintaining the ph of the electrolyte at 6.0, by adding a solution to 2.0 weight percent chromic acid, the purity of the product was increased. Electrolysis of the same bath using periodically reversed direct current yielded 4.53 grams of lead chromate per ampere-hour, the purity being 93.9 percent lead chromate. The time ratio was 20.0, the anode current density was 0.0049 amperes per square centimeter, and the current efficiency was 66.75 percent. Decreasing the direct to reverse time ratio gave lower yields and purities. Apparently, there is no advantage in using periodically reversed direct current over the use of direct current for this reaction under the above conditions. Electrolysis of the same bath with alternating current superimposed on direct current yielded 5.49 grams of lead chromate per direct current ampere-hour, at a purity of 99.4 percent lead chromate, when using 494.7 cycle alternating current. The alternating and direct current densities were 0.0078 and 0.0048 amperes per square centimeter, respectively. This was the purest product obtained in this investigation. Use of 60 cycle alternating current yielded 3.83 grams of lead chromate per direct current ampere-hour, at a purity of 93.9 percent lead chromate. The alternating and direct current densities were 0.00141 and 0.00484 amperes per square centimeter. Further experiments were made using direct current and periodically reversed direct current on a bath containing 6.80 grams of potassium chromate, 8.14 grams of sodium nitrate, and 1000 grams of water. Results from these electrolytes were much poorer than those obtained with the previous bath, so no experiments with superimposed alternating current on direct current were carried out with this latter bath. / Master of Science

No description available.

No description available.

A probe for measuring the specific heat of superconductors at low temperatures and in high magnetic fields has been built and commissioned. The probe has been tested using the relaxation method on samples of copper and the accuracy of the data is 1.3 % between 5 K and 30 K, data taken using the long range pulse method has a resolution of 10 mK. Specific heat measurements have been performed on members of the series (Pb(_1)-(_x))Cu(_1.8x)Mo(_6)S(_8), (Sn(_1-x))Eu(_x)Mo(_6)S(_8) and (Pb(_1-x)M(_x))Mo(_6)S(_8) where M = Gd and Eu, from 3 K up to 30 K and in magnetic fields up to 15 T. Additional results from resistivity, susceptibility, magnetisation. X-ray diffraction, transmission electron microscopy and electron dispersive-ray measurements are also presented. These data have been compared to results from other authors and are analysed in terms of the BCS and GLAG theories of superconductivity and the magnetic properties of these materials. The mean field model has been used to calculate numerically the magnetic contribution to the specific heat (cm) of both ferromagnetic and antiferromagnetic systems as a function of temperature and applied field both above and below the ordering temperature. In addition an approximate analytic form for the magnetisation has been used to calculate Cm above the ordering temperature. Expressions have been derived for the saturation value of the peak in C(_m): C(^sat)(_m) = 1.1245n(_cell)RJI(J+1) and the temperature dependence of the peak with applied field ȡ(μ(_o)H(_ext))/ȡT(_peak)=6.540/g(_J)(J+1). They allow the simple calculation of the values of J and g(_J)(J + 1) from specific heat data. The magnetic contribution to the specific heat of the samples (Sn(_0.65)Eu(0.35)Mo(_6)S(_8)) and (Sn(0.50)Eu(_0.50)Mo(_6)S(_8)) have been modelled using these calculations and excellent agreement is found by considering the magnetic ions as free ions. The sample is accurately modelled by including an additional minority phase (Gd(_2)S(_3)). The approximate expressions have also been used to analyse data on high temperature superconductors producing values of J and g(_J)}{J + 1) consistent with a doublet ground state. The properties of Chevrel phase materials have been determined as a function of doping level. The critical temperature is degraded by doping but an increase in the critical current density is observed in the series (Pb(_1-x)Cu(_1-8x)Mo(_6)S(_8) for very low levels of doping. Increases of up to 28 % in the upper critical field, that are probably due to the compensation effect and an increase in the normal state resistivity, are also observed in the series (Sn(_1-x)Eu(_x)Mo(_6)S(_8)) at high levels of doping and in the series (Pb(_1-x)Gd(_x)Mo(_6)s(_8) for low levels of doping.

