Browsing by Author "Derksen, Darren Jason"
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Item Open Access Computer-aided drug design of activators of the cardiac Kv7.1 potassium channel(2023-08) Castro Gonzalez, Laura Maria; Tieleman, Peter; Zaremberg, Vanina; Derksen, Darren Jason; Fraser, Marie ElizabethLong QT syndrome is a heart disease that ends the lives of numerous children and young adults every year. This condition is triggered by the malfunction of some ion channels, including the voltage-gated potassium Kv7.1. In this thesis, multiple computational tools were employed to identify compounds that potentiate the activity of this ion channel. First, a Kv7.1 computational model was created from the Xenopus laevis structure. Then, suitable binding sites in the channel were identified using libraries of known activators of the channel: polyunsaturated fatty acids and endocannabinoids. Selected sites were in silico screened against a large library of small molecules. Multiple criteria such as binding energies, bioavailability and selectivity were employed to finally select compounds for experimental evaluation. This work identified two compounds with high potency and specificity for each binding site studied in the Kv7.1 channel.Item Open Access Development of Site-Selective C-H Functionalization Strategies for Azaheterocycles(2024-07-26) Kaur, Milanpreet; Van Humbeck, Jeffrey Francis; Derksen, Darren Jason; Sutherland, Todd C.; Shimizu, George Kisa Hayashi; Watson, Allan J. B.C-H activation is an area of major ongoing research exploration and has emerged as a valuable addition to the organic chemist’s toolbox for the rapid construction of compounds that are of great interest to the pharmaceutical industry. More specifically, recent work has focused on C-H activation at a late stage in complex and biologically relevant molecules. Recently, activation of C-H bonds in heterocycles has emerged as a new route in the synthesis of heterocycles. In particular, the transformation of the C-H bond into C-X bond (where= carbon, oxygen or nitrogen) in heterocycles has gained interest due to its availability in biologically active pharmaceuticals, agrochemicals, and natural products. Although various approaches have been developed for activating C-H bonds in azaheterocycles, there has been a noticeable challenge in a) carrying competitive C-H functionalization when several sites of comparable reactivity are present; and b) accessing many possible reactive sites within a substrate. This work showcases the development of a novel site-selective C-H functionalization strategy in azaheterocycles by taking substrates with different C-H bonds of comparable reactivity and selectivity and converting only one of those C-H bonds predictably into a new carbon-element bond. The goal was to do so using catalyst control and without including any directing groups. This research begins with the development of a new site-selective benzylic C-H hydroxylation in electron-deficient azaheterocycles, encompassing a diverse range of substrates. The latter part of the thesis addresses the challenges associated with the site-selective amination strategy previously developed by our group. In-depth research was conducted to develop catalytic systems capable of selectively and predictably aminating the C-H bond adjacent to an azaheterocycle. Additionally, extensive research was conducted towards synthesizing and deprotecting aminating reagents as well as utilizing photochemistry to install a selective hydrazine/amine unit that can be used to direct other C-H functionalization chemistries.Item Open Access Synthesis of 2-arylpyridines by the Suzuki-Miyaura cross coupling of PyFluor with hetero(aryl) boronic acids/esters and Synthesis of ring oxidized phthalocyanine metal fluorides(2024-10-02) Ramanayake, Dewni Jayathma; Love, Jennifer Ann; Derksen, Darren Jason; Welch, Gregory CharlesRecently, there has been considerable interest in Sulfonyl fluorides owing to their distinctive chemical and biological characteristics. The exceptional strength of the S-F bond and the S(VI) center is responsible for the inertness and stability of sulfonyl fluorides against reactions such as hydrolysis, and reduction. However, the C-S bond of sulfonyl fluorides has been considered unreactive until recently. In particular, the activation of the C-S bond under Suzuki-Miyaura coupling conditions has not been extensively investigated. In chapter 2, we present the Suzuki-Miyaura cross-coupling reaction of pyridine-2-sulfonyl fluoride (PyFluor) with hetero (aryl) boronic acids and pinacol boronic esters. With Pd(dppf)Cl2 as the catalyst, the reaction can be carried out within a temperature range of 65 °C to 100 °C to produce 2-aryl pyridines as the product with yields spanning from moderate to good. This approach enables the synthesis of heteroatom-rich biaryls, which are important in the field of drug discovery. Phthalocyanine (Pc) ligands are chemically and thermally stable symmetric 18 π electron aromatic macrocycles, closely related to the naturally occurring porphyrins. They have been widely used as pigments/dyes, photoconducting materials, industrial catalysts, and photosensitizers in biomedical applications. The characteristics of the Pc ring, such as its solubility and electronic properties, are strongly influenced by incorporating metals inside the Pc macrocycle and by adding substituents in the alpha or beta positions of the ring. The most stable oxidation state of Pc is Pc-2, but it is redox active and can access oxidation states from Pc0 to Pc-6. The oxidation of the Pc ring can be confirmed by UV-Visible spectroscopy, Nuclear Magnetic Resonance (NMR) Spectroscopy, and single-crystal X-ray diffraction. Ring oxidized and reduced metallophthalocyanine (PcM) compounds have not been extensively investigated (and especially, not generally isolated) possibly due to the high reactivity of these complexes. In chapter 3, we detail a preliminary study on the synthesis of substituted and unsubstituted ring-oxidized phthalocyanine metal fluorides, using a range of strong oxidizing agents which also incorporate fluorides.Item Open Access 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 MartinParasitic 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.Item Open Access 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, MarioCampylobacter 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.