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

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

Network topologies and properties of cyanoplatinate coordination polymers

Author: 
Date created: 
2019-06-26
Abstract: 

This work is a contribution to the rich literature on cyanoplatinate chemistry, with a focus on the synthesis and materials properties of coordination polymers that incorporate [Pt(CN)4]2– and [PtX2(CN)4]2– (X = Cl, Br) as linkers. Furthermore, fundamental Pt2+ chemistry is explored in the synthesis of new linkers incorporating the ligand iso-maleonitriledithiolate (i-mnt) for use in chemical sensors and negative thermal expansion materials. Combination of M2+ with [PtX2(CN)4]2– (X = Cl, Br) results in the formation of solvent-templated coordination polymers with networks of varying hydration, M(H2O)n[PtX2(CN)4]·m/3H2O (n = 0 to 2; m = 0 to 8). The structures of the coordination polymers are described; characterization methods include IR, Raman, TGA, EA, and variable temperature XRD. A comparative study between the thermal expansion properties of Cu(H2O)2[PtX2(CN)4] and Cu[PtX2(CN)4] highlights the impact of solvent on the thermal expansion of these materials. The ability of Cu(H2O)2[PtX2(CN)4] (X = Cl, Br) to act as vapochromic sensors and their vapour adducts Cu(L)2[PtX2(CN)4] (L = DMSO, DMF, Pyridine; X = Cl, Br) are reported. Some simple amine-containing compounds were also prepared, and a structural analysis carried out on the pyrazine-containing M(H2O)2[PtBr2(CN)4]·2pyz (M = Co2+, Zn2+, and Cd2+) and Cu(pyz)[PtBr2(CN)4] compounds. The structures, optical, and thermal properties of new [Pt(CN)4]2– coordination polymers prepared by combination with Pb2+, Cd2+, and Mn2+ are reported. The interplay between the Pt4+ halogenated and Pt2+ non-halogenated materials for X2 (X = Cl, Br) sensing is also studied. Attempts to isolate [Pt(i-mnt)2]2– and combination with d10 M2+ for chemical sensors, and conditions for oxidation to [Pt(i-mnt)3]2– are discussed. A series of new asymmetric i-mnt-containing Pt complexes have also been prepared. Metal organic frameworks formed from the combination of the Pd2+ analogues and M2+, M(H2O)4[Pd(i-mnt)2] (M = Mn2+, Co2+, Zn2+), have also been prepared and fully characterized.

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

Exploring main group radicals using an isotope of hydrogen

Date created: 
2019-10-07
Abstract: 

Muonium, which is considered a light isotope of the H atom, is a radioactive atom with a lifetime of 2.197 µs. Muonium adds to unsaturated molecules to form muoniated radicals. The collection of spectroscopic techniques that are used to observe muoniated radicals are known as µSR. To determine the identity of the muoniated radicals, experimental hyperfine coupling constants (hfcs) of the muoniated radicals obtained from µSR techniques were compared with hfcs of the muoniated radicals calculated using Density Functional Theory (DFT) methods available in the Gaussian 09 software package. µSR studies help us understand the reactivity of molecules towards the H atom and the configuration and conformation of the radicals formed. The polyether ether ketone (PEEK) polymer was tested for suitability in µSR sample cell fabrication. Muoniated radicals formed from monomers of PEEK, 4,4-dihydroxybenzophenone and para-dimethoxybenzene were detected. Since similar radicals expected in PEEK could interfere with sample signals it is concluded that PEEK is unsuitable for µSR sample cells. Phosphaalkene reactions with muonium were studied to understand their behaviour in radical polymerization. The model compound mesPC(Me)2 was studied and two muoniated free radicals, mesP-MuC•(Me)2 and mesP•-C(Mu)Me2 were detected. The mesP•-C(Mu)Me2 radical was compared with its isotopologue mesPH-C•(Me)CH2Mu formed from mesPH(CMe=CH2). A number of phosphaalkenes that differ from each other with respect to electronegativity and the bulkiness of the attached substituent groups were studied. Adamantyl phosphaalkene (AdP=CtBuH) produced only the AdMuP-C•(tBuH) radical while a sample of (CF3)2-mesP=C(Me)2 showed muoniation at both the P and C centers of the P=C bond. Muoniated radicals formed by mesP=CPh2 were identified. This helped to resolve ambiguity in identifying the initiation products of the radical polymerization pathway of mesP=CPh2. The reaction of Mu with 2,4,6-tri-tert-butyl-1,3,5-triphosphosphabenzene (TPB) resulted in two muoniated radicals. Mu addition to the C atoms of the ring resulted in rearrangement to form a bicyclic product. TPB undergoes hydrogenation via a cationic route forming a bicyclic product. In this thesis I propose a radical route for this hydrogenation pathway.In summary we have utilized µSR techniques to broaden the understanding of neutral radical formation from phospha-organic compounds.

