Chemistry - Theses, Dissertations, and other Required Graduate Degree Essays

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Synthesis of conformationally constrained inhibitors for glycoside hydrolases

Author: 
Date created: 
2019-09-10
Abstract: 

Glycoside hydrolase (GH) enzymes are clinically relevant biological targets for drug development. Disfunction of the two lysosomal GHs β-glucocerebrosidase and α-galactosidase can lead to Gaucher and Fabry’s disease, respectively. With knowledge of their mechanisms of action it is possible to create compounds that would effectively modulate their activity and potentially restore the activity of dysfunctional enzymes. Therefore, this work considers the approach to the synthesis of such compounds and determination of their mode of action. In the future, these compounds can be used for the development of drug candidates.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Andrew Bennet
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Development and evaluation of a library of thiazoline-sugar based inhibitors

Author: 
Date created: 
2017-04-20
Abstract: 

Thiazoline-sugar based inhibitors are known transition state analog inhibitors of N-acetylhexosaminidases that utilize a substrate assisted catalysis mechanism. Although selective inhibitors have been developed with modifications at the 2-OH and 6-OH positions, modifications at the 3-OH and 4-OH positions have not been explored. Many endo-N-acetylglucosaminidases that act on oligosaccharide or polysaccharide substrates comprised of monosaccharides glycosylated at the 4-OH position have fascinating roles in disease. A library of inhibitors were developed by selectively alkylating the 4-OH position of NAG-thiazoline and tested for inhibition against bacterial virulence factors Endo D, Auto, and FlgJ. These thiazoline based inhibitors were found ineffective in inhibiting Endo D and unsuited to the acidic pH profile of Auto and FlgJ. Hex D is a mammalian N¬-acetylgalactosaminidase that hydrolyzes O-GalNAc substrates. Although the mechanism and substrate selectivity of this enzyme is known, the exact biological substrates and functions of this enzyme are unknown. Gal-thiazoline is known to inhibit Hex D competitively (K¬I = 420 nM) and a recent co-crystal structure of Gal-thiazoline bound to Hex D showed a pocket near the 3-OH position of the inhibitor. To further study the physiological role of Hex D, more potent and selective inhibitors with modifications at the 3-OH position of Gal-thiazoline were synthesized and tested for inhibitory potential. Unfortunately, modifications at this position resulted in decreased inhibition. We hypothesize that the 3-OH position is responsible for a key hydrogen bonding interaction that is compromised upon alkylation.

Document type: 
Thesis
File(s): 
Senior supervisor: 
David Vocadlo
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Epitaxial growth of single crystal noble metals for plasmonic and nanophotonic applications

Date created: 
2019-01-17
Abstract: 

Material quality and crystallinity play an important role in the activity of plasmonic devices. Plasmonic structures made from monocrystalline metals may be expected to display much higher efficiency and stability than polycrystalline devices which are subject to many losses due to the presence of grain boundaries and defects. With the help of a novel epitaxial electroless deposition (EED) chemistry, ultrasmooth gold films can be grown on monocrystalline silver surfaces. In this approach, the electrochemical incompatibility of gold and silver can be overcome in concentrated sodium hydroxide (NaOH) solution (1 M), where the presence of OH⁻ causes a decrease in the reduction potential of gold cations by forming Au(OH)4⁻ complexes (E≈0.56 V), an increase in the oxidation potential of the silver electrode (E≈1.40 V), and acts as a reducing agent. As a result, ultrasmooth monocrystalline gold films are grown with the same crystalline orientation as the underlying silver film. This chemistry enables the growth of gold from a few monolayers up to few hundreds of nanometers uniformly over a large area. Furthermore, this approach enables the fabrication of large area metasurfaces made of gold and silver epitaxially grown nanostructures that can be used in a variety of different applications. The growth of gold films and nanostructures can also be manipulated by the introduction of anionic species during the deposition, and leads to the formation of surface nanostructures with specific shape, due to preferential interaction of the anions with certain facets of the growing crystalline structures. Subtractive fabrication of bowtie nanoantenna devices by focussed ion beam milling of gold films deposited by EED chemistry are compared to those deposited by conventional physical vapour deposition (PVD) methods using two-photon photoluminescence spectroscopy and imaging methods, employed as a proxy for plasmonic excitation. The monocrystalline EED gold films demonstrate excellent pattern transfer characterisitics, functional device yield, improved tailoring of local near fields, as well as increased thermal and mechanical stability compared to devices patterned identically on polycrystalline PVD films. Taken together, the work described in this thesis represents a novel and powerful new approach to the fabrication of monocrystalline noble metal films and nanostructures useful for plasmonic and metamaterial research and application.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dr. Gary W. Leach
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Elucidation of glycoside hydrolase mechanisms by measuring kinetic isotope effects using direct NMR method

