Browsing by Author "Back, Thomas George"

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    Antioxidant Activity and Proton Coupled Electron Transfer Processes in Conformationally Restricted Naphthalene peri-Dichalcogenides
    (2019-08-23) Tuck, Tyler A.; Back, Thomas George; Sutherland, Todd C.; Ling, Changchun; Welch, Gregory C.
    Conformationally restricted naphthalene peri-dichalcogenides are powerful mimetics of the selenoenzyme glutathione peroxidase (GPx), and form charge transfer complexes with the electron acceptor tetracyanoquinodimethane (TCNQ). More recently, the Back group has discovered that these molecules display unusual NMR behaviour. This thesis describes a thorough investigation into this NMR behaviour, which is attributed to a proton-coupled electron transfer process (PCET) between the dichalcogenide and its own conjugate acid to form a radical and a radical cation. Evidence supporting this conclusion comes from NMR experiments, EPR spectroscopy, reversibility with sodium dithionite, as well as computational results. Most conformationally restricted naphthalene peri-diselenides synthesized thus far have poor water solublity, a major limitation to serve as GPx mimetics. The second part of this thesis will describe attempts to alleviate this issue by describing the synthesis and GPx like activity of more polar conformationally restricted naphthalene peri-diselenides.
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    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.
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    Asymmetric Synthesis with Organoselenium Compounds – The Past Twelve Years
    (Wiley-VCH, 2024) Stadel, Jessica T.; Back, Thomas George
    The discovery and synthetic applications of novel organoselenium compounds and their reactions proceeded rapidly during the past fifty years and such processes are now carried out routinely in many laboratories. At the same time, the growing demand for new enantioselective processes provided new challenges. The convergence of selenium chemistry and asymmetric synthesis led to key developments in the 1970s, although the majority of early work was based on stoichiometric processes. More recently, greater emphasis has been placed on greener catalytic variations, along with the discovery of novel reactions and a deeper understanding of their mechanisms. The present review covers the literature in this field from 2010 to early 2023 and encompasses asymmetric reactions mediated by chiral selenium‐based reagents, auxiliaries and, especially, catalysts. Protocols based on achiral selenium compounds in conjunction with other species of chiral catalysts, as well as reactions that are controlled by chiral substrates, are also included.
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    Design and Synthesis of Multi-cavity Cyclodextrin Hosts
    (2019-04-18) Zhang, Zhuge; Ling, Changchun; Back, Thomas George; Sutherland, Todd C.
    Cyclodextrins (CDs) are cyclic oligosaccharides made of α-(1→4)-linked D-glucopyranosyl units. They have found widespread utility in host-guest chemistry, drug delivery, artificial enzymes, and biosensors because of their hydrophobic cavities, which can be used to form inclusion complexes with different organic compounds. Covalently linking CD monomers together in a pre-defined geometry constitutes an attractive strategy to form structurally well-defined multi-cavity hosts. Such novel hosts are expected to have enhanced inclusion capability and furthermore, when interacting with guest molecules of complementary geometry and sizes, the CD cavities can work together, creating the much desired cooperativity effect. In this thesis work, the design and synthesis of two families of multi-cavity CD hosts are reported. Chapter two and three are concerned with the design, synthesis and characterizations of two families of multi-cavity CD hosts. The first family consists of linear hetero-trimers of CDs and the second family includes oligomeric CD hosts linked in a macrocyclic fashion. All these multi-cavity hosts were synthesized using partially O-methylated α-, β- and γ-CDs as building blocks. The highly-efficient copper(I)-catalyzed alkyne/azide 1,3-dipolar cycloaddition reaction was used in all syntheses that shows unparalleled efficiencies. Some initial attempts to characterize the inclusion complexes using isothermal titration calorimetry are also reported in Chapter four, but encountered some difficulties. Finally, the experimental procedures are included in Chapter five.
