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

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Development of tools and methods for studying glycan processing proteins in living systems

Date created: 
2016-05-12
Abstract: 

Carbohydrates are a class of biomolecules present in all domains of life that provide energy for cellular processes, afford structural support, and take part in molecular recognition and signalling. Given the ubiquity of carbohydrates in living systems, gaining an improved understanding of the proteins that process them – glycosyl transferases, glycoside hydrolases, lectins, and sugar transporters – is of key interest. Compared to in vitro assays, few live-cell or in vivo assays of carbohydrate-processing proteins have been developed, despite the wealth of knowledge that they provide. This discrepancy is largely due to the difficulties associated with live-cell and in vivo examination of protein function, namely issues of substrate selectivity, sensitivity, reactivity, and cell permeability. This thesis aims to develop substrates and methods to study two carbohydrate-processing proteins: human O-GlcNAcase, a glycoside hydrolase involved in Alzheimer’s disease, cancer, and the stabilization of nascent proteins; and bacterial AmpG, a sugar transporter implicated in β-lactam antibiotic resistance. In doing so, I hope to not only provide insight into the function of these proteins, but to also lay a foundation for live-cell or in vivo study of these and related proteins in the years to come.

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

Design and synthesis of a photoaffinity labelling analogue of ivacaftor to probe its putative binding site on mutant CFTR

Date created: 
2017-03-06
Abstract: 

The cystic fibrosis (CF) therapeutic, ivacaftor, restores activity to certain cystic fibrosis transmembrane regulating protein (CFTR) mutations; however, the nature of ivacaftor's interaction with mutant CFTR is still under investigation. This study aimed to generate photoaffinity labelling (PAL) probes that will be used to elucidate putative ivacaftor binding sites on mutant CFTR. Structure activity relationship studies indicated retention of ivacaftor's potentiating activity despite deletion of either of the t-butyl groups from the ivacaftor structure. These results initiated a synthesis program to prepare PAL probes incorporating a carbene-generating diazirine moiety in place of a t-butyl group on the ivacaftor scaffold. Initial synthetic approaches towards creating the diazirine PAL probe were devised with the ability to afford diversification at a late stage in the synthesis to allow incorporation of reporter tags into the PAL probe. While these approaches were unsuccessful, ultimately a linear synthetic approach successfully afforded the target diazirine PAL probe.

Document type: 
Thesis
Senior supervisor: 
Robert Young
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Growth and Characterization of Lead Zirconate-Titanate (PbZr1-xTixO3)-Based Novel Piezo-/Ferroelectric Single Crystals

Author: 
Date created: 
2016-04-18
Abstract: 

Piezo-/ferroelectric materials form an important class of functional materials that can transduce mechanical energy to electrical energy and vice versa. PbZr1-xTixO3 (PZT) ceramics are the most extensively used piezoelectric materials owing to their good piezoelectric and electromechanical properties near the morphotropic phase boundary (MPB). However, the microstructures of this class of materials and the atomistic phenomena that cause the outstanding performance have not been thoroughly understood yet. Therefore, it is of particular interest to grow single crystals of PZT, which are not only necessary for thorough characterization of the anisotropic properties of this system, but also are expected to exhibit superior piezo-/ferroelectric performance over their ceramic counterparts. In this work, PZT single crystals with compositions of x = 0.54 and 0.45 were grown successfully by a top-seeded solution growth (TSSG) method, and characterized by X-ray diffraction, polarized light microscopy (PLM), piezoresponse force microscopy (PFM), and dielectric, ferroelectric, and piezoelectric measurements. On the other hand, given that PZT ceramics used in industry are always chemically modified to obtain desired and enhanced properties for specific applications, we extended our work to grow donor (La3+ and Bi3+)- and acceptor (Mg2+ and Mn2+)-doped PZT single crystals and to investigate the effects of the doping on the structure and properties. The compositions and homogeneity of the as-grown doped PZT single crystals were investigated by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and energy dispersive spectroscopy (EDS). The dielectric, ferroelectric and piezoelectric properties of these single crystals were investigated. These very first set of data on doped PZT single crystals not only provide a better understanding of structure-property relationship of PZT-based single crystals and their doping mechanisms, but also points to the possible applications of doped PZT single crystals as a new high-TC, high-performance piezo-/ferroelectric material. Moreover, there have been pressing demands for lead-free or lead-reduced replacement materials because of the environment concerns arising from the potential toxicity of the lead in high-performance piezo-/ferroelectric material such as PZT. In our search for high-temperature, lead-reduced piezoelectric materials, novel ferroelectric single crystals of complex perovskite ternary solid solution Bi(Zn0.5Ti0.5)O3-PbZrO3-PbTiO3 (BZT-PZ-PT) have been grown for the first time. The structure and properties of these crytals suggest that the BZT-PZ-PT ternary single crystals constitute a new family of high-TC ferroelectric materials, which are promising for various applications such as high-power electromechanical transducers that can operate in a wide temperature range.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Zuo-Guang Ye
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

