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

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Upgraded resolution and enhanced sensitivity of optical disc-based bioassays: from CD to BD

Date created: 
2016-08-03
Abstract: 

Conventional biomedical diagnosis and chemical analysis are performed by trained professionals in centralized laboratories using specialized instrumentation. Our group has been working on the development of optical disc technology-based molecular detection platforms for on-site chemical analysis and point-of-care diagnosis for the past 15 years. In particular, computer-readable assays on compact discs (CDs) have been demonstrated for the quantitation of various target analytes, such as DNA, proteins, and metal ions. In this thesis, two more advanced disc formats, digital versatile disc (DVD) and Blu-ray disc (BD) have been adapted to improve the assay resolution and detection sensitivity. The DVD assay for quantitative analysis of human chorionic gonadotropin is described first. A multiplex assay-on-a-BD system for the detection of a set of key cardiac markers is then explained in detail. Beyond a different error correction protocol, a new surface activation method has been established for the immobilization of probe molecules on the surface coating of BD-Rs. In addition to the upgraded lateral resolution, the sensitivity of the BD-based bioassays is significantly improved in comparison with those prepared on CDs and DVDs, which is comparable to the well-established enzyme-linked immunosorbent assay (ELISA).

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

Studies Toward the Total Synthesis of Tetrahydrofuran-Containing Natural Products

Author: 
Date created: 
2016-07-14
Abstract: 

Natural products have played a significant role as leads and inspiration for many novel therapeutics. Among the most common structural fragments found in biologically active natural products is the tetrahydrofuran, a five membered oxygen-containing heterocycle. As oftentimes very little natural product is available from the producing organism, there has been a longstanding interest in the development of efficient and general synthetic methods to access tetrahydrofurans and tetrahydrofuran-containing natural products. This thesis summarizes recent efforts directed towards the total synthesis of amphirionin-4 and biselide A, two tetrahydrofuran-containing natural products with potentially useful biological activities. Amphirionin-4 is a polyketide isolated from Amphidinium sp. dinoflagellates, and has demonstrated potent proliferation activity in ST-2 stem cells. Biselide A is a marine macrolide isolated from the Okinawan ascidian Didemnidae sp., and has demonstrated potent cytotoxicity towards a variety of human cancer cell lines. Notably, the unifying element in our synthetic approaches to both of these natural products is a reliance on chlorohydrin-based strategies to access the tetrahydrofuran cores in an efficient, diastereoselective and enantioselective manner.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Robert A. Britton
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Preparation and applications of perfluoroalkoxides bearing α-fluorines

Date created: 
2016-04-27
Abstract: 

Partially fluorinated ethers, known as hydrofluoroethers, have been introduced as inert replacements of chlorofluorocarbons and predominately find use as refrigerants and solvents. However, these materials are not inert as purported but readily methylate Group 15 nucleophiles. Not only are hydrofluoroethers reactive, when the reaction is performed under a moisture-free environment, the sole reaction products from the interaction of tertiary amines are quaternary ammonium perfluoroalkoxides bearing α-fluorines. This general route allows for the single-step synthesis of a highly under-represented organofluorine functional group from commercially available reagents negating the use of air-sensitive reagents, anhydrous fluorides, and often highly toxic, expensive precursors. Hence, 30 new perfluoroalkoxides have been prepared from a series of methoxy hydrofluoroethers from CH3OCF3 through to CH3OC4F9 including clinical inhalation anaesthetic methoxyflurane. The products were isolated in 9-99% yield with product conversions commensurate with increasing length of the fluorinated segment of the hydrofluoroether in the presence of sterically unhindered, nucleophilic tertiary amines. Thermal analysis of isolated tetramethylammonium perfluoropropoxides and butoxides indicated stability to 150 degree Celsius before partially decomposing under vacuum at 180 degree Celsius to NMe3 and CH3F as evidenced by thermogravimetric analysis. In two divergent studies, a series of experiments were devised to develop a functional group tolerant protocol for the trifluoromethoxylation of arenes, a current and largely unsolved synthetic problem. A wide range of strategies towards C(aryl)–OCF3 bond formation were attempted using the prepared tetraalkylammonium trifluoromethoxides including both metal and non-metal-mediated protocols. By considering traditional cross-coupling methods with state-of-the-art Ni0-NiII, Pd0-PdII, CuI-CuIII, AgI-AgII, and AuI-AuIII manifolds, it was determined that β-fluorination of aryl precursors from the coordinated OCF3 ligand outcompetes C-O bond formation at temperatures necessary for reductive elimination. The poor nucleophilicity, high moisture sensitivity, and propensity for β-fluoride elimination from -OCF3 precluded its use as a general synthetic building block for many metal-mediated cross-couplings. In a second study, the efficacy of the ostensibly fluoride-free tetraalkylammonium perfluoroalkoxides were tested as initiators for the anionic ring-opening polymerization of the perfluorooxirane monomer, hexafluoropropylene oxide (HFPO). While these perfluoroalkoxides did not outperform the industry optimized CsF/tetraglyme conditions, it was demonstrated that tetraalkylammonium perfluoroalkoxides can successfully ring-open HFPO, provide a direct study of the cation, and a means to measure chain transfer while providing oligomers with DPn = 1-3. The inoperative chain transfer process is likely a multi-faceted problem involving physical properties of the polymerization process. For instance, the phase-transfer mechanism and solvent choice play a critical role in propagation of polymeric based perfluoroalkoxides. Initial synthetic efforts were undertaken to design oligio(HFPO) terminated ethylene glycol surfactants or soluble oligio(HPFO) hydrofluoroethers to overcome the need for polar organic solvents required to dissolve the ionic initiators.