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    The Development of Di-N-Acetyl-L-Pyranosides for the Synthesis of Pseudaminic Acid and 8-epi-Legionaminic Acid
    (2019-12-19) Sequeira, Carita-Louise Aurelle; Ling, Changchun; Sutherland, Todd C.; Derksen, Darren J.; Back, Thomas George; Roesler, Roland
    Pseudaminic acid, Legionaminic acid, and epimers are key bacterial nonulosonic acids found in the flagella of pathogenic bacteria. These sugars are found to be crucial to flagellar assembly and are thus attractive targets for raising an immune response against. By retrosynthetic analysis, we hypothesized that using L-sugars as starting materials for synthesis of the key hexose intermediates was a novel and practical route. The primary goal of the thesis was to develop a synthetic methodology that was adaptable to synthesizing both di-2,4-N-acetyl-2,4,6-trideoxy-altropyranoside and di-2,4-N-acetyl-2,4,6-trideoxy-Lgulopyranoside: the key intermediates in the biosynthetic pathways of Pseudaminic acid and 8-epiLegionaminic acid from L-fucose and L-rhamnose respectively. Chapter 1 gives a brief introduction to immunity and bacterial nonulosonic acids; particularly, Pseudaminic acid and 8-epi-Legionaminic acid. The biosynthetic pathways of Pseudaminic acid and Legionaminic acid are also summarized. Chapter 2 provides detailed reviews on the chemical methodologies reported in the literature for the synthesis of Pseudaminic acid and 8-epi-Legionaminic acid. Chapter 3 contains the bulk of the work of this thesis toward the development of a new methodology toward the synthesis of the key hexoses di-2,4-N-acetyl-2,4,6-trideoxy-altropyranoside and di-2,4-Nacetyl-2,4,6-trideoxy-L-gulopyranoside. Chapter 4 details the experimental procedures and spectroscopic data of all synthesized compounds given in Chapter 3.
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    Synthesis and optical characterization of amphiphilic benzimidazole-based cyanine dyes
    (2020-04-14) Roth, Sophia Marie; Heyne, Belinda; Sutherland, Todd C.; Back, Thomas George; Anikovskiy, Max; Prenner, Elmar J.
    Cyanine dyes have seen use in a plethora of applications since the first report of their synthesis in 1856. While historically the utility of this class of compounds has been derived from their ability to act as photographic sensitizers in silver halide photography, they have maintained relevance through their applicability to other fields, including bioimaging and organic photovoltaics. The capacity of cyanine dyes to stand the test of time is due predominantly to their favourable optical properties. One attribute known to alter these photophysical characteristics, however, is the propensity of many cyanine dyes to aggregate in solution; when going from monomeric compounds to self-assembled structures, absorption and emission features change. To effectively obtain the optical properties desired of cyanine dyes for diverse use, their aggregation tendencies must be understood. The work outlined herein focuses on studying the structure-aggregation relationships of a family of amphiphilic benzimidazole-based trimethine cyanine dyes, whose chlorinated derivatives are known to form aggregates of distinct morphology in aqueous solution. By systematically modifying the chromophore’s core, it was hoped that the structural features that dictate their aggregation could be elucidated. Synthetic efforts to attain the dyes under investigation are highlighted in the first research chapter of this thesis. While the conventional means of preparing these compounds worked for some of the target derivatives, they failed for others. This deficiency in the traditional route warranted the development of a new synthetic method, which saw success in preparing a set of previously elusive compounds. Next, the optical properties of these newly-synthesized dyes were explored, under monomer and aggregate conditions, in the second research chapter. Through both empirical and computational means, it was found that the presence and positioning of halogens on the studied dyes had an effect on the photophysical properties of the monomers as well as aggregation tendencies. This thesis concludes with a summation of the work completed to date, and an accompanying perspective on what the future of this project may bring.
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    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.
