Browsing by Author "Derksen, Darren J."

Now showing 1 - 16 of 16
  • Thumbnail Image
    ItemOpen Access
    Bay-region Expanded Perylene Diimides for Green Printed Electronics
    (2021-01-13) Harris, Dylan Henry; Welch, Gregory C.; Derksen, Darren J.; Ling, Changchun; Kimura, Susana Y.
    Reported within is the development of a new acid-catalyzed synthesis that provides access to alcohol-processable bay-substituted N-H functionalized PDI derivatives. The results were published in a recent manuscript and have been included in Chapters 1 and 2 of this thesis. Full structural and optoelectronic characterization was performed including optical absorption spectroscopy, cyclic voltammetry (CV), single crystal X-ray diffraction (SC-XRD), H-NMR spectroscopy, C-NMR spectroscopy, MALDI-TOF mass spectrometry, CHN elemental analysis, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Molecular design considerations are presented in the context of density functional theory (DFT) energy level diagrams from collaborators in the Rondeau-Gagné lab at University of Windsor. Organic field effect transistor (OFET) device data was collected via our collaboration with the Lessard lab at University of Ottawa. This thesis strives to highlight multiple ways in which our new synthetic method can be utilized to provide high performing and green solvent processable OFET materials. Successes and failures of the synthesis of new targets are documented and discussed with respect to electronic structure considerations.
  • Thumbnail Image
    ItemOpen Access
    Beyond geminal diesters: increasing the scope of metal-mediated vinylcyclopropane annulations while decreasing pre-activation
    (2018-01) Brownsey, Duncan K.; Gorobets, Evgueni; Derksen, Darren J.
    The utilization of unactivated substrates in annulation reactions provides access to complex products without the need for subsequent removal of the activating group. Vinylcyclopropanes (VCPs), occurring naturally in several monoterpene natural products, are an important building block for organic chemistry, and can be activated by electron withdrawing substituents directly on the cyclopropane to facilitate ring opening reactions. However, many VCPs that lack these activated groups remain reactive with several group 8, 9 and 10 transition metals, by alternative modes of activation, forming metallacycles. These useful intermediates produce annulation products in reactions with unsaturated π-units, providing rapid access to new carbocycles. Several formal cycloadditions that incorporate unactivated VCPs as substrates have been developed, including [5 + 2], [5 + 2 + 1], [5 + 1 + 2 + 1], [3 + 2], [3 + 2 + 1], [5 + 1], and others, using Rh, Ni, Ru, Ir, Fe and Co based catalysts. Mono- and polycyclic ring systems have been made using these methods with their utility demonstrated through the synthesis of complex natural products. This review will summarize the annulations of VCPs that lack geminal diesters, but retain reactivity via transition metal catalysts.
  • Thumbnail Image
    ItemOpen Access
    Chemical Modifications of Cyclodextrins for Ion Conduction, Sensing and Metal Sequestration
    (2019-08-14) Champagne, Pier-Luc; Ling, Changchun; Derksen, Darren J.; Heyne, Belinda; Li, Quan; Shimizu, George K. H.