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

Copper catalysed formation of copper chelators: A new approach to the treatment of Wilson’s disease

Date created: 
2016-01-05
Abstract: 

Wilson’s disease is characterized by an increased concentration of copper in the liver, which damages liver tissue and eventually leads to neurological impairment. This disease affects an estimated 1/30,000 people worldwide. Current treatments for this disease can have severe side-effects, including neurological problems in approximately 20-50 % of the patients. The goal of this thesis is to develop compounds that will strongly bind to copper to remove it from the liver. The mechanism for selectivity in binding copper over other endogenous metals (e.g, zinc and iron) is to utilize copper-activated alkyne-azide cycloaddition to couple two moderate binding moieties to form a ligand with a much greater metal-binding affinity. The HepG2 cell line was used as an in vitro model for Wilson’s disease. A methodology to evaluate the efficacy of chelators to remove copper from the cell model was developed, and tested with a series of new copper chelating compounds.

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

Co(III) Complexes as Pro-drugs for Cancer Therapy

Author: 
Date created: 
2016-05-13
Abstract: 

Cancer is the leading cause of death in Canada and is characterized by irregular and uncontrolled cell growth. In many cases this uncontrolled cell growth results in a solid mass of cells called a tumor. When the inner part of a tumor is sequestered from blood vessels, the nutrient and oxygen levels decrease. The term “hypoxia” is used to describe low oxygen level in tissue. Hypoxia induces more reducing conditions in a tumor in comparison to normal tissue. The objective of this project was to generate a series of octahedral Co(III) complexes for the treatment of cancer. We designed pro-drugs that are initially administered to the body in an inactive form, and can be selectively activated under the hypoxic (reducing) conditions in tumors. In this work, a series of octahedral Co(III) salen complexes were synthesized incorporating 1-methylimidazole in axial positions. We investigated the stability of the complexes in solution, and the effect of different para-ring substituents on the Co(III) / Co(II) reduction potential. We concluded that the reduction potentials of the complexes were correlated with the electron donating ability of the para-ring substituents, and that a geometry change from octahedral to square-planar upon reduction leads to axial ligand release. Building on these results, coumarin fluorophores were then attached to the Co(III) complexes via a functionalized imidazole. We found that the fluorescence of the coumarin was largely quenched while bound to the Co(III) center. Ligand release was then studied in the presence of excess competing ligands and in the presence of a reducing agent. Our results suggest that both ligand exchange and reduction play a role in axial ligand release in these systems.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Tim Storr
Charles Walsby
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Synthesis and evaluation of novel carbocyclic carbohydrate analogues

Date created: 
2016-04-15
Abstract: 

Carbohydrate analogues play an indispensible role in the study of glycan processing enzymes. These compounds have attracted attention as probes of enzyme mechanisms, as chemical tools for the elucidation of enzyme function and as potential pharmaceuticals. The development of organocatalytic aldol chemistry has fundamentally altered the way chemists approach the synthesis of carbohydrate analogues. In this thesis I highlight a novel strategy toward the synthesis of carbocyclic carbohydrate analogues which utilizes a proline-catalyzed aldol reaction and a metal-catalyzed carbocyclization as key steps. This strategy was successfully implemented in the synthesis of an ensemble of galactose and N-acetylgalactosamine analogues. Furthermore, I present preliminary results toward the biological evaluation of these compounds.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Robert A. Britton
Andrew J Bennett
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

The Photochromism of a Diester Linked Bisanthracene

Author: 
Date created: 
2016-04-15
Abstract: 

A bisanthracene diester was synthesized in an effort to increase the rate of the anthracene photochemical dimerization. Preliminary reactions of the bisanthracene resulted in the formation of an intramolecular product that cyclizes across the 9, 10, 1’, 4’-position of the anthracenes. This results in an unsymmetrical dianthracene that possesses an isolated alkene group. The research in this thesis describes the photochromic properties of the bisanthracene, as well as studies into the reactivity of the isolated alkene. Different photochromic properties of the bisanthracene were investigated. The optimized conditions were found using a dilute solution in benzene while selectively exciting the bisanthracene. The addition of a peroxycarboxylic acid to the photoproduct resulted in the formation of an epoxide, which caused the intramolecular product to become more photochemically and thermally stable. This resulted in a locked state. Attempts to unlock this system by removal of the epoxide resulted in only low yields of the bisanthracene, but does represent a preliminary gated system for anthracene photochemical reaction.