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    Synthesis of Nucleoside-Based Antiprotozoan Compounds and Total Synthesis of Cylindricine C and its 2,13-Di-epi Stereoisomer
    (2023-07) Pastor, Arnaud Mario Denis; Back, Thomas George; Derksen, Darren Jason; Sutherland, Todd Christopher; Roesler, Roland; Sammis, Glenn Martin
    Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleosides and nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of adenosine analogues was prepared by members of our group with modifications at the 2-, 6- and 5'-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The altered nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base and uptake by the parasite. One adenosine derivative that is described in this thesis proved highly effective against Plasmodium falciparum (malaria): IC50 = 110 nM and selectivity index (SI) versus a mammalian cell line of 1010. Consequently, its synthesis was optimized and several new analogues containing different amino groups were prepared and assayed. Furthermore, one 7-deazaguanosine derivative proved effective against Leishmania donovani (leishmaniasis): IC50 = 60 nM and SI = 2720, as well as against several other pathogenic protozoa. Therefore, a new synthesis leading to the antileishmaniasis compound was also designed and optimized. Cylindricine alkaloids possess a rather uncommon tricyclic pyrrolo[2,1-j]quinoline framework containing a cis-fused azadecalin skeleton, making them unique molecules. They are difficult to isolate from natural sources and novel approaches to synthesize these compounds are thus required. Our research group has synthesized 2,13-di-epi-cylindricine C and cylindricine C via a tandem conjugate addition and intramolecular cyclization of a key intermediate ß-amino ester and an acetylenic sulfone. Following consecutive desulfonylation and reduction of the resulting enaminone double bond moiety yielded 2,13-di-epi-cylindricine C and cylindricine C in a diastereomeric ratio of 3:1. The former molecule appears to be novel, and its spectroscopic data failed to match those of any existing stereoisomers in the literature. Crystallization methods were attempted and 2D NMR techniques, as well as computational calculations, were employed in order to fully characterize the proposed structure of 2,13-di-epi-cylindricine C. Furthermore, an enhancement of the 3:1 d.r. was attempted by means of chiral selenium electrophiles in another key cyclization step.
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    Synthetic Studies toward 2,3-di-N-Acyl-2,4,6-Trideoxy-L-Altropyranoses as Synthetic Precursors to Pseudaminic Acid
    (2023-07) Niedzwiecka, Anna; Ling, Chang-Chun; Back, Thomas George; Van Humbeck, Jeffrey; Derksen, Derren; Auzanneau, France-Isabelle
    With the growing therapeutic inefficiency of traditional antibiotics by rapidly spreading antimicrobial resistance (AMR) through different mechanisms, and a significant slow-down in the development of novel antimicrobials, especially in the pharmaceutical industry during recent years, it is of utmost importance to maintain research to address this global challenge. The chemical synthesis of carbohydrate antigens that are unique to pathogenic bacteria can benefit the search for antibacterial therapeutics with the development of prophylactic vaccines such as polysaccharide conjugates. Bacterial nonulosonic acids (NonAs) that include pseudaminic (Pse) and legionaminic (Leg) acids are found in important structural components that contribute to certain pathogens’ virulence, like Pseudomonas aeruginosa and Campylobacter jejuni: they have been recently shown to be good candidates for use as antigen epitopes in vaccination, and their biosynthetic precursors can also be used towards the development of other types of antibacterial therapeutics. The research presented here begins with preliminary investigations into a synthesis from L-arabinose that has the potential to produce 5 different NonA structures with only a few appropriate variations in the scheme. The synthesis of two C5-(R)/(S) hexose diastereomers was achieved with different selectivity, and those can further undergo an inversion and installation of nitrogen functionalities on C-2 and C-4, before the final three-carbon extension with a phosphoenolpyruvate (PEP) equivalent to produce the target NonA. The work showed promise, justifying future development. Next, a short, mild and scalable synthetic scheme towards 2,4-di-acetamido-2,4,6-trideoxy-L-altrose (Alt-diNAc), the biosynthetic precursor to Pse, is presented: the desired product was obtained from commercially available L-fucose in 10 steps and 23% overall yield, making it the most efficient synthesis published to-date. A further optimized shorter version of synthesis is described as well through regioselective sulfonyl activation to form a key epoxide intermediate, ultimately giving Alt-diNAc in 7 steps and 27% overall yield. Based on these achievements, a new and elegant methodology for the differentiable functionalization of the N2/N4 amide groups of Alt-diNAc was developed, which relies on a regiospecific O→N migration of acyl groups during a Staudinger reduction of the O-acylated di-azido precursor. The new methodology was proved to have broad scope and provides unprecedented versatility to introduce different N-acyl functionalities to the N5 and N7 positions of Pse. Finally, preliminary work towards a potentially stereoselective three-carbon extension of hexose precursors to NonAs is described, with the synthesis of a phenol-based cleavable linker containing an α-methyl ketone that can potentially undergo aldol addition intramolecularly, and then ruthenium-catalyzed oxidation to produce the required carboxylic functionalities for Pse. A successful selective coupling of this linker to one of the two amido groups on the L-altro-configuration precursor was then achieved, paving the way to investigate the diastereoselectivity of intramolecular aldol additions with this strategy in the future. Several possible variations to the linker functional groups and length can easily be incorporated in this synthetic plan , and provide an exciting prospect for future developments.
