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

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Modification of amyloid-beta peptide aggregation via photoactivation of Ru(II) polypyridyl complexes

Date created: 
2020-07-28
Abstract: 

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by progressive and irreversible damage to the brain. One of the hallmarks of the disease is the presence of both soluble and insoluble aggregates of the amyloid beta (Ab) peptide in the brain. In this work we investigate how photoactivation of three Ru(II) polypyridyl complexes [Ru(6,6’-dimethyl-2,2’-dipyridyl)2(2-thiophen-2-yl-1H-imidazo(4,5-f) (1,10)phenanthroline)] (Ru1), [Ru(6,6’-dimethyl-2,2’-dipyridyl)2(2-phenyl-1H-imidazo (4,5-f)(1,10)phenanthroline)] (Ru2), and [Ru(6,6’-dimethyl-2,2’-dipyridyl)2(2,2’-bipyridine)] (Ru3), alters the aggregation profile of the Ab peptide. Both Ru1 and Ru2 contain an extended planar (4,5-f)(1,10)phenanthroline ligand, as compared to a 2,2’-bipyridine ligand for Ru3, and we show that the presence of the phenanthroline ligand leads to a greater effect on peptide aggregation. The ability of photoactivated Ru1-3 to bind to the Ab peptide was evaluated by Nuclear Magnetic Resonance (NMR) which indicated the loss of the 6,6’-dimethyl-2,2’-bipyridyl (6,6’-dmb) ligand for all three complexes and the formation of a covalent bond with the Ab peptide via His residue shifts for Ru1 and Ru2. By comparison, no shift in His residues was observed for Ru3, or for the unactivated Ru1-3 samples. The influence of Ru1-3 on peptide aggregation was investigated using gel electrophoresis / Western blot, Transmission electron microscopy (TEM) and a Bicinchoninic acid assay (BCA assay). Upon photoactivation, the Ab aggregation was greatly enhanced in the presence of Ru1 and Ru2 relative to Ru3, in agreement with initial binding studies by 1H NMR. However, the three complexes resulted in a similar aggregate size distribution at 24 h, forming mostly insoluble amorphous aggregates. Excitingly, the complexes also changed Ab1-42 fibrils to amorphous aggregates upon photoactivation. The unactivated Ru1 and Ru2 complexes exhibited a much stronger binding affinity for Ab (via Tyr10 fluorescence) in comparison to Ru3, further indicating the important role of hydrophobic interactions between the Ru complexes and the insoluble fibrillar peptide aggregates. Overall, our results show that upon photoactivation the extended planar ligand of Ru1 and Ru2 promotes immediate covalent binding and formation of soluble high molecular weight Ab aggregates in comparison to Ru3, however similar aggregate size and morphology is observed after 24 h for all three Ru complexes.

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

Quantitative electroanalysis of host-guest binding at organized supramolecular interfaces

Author: 
Date created: 
2020-10-07
Abstract: 

As a young and important class of supramolecular host-guest chemistry, the macrocyclic cucurbit[n]uril (CB[n]) hosts consisting of one hydrophobic inner cavity and multiple carbonyl portals have shown dramatically increased research interests since 1980s, with tens of thousand publications focusing on their synthesis, distinct structural features, exceptional physical and chemical properties. More importantly, their excellent host-guest recognition behavior leads to their great application potentials in many fields, such as nanofabrication, biomedical/pharmaceutical science, analytical chemistry, catalytic chemistry, and adaptive chemistry, which have been explored extensively in the past two decades. Particularly, CB[7], an attractive member of CB[n] family, shows ultra-strong host guest binding ability towards small aromatic or ring-structured organic compounds, which is mainly attributed to its proper-sized inner cavity. As a representative, the host-guest complexes formed between CB[7] and various redox-active ferrocene (Fc) derivatives have extremely high binding affinities (109 to 1012 M-1), which have been employed as an alternative of natural binding pairs (e.g., antigen-antibody, biotin-avidin) for fabricating versatile functional molecular and biomolecular interfaces. In order to gain further understanding of this particular host-guest binding pair formed at molecular interfaces, in this thesis, based on both conventional cyclic voltammetry and advanced structural characterizations, the binding thermodynamics and kinetics were investigated on mixed ferrocenylundecanethiolate/octanethiolate self-assembled monolayers on gold as a highly-organized model system. The results show that the inclusion binding behavior of this host-guest pair, while significantly affected by the surface, still has satisfactory stability for practical application. In addition, the broad potential of this new interfacial Fc@CB[7] host-guest binding system is manifested as nanoscale probes for the distribution of Fc terminal groups on SAMs (as an indicative of their structural heterogeneity), as an environmental regulator of long-range electron transfer process, and as an electrochemical sensor for pharmaceutical drugs via competitive host-guest assay strategy. It is expected that this new interfacial host-guest binding system can be further explored for fabricating well-controlled, ratiometric electrochemical biosensors.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Hua-Zhong Yu
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Selective isolation of Burkholderia, untargeted metabolomics, and biofilm inhibition screening for the discovery of bacterial natural products