The investigation of the beta decay of 46K: Detailed spectroscopy of the low-lying structure of 46Ca with the GRIFFIN Spectrometer

Date created: 
2016-11-25
Abstract: 

The calcium region is currently a new frontier for modern shell model calculations, and detailed experimental data from these nuclei is critical for a comprehensive understanding of the region.Due to its very low natural abundance of 0.004%, the structure of the magic nucleus 46Ca has not been studied in great detail. Some excited states were previously identified by various reaction mechanisms, and few gamma rays were placed in the level scheme from results of beta-decay experiments equipped with limited detection capabilities. A high-statistics data set of the beta decay of the 46K 2- ground state into the excited states of 46Ca was measured with the GRIFFIN spectrometer located at TRIUMF-ISAC in December of 2014. A radioactive beam consisting almost entirely of 46K was implanted at the center of the GRIFFIN array, and the emitted gamma rays were detected by 15 high-purity germanium clover detectors. From forty hours of data collection, 430 million gamma-gamma coincidences were observed and analysed to construct the 46Ca level scheme. In total, 194 gamma rays were identified and placed into the level scheme; 150 of these transitions were observed for the first time. Angular correlations between pairs of gamma rays were analysed to investigate the spin assignments of the observed excited states. Correlations were investigated for 18 of the 42 observed excited states, and it was possible to confirm 7 previously reported spin assignments, and assign 3 new spins of 3-, 2-, and 3- for the 4435, 5052, and 5535 keV states, respectively. The measured half-life of the 96.41(10) s is in agreement with previous results. From the observed beta feeding intensities of this work, it is suggested that the 46K 2- ground state may contain more proton s1/2 character than has been previously believed. This is due to the strong population of the 5052 keV 2$^-$ state and the absence of observed feeding to the 46Ca ground state.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Corina Andreoiu
Department: 
Science: Department of Chemistry
Thesis type: 
(Dissertation) Ph.D.

Oxidation of 3-Chloroindole and Biodegradation of Dialkoxybenzenes with Cytochrome P450cam (CYP101A1)

Author: 
Date created: 
2016-12-06
Abstract: 

Cytochrome P450cam (a camphor hydroxylase) isolated from soil bacterium Pseudomonas putida shows potent importance in environmental applications such as the degradation of chlorinated organic pollutants and insect control agents. Introducing such chemicals can be hazardous to the environment due to their lack of biodegradation. In this thesis, I have studied the role of several P450cam mutants in the oxidation of 3-chloroindole to isatin and the role of wild type P450cam in the dealkylation of 1,4-dibutoxybenzene, a potent feeding-deterrent against stored product pests. Mutant (E156G/V247F/V253G/F256S) was the most active in the conversion of 3-chloroindole by P450cam. We propose two mechanisms for the dechlorination of 3-chloroindole by P450cam. To investigate structure-activity patterns of 1,4-dialkoxybenzenes against beetles, the octanol-water partition coefficients of selected dialkoxybenzenes were investigated. Furthermore, P. putida strain ATCC17453 was able to metabolize 1,4-dibutoxybenzene. Results revealed that cytochrome P450cam catalyzed the first and second dealkylation steps in the biodegradation mechanism.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dr. Erika Plettner
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Mechanisms of new Ru-ferrocene and binuclear Ru metallochemotherapeutics and the Ru metastasis inhibitor NAMI-A