    Supramolecular assemblies generally consist of molecules held together via non-covalent interactions of various strengths. These assemblies possess an astonishing variety of potential applications in numerous fields. In this thesis, several families of new cyclodextrin (CD) derivatives were synthesized, characterized and discussed. The novel derivatives were prepared with the intention to study their supramolecular assembly in solid states and solutions and develop novel applications. In the solid states, studies on structure-property relationships uncovered the influence of substitution patterns of amphiphilic CDs on their ability to form various liquid crystalline mesophases. A novel family of amphiphilic CD-based liquid crystals bearing O-acetylated oligoethylene glycol (OEG) chains at the secondary face is presented in Chapter Three. Unlike most of the previously reported liquid crystals based on chemically modified CDs which rely on H-bonding as the primary intermolecular force, the present CD derivatives self-assemble into highly ordered smectic liquid crystal phases via the weaker dipole-dipole intermolecular forces. The obtained materials were found to possess much improved properties, such as improved thermostability, reduced clearing temperatures and better fluidity. Chapter Four reports another family of amphiphilic CDs bearing O-acetylated oligoethylene glycol chain by inverting the substitution patterns on β-CDs by simply placing hydrophobic chains to the secondary face and O-acetylated OEG groups at the primary face; we showed that it is possible to transform the nature of mesophases from smectic to columnar. This investigation reveals some intriguing properties of CD scaffolds as a unique class of host mesogens. In addition to introducing OEG groups to CDs, we also attempted to introduce an OEG linker to the known cholesterol mesogen in Chapter Five to obtain either monomeric or dimeric cholesterol mesogens which showed interesting LC properties. A portion of this monograph focused on the potential applications of amphiphilic CD-based liquid crystalline materials. To this aim, we extended the design of our systems by introducing different functional groups at the end of OEG chains. For example, in Chapters Six to Eight, a group amphiphilic CD bearing non-polar alkyl chains at the primary face while multiple OEG groups of different lengths, terminated with a polar nitrile group, was developed; the addition of a nitrile functionality at the end of each OEG chain was found to increase the stability and temperature range of the mesophases; we found the smectic mesophases formed by these novel amphiphilic CDs have great ability to act as electrolytes for the conduction of lithium (Chapter Six and Eight) as well as sodium (Chapter Seven). Furthermore, when the terminal nitrile functionality was replaced with a carboxylic acid, a new family of amphiphilic CD polycarboxylic acids was obtained which constitutes the main topic of Chpater Nine; the introduction of numerous carboxylic acid functionalities at the secondary face of CD serves as a preorganization, that facilitate the formation of complex intra- and intermolecular hydrogen-bond networks in the formed smectic mesophases; introducing water molecules in the mesophases further strengthen H-bond networks by bridging adjacent carboxylic acids groups. We investigate the ability of this novel system for proton conduction and have found very encouraging results. Following our work using different amphiphilic CD-based LC materials for ion-conductions, we noticed that the room temperature crystalline phase can significantly affect the conductive properties of the material. Thus, we designed novel CD heptols displaying liquid crystalline phases at room temperature by inserting unconventional alkyl groups such as those containing cis-alkenic or/and branches at the secondary face. The newly synthesized series of amphiphilic CD derivatives were estimated to have crystal-liquid crystalline transitions below -40 °C. This research is the first to shed light on how to affect the mesomorphic properties of amphiphilic CDs with alkyl groups of bent conformation or containing branches. Copper (I)-mediated alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction was used as the key reaction for the prepartion of all amphiphilc CD derivatives mentioned above. By taking adavantage of the methodology, Chapter Eleven reports an extension of my thesis work by investigating the synthesis of a novel chemically modified polyaminocarboxylate based on beta-CD scaffold using CuAAc and its coordination chemistry for lanthanides. A 1,2,3-triazolmethyl residue was created from each CuAAc reaction that advantageously serves as a competent chelating group while displacing the metal coordination center away from the primary rim of β-CD. With the participation of four N-acetate groups from two adjacent glucopyranosyl units of β-CD, a unique octavalent coordination sphere was created to bind each lanthanide with high affinity, while the lanthanide metal still has one open site available for dynamic water coordination. Furthermore, the CuAAC chemistry allowed us the synthesize another pyrene-appended β-CD fluorescent probe (Chapter Twelve), which self-assembles into nanoaggregates in water driven by hydrophobic π–π interactions. The formed fluorescent nanoaggregates were found to exhibit an efficient and selective ratiometric detection of pirimicarb, a potent toxic carbamate pesticide as well as differentiating nitro-aromatic explosives such as 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitrobenzene (TNB) and picric acid (PA).