Author: 
Date created: 
2019-10-25
Abstract: 

The study of natural products is dedicated to the discovery, evaluation, and use of specialized metabolites from natural sources for crop, animal, and human health. The methods required to isolate, characterize, and find utility for these important compounds are continually developing and finding new methods for exploring the diversity of chemistry available in the natural world. This work explores methods in selecting source organisms, comparison of the resulting natural products extracts with an established source of bioactive compounds, and biological screening of a vast library for the discovery of compounds for potential medical use. In the course of this work, a new and robust selection method is described for the one-step isolation of Burkholderia from complex environmental samples. This method introduces a systematic methodology for isolation of other priority organisms. The comparative untargeted metabolomics of the extracts from the Burkholderia library with an existing library of marine actinobacteria highlights the value of continued exploration of both new taxa and additional strains of known organisms for the discovery of important natural products. Finally, the high-throughput image-based screening of extracts and pure compounds for the inhibition and dispersion of V. cholerae biofilms highlights the difficulty and utility of natural products drug discovery for potential medical applications. This work demonstrates the various and important facets of natural products research from the beginning acquisition of organisms and their resulting compounds to the evaluation of these molecules prior to clinical use.

Document type: 
Thesis
Supervisor(s): 
Roger G. Linington
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Tuning self-assembly of rod-shaped liquid crystals

Author: 
Date created: 
2019-10-08
Abstract: 

Liquid crystals (LCs) exhibit a unique combination of an ordered supramolecular structure and a dynamic nature, which makes them attractive for a wide range of applications. Rod-shaped molecules can self-assemble into numerous types of liquid crystalline phases including lamellar phases with varying degrees of order and fluidity. The suitability of an LC material for a given application is strongly dependent on the type of phases, the phase sequence, and their thermal stabilities. Since these three factors are highly sensitive to molecular structure, it is imperative to possess a deep understanding of their structure-property relationships in order to rationally design materials with desirable properties for a given application. The studies herein investigate how changes in molecular structure can be employed to tune the self-assembly and opto-electronic properties of LC materials. The first part of this thesis explores “molecular symmetry breaking” to improve the thermal stability of LC phases. Two series of compounds were studied: 2,6-di(4ʹ-n-alkoxybenzoyloxy)naphthalenes, which form relatively disordered phases, and 4,4’-dialkanoyloxybiphenyls, which form highly ordered phases. The degree of symmetry was varied by appending terminal alkyl chains of different lengths. A systematic comparison of the LC phase behaviour revealed that symmetry breaking leads to a pronounced depression in the melting point with a limited effect on the clearing point, resulting in broader LC phase ranges for less symmetric isomers. This presents a strategy to tune the LC properties of a material while maintaining the inherent opto-electronic properties. The second part of this thesis focuses on strategic molecular design to optimize LC materials for organic semiconductors. Initially, the effect of replacing the central thiophene in 5,5”-dialkyl-α-terthiophene with an oxadiazole or thiadiazole ring was explored. The oxadiazole analogue is not LC whereas the thiadiazole analogue exhibits several potential advantages in LC phase behaviour compared to the parent terthiophene derivative. Inspired by these results, we studied a series of 2,5-bis(2,2’-bithiophene-5-yl)-1,3,4-thiadiazole derivatives, unsymmetrically substituted with an alkyl chain on one side and an aromatic ring on the other. Through variation of the aromatic ring, both the LC and opto-electronic properties can be tailored, making these compounds highly tunable materials.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Vance E. Williams
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Functionalization of silica-coated iron oxide nanoparticles via the silanol-alcohol condensation reaction