Author: 
Date created: 
2016-11-14
Abstract: 

Ruthenium-based anticancer compounds have become a leading area of development in medicinal chemistry. Ru(III) complexes, such as the antimetastatic compound imidazolium [trans-RuCl4(1H-imidazole)(DMSO-S)] (NAMI-A), where DMSO = dimethyl sulfoxide, have shown promising results in clinical trials. Furthermore, reports of organometallic Ru(II) arene complexes, such as [RuCl2(η6-p-cymene)(pta)] (RAPTA-C), where pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.13,7]decane, demonstrate that these types of compounds also have excellent chemotherapeutic potential. In this work, three families of new bimetallic drug candidates based on these types of Ru anticancer compounds have been developed, with the goal of generating multifunctional complexes with new biological activities. The first type of complex is ferrocene-functionalized pyridine analogues of NAMI-A. Inclusion of ferrocene generates bifunctional complexes with cytotoxicity from the ferrocene groups and antimetastatic activity from the Ru center. The second family of complexes described in this work is analogues of RAPTA-C with the pta ligand replaced with ferrocene-functionalized pyridine, imidazole, and piperidine ligands. These compounds have strong anticancer and antibiotic activities, which correlate quantitatively with the reduction potential of the ferrocene centers, implicating generation of reactive oxygen species as the origin of activity. The third family of complexes, asymmetric bimetallic complexes comprised of a Ru(III) NAMI-A-type center coupled to Ru(III) DNA intercalating groups via pyrimidine, have been synthesized. Functionalization with dipyrido[3,2-a:2’, 3’-c]phenazine (dppz) in particular led to strong DNA interactions and high cytotoxic activity. In this work, electron paramagnetic resonance (EPR) and NMR have been used to study the ligand-exchange processes of the complexes and their interactions with proteins. In particular, NMR was used to investigate the complicated solution behavior of NAMI-A. Furthermore, NMR studies of the complex with human serum albumin and human serum transferrin indicate non-specific coordination to histidine residues and changes in ligand exchange kinetics due to protein interactions.

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

Physical modeling of water fluxes in the catalyst layers of polymer electrolyte fuel cells

Author: 
Date created: 
2016-12-02
Abstract: 

The ability to predict the electrochemical performance of the catalyst layer (CL) in polymer electrolyte fuel cells (PEFCs) hinges on a precise knowledge of the water balance. The key effective properties of this layer, like gas diffusivity and vaporization exchange rate constant, control water distribution and fluxes in the complete cell. Unfortunately, the knowledge of relevant properties of CLs is rare and not available with sufficient accuracy. A physical model of water fluxes in CLs is proposed to develop a methodology for the determination of the effective properties of CLs. For the purpose of this work, the CL is considered exclusively as a medium for vapor diffusion, liquid water permeation, and vaporization exchange. The presented model exploits an analogy of the water transport problem to the processes involved in charge transfer in a porous electrode, which is represented by the famous transmission line model (TLM). The expectation is that this analogy could lead to a diagnostic tool with similar capabilities as electrochemical impedance spectroscopy (EIS) in rationalizing the response of CLs to varying conditions and in extracting parameters of water transport and vaporization exchange. An analytical solution under steady state and isothermal conditions is presented that rationalizes the relation between controlled environmental conditions and the net water flux under partial saturation. The analysis of water flux data using this solution provides a method for the extraction of the net vaporization exchange rate, the activation energy of vaporization, vapor diffusivity, and the temperature exponent of the vapor diffusivity, which allows the transport mechanism of vapor diffusion in the CL to be identified. Transient analysis with a periodic perturbation is then explored. The overall impedance of water transport and the response function of a voltage change to a vapor change are analyzed for a specific scenario, where no effluence of liquid water from the CL is permitted. The methodology based on the transient analysis provides not only a way to extracting the effective properties of the CL, but also a way to estimate the liquid saturation in the CL.