Choi Wai-wah. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 120-138). / Abstracts in English and Chinese. / Statement --- p.i / Acknowledgements --- p.ii / Abstract --- p.iii / Abstract (Chinese Version) --- p.v / Table of Contents --- p.vii / List of Tables --- p.xii / List of Figures --- p.xiii / List of Abbreviations --- p.xv / Chapter Chapter 1 --- General Introduction / Chapter 1.1 --- "Hemoglobin ´ؤ Structures, Types and Functions" --- p.1 / Chapter 1.1.1 --- Structures of Hemoglobin --- p.1 / Chapter 1.1.2 --- Types of Hemoglobin --- p.2 / Chapter 1.1.3 --- Functions of Hemoglobin --- p.3 / Chapter 1.2 --- Human Globin Genes and Their Regulation --- p.5 / Chapter 1.2.1 --- Organization of the Human Globin Genes --- p.5 / Chapter 1.2.2 --- Regulation of Globin Gene Expression --- p.6 / Chapter 1.2.2.1 --- The Locus Control Region (LCR) --- p.6 / Chapter 1.2.2.2 --- Cis-Regulatory Elements --- p.7 / Chapter 1.2.2.2.1 --- Promoters --- p.7 / Chapter 1.2.2.2.2 --- Enhancers --- p.7 / Chapter 1.2.2.2.3 --- Silencers --- p.8 / Chapter 1.2.2.3 --- Trans-Acting Factors --- p.8 / Chapter 1.2.2.3.1 --- GATA Family --- p.9 / Chapter 1.2.2.3.2 --- Kruppel-like Factors --- p.9 / Chapter 1.2.2.3.3 --- Nuclear Factor-Erythroid (NF-E) --- p.9 / Chapter 1.2.2.4 --- Chromatin Remodelling --- p.10 / Chapter 1.2.2.5 --- Intergenic Sequences --- p.11 / Chapter 1.3 --- Mechanisms of Hemoglobin Switching --- p.12 / Chapter 1.3.1 --- Autonomous Silencing --- p.12 / Chapter 1.3.2 --- LCR and Globin Gene Interaction --- p.12 / Chapter 1.4 --- Hemoglobinopathies --- p.14 / Chapter 1.4.1 --- α -thalassemia --- p.14 / Chapter 1.4.2 --- β -thalassemia --- p.14 / Chapter 1.4.3 --- Sickle Cell Anemia --- p.16 / Chapter 1.5 --- Therapies for β-thalassemia --- p.16 / Chapter 1.5.1 --- Blood Transfusion --- p.16 / Chapter 1.5.2 --- Bone Marrow Transplantation --- p.17 / Chapter 1.5.3. --- Gene Therapy --- p.17 / Chapter 1.6 --- Gene Switch Therapy --- p.18 / Chapter "1.6,1" --- Pharmacological Induction of HbF --- p.18 / Chapter 1.6.1.1 --- Hydroxyurea --- p.19 / Chapter 1.6.1.2 --- Butyrate --- p.20 / Chapter 1.6.1.3 --- Summary --- p.21 / Chapter 1.7 --- Objectives --- p.22 / Chapter Chapter 2 --- Induction of HbF by LC978 in K562 / Chapter 2.1 --- Introduction --- p.23 / Chapter 2.2 --- Materials --- p.26 / Chapter 2.2.1 --- Chemicals and Reagents --- p.26 / Chapter 2.2.2 --- Kits --- p.27 / Chapter 2.2.3 --- Buffers and Solutions --- p.27 / Chapter 2.2.4 --- Primers --- p.30 / Chapter 2.2.5 --- Equipment and Other Consumables --- p.30 / Chapter 2.2.6 --- Maintenance of K562 --- p.31 / Chapter 2.2.7 --- Handling and Treatment of utilities for RNA isolation --- p.31 / Chapter 