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

The surface properties of nanoparticles play an important role in their interactions with their surroundings. Silane reagents have been used for surface modifications to silica shells on iron oxide nanoparticles, but using these reagents presents some challenges. Some of these challenges include the moisture sensitivity of silane reagents and the formation of multilayers. An alternative approach to modifying the surfaces of these silica shells was developed to impart different terminal functional groups, such as a thiol, alcohol, or carboxylic acid, through the use of alcohol-based reagents. This reaction was initiated through convective heating and microwave-assisted heating. This approach to surface functionalization of the core-shell particles was verified through analytical measurements and the attachment of gold nanoparticles. The silanol-alcohol condensation reaction was also extended to the mixed functionalization of the silica-coated iron oxide nanoparticles with both thiol and carboxylic acid functionalized alcohol reagents. The processes and results for the silanol-alcohol condensation reaction were also compared with silanization process. The use of the silanol-alcohol condensation reaction could be extended further to other surface functionalization through the use of additional alcohol-based reagents.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Byron Gates
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Poly(arylene imidazolium)s: Towards stable hydroxide ion exchange membranes

Author: 
Date created: 
2019-08-22
Abstract: 

Four novel and sterically-protected arylene imidazole monomers were prepared by the Debus-Radziszewski imidazolium synthesis. Homopolymerization of these monomers was carried out via Yamamoto coupling. Only one of the four monomers yielded high molecular weight poly(arylene imidazole) (PAIM) polymer. Methylation and ethylation of this polymer yield poly(arylene imidazolium), which could be cast into tough, free-standing membranes. By adjusting the degree of methylation from 50% to 100%, the ion exchange capacity (IECcl- : number of functional groups per unit mass of polymer) of the membranes were varied from 0 to 2.58 mmol·g-1. By controlling the degree of ethylation from 50% to 100%, the IECcl- were varied from 0 to 2.40 mmol·g-1. The IECcl- affected the water uptake and dimensional swelling of membranes. With IECcl- increased, both water uptake and dimensional swelling became larger. The chloride ion conductivity of membranes increased up to 15 and 10 mS·cm-1 by increasing the IECcl- of the methylated and ethylated membranes to 2.58 mmol·g-1 and 2.40 mmol·g-1, respectively. The membrane with ethylation exhibited more excellent stability in caustic solutions, showing only 2% degradation in 10 M KOH at 80 °C after 168 hours, and longer elongation at break under ambient conditions compared to the membrane with methylation.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Steven Holdcroft
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

A de novo nucleoside synthesis and late-stage heterobenzylic fluorination strategy

Author: 
Date created: 
2020-07-30
Abstract: 

Nucleoside analogues constitute almost half of today’s major anticancer and antiviral therapeutics. Despite this, synthetic routes to these valuable molecules have typically relied on carbohydrate starting materials, which can significantly impair efforts in medicinal chemistry. Moreover, nucleoside scaffolds with increased complexity (e.g., C2’ or C4’ substitution) often require lengthy syntheses (up to 18 steps). Toward a goal of streamlining nucleoside synthesis, we have developed a one-pot proline-catalyzed α-fluorination/aldol reaction that generates enantiomerically enriched fluorohydrins that can serve as versatile building blocks for the construction of nucleoside analogues. Most importantly, this process enables access to variously functionalized nucleoside analogues in only 3 steps from commercial starting materials. The development of this process and practical application in rapidly accessing C2’- and C4’- modified nucleoside analogues, locked nucleic acids (LNAs), and iminonucleosides should inspire future efforts in drug design. Similar challenges also obstruct the synthesis of carbohydrate analogues (CAs), another important class of molecules to drug discovery efforts. To streamline CA synthesis, we developed several new proline-catalyzed α-functionalization/aldol reactions for constructing stereochemically rich and densely functionalized aldol adducts. In only 2 steps, these aldol adducts were then readily converted into a structurally diverse collection of CAs including iminosugars, annulated furanoses, bicyclic nucleosides, and fluorinated carbacycles. Incorporation of a fluorine atom can have several profound effects on a drug’s physiochemical properties – including metabolic stability, membrane permeability, and potency. However, the introduction of fluorine into the heterobenzylic position of drug molecules has remained an unsolved synthetic challenge. Towards this goal, we describe the first unified platform for the late-stage mono- and difluorination and trifluoromethylthiolation at heterobenzylic positions. This technology should become a dynamic tool for drug-lead diversification.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Robert Britton
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Expanding non-natural chemical space through synthetic diversification of natural product extracts

