PRISM :: Browsing by Author "Derksen, Darren"

Browsing by Author "Derksen, Darren"

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Open Access
An Exploration of Cross-dehydrogenative Coupling Methodology and The Synthesis of Transient Receptor Potential Melastatin Member 8 (TRPM8) Channel Modulators
(2017) LeGay, Christina; Derksen, Darren; Back, Thomas; Sutherland, Todd; Ro, Dae-Kyun
Structure-activity relationship (SAR) studies of natural product analogues that modulate transient receptor potential (TRP) channels have been a useful tool for the development of potent and selective channel modulators. TRP channels play numerous physiological roles, including temperature and pain sensation, and have emerged as viable therapeutic targets. Recently, the Derksen group produced a library of TRP melastatin member 8 (TRPM8) channel modulators based on the natural product menthol. The first library of menthol analogues was prepared via an optimized and cost-effective synthetic route from commercially available starting materials. The biological evaluation of the first library revealed three novel TRPM8 channel modulators: an agonist with an EC50 of 11 ± 1 μM, an antagonist with an IC50 of 2 ± 1 μM, and an allosteric modulator that boosted the channel response towards consecutive applications of menthol. This thesis describes the results of the first library, and the tailoring of established synthetic methods to prepare a second generation library of natural product analogues based on the TRPM8 antagonist from the first library. Also described is the exploration of the organo-mediated cross-dehydrogenative coupling (CDC) of silyl enol ether and ketone substrates with the goal of preparing aldol adducts, which are key moieties in bioactive compounds including TRP channel modulators. CDC was employed for the direct functionalization of carbon-hydrogen bonds to prepare aldol adducts in an effort to overcome the issues of controlling reactivity and selectivity in aldol addition reactions. This thesis describes the variety of substrates and reaction conditions screened, and the measurements and calculations conducted in an attempt to optimally produce aldol like adducts directly from silyl protected alcohols. The highest yield achieved was an 18% GC-MS yield despite considerable effort and exploration of the reaction mechanism.
Open Access
Assessing Ryanodine Receptor Inhibition and Antioxidant Ability of Carvedilol and its Abilities
(2016) Malig, Thomas; Back, Thomas George; Ling, Chang-Chun; Derksen, Darren; Heyne, Belinda
The antioxidant ability of the commonly prescribed antiarrhythmic medication carvedilol was assessed using two distinct assays. The first assay monitored the depletion of the stable radical DPPH via hydrogen atom abstraction utilizing UV-VIS spectrophotometry. The second assay involved monitoring the inhibition of a radical chain reaction initiated by UV light. Three metabolites of carvedilol were synthesized and assessed in each assay along with carvedilol and several benchmark antioxidants to ensure assay validity. It was determined that carvedilol possessed negligible antioxidant ability in both assays, while the metabolites possessed moderate-high antioxidant strength. It is therefore concluded that the antioxidant ability of carvedilol originates from the phenolic metabolites and not from carvedilol itself. The primary function of carvedilol to regulate calcium handling in cardiac myocytes was also assessed for each metabolite using a mutant embryonic cell line. It was determined that metabolic deactivation via hydroxylation pathways is minimal.
Open Access
Characterization of Proteoglycan 4 Supramolecular Structure and its Effect on Lubricating Function
(2018-09-14) Martens, Kayla; Schmidt, Tannin; MacCallum, Justin; Derksen, Darren; Sen, Arindom
Proteoglycan 4 (PRG4) is a mucin-like glycoprotein that is a key synovial fluid constituent, functioning as a cartilage boundary lubricant. PRG4 has been suggested to exist as a supramolecular structure. The objectives of this thesis were to (1) characterize the supramolecular structure of recombinant human PRG4 (rhPRG4) and its dependency on concentration, (2) elucidate the molecular forces underlying the formation of the supramolecular structure, and (3) assess the lubricating ability of the supramolecular structure. rhPRG4’s ability to form a supramolecular structure and reduce friction was concentration dependent. Arginine (0.2M) disrupted the formation of the supramolecular structure of rhPRG4 and diminished its lubricating ability. Conversely, 20 mM calcium enhanced the formation of rhPRG4 supramolecular structure and enhanced its lubricating ability. These results suggest non-covalent interactions mediate rhPRG4’s supramolecular structure, shown here to exist for the first time, which in turn is a functionally (lubrication) determinant property.