Author: 
Date created: 
2018-12-12
Abstract: 

Enzymes that catalyze the removal of carbohydrate units from biological molecules are called glycoside hydrolases (GH). These enzymes have been categorized into more than 150 different families. This thesis presents an analysis of the mechanistic aspects of three glycoside hydrolases elucidated by measuring kinetic isotope effects (KIEs) by a direct nuclear magnetic resonance (NMR) spectroscopic method. A review of scope and limitations of the NMR method for competitive heavy atom (13C, 18O, 15N) and secondary deuterium KIEs measurement in biological systems is provided. A method for continuous monitoring of isotopically enriched materials is described in detail including the current state of instrumentation and computer programs for data acquisition and analysis. In order to refine the mechanistic understanding of the glycoside hydrolase family 4 (GH4) α-galactosidase from Citrobacter freundii (MelA), leaving group effects were measured with various metal cations and competitive deuterium KIEs were measured with singly and doubly deuterated activated substrates, 2-fluorophenyl and 4-fluorophenyl α-D-galactopyranosides, in the presence of Sr2+, Y3+, and Mn2+. The observations are consistent with hydride transfer at C-3 to the on-board NAD+, deprotonation at C-2, and a non-chemical step contributing to the virtual TS for V/K. The α-D-glucopyranosyl fluoride (α-GlcF) hydrolysis catalyzed by GH15 inverting α-glucoamylases from A. niger and Rhizopus sp. has been studied by use of multiple competitive kinetic isotope effect measurements. The experimental KIEs are consistent with the enzymatic reaction occurring via an SN1-type mechanism, in which the transition state has significant pyranosylium-ion like character and is late with respect to C−F bond cleavage. α-D-Glucopyranosyl fluoride is hydrolyzed by the family 55 inverting exo-1,3-β-glucanase from Trichoderma virens via the Hehre resynthesis–hydrolysis mechanism. The transition state for the Hehre resynthesis-hydrolysis mechanism for the GH55 catalyzed hydrolysis of α-GlcF has been studied by the use of multiple kinetic isotope effect measurements. The transition state for the Hehre resynthesis-hydrolysis reaction is late with respect to both C–F bond cleavage and proton transfer.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Andrew Bennet
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

On-site detection of total arsenic in water with DNA aptamer/CeO2 nanoconjugates on arrayed paper strips

Author: 
Date created: 
2019-07-04
Abstract: 

An on-site fluorometric method for the qualitative detection of major arsenic species, arsenite, As(III), and arsenate, As(V), in water is presented in this thesis. Both As(III) and As(V) are toxic ions that are found in drinking water or water effluents worldwide. Building upon DNA-capped metal oxide nanoparticles, it has been shown that both As(III) and As(V) can be quantitated with a paper-based fluorometric assay. In particular, fluorescently labelled DNA aptamers were first adsorbed onto CeO2 nanoparticles where the fluorescence was initially quenched. After the addition of either As(III) or As(V), the DNA strands were released from the surface due to strong and specific DNA (aptamer)-As(III/V)(ligand) interactions which resulted in fluorescence recovery. It was demonstrated that such a detection scheme can be realized on an arrayed paper substrate; glass fiber filter paper was first modified to be superhydrophobic and then patterned photochemically to create arrayed reaction sites. The signal readout is based on smartphone-imaging, i.e., analyze the RGB intensities of the assay photo taken under UV irradiation with a smartphone. These paper assays provided great performance for testing water samples containing As(III) and As(V), with detection limits of 29 nM and 38 nM, response ranges from 20 nM to 100 µM and from 10 nM to 100 µM, respectively. The satisfactory detection sensitivity (below the WHO standard, 80 nM), high selectivity, and wide response range augment the potential application of these paper-based fluorometric assays for on-site arsenic detection in water.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Hua-Zhong Yu
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Metalloporphyrins bearing a single proton relay or rhenium-diimines for electrochemical reduction of oxygen and carbon dioxide

Author: 
Date created: 
2019-04-15
Abstract: 