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    The Design and Properties of Organoselenium Compounds with Glutathione Peroxidase-Like Activity
    (2013-12-04) Press, David James; Back, Thomas George
    The selenoenzyme glutathione peroxidase protects against oxidative stress by reducing peroxides in the presence of glutathione, a tripeptide thiol. Under conditions of extreme oxidative stress, for example during ischemic reperfusion, this process can become overwhelmed. Glutathione peroxidase mimetics are organoselenium compounds which catalytically destroy peroxides and can be used to treat oxidative stress associated with ischemic reperfusion and related conditions. The majority of this Thesis describes the design of efficacious glutathione peroxidase mimetics. An investigation of substituent effects upon the glutathione peroxidase-like activity of aromatic cyclic seleninate esters and spirodioxyselenuranes was initiated. It was found that para-substitution with electron-donating groups resulted in the greatest increase in catalytic activity. Hammett analysis established that the rate-determining step in each compound’s catalytic cycle was the oxidation of Se(II) to Se(IV). Overall, para-methoxy substitution caused the greatest increase in thiol peroxidase activity, while dimethoxy and trimethoxy substitution did not ensure superior thiol peroxidase activity. Included in this study were 3-hydroxypropyl and 2,3-dihydroxypropyl (2-hydroxymethyl)phenyl selenides, which are new classes of glutathione peroxidase mimetics that displayed strong peroxide destroying activity. The former class of compounds includes the most active organoselenium glutathione peroxidase mimetic prepared in our group to date, while members of the latter class are sufficiently water soluble to allow for their activity to be monitored in aqueous environments. Additionally, naphthalene peri-diselenides were found to have significantly improved thiol peroxidase activity relative to acyclic diselenides. This was due to the severely reduced dihedral angle found in the naphthalene peri-diselenides, which leads to a destabilized ground state, lower ionization potential and an increased rate of reaction with peroxides. These diselenides also produced stable charge-transfer complexes with tetracyanoquinodimethane that are of potential interest as photovoltaic materials. Finally, configurational stability of the cyclic seleninate esters and spirodioxyselenuranes was investigated by variable-temperature NMR spectroscopy. These compounds were configurationally stable at high temperatures, while the spirodioxyselenuranes displayed unexpected proton NMR behaviour, caused by temperature-dependant chemical shifts.