Open Access
Designing Peptide-Based Biosensors for the Diagnosis of Crystal Arthropathies
(2023-05-15) Meyer, Jessica Marie; Derksen, Darren; MacCallum, Justin; Ling, Chang-Chun; Kimura-Hara, Susana
Peptides play a vital role in nature as they engage in many complex interactions which include forming proteins and binding with other biomolecules. The interactions between peptide and various biomolecules, such as proteins, carbohydrates, and enzymes, have been well-studied as they guide many processes in the human body. However, peptide interactions with solid surfaces are not well understood. This work explores the binding of peptides to the surfaces of monosodium urate (MSU) crystals. MSU crystals accumulate in the joints of patients with acute gout, one of several types of crystal arthropathy. Other arthritides, including pseudo-gout and osteoarthritis, present similar symptoms to gout, but are characterised by accumulation of calcium pyrophosphate and hydroxyapatite crystals respectively. Misdiagnosis between these diseases when using current methods of crystal analysis. This thesis aimed to produce a fluorescent, peptide-based biosensor with specific binding to MSU crystals for the purpose of future development of a more accurate and efficient method for diagnosing gout. This was accomplished by first analysing data provided by characterising the MSU surface, peptide binding interactions, and proposing optimal peptide sequence candidates through computational analysis. Methods were then developed to synthesise, fluorescently label, and purify the peptide candidates. Analytical methods, including RP-HPLC-UV, fluorescence spectrometry, and CD polarimetry, were employed to investigate the peptide’s binding affinities, fluorescent activity, and secondary structure. Finally, fluorescence microscopy images of the MSU-bound fluorescent peptides were analysed to compare relative binding of different peptide sequences to MSU crystals. Ultimately, this work was successful in identifying and synthesising fluorescent peptides that display strong, uniform binding to MSU crystals and enhance detection of the crystals via fluorescence microscopy. The findings of this thesis could be used in further studies to potentially develop an effective, peptide-based biosensor for gout.
Open Access
Developing Structure-Property Relationships for N-Annulated Perylene Diimides
(2021-05-12) Cann, Jonathan Robert; Welch, Gregory; Trudel, Simon; Derksen, Darren; Maly, Kenneth; Shimizu, George
This thesis presents structure-property relationships of a series of functionalized N-annulated perylene diimide chromophores. Chapter one introduces the perylene diimide (PDI) chromophore and covers functionalization through bay annulation. Chapter two of this thesis explores the impact of electron deficient nitro groups on N-annulated PDI (NPDI) and further evaluates the impact of varied alkyl substituents (M2-M4). Chapter three explores a set of NPDI dimers and the importance of the dihedral angle between the two fragments (M5-M7). Chapter four explores the modified the optical and electronic properties of M7 by incorporating small organic chromophores between the two halves of the NPDI dimer (M8-M10). Chapter five explores derivatives of the NPDI where small electron rich aryl groups have been appended to the periphery (M11-M15). Finally, in chapter six a pair of highly related NPDI tetramers (M17, M17) are examined and found to have unusually disparate properties. Each of these derivatives was characterized by 1H NMR, CV, UV-Vis absorption and emission as well as X-Ray crystallography and spectroelectrochemistry as needed.