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

Evolutions of chemical and polar structures and electric properties in the Barium-Lead Zirconate-Titanate (BPZT) system

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

Ceramics of the perovskite (1-x)[Ba(Zr0.30Ti0.70)O3] - x[Pb(Zr0.30Ti0.70)O3] (BZT-PZT) solid solution were prepared by solid state reaction method with complete solubility throughout the series. The ceramics were examined by X-ray diffraction and dielectric spectroscopy to investigate the crystal structure, phase transition and electric properties. The XRD results reveal that all ceramics exhibit a pure perovskite structure, and with increasing x, the cubic phase gradually transforms into a tetragonal phase. Detailed structural analysis and Rietveld refinements based on XRD data. The dielectric permittivity was measured as a function of frequency (0.1 Hz - 100 kHz) in the temperature range of 123 K to 573 K. For 0 < x < 0.40, the ceramics exhibit a typical relaxor behaviour. With the increase of the PZT concentration, the temperature of the dielectric maximum (Tmax) shows a non-monotonic variation, which first decreases and then increases at a critical composition (xC1 = 0.10). The maximum of dielectric permittivity (e’max) at Tmax shows frequency dispersion following the Vogel-Fulcher law. The difference between Tmax and the fitting parameter TVF, (Tmax-TVF), first increases and then decreases at another critical composition (xC2 = 0.30), with the increase of PZT concentration, showing the same trend as the shift of Tmax with frequency (DTmax). The high-temperature slope of the diffuse dielectric peak (T > Tmax) is scaled by the empirical Lorenz-type quadratic relation. The transition from the high-temperature paraelectric state, in which the dielectric constant follows the Curie-Weiss law, to the ergodic cluster state is found to occur over all the studied compositions. Single crystals of (Ba1-xPbx)(Zr1-yTiy)O3 were grown by a high-temperature solution growth method using (PbO + B2O3) as a flux upon slow cooling from 1100 °C. The size of the as-grown crystals varies from 1 to 5 mm. The X-ray powder diffraction analysis shows that the crystals have a tetragonal perovskite structure. The composition of the crystal is found to be (Ba0.46Pb0.54)(Zr0.12Ti0.88)O3 by X-ray photoelectron spectroscopy (XPS). The measurements of dielectric properties indicate that the crystal undergoes a single phase transition from the cubic to the tetragonal phase at Curie temperature, TC = 554 K, upon heating. Polarized light microscopic studies of the domain structure confirm that the crystals are of tetragonal symmetry at room temperature. A typical ferroelectric hysteresis loop is displayed at room temperature, indicating the ferroelectric nature of the (Ba0.46Pb0.54)(Zr0.12Ti0.88)O3 crystals.

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

Modeling novel ionenes for electrochemical devices with first principles and machine learning methods

Author: 
Date created: 
2020-04-06
Abstract: 

Polybenzimidazole-based ionenes are being developed for use in both alkaline anion-exchange membrane fuel cells and alkaline polymer electrolysers. The first part of this work explores the impact of the degree of methylation on the conformations and electronic structure properties of poly-(hexamethyl-p-terphenylbenzimidazolium) (HMT-PMBI), the materials of interest in this thesis. For this purpose, HMT-PMBI oligomers, from monomer to pentamer, are studied with density functional theory calculations. Next, molecular dynamics simulations are used to calculate the trajectory paths of all atoms of the fully methylated HMT-PMBI tetramer. Lastly, recurrent neural networks are explored as a means to accelerate the statistical sampling of molecular conformations of polymeric systems, thereby providing complementary tools for molecular dynamics simulations. It is demonstrated that these types of artificial neural networks can be learned from the distribution of the coordinates of atoms over molecular dynamics simulations. As shown, the trained multivariate time series model enables forecasting trajectory paths of atoms accurately and in much reduced time with over 96% accuracy.