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

Synthetic design and development of sterically-protected hydroxide-conducting polymers for energy conversion devices

Date created: 
2016-10-06
Abstract: 

The production of renewable energy conversion devices is crucial in reducing greenhouse gas emissions and sustaining the energy required for future generations. However, most energy conversion devices currently available have high costs, which greatly slow down any transition from non-renewable combustion devices. The most promising low-cost, renewable energy conversion devices are based on anion-conducting membranes, such as those found in hydrogen fuel cells, water electrolyzers, redox flow batteries, and electrodialysis. Unfortunately, the current lifetime of such devices is too short for wide-spread adoption. The main issue is the instability of the alkaline anion exchange membrane towards caustic hydroxide. While a significant amount of research has been on demonstrating materials that have longer lifetimes, little work has been concentrated on investigating the degradation pathways on small molecule model compounds. By understanding the chemistry behind their weakness, materials can be specifically designed to counter such pathways. This then leads towards specifically designed polymers with high endurance. The development towards permanently-stable, alkaline anion exchange membranes is the focus of this thesis. Throughout this thesis, new model compounds are developed and extensively characterized. Using new stability tests, the degradation pathways are identified and the stability is quantitatively compared. Novel polymers are then prepared, which are designed to mimic the highest stability small molecule compounds. Steric hindrance is found to be the most promising method towards durable cationic polymers. From Chapter 2 to Chapter 5, the prepared materials become more and more resistant to hydroxide, demonstrating development in the correct direction.

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

Calculation of rates for radioactive isotope beam production at TRIUMF

Author: 
Date created: 
2016-11-15
Abstract: 

Access to new and rare radioactive isotopes is imperative for establishing fundamental knowledge and for its application in nuclear science. Rare Isotope Beam (RIB) facilities around the world, such as TRIUMF, work towards development of new target materials to generate increasingly exotic species, which are used in nuclear medicine, astrophysics and fundamental physics studies. At Simon Fraser University and TRIUMF, a computer simulation of the RIB targets used at the Isotope Separation and ACceleration (ISAC) facility of TRIUMF was built, to compliment existing knowledge and to support new target material development. The simulation was built using the GEANT4 nuclear transport toolkit, and can simulate the production rate of isotopes from user-defined beam and target characteristics. The simulation models the bombardment of a production target by an incident high-energy particle beam and calculates isotope production rates via fission, fragmentation and spallation. In-target production rates from the simulation were analysed and compared to production mechanisms within the simulation environment, other nuclear transport algorithms and to the experimentally measured yield rates from the ISAC yield station. Additionally, preliminary studies were conducted using these in-target production rates as illustrative examples, showing the capabilities and power of the simulation.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Corina Andreoiu
Peter Kunz
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

A microfluidic antibody bioarray for detection of human interleukins

Date created: 
2016-12-16
Abstract: 

The purpose of the present work is to investigate the factors affecting antibody immobilization, and antibody-antigen interactions on a microfluidic chip. The results of this study will be utilized for the development of a microfluidic antibody bioarray for detection of two target proteins. Two interleukins of diagnostic value have been selected: Interleukin-6 (IL-6), and Interleukin-2 (IL-2). The micromosaic array is used for detection of IL-2 and IL-6 on a microfluidic chip. This method is used to optimize a variety of factors that affect antibody immobilization on the surface of a microfluidic chip, as well as bioarray conditions for enhancement of signals. Surface Plasmon Resonance (SPR) spectroscopy is used to obtain the association and dissociation rate constants for antibody-antigen binding in this work.

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