Open Access
Examination of Brain-Fatty Acid Binding Protein Interaction with Hydrophobic Ligands and Micelles
(2021-05-13) Bodnariuc, Iulia; MacCallum, Justin; Derksen, Darren; Williams, Gareth
Members of the fatty acid binding protein (FABP) family function as intracellular transporters of hydrophobic molecules, facilitating both fatty acid and lipid metabolism. FABPs share a common tertiary structure of beta barrel pocket for ligand incorporation with a flexible lid domain. Dysfunction of brain fatty acid binding protein (FABP7) has been associated with a variety of neurological disorders relating to sleep, autism, and schizophrenia. FABPs have been shown to bind small hydrophobic molecules such as fatty acids, endocannabinoids, and phytocannabinoids. Transport of these ligands is mediated through both protein-membrane and protein-protein interactions. FABP7 bears a nuclear localization signal that allows ligand-dependent transport to the nucleus through the nuclear pore complex. Once in the nuclear pore complex, FABP7 can then exchange its cargo with transcription factors. FABP7 can also exchange cargo and interact with cytosolic proteins when its cargo does not result in nuclear localization. It has been suggested that the model for ligand-dependent nuclear localization is mediated by tighter binding interactions with ligands that preferentially translocate FABP7 to the nucleus. FABP7 bound with docosahexaenoic acid results in nuclear localization, however other similar fatty acids such as oleic acid and stearic acid do not. Here a combination of biophysical experimental and computational methods is used to provide a model for the observed ligand-dependent nuclear transportation. We show with NMR experiments and computational simulations that ligand-dependent nuclear localization is associated to specific protein dynamics in the lid domain and not preferential binding to different ligands. Furthermore, we show that highly dynamic apo protein equilibria and heterogenous ligand conformations make FABP7 ligand binding resistant to mutations. NMR experiments reveal that FABP7 interacts with micelles through the lid domain. Finally profound changes in the lid domain region are observed in biologically relevant T60M mutation of FABP7.
Open Access
Functional Genomics and Metabolite Profiling as Tools for Alkaloid Biosynthetic Gene Discovery
(2015-12-16) Dinsmore, Donald Reed; Facchini, Peter James; Moorhead, Gregory; Schriemer, David; Derksen, Darren
The benzylisoquinoline alkaloids (BIAs) are diverse group of plant specialized metabolites found in the families Papaveracea, Ranunculaceae, Berberidaceae and Menispermaceae. Plants remain the only commercial source for BIAs and their biosynthesis is poorly understood. O-methyltransferases (OMTs) are wide spread in BIA biosynthesis. Putative OMTs were found in stem and root Next-Generation Sequencing transcriptomic databases. Putative OMT cDNAs were isolated from Papaver somniferum and commercially synthesized. Recombinant protoberberine 2-O-methyltransferase (2OMT) was heterologously expressed in Escherichia coli and assayed. 2OMT demonstrated the 2-O-methylation of protoberberine alkaloids and the 7-O-methylation of simple BIAs. The substrate range and tissue specific expression of 2OMT suggest its in vivo role is converting (S)-cheilanthifoline to (S)-sinactine. A LC-MS based targeted alkaloid profiling of twenty BIA producing species from the families Papaveracea, Ranunculaceae, Berberidaceae and Menispermaceae was conducted.
Open Access
A General Strategy for the Preparation of Thalidomide-Conjugate Linkers
(2017-01) Papatzimas, James; Gorobets, Evgueni; Brownsey, Duncan; Maity, Ranjan; Bahlis, Nizar; Derksen, Darren
The synthesis of small-molecule linkers for installation of thalidomide-based conjugates is described. Linker properties have been recognized as vital to conjugate success in drug discovery and delivery systems. These small-molecule tethers act as linkages between molecules, can also aid in cell permeability, and act as solubilizing agents. This work shows our progress in synthesizing conjugates with a variety of linker characteristics. The adaptability and manipulation of these and other linkers holds potential in improving synthetic control of chemical connectivities toward therapeutic development.