Author: 
Date created: 
2019-08-07
Abstract: 

Natural products are structurally diverse compounds that often possess biological activity, making them the most prominent source for the discovery and development of drugs. Existing discovery methods often lead to the re-discovery of known compounds, causing the pharmaceutical industry to deprioritize natural products as a source of drug leads. Examination of natural products chemical space indicates that there are gaps that have yet to be filled in, suggesting that new methods are needed expand chemical space to access novel chemistry. This work expands chemical space by using synthetic transformations to derivatize natural product extracts. A library of 540 prefractionated derivatized natural product extracts was generated and screened against bacterial pathogens and cancer cells. A change in the antimicrobial and anticancer activity was observed as a result of the derivatizations. Derivatization of extract via a strain release reaction produced a novel staurosporine derivative with increased activity against human osteosarcoma cells.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Roger Linington
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Synthetic design and development of proton conducting polyphenylenes for electrochemical energy conversion devices

Author: 
Date created: 
2019-07-15
Abstract: 

Approximately 10% of the global energy demand is currently satisfied by renewable resources. To meet the United Nations’ 2015 climate change target, this value must shift to upwards of 50% before 2030. Electrochemical energy devices offer an array of solutions which may complement or enhance current (non)renewable energy technologies. Unfortunately, mass-adoption of such devices is to date impeded by their prohibitive costs and poor lifetimes. A major contributor to these deficits is the solid polyelectrolyte membrane, which is used internally as both an electrical resistor and highly selective ion transporter. Despite preparation from controlled substances, with nominally toxic degradation by-products, perfluorinated structures remain the technological standard in electrochemical energy devices. The focus of this thesis is the development of hydrocarbon-based, fluorine-free polymers which may collectively exhibit comparable or superior performance to those possessing perfluorinated structures. Sulfonated, phenylated poly(phenylene)s are prepared exhibiting precisely controllable degrees of functionalization, incorporating aryl spacer units with increasing size. This serves to both decrease membrane hydrophilicity, and increase electrochemical performance both ex-situ, and in-situ when integrated into hydrogen fuel cells. Polymer durability, with emphasis on the latter is investigated. The demanding thermal polymerization conditions used to prepare this class of materials are addressed through development of novel, rapid microwave-assisted methods. Thorough material characterizations are performed to assess the advantages and deficits over traditional, thermal synthetic methodologies. Concurrently, materials are prepared in larger batches to investigate their scalability. Poor hydrocarbon membrane water sorption, structural integrity, and chemical stability limit their application in electrochemical devices. The incorporation of molecular branching into polymers is evaluated as a facile means of universally improving these properties. The materials reported show steady advancements in their stabilities and membrane properties, which culminates in ever-increasing and best-in-class performance when assessed within fuel cells.

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

Development and application of synthetic methods that enable medicinal research

Author: 
Date created: 
2019-06-14
Abstract: 

The development of modern pharmaceuticals relies heavily upon the drug discovery process to uncover new molecular entities able to modulate disease states. Integral to this process is the ability of scientists to quickly synthesize analogues of a hit or lead compound to improve critical qualities. Ease of synthesis is directly related to existing methodologies which facilitate key chemical transformations necessary to assemble potential drug molecules. In this thesis, a medicinal chemistry program is described that relies on the well-established Suzuki-Miyaura coupling to assemble small molecule inhibitors of protein arginine methyl transferase 4, a potential target for cancer therapy. Significant advances are made towards obtaining a potent, selective, and cell-active pharmacological probe. A concise synthesis of the therapeutic 1-deoxygalactonojirimycin is also described, which utilizes a tandem α-chlorination aldol reaction developed by the Britton group to install several stereocenters in one step. In addition, a novel route to access enantioenriched acid-sensitive α-substituted aldehydes via a bench-stable intermediate was investigated.

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