Electrochemical reduction of dioxygen (O2) and carbon dioxide (CO2) are two examples of redox reactions that have captured interest as renewable energy solutions. For example, fuel cell technologies demand improvement for reduction of O2 to H2O selectively at low energy costs. The basic requirements for transformations of O2 and CO2 are input of multiple protons (H+) and electrons (e–) (e.g., 4H+/4e– for O2 to H2O). The first half of this thesis focuses on the O2 reduction reaction (ORR) using heterogeneous catalytic platforms. The work starts from Fe-tetra(aryl)porphyrins, which are known ORR catalysts (producing H2O). However, they exhibit high overpotentials and poor stability, making them ill-suited for application. In comparison, heterogeneous Co-derivatives show ORR at lower overpotentials but make mostly H2O2. This is undesirable for fuel cell applications. Following an introduction to proton-coupled redox catalysis (Chapter 1), Chapter 2 presents my work on asymmetric Fe-porphyrin derivatives bearing a single pendant proton relay. Work on heterogeneous ORR shows improvement in catalytic stability on graphite electrodes without compromising selectivity. Chapter 3 shows that Co-derivatives are better catalysts than Fe analogs and use of asymmetric porphyrins shifts selectivity from production of H2O2 to H2O. The electrochemical CO2 reduction reaction (CO2RR) provides a route to turn a greenhouse gas into value-added products. The 2H+/2e– reduction of CO2 to CO is the central attention because CO could be used as a precursor to produce many products, including fuels. Benchmark Fe-porphyrins bearing up to 8 proton relays are known for homogeneous CO2RR. In Chapter 4, I show that an iron porphyrin with one proton relay at a meso-position can achieve a similar benchmark depending on the choice of solvent. Chapter 5 presents that these asymmetric metalloporphyrin derivatives are excellent heterogeneous CO2RR catalysts once immobilized on graphite surfaces, with activation of CO2 near the thermodynamic potential. Another family of CO2RR catalysts, based on ClRe(CO)3 fragments, is described in Chapter 6. Here, I show that Re complexes containing derivatives of 2,2’-pyridylimidazole reduce CO2 at rates that are competitive with state-of-the-art Re derivatives. Immobilization strategies for these Re-complexes onto electrodes are also proposed.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dr. Jeffrey J. Warren
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Study of 28Mg and 22Ne using fusion-evaporation and Doppler shift techniques

Date created: 
2019-04-25
Abstract: 

Investigations of nuclear structure via high precision measurements of energies and lifetimes of excited nuclear states has been the focus of an ongoing experimental program carried out at TRIUMF, Canada’s particle accelerator centre, using the TIGRESS Integrated Plunger (TIP) infrastructure. As part of this work, methods have been developed to determine energies and lifetimes of excited states in nuclei populated using the fusion-evaporation reaction mechanism and measured using the Doppler-shift attenuation method (DSAM). These methods include a comparison of experimental data to Monte-Carlo simulations in order to determine lifetimes of observed states. Methods were validated using data collected for the benchmark nucleus 22Ne at the ISAC-II facility at TRIUMF. Additionally, an array of 128 CsI(Tl) charged particle detectors has been constructed at Simon Fraser University. This new ‘CsI ball’ array replaces a 24-detector array used in previous TIP experiments and offers improved charged particle detection efficiency due to its increased solid angle coverage (nearly 4π in the lab frame). A subset of the CsI ball array was used to study excited states of 28Mg in an experiment at ISAC-II/TRIUMF, with the goal of investigating the evolution of nuclear shells and searching for evidence of the lowering in energy of pf negative parity orbitals predicted in this region. For the first time 28Mg was investigated using a fusion-evaporation reaction, leading to preferential population of states at high spin and excitation energy where the influence of the pf negative parity orbitals is expected. Analysis methods developed for 22Ne were applied to the 28Mg DSAM data to extract lifetimes of observed states. 3 new excited states of 28Mg were identified. Multiple candidates for negative parity states were also observed, providing an explicit indication of pf negative parity orbital population. Underlying principles and theories of nuclear structure, a technical overview of the CsI ball array and other TIP infrastructure, along with results from the 22Ne, CsI ball commissioning, and 28Mg experiments are presented. A comparison of the data to the predictions of various theoretical models is shown and implications for the structure of 28Mg are discussed.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Krzysztof Starosta
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

In-situ infrared spectroscopy of organic electrochemical devices

Author: 
Date created: 
2019-04-15
Abstract: 