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    Towards a Fully Synthetic Glycoconjugate Vaccine: Synthesis of Antigenic Oligosaccharides Related to Campylobacter jejuni HS:4c
    (2024-01-18) Homayonia, Saba; Ling, Chang-Chun; Back, Thomas George; Derksen, Darren Jason; Fraser, Marie Elizabeth; Monteiro, Mario
    Campylobacter jejuni is a bacterial pathogen that causes hundreds of millions of cases of food-borne gastroenteritis worldwide annually. The infection caused by this bacterium is also associated with several forms of post-infectious autoimmune sequelae that can be very serious, including the life-threatening Guillain-Barré syndrome. The capsular polysaccharides (CPS) of C. jejuni HS:4c consist of a unique repeating disaccharide unit that is characterized with a β-1,4-linked 6-deoxy-β-D-ido-heptopyranose and an N-acetyl-β-D-glucosamine. The 6-deoxy-ido-configuration of the heptose combined with its β-anomeric configuration makes the chemical synthesis of the disaccharide very challenging. Interestingly, the bacterial CPS is found to be partially modified with an O-methyl phosphoramidate (MeOPN) functionality at the O-2 or O-7 position of the 6-deoxy-β-D-ido-heptopyranosides. Building upon our previously established methodologies, in chapter Two the first synthesis of three analogues of β-D-ido-octopyranosides that contain a 6,7-dideoxy-functionality and either a terminal methyl ester or carboxylic acid or amide is reported. Since carboxylic acids have been reported as bioisosteres of a phosphate group, these analogues can be regarded as carbon-based bioisosteres of 6-deoxy-β-D-ido-heptopyranoside containing a MeOPN group without a chiral center. The three octopyranosides were efficiently synthesized from a O-2 activated β-D-galacto-octopyranuronate that was smoothly converted to the desired β-D-ido-octopyranuronate configuration using an elegant one-pot process. Furthermore, an efficient synthetic scheme to obtain oligosaccharides related to CPS structures of C. jejuni HS:4c is developed in chapter Three. The synthesis is featured with a highly efficient, one-step stereo and regioselective conversion of β-D-galacto-heptopyranosides to 6-deoxy-β-D-ido-heptopyranosides via an intermediate 2,3-anhydro-β-D-talo-heptopyranoside. The key repeating disaccharide and its analog in reverse order plus a trisaccharide were synthesized as the target compounds. Originated from the fact that enzyme-resistant thioglycosides are highly valuable immunogens due to their enhanced metabolic stability, in chapter Four the first synthesis of a family of thiooligosaccharides related to the capsular polysaccharides (CPS) of Campylobacter jejuni HS:4c for potential use in conjugate vaccines is reported. So far, no synthesis of the thioanalogues of the CPS antigens have been reported. The unprecedented synthesis presented in this work is built on an elegant approach by using β-glycosylthiolates as a glycosyl donor to open the 2,3-epoxide functionality of pre-designed 6-deoxy-β-D-talo-heptopyranosides. The results illustrated that this key transformation can be designed in a modular and highly regio and stereo-selective manner. Built on the success of this novel approach, I succeeded in the synthesis of a family of thiooligosaccharides including a thiohexasaccharide which is considered to have the suitable length and complexity for use as an antigen in future immunizations. The first direct conversion of base-stable but acid-labile 2-trimethylsilylethyl glycosides to glycosyl-1-thioacetates in a one-pot manner is also reported. MeOPN-containing carbohydrates are important targets as such structures can play a critical role in understanding the biosynthetic pathway and immunological importance of this phase-variable modification. As a result, in chapter Five the synthesis of two β-D-ido-heptopyranose monosaccharides with the MeOPN functionality either on O-2 or O-7 position is commenced which mimics the native repeating disaccharide unit related to the CPS structures of C. jejuni HS:4c.
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    The Unexpected Role of Se(VI) Species in Epoxidations with Benzeneseleninic Acid and Hydrogen Peroxide
    (2019-12-24) Back, Thomas George; Sands, Kai N; Mendoza Rengifo, Emerita; George, Graham N; Pickering, Ingrid J; Gelfand, Benjamin S
    Benzeneperoxyseleninic acid has been proposed as the key intermediate in the widely used epoxidation of alkenes with benzeneseleninic acid and hydrogen peroxide. However, it reacts sluggishly with cyclooctene and instead rapidly decomposes in solution to a mixed selenonium-selenonate salt that was identified by x-ray absorption, 77 Se NMR spectroscopy, and by single crystal x-ray diffraction. This process includes a selenoxide elimination of the peroxyseleninic acid with liberation of oxygen and additional redox steps. The salt is relatively stable in the solid state, but generates the corresponding selenonic acid in the presence of hydrogen peroxide. The selenonic acid is inert towards cyclooctene on its own; however, rapid epoxidation occurs when hydrogen peroxide is added. This shows that the selenonic acid must first be activated through further oxidation, presumably to the heretofore unknown benzeneperoxyselenonic acid. The latter is the principal oxidant in this epoxidation.