2.3 --- Methods --- p.32 / Chapter 2.3.1 --- Dose-response and time-response study of LC978 in K562 by TMB assay --- p.32 / Chapter 2.3.2 --- Detection of γ -Globin Gene Expression in LC978-induced K562 by RT-PCR --- p.33 / Chapter 2.3.3 --- Fetal Hemoglobin Analysis by Human Fetal Hemoglobin (HbF) ELISA Quantitation Kit --- p.36 / Chapter 2.3.4 --- Statistical Analysis --- p.38 / Chapter 2.4 --- Results --- p.39 / Chapter 2.4.1 --- Dose-response and time-response study of LC978 in K562 by TMB assay --- p.39 / Chapter 2.4.2 --- Detection of γ -Globin Gene Expression in LC978-induced K562 by RT-PCR --- p.45 / Chapter 2.4.3 --- Fetal Hemoglobin Analysis by Human Fetal Hemoglobin (HbF) ELISA Quantitation Kit --- p.48 / Chapter 2.5 --- Discussions --- p.51 / Chapter Chapter 3 --- Signal Transduction Pathways Modulated by LC978 / Chapter 3.1 --- Introduction --- p.54 / Chapter 3.2 --- Materials --- p.57 / Chapter 3.2.1 --- Chemicals and Reagents --- p.57 / Chapter 3.2.2 --- Kits --- p.57 / Chapter 3.2.3 --- Buffers and Solutions --- p.58 / Chapter 3.2.4 --- Primers --- p.59 / Chapter 3.2.5 --- Equipment and Other Consumables --- p.60 / Chapter 3.2.6 --- Maintenance of K562 --- p.60 / Chapter 3.2.7 --- Handling and Treatment of utilities for RNA isolation --- p.60 / Chapter 3.3 --- Methods --- p.61 / Chapter 3.3.1 --- Identification of Signaling Pathways by Microarray --- p.61 / Chapter 3.3.2 --- Real-time RT-PCR --- p.65 / Chapter 3.4 --- Results --- p.67 / Chapter 3.4.1 --- Identification of Signaling Pathways by Microarray --- p.67 / Chapter 3.4.2 --- Real-time RT-PCR --- p.74 / Chapter 3.5 --- Discussions --- p.80 / Chapter Chapter 4 --- MAPK pathways and HbF induction by LC978 / Chapter 4.1 --- Introduction --- p.84 / Chapter 4.2 --- Materials --- p.87 / Chapter 4.2.1 --- Chemicals and Reagents --- p.87 / Chapter 4.2.2 --- Kits --- p.88 / Chapter 4.2.3 --- Buffers and Solutions --- p.88 / Chapter 4.2.4 --- Equipment and Other Consumables --- p.90 / Chapter 4.2.5 --- Maintenance of K562 --- p.90 / Chapter 4.3 --- Methods --- p.91 / Chapter 4.3.1 --- "Roles of three MAPKs ´ؤ ERK, JNK and p38 in LC978-mediated γ -globin gene induction in K562 using CASE´ёØ Kits" --- p.91 / Chapter 4.3.2 --- Effect of p38 inhibitor SB203580 on HbF induction --- p.94 / Chapter 4.3.3 --- Statistical Analysis --- p.97 / Chapter 4.4 --- Results --- p.98 / Chapter 4.4.1 --- "Roles of three MAPKs - ERK, JNK and p38 in LC978-mediated γ -globin gene induction in K562 using CASETM Kits" --- p.98 / Chapter 4.4.2 --- Effect of p38 inhibitor SB203580 on HbF induction --- p.106 / Chapter 4.5 --- Discussions --- p.110 / Chapter Chapter 5 --- Summary and Prospects / Appendix / References