Embargo
Individual and mixture toxic effects of monohaloacetonitriles to a human cell model
(2023-12-20) Jayawardana, Amarasinghe Senadeerage Dona Prabhani Thilina Kumari; Kimura-Hara, Susana; Gailer, Jurgen; Goodarzi, Aaron; Derksen, Darren; Charrois, Jeff
Haloacetonitriles (HANs) are an emerging class of nitrogen-containing disinfection by-products (DBPs) and have been reported up to a maximum of 41 µg/L in treated drinking water. There is a growing interest in HANs because they are more cyto- and genotoxic than the regulated carbon-based DBPs and have been recently reported as key drivers in overall drinking water toxicity. However, most data presented thus far has focused on monitoring cell toxicity in animal and human cancer-derived cell models with an uncertain relevance to human health. Additionally, those studies have not addressed the possibility of HAN degradation in cell culture conditions. Therefore, the observed effects may come from HANs or HAN-degradation products. In this study I aimed to assess the stability of HANs in cell culture media and the toxic effects of DBPs to a normal tissue-derived human cell model. First, the stability of 8 HANs was evaluated under cell culture conditions used in in vitro toxicological studies (37°C, pH=7.4, for 3 days). Mono-HANs were stable during the incubation period; however, the stability of di- and tri-HANs declined significantly. Di- and tri-HANs transformed into their corresponding haloacetamides and haloacetic acids (HAAs), which are less cytotoxic than HANs. To obtain a more accurate measurement of HAN toxicity, it is recommended to consider changing cell culture media for di- and tri-HANs daily. Then, individual mono-HANs and their mixtures were evaluated for chronic cytotoxicity to a normal tissue-derived human cell model. Cytotoxicity was measured using cell viability and cell growth. HAN toxicity increased in the order of ClCH2CN << BrCH2CN < ICH2CN. At lower concentrations, the mixture of BrCH2CN+ICH2CN had the highest combined cytotoxicity. ClCH2CN demonstrated additive/synergistic effects in the presence of BrCH2CN and ICH2CN. Those results confirmed the previous conclusions from Chinese hamster ovary cell-based assays: cytotoxicity of HANs increased in the order of ClCH2CN << BrCH2CN < ICH2CN. In addition, the cytotoxicity of mono-HAAs and their binary and tertiary mixtures were also evaluated. From the tested HAAs, ClCH₂COOH was the least cytotoxic compound. BrCH₂COOH and ICH₂COOH had similar cytotoxicity. ClCH₂COOH + BrCH₂COOH had the least combined cytotoxicity, and ClCH₂COOH + IAA had the highest combined cytotoxicity. Afterward, the experimental results were compared with toxicity models to evaluate the type of toxic interactions (i.e., additivity, synergism, and antagonism). This study provided a primary understanding of the DBPs as mixtures. Lastly, cell metabolites were extracted and identified after cell exposure to CH3CN. The lowest concentration that negatively affects cells was determined using the non-monotonic dose-response curves for the reduction of cell viability and growth of RPE-1hTERT cells. From these experiments, 1 mM CH3CN was chosen as the non-cytotoxic concentration to treat cells for the metabolomic study. Then, two solvent mixes were evaluated to identify the solvent mix that extracted the most metabolic features. A solvent mix of 80% methanol and 20% H2O was selected. Cells treated with CH3CN for 72 h did not induce a significant change in the metabolic profile of RPE-1hTERT cells. To my knowledge, this is the first attempt to characterize the toxicity of HANs and HAAs to a normal tissue-derived human cell model. Mono-HANs' and mono-HAAs' toxicity to RPE-1hTERT cells increased with the change of halogen substitute from chlorine to bromine/iodine. Although the combined effects of mono-HANs were antagonistic, the combined effects of mono-HAAs were synergistic, implying that HANs and HAAs may affect different cellular mechanisms. Moreover, to the best of my understanding, this study is the first to measure the cytotoxicity of CH3CN to a normal tissue-derived human cell model. The observation of this study concludes that exposure to a lower dose (< 1mM) of CH3CN does not cause cytotoxic effects to RPE-1hTERT cells nor significantly alter the metabolic profile of RPE-1hTERT cells.