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

Synthesis and assessment of ethylene diamine-based self-immolative linkers for use in the selective delivery of drugs to bones

Author: 
Date created: 
2019-04-30
Abstract: 

Self-immolative linkers containing bisphosphonates may be an ideal approach to delivering drugs to bone for treatment of diseases such as osteoporosis. Bisphosphonates can be used to target pro-drugs to bone and can be linked to active drugs via a self-immolative linker such as an ethylene diamine carbamate. Such prodrugs can be inactive until reaching and attaching to bone where they then slowly release the active drug. Several prodrug models with an ethylene diamine linker attached to a model drug, 1-phenyl-2,2,2-trifluoroethanol (which represents a structural component of a proprietary bone stimulating drug) were prepared and used to study the effect of the position of attachment of the model drug and the bisphosphonate and of substitutions on the linker on the rate of self-immolation and drug release. This study concluded that attachment of the bisphosphonate, steric hindrance, and steric compression (attributable to substitutions) can be used to alter the rate of self-immolation.

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

Multifunctional ligand design for modulating protein stability and aggregation for cancer treatment

Author: 
Date created: 
2020-03-30
Abstract: 

Referred to as the “guardian of the genome”, p53 is the most frequently mutated protein in cancer and accounts for over 50% of cancer diagnoses. p53 regulates the cellular network by signaling for the activation of various pathways including apoptosis and cell cycle arrest to avoid propagation of damaged cells. Consequently, in 50% of cancer diagnoses, single point mutations render the protein inactive, prohibiting its antiproliferative response and allowing for accumulation of damaged cells. The majority of mutations are localized to the DNA-binding domain, a domain that contains a Zn2+ ion that is essential for proper protein folding and function. These mutations typically affect the proteins’ tertiary structure, resulting in a loss or alteration of Zn-binding which can lead to unfolding and enhanced aggregation. As an overexpressed and tumour-specific target, the past two decades have seen considerable dedication to the development of small molecules that aim to restore wild-type function in mutant p53. Previous efforts have been monofunctional in design, targeting specific characteristics of a given p53 mutant including thermal denaturation, aggregation, or loss of zinc. This thesis explores small molecule design strategies to restore wild-type function in mutant p53. Considering the multifaceted nature of p53 mutants, a multifunctional approach was employed to simultaneously target various characteristics. Chapter 2 features a bifunctional scaffold targeting zinc loss and thermal denaturation. The utility of this scaffold in increasing intracellular zinc and restoring transcriptional function in mutant p53-Y220C is described. Modifications to the ligand scaffold to extend the structures into subsite cavities of this mutant are explored in Chapter 3. These modifications increased the cytotoxicity of the ligands and restored apoptotic activity, however, resulted in a loss in their ability to serve as zinc metallochaperones. Lastly, a combination of fragments targeting zinc loss and protein aggregation found success in restoring wild-type function in mutant p53 in Chapter 4. These studies highlighted the possible advantages of halogenation in modulating mutant p53 aggregation, as an iodinated scaffold limited mutant p53 aggregation and restored wild-type function. This work represents a foundation to simultaneously target the multiple characteristics of p53 mutants and provides important information for drug design moving forward.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Tim Storr
David Vocadlo
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Reaction of hydroxyl radicals with sulfonated phenylated polyphenylenes

Author: 
Date created: 
2019-04-18
Abstract: 

The perceived poor durability of non-fluorous, hydrocarbon solid polymer electrolyte membranes in the presence of reactive hydroxyl radicals remains a significant hurdle for their integration into electrochemical systems such as fuel cells. However, recent reports point to sulfonated phenylated polyphenylenes (sPPP) being considerably stable in accelerated fuel cell tests. In order to investigate the possible reaction of hydroxyl radicals with this promising class of hydrocarbon polymer electrolytes, a structurally-analogous oligophenylene model compound was synthesized and its degradation route was studied in the presence of hydroxyl radicals. Using NMR spectroscopy and mass spectroscopy, all significant degradation products are characterized and based on their chemical structures, along with changes in concentration over time, a degradation route is proposed. Hydroxyl-radical degradation was observed and found to be initiated by the oxidation of pendant phenyl rings to form fluorenone sub-structures which, upon further oxidation, lead to ring-opening of a main chain phenyl ring which, if occurring in sPPP, leads to chain-scission of the polymer backbone. In keeping with this hypothesis, molecular weights of sPPP were found to decrease when subject to hydroxyl radicals. Although degraded polymer NMR spectra remain unchanged, resonances consistent with the elimination of sulfobenzoic acid emerge. The results outlined in this work point towards a promising future for sPPP membranes and suggest a simple modification which should enhance their lifetime within fuel cell systems.