Organic electrochemical transistors (OECTs) offer low voltage operation and a feasible platform for flexible, large-area, and low-cost devices, especially in the context of printed electronics. However, these devices often suffer from sluggish performance as a result of ion intercalation into the bulk of the organic semiconductor. We have characterized the time dependent behaviour of OECTs based on poly(3-hexylthiophene) (P3HT) and a poly(ethylene oxide): lithium perchlorate (PEO:LiClO4) gate dielectric using in-situ infrared spectroscopy. Because charge carriers in P3HT have a characteristic absorption in the mid infrared, we can monitor the rate of device charging and discharging spectroscopically. The dependence of the charging rate on parameters such as channel length, semiconducting polymer thickness and dielectric thickness have been investigated. Our results indicate that several distinct mechanisms are at play, with the rate limiting step being determined by device geometry. Using these results, we have also examined the effect of the structure of the counter-ion on its diffusivity in the organic semiconductor once doping occurs.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Loren Kaake
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Statistical physics-based modeling and simulation of chemical and mechanical degradation in lithium ion batteries

Author: 
Date created: 
2019-04-09
Abstract: 

Lithium ion batteries undergo chemical and mechanical degradation during operation. The main chemical degradation mechanism is the growth of the solid electrolyte interphase (SEI) in the negative electrode of lithium ion batteries. The growth of the SEI layer causes a loss of lithium ions that induces capacity fade. In addition, it increases the ion transport resistance and decreases the total porosity. Mechanical degradation includes nucleation of nano-cracks and their growth caused by the impact of diffusion- induced stress during Li-ion intercalation. Particle agglomeration and breakage are other mechanical effects that contribute to morphological changes. This thesis presents a physical-statistical model of chemical and mechanical degradations in the negative electrode of lithium ion batteries. The model employs a population balance formalism based on the Fokker-Planck equation to describe the propagation of the particle density distribution function in the electrode. Structure-transforming processes at the level of individual particles are accounted for by using a set of kinetic and transport equations. These processes alter the particle density distribution function, and cause changes in battery performance. The population balance model is integrated into porous electrode theory to study the temporal evolution of the particle density across the electrode thickness. A parametric study of the model singles out the first moment of the initial SEI thickness distribution as the determining factor in predicting the capacity fade due to chemical degradation. Another parametric study reveals the population of small particles and the width of the initial particle size distribution as the main parameters that determine changes in electrochemical performance and capacity fade due to chemical and mechanical degradation. The model-based treatment of experimental data allows analyzing processes that control SEI growth, crack growth, particle breakage, and particle agglomeration and extracting their controlling parameters. The model is applied to experimental data in order to isolate and quantify the impact of different degradation mechanisms.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Michael Eikerling
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Spectroscopy and mechanisms of redox-active copper-based anticancer complexes

Author: 
Date created: 
2019-04-17
Abstract: 

Copper complexes are increasingly gaining prominence as potential anticancer agents. However, an ongoing challenge to their continued development is characterization of their fundamental behaviours in physiological environments and their mechanisms of action. This work has addressed these issues through: i) development of new Cu(II) anticancer candidates with functional ligand architectures, ii) implementation of novel spectroscopic approaches to characterize the biochemical behaviour of these compounds, and iii) correlation of these approaches with biological studies to develop structure-activity relationships. The complexes developed in these studies include benzimidazole and Schiff-base ligand scaffolds, with systematic derivatization to modify properties such as lipophilicity and reduction potentials. A particular focus was given to tuning the electronics of the Cu(II) compounds to examine their suitability as hypoxia (lower oxygen level) targeting metallodrugs. To determine the biologically active species, ligand exchange processes and interactions with biological molecules were characterized using magnetic resonance methods. The interactions of Cu(II) compounds with serum proteins, important for in vivo transport following administration, were studied using both frozen-solution and room-temperature electron paramagnetic resonance (EPR) experiments. For a series of hypoxia targeting fluorinated Cu(II) theranostic (therapeutic + diagnostic) compounds, 19F nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) were employed to characterize the oxidized and reduced species, and novel NMR experiments demonstrated selective accumulation of a copper species in hypoxic cellular nuclei. Given the nuclear accumulation, the ability of Cu(II) compounds to interact with and cleave DNA through the generation of reactive oxygen species (ROS) was determined using both spectroscopic and molecular biology techniques. In a final study, non-conventional NMR methods were employed to characterize the interactions of a hydrophobic, first-in-class, chemotherapeutic with metal ions. Experiments utilizing both paramagnetic Cu(II) and diamagnetic Zn(II) ions facilitated the assignment of the coordination of the therapeutic to the metal ions. These results explained how the metal-ion interactions promoted increased aqueous solubility, a desirable property for further clinical development.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Charles Walsby
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.