Open Access
Mapping the Unexplored Reactivity Landscape of Benzo[ghi]perylene
(2024-04-16) Hogan, David Thomas; Sutherland, Todd Christopher; Derksen, Darren; Heyne, Belinda; Thurbide, Kevin; Zhao, Yuming
This thesis describes the learning opportunities, failures, and successes surrounding a polycyclic aromatic hydrocarbon of interest, benzo[ghi]perylene. Neglected in the chemical synthesis literature but fundamentally interesting due to its composition and molecular symmetry, the work contained herein contributes a small work to a small field. The efforts are found in three chapters for three chronologically and ideologically related topics: the construction and optimization of a flow photoreactor to produce benzo[ghi]perylene; the exploration of structure and reactivity of benzo[ghi]perylene; the development of a strategy to improve the flow photochemical productivity of benzo[ghi]perylene.
Open Access
Microbial natural products that inhibit c-di-GMP signalling and biofilm formation in Pseudomonas aeruginosa
(2017) McCartney, Nathan; Harrison, Joe; Derksen, Darren; Storey, Douglas; Parkins, Michael; Lewenza, Shawn
Pseudomonas aeruginosa is a notorious opportunistic pathogen that forms highly antibiotic resistant biofilms to establish chronic infections. Antibiotic resistance of this organism is a significant contributor to mortality in immunocompromised patients. In this thesis, a high-throughput screening protocol was used to identify microbial spent media with inhibitory activity against P. aeruginosa c-di-GMP signalling. The biocontrol agent Pseudomonas protegens Pf-5 was identified to have significant inhibitory activity against the c-di-GMP signalling and biofilm forming capacity of P. aeruginosa. The natural product secreted by P. protegens was shown to be dependent on the PSL polysaccharide produced by P. aeruginosa and may exert its effect through the dipA pathway. Results demonstrated that this natural product had activity against a range of clinically-isolated P. aeruginosa and holds promising translational benefits to the eradication of chronic biofilm infections.
Open Access
Pi-Extension and Hypervalency of Conjugated Organophosphorus Compounds
(2017) Grenon, Nicole; Baumgartner, Thomas; Sutherland, Todd; Derksen, Darren; MacCallum, Justin
The work of this thesis focuses on synthesizing and analyzing new electron-accepting materials that could be beneficial for the development of organic n-type materials for application in organic electronics. The first research chapter focuses on the synthesis of pyridine-extended dithienophosphole oxide compounds in attempts to combine the strong emission of the dithienophosphole oxide backbone with the exciting electrochemical properties of methylated viologens. The motivation for this research and the various synthetic approaches attempted will be discussed in detail. Further, reasoning for the unsuccessful nature of this project will be offered. In the second research chapter, intramolecular Lewis acid/base interactions are formed to produce new hypervalent phosphorus compounds with electron-accepting capabilities. Systematic phosphorus functionalization is performed to allow for manipulation and exploitation of the electrochemical and optical properties of the molecule. Finally, the interactions present in the compounds are rationalized using theoretical calculations.
Open Access
Serendipitous Synthesis of Sulfur and Selenium-Containing Macrocycles and Their Application as GPx Mimetics
(2022-11-01) McMillan, Jacob Daniel Roy; Back, Thomas; Ling, Chang-Chun; Derksen, Darren; Sutherland, Todd
Glutathione peroxidase, or GPx, is a selenocysteine based enzyme whose role is to prevent oxidative stress in mammalian cells by catalytically reducing harmful hydrogen peroxide and hydroperoxides, to water or their corresponding alcohols, respectively. This process simultaneously results in the oxidation of glutathione, a naturally abundant thiol, to glutathione disulfide. While GPx generally works well at preventing oxidative stress, there are certain circumstances where GPx can become overwhelmed, such as during reperfusion after a heart attack or stroke, that can result in excessive oxidative stress. Therefore, there is interest in the development of small molecule selenium compounds that could act as mimetics of GPx and aid it in the reduction of harmful peroxides. Spirodioxyselenuranes have been reported to be particularly effective GPx mimetics and analogues that contain heteroatoms other than oxygen are also of interest. During attempts to prepare spirodithiaselenuranes, which would be a novel class of compounds, a series of macrocyclic dimers containing both selenide and disulfide moieties was obtained instead. Chapter two describes attempts toward the synthesis of spirodithiaselenuranes and the characterization of the isolated macrocyclic species. Based on these results, the remainder of chapter two describes the synthesis of a range of these macrocyclic dimers. Chapter three focuses on the application of these dimers as GPx mimetics and the assays used to measure their activity. During this study a surprising induction period in the catalysis was observed which was determined to be due to autocatalysis by the oxidized macrocycle.