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

Synthesis of sulfo-phenylated terphenylenes: molecules, polymers and copolymers

Author: 
Date created: 
2019-04-16
Abstract: 

This thesis reports the synthesis and study of a new class of fluorine-free, acid-bearing polymers for potential usage in proton exchange membrane fuel cells. The polymers were prepared via the synthesis of a pre-sulfonated monomer, followed by homo- and co-polymerization by [4+2] Diels-Alder cycloaddition. Molecular structures were determined by mass spectrometry, infrared spectroscopy, 1H NMR and 2D COSY spectroscopies, and single crystal X-ray diffraction. Disulfonated tetracyclone and tetrasulfonated bistetracyclone molecules were used to synthesize two model compounds to determine the potential isomers present. Tetrasulfonated bistetracyclone was polymerized with 1,4-diethynylbenzene co-monomer. The resultant polymer, sPPP-HNEt3+, was prepared with a high molecular weight and converted into its acid form, prior to casting as a membrane. The membranes possessed a high ion exchange capacity (IEC) of 3.49 meq/g and a proton conductivity of 118 mS/cm at room temperature and at 95% relative humidity (RH), respectively, four and a half time superior as the current benchmark NRE 211®. The polymer film was found to become soluble during exposure to aggressive oxidative solutions no significant chemical changes were observed. The final part of this work focused on increasing the polymer film stability by judiciously tuning the hydrophilic content of the polymer. A family of random-copolymers was prepared based on the above monomers. The parameters for polymerization were studied and the optimal conditions were found using size exclusion chromatography to determine molecular weight. The measured IEC for these copolymers correlated well with the theoretical IEC, ranging from 1.86 to 3.50 meq/g. The conductivity of these polymers at 80°C and 95% RH was found to reach 338 mS/cm. Fuel cell tests were performed using the membranes and provided a peak power density of 770 mW/cm2.

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

Total synthesis of biselide A and studies towards the synthesis of a chimeric glycopeptide to probe peptide-carbohydrate mimicry

Date created: 
2019-12-11
Abstract: 

The primary focus of the research described in this thesis deals with the studies geared towards the total synthesis of biselide A and phormidolide A, two tetrahydrofuran containing natural products with potentially useful biological activities. Additionally, efforts towards the synthesis of a chimeric glycopeptide is described. Biselide A, is a chlorinated macrocyclic polyketide isolated from the Okinawan ascidian Didemnidae sp., possessing potent cytotoxicity against a variety of human cancer cell lines. The core molecular structure contains a densely substituted tetrahydrofuran ring and 5 stereogenic centres as a part of 14-membered macrolactone. To access this potentially useful marine macrolide we have utilized an asymmetric aldol reaction with enantiomerically-enriched chlorohydrins that affords a rapid and stereocontrolled access to the tetrahydrofuran core. The macrocycle was constructed through a series of transformations that include a cross metathesis, regioselective enzymatic acetylation, and Reformatsky macrocyclization. In this thesis we highlight a flexible and stereoselective total synthesis of biselide A. Phormidolide A is a complex macrocyclic polyketide isolated from the cyanobacteria Leptolyngbya sp. It possess a highly oxygenated side chain and a macrocyclic core with an embedded substituted tetrahydrofuran. We exploit our previously developed α-chlorination/aldol reaction strategy to access the tetrahydrofuran motif. Synthesis of three model acetonide tetrahydrofuran derivatives allowed for the NMR comparison with the same previously reported triacetonide derivative of phormidolide A. NMR spectroscopic analysis supports a reassignment of seven of the eleven stereogenic centres initially reported for phormidolide A. The second part of this thesis describes the progress made towards the synthesis of a chimeric glycopeptide. Two haptens, a pentasaccharide and a mimetic octapeptide bind with moderate affinity to a monoclonal antibody SYA/J6, specific for the O-polysaccharide of the S.flexneri Y bacterium. Based on the X-ray crystallography data and molecular docking studies, two chimeric glycopeptides (α-glycopeptide and β-glycopeptide) were designed in an attempt to improve the binding affinity to SYA/J6 antibody. Our group has previously synthesized α-glycopeptide and showed no inhibition of SYA/J6 antibody to the O-polysaccharide. Preliminary docking studies indicated that the β-glycopeptide might provide a better fit within the antibody combining site. The molecule consists of a rhamnose trisaccharide linked through a β-glycosidic linkage to an MDW moiety of a mimetic octapeptide. Our strategy involved linking three fragments, synthesized using solution and/or solid phase methodology. The key step in the synthesis was the formation of the thermodynamically less favoured β-linkage between the sugar and peptide. This was achieved following an ulosyl bromide approach. We herein describe our efforts towards the synthesis of a β-glycopeptide.

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