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

Development of an in vitro method to study heterogeneous particle mimic exposures

Date created: 
2016-04-12
Abstract: 

Particulate matter, a heterogeneous mixture of solid and liquid particles suspended in the atmosphere, has been strongly linked to several respiratory diseases and cardiovascular disease. Due to its impact on human health, epidemiological, in vivo, and in vitro studies are used to assess toxicity of diverse types of particulate matter, and mechanisms behind disease pathogenesis. To enable insight on how particle composition affects cellular response, an in vitro dose-response apparatus and methodology were developed to deliver heterogeneous particles of controlled compositions onto human lung cell mono- and co-cultures. Silica particles, an ambient particle type sourced from crustal matter, were generated using the apparatus and were delivered onto cultures of alveolar epithelial cells (A549) up to an estimated 3.2 µg cm-2. No change was observed in membrane bound protein intercellular adhesion molecule-1 (ICAM-1) expression. In a proof of concept study, tumor necrosis factor (TNF)-α, a potent cytokine, was introduced as a secondary component to silica. This binary particle type was also delivered onto A549 monocultures, and ICAM-1 signal increased with an increase in dose. Silica particles were also delivered onto co-cultures containing A549 cells and macrophages differentiated from blood monocyte cells (THP-1). Cytokine interleukin (IL)-6 was significantly up-regulated in co-cultures, but IL-8 was not. Lipopolysaccharide (LPS), a component of the cell wall in Gram negative bacteria, and nickel, in the form of Ni(NO3)2·6H2O, were introduced as secondary components to silica. These binary particle types were generated at ratios representative of respirable agricultural soils and dosed onto co-cultures. It was observed that silica plus LPS particles caused an up-regulation of IL-6 and IL-8 response relative to silica particles, whereas silica plus nickel particles did not. LPS bioavailability was determined as 10±3% and 1.0±0.6% for silica plus LPS particles at atmospherically-relevant LPS to silica mass ratios of 91 ppm and 910 ppm, respectively. The reduction in bioavailability showed how interactions between compositions in a heterogeneous particle type can affect cellular response.

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

Investigations into O-GlcNAcylation through analytical mass spectrometry

Author: 
Date created: 
2014-12-17
Abstract: 

The modification of proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) is found on many proteins in the nucleus and cytoplasm. O-GlcNAc has been implicated in many physiological processes but much remains to be learned about the effects of this modification on protein function. In this thesis I detail two studies aimed to improve our understanding of protein modification by O-GlcNAc. First, I describe a bioinformatics study focused on uncovering the protein structural features that favour O-GlcNAcylation by the enzyme O-GlcNAc transferase. The search for a sequence or structural motif to be found amongst the many substrates O-GlcNAcylated by OGT is a path well-trodden. On the basis of our analysis of site mapping data accumulated from the literature and also through targeted site mapping of an entirely intrinsically disordered protein by mass spectrometry, I counter argue that OGT preferentially targets substrates which can be intrinsically disordered.Second, I describe a study aimed to gain insight into cellular proteomic response due to lowering of O-GlcNAc levels. There is mounting evidence O-GlcNAcylation is both linked with protein folding and intracellular proteome stability. While stability is measured by turnover it is also tied to misfolding. We investigated a possible relationship between lowered O-GlcNAc levels and instability of a segment of the proteome using stable isotope labelling by amino acids in cell culture mass spectrometry.

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

New approaches to remediation of nanoscale contaminants in the workplace

Date created: 
2014-12-15
Abstract: 

It is important that all workers understand the health and safety risks of their work environment. It has been demonstrated that exposure to nanoparticles can lead to potential health concerns. A 1 mL nanoparticle solution spill can contain >10^9 nanoparticles, with the particles invisible to the human eye. This nanoparticle spill can cause further contamination in the work environment as workers transfer the particles from one area to another if the nanoparticles are not properly remediated. Therefore, it is essential that effective methods be developed for early identification and clean-up of such spills to avoid potential hazards to those working with these particles. One goal of this research is to develop a methodology that is simple to implement on a global scale to rapidly detect the presence of nanoparticles in different workplace environments to accompany methods for the remediation of spills containing nanoparticles. X-ray fluorescence spectroscopy was identified as a portable solution to potentially identify the presence of and the extent of a spill containing nanoparticles. Many other techniques could also be utilized, but the ease of use at the point of contamination without the requirement of sample preparation makes this an attractive solution in nanoparticle remediation. Another goal of this research is to develop an efficient, effective and inexpensive means to remediate spills containing nanoparticle contaminants. The implementation of these remediation procedures would change how nanoparticles are treated in the workplace and promote a healthy work environment when using materials that would otherwise go unnoticed due to their small size. Remediation of nanoparticles spilled in the workplace requires a method of acknowledging that these unseen particles are appropriately being removed and to avoid spreading these particles to a wider extent throughout the workplace. Analytical techniques were used to monitor the presence of nanoparticle contaminants and, in combination with techniques to encapsulate nanomaterials within a spill, were used to assess the appropriateness of these remediation techniques for cleaning up simulated spills. These studies demonstrate a series of methods to progressively remove nanoparticle contamination from countertops in the workplace.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Byron D. Gates
Department: 
Science: Chemistry
Thesis type: 
(Thesis) M.Sc.