Open Access
Synthesis and Characterization of Azaheterocycle Containing Non-Fullerene Acceptors
(2022-12-12) Turnbull, David Robert; Van Humbeck, Jeffrey; Derksen, Darren; Sutherland, Todd
This thesis details the synthesis and characterization of new azaheterocycle containing non-fullerene acceptors for use in organic photovoltaics (OPV). Herein, we present two independent studies where azaheterocycles serve different uses. Chapter one introduces non-fullerene acceptors including current limitations in the field and the different azaheterocycles to be used within this work. Chapter two goes over the computational studies undertaken prior to synthetic work to confirm the validity of synthetic targets. Chapter three details the design, synthesis, and characterization of two fused electron acceptors using bis trifluoromethyl naphthyridine as an endcap. These molecules were implemented in devices via our collaborator Dr. Greg Welch where devices gave a performance of around 0.1% PCE. Chapter four includes the design, synthesis, and characterization of three new non-fused electron acceptors using diazaheterocycles as the central unit to influence morphology and the effects from different isomer conformation. All final compounds were further characterized via UV-vis spectroscopy and cyclic voltammetry.
Open Access
Synthesis and Use of Selenonic Acids as Epoxidation Catalysts and Mechanistic Investigation of the Antioxidant Drug Ebselen
(2023-08) Sands, Kai Neil; Back, Thomas George; Derksen, Darren; Ling, Chang-Chun; Gailer, Jurgen; Gravel, Michel
Selenium and selenium dioxide have long been known to effect the oxidation of organic substrates, first appearing in the early 20th century as a method of dehydrogenating hydrocarbons. Little progress was made in the use of organoselenium reagents in organic synthesis until the early 1970’s when the selenoxide syn-elimination was shown to be a general method for the installation of double bonds. This reinvigorated the field of organoselenium chemistry, and over the ensuing decade several new selenium-mediated oxidations were developed, including the epoxidation and dihydroxylation of alkenes, Baeyer-Villiger oxidations and the oxidation of phenols to quinones. Many studies of these reactions have invoked a peroxyseleninic acid as the active oxidant, though little evidence was provided at the time to support these claims. Contrary to these early reports, we found that the peroxyseleninic acid is a relatively poor epoxidizing agent due to its facile decomposition to a mixed selenonium-selenonate salt. This salt is stable in the solid state, but generates the corresponding selenonic acid in the presence of hydrogen peroxide. The selenonic acid itself is inactive towards epoxidations; however, in the presence of excess peroxide, rapid epoxidation occurs. This shows that the selenonic acid must be further activated, presumably to the benzeneperoxyselenonic acid. Although selenonic acids were first reported more than a century ago, they have been studied far less frequently and have found little application as synthetic reagents when compared to their seleninic acid analogues. This is in large part due to difficulties in their preparation and characterization, which led to errors in their structure identification in earlier work. Given the newfound importance of selenonic acids in oxidation reactions, a new protocol for the efficient and expedient synthesis of selenonic acids was needed. This was achieved in a one-pot reaction starting from readily available aryl bromides to furnish a range of aryl selenonic acids bearing electron-donating and -withdrawing groups in good to high yields. Finally, organoselenium compounds can mimic the selenoenzyme glutathione peroxidase, which protects cells against oxidative stress by reducing peroxides in the presence of the tripeptide thiol glutathione. Ebselen is arguably the most studied such mimetic; however, there is still considerable uncertainty in its mechanism of action. The final portion of this thesis is a systematic reinvestigation of several key reactions of the proposed catalytic cycles in order to gain further insight into its mechanism which may allow for the design of better glutathione peroxidase mimetics.
Open Access
Synthesis of Polyionic Cyclodextrin Hosts and the Characterization of Their Inclusion Complexes with Steroids
(2022-06) Achebe, Nnenna E; Ling, Chang-Chun; MacCallum, Justin; Derksen, Darren; Anikovskiy, Max
The work presented in this thesis is concerned with modified polyionic cyclodextrins and their structural functionality with regards to forming host-guest inclusion complexes. Cyclodextrins are well-known to encapsulate a variety of hydrophobic molecules: however, only a few studies have been conducted to understand the impact of extending the cavity of well-defined cyclodextrins using alkyl side-chains with like charges on their termini. In Chapter 1:, the history and background information about cyclodextrin inclusion complexes was provided, along with a discussion of the precedence in literature and the theory surrounding the study of these supramolecular systems. Subsequently, Chapter 2: presented an outline of the synthetic schemes, and the work that was done, along with characterizations towards the polyionic cyclodextrin hosts that were then used for the analysis. Finally, in Chapter 3:, inclusion complexes between the synthesized polyionic hosts and a selection of steroid guest molecules were studied. NMR studies and ITC were used to gain a better understanding that the role the extension of the cavity played, as well as the impact of charges on the host molecule on the interaction with neutral and charged guest molecules. The guest molecules of choice were primarily steroid molecules, which are known to form complexes with cyclodextrin. Through these studies, binding constants, along with the thermodynamic parameters were obtained.
Open Access
The Synthetic Pursuit of meso-tetrakis(arylethynyl)porphyrins
(2017) Viccars, Joel; Heyne, Belinda; Sutherland, Todd; Ling, Chang-Chun; Prenner, Elmar; Derksen, Darren
The developments of liquid crystalline porphyrins are of interest to chemists in the field of applied chemistry and material science due to their potential as functional organic materials. This pursuit involved synthesizing 5, 10, 15, 20- meso-tetrakis(3,5- or 4-alkoxyphenyl)ethynylporphyrins. Incorporating an ethynyl linker at the meso-positions first involved the preparation of 3-(3,5- or 4-alkoxyphenyl)propynals, then subjecting them to porphyrin syntheses under Lindsey’s conditions. Good overall yields of 3-(4-alkoxyphenyl)propynals were achieved by optimization at each synthetic step: alkylation, Sonogashira cross – coupling reaction combined with desilylation, and formylation. Adjusted Sonogashira reaction conditions and a optimized co-catalyst ratio of 0.05: 0.03 molar equivalence of palladium(0) and copper(I) catalyst respectively, 100% conversion according to 1H NMR spectroscopy was achieved and yields nearing 80% was calculated after desilylation. The successful preparation of 3-(4-alkoxyphenyl)propynals and not 3-(3,5-alkoxyphenyl)propynals with a high yield of 85% was achieved. However, further optimization of meso-tetrakis(4-alkoxyphenyl)ethynylporphyrin reactions involving cobalt carbonyl protected 3-(4-alkoxyphenyl)propynal needs to be accomplished.
Open Access
Total synthesis of 6-deoxy-β-D-ido-heptopyranosides
(2017) Zhang, Pengfei; Ling, Chang-Chun; Back, Thomas; Sutherland, Todd; Derksen, Darren
Campylobacter jejuni is a Gram-negative bacterium and is the main cause of illnesses related to gastroenteritis in humans. As the outermost structure of Campylobacter jejuni, CPS were made into glycoconjugate vaccines to fight Campylobacter jejuni infection and and have shown promising results. Structural analysis of CPS related to C. jejuni serotype HS:4 revealed a repeating unit consisting of 4-substituted N-acetyl-β-D-glucopyranosamine and 3-substituted 6-deoxy-β-D-ido-heptopyranose. To this end, the focus of the thesis are synthetic studies on 6-deoxy-β-D-ido-heptopyranosides which could be attached to a carrier protein such as CRM197 for immunological studies. Two 6-deoxy-β-D-ido-heptopyranosides (115 and 116) have been successfully prepared for the first time. An efficient protocol to regioselectively convert one O-isopropylidene into di-O-acetates via acetolysis has been established for di-O-isopropylidene-protected D-galacto- and D-fructo-pyranosyl systems (Chapter 3). Trifluoroacetic acid (TFA) was found to achieve the regioselective acetolysis of a series of di-O-isopropylidene-protected hexopyranosides in acetic anhydride.
Open Access
Towards Self-assembling Multichromophoric Materials for Organic Semiconductors
(2016) Thériault, Kim; Sutherland, Todd; Williams, Vance; Baumgartner, Thomas; Ling, Chang-Chun; Derksen, Darren
Organic semiconductors are generally lightweight, flexible materials that can be solution processed. These properties make them an economical alternative to inorganic semiconductors, as they can be more easily manufactured and integrated into existing infrastructure. However, organic electronic devices have seen only marginal improvements in charge carrying ability over the last few decades due to a compromise between ease of manufacturing and efficient charge transport. The field of organic electronics has been developing new molecular systems with attention to the electronic properties of the individual molecules, in addition to understanding the self-assembly of these molecules in the solid state. The goal of this thesis was to investigate the molecular and supramolecular properties of novel multichromophoric molecules as organic semiconductors, which could be an alternative to the bimolecular systems that are commonly used in electronic devices. First, phenothiazine derivatives were synthesized and optical and electrochemical properties were studied as potential electron donor chromophores. These phenothiazine derivatives were found to have large Stokes shifts associated with a large geometry change upon excitation. Second, analogous acridone derivatives were synthesized and investigated to explore the differences in optical properties. They did not exhibit a large geometry change upon excitation but underwent intramolecular charge transfer, enhancing the absorption properties compared to phenothiazine. Lastly, a multichromophoric triad comprised of a naphthalene diimide core flanked by two phenothiazine derivatives separated by an alkyl spacer was synthesized. The optical and electrochemical properties of the triad in solution were investigated as well as self-assembly and photocurrent responses in films. It was demonstrated that the chromophores in the triad behaved independently both optically and electrochemically. In the solid state, the triad formed ordered films and generated small currents upon exposure to light, which are encouraging preliminary results towards the development of new multichromophoric photoactive materials.
Open Access
β-cyclodextrins modified with different chain lengths and their physical characterization with and without the attachment to gold nanoparticles.
(2017) Lam, Wing Man; Heyne, Belinda; Ling, Chang-Chun; Cramb, David; Derksen, Darren; Anikovskiy, Max
Beta-cyclodextrins (β-CDs) are a family of water soluble, naturally occurring cyclic oligosaccharides with a hydrophobic cavity that is used to host hydrophobic guest molecules. The numerous hydroxyl groups allow the native β-CD to be easily functionalized via synthetic modifications. By attaching modified CDs to the surface of gold nanoparticles (AuNPs) through a thiol moiety, its surface plasmon resonance effect can be taken advantage of. The AuNPs exhibit a photothermal effect upon irradiation which can alter the binding constant of guest molecules in β-CD hosts. Therefore, we attached novel β-CDs with different length ethylene glycol chains in hopes of studying in a distance-dependent manner the changes in the binding between the host and guest molecules. Prior to the attachment of the modified β-CDs to the surface of the AuNPs, Nile Red (NR) was utilized as a fluorescent guest to physically characterize the modified β-CDs.