  • Thumbnail Image
    ItemOpen Access
    Cytotoxic, Cellular Uptake, and Photophysical Properties of Various Re(I) Tricarbonyl Complexes
    (2019-09-20) Capper, Miles S.; Jalilehvand, Farideh; Heyne, Belinda; Roesler, Roland; Gailer, Jürgen; Derksen, Darren J.
    A series of Re(I) tricarbonyl complexes with the general formula, fac-[Re(CO)3(2,2’-bipyridine)(X)]-/0 (X= L-cysteine; N-acetyl-L-cysteine; thiosulfate) were characterized using spectroscopic techniques and single-crystal X-ray diffraction. Photophysical, as well as singlet oxygen (1O2) generation and CO releasing properties were assessed. Cell viability of the complexes against the MDA-MB-231 breast cancer cell line were determined. Cellular localization and accumulation were investigated using synchrotron-based X-ray fluorescence microscopy (XFM). The results of this study show the cytotoxicity, cellular uptake and photophysical properties of fac-[Re(CO)3(bpy)X]+/0/- complexes (X= H2O, HCys-, NAC2-, S2O32-; bpy=2,2’-bipyridine). The cytotoxicity of fac-[Re(CO)3(bpy)(H2O)]+ is diminished when the aqua ligand is replaced by cysteine or thiosulfate.
  • Thumbnail Image
    ItemOpen Access
    Design and Synthesis of a New Family of Amphiphilic beta-Cyclodextrin Liquid Crystals.
    (2020-06-30) Trudel Lachance, Simon; Ling, Changchun; MacCallum, Justin L.; Derksen, Darren J.
    The field of liquid crystals has fascinated scientists since 1888 when a molecule of cholesteryl benzoate exhibited two different melting points. It corresponds to a state of matter between the isotropic liquid and the crystalline solid-state. Since then, the field has grown, and liquid crystal-based materials have become an important component of our lives. Cyclodextrin (CD) are polyhydroxylated macrocycles containing 6-8 units of beta-D-glucopyranose units linked together via a series of alpha-1,4-glycosidic linkages. The formed macrocycles are shaped like a truncated cone that combines two hydrophilic surfaces and a hydrophobic cavity that can be used to form inclusion complexes with different organic molecules. Our group has been developing chemistries to modify the two hydrophilic surfaces of CDs by a variety of chemical methodologies to generate amphiphilic molecules capable of self-assembling into liquid crystalline mesophases. This thesis focuses on the synthesis a new family of amphiphilic CDs for liquid crystal research. These CD-derivatives can be easily obtained via polyesterification at one of the hydrophilic faces with hydrophobic aliphatic chains and installation of functionalized oligoethylene glycols at the other surface via the copper(I)-catalyzed Huigsen 1,3-dipolar cycloaddition. These novel amphiphilic CD derivatives have been characterized by polarized optical microscopy, thermogravimetric analysis and differential scanning calorimetry.
  • Thumbnail Image
    ItemOpen Access
    Design, Synthesis and Evaluation of Novel Pannexin 1 Channel Modulators
    (2020-10-26) Navis, Kathleen E.; Derksen, Darren J.; Sutherland, Todd C.; MacCallum, Justin L.; Van Humbeck, Jeffrey F.
    Pannexin 1 (Panx1) channels are transmembrane proteins that release ATP and play an important role in intercellular communication. They are widely expressed in somatic and nervous system tissues, and their activity has been associated with many pathologies including stroke, epilepsy, addiction, inflammation and chronic pain. While there are a variety of known Panx1 inhibitors, there is a dearth of sufficiently potent and selective drugs targeting Panx1, and relatively little is known about the mechanism of channel inhibition. Structure-activity relationship (SAR) studies can provide information about the critical functional groups controlling substrate activity and lead to the development of more potent inhibitors. This thesis outlines the importance of Panx1 channels as a potential therapeutic target and describes the synthesis, SAR and evaluation of novel inhibitors based on biological assays. In silico modeling was also used to identify compounds from the ZINC database with similar pharmacophore characteristics to known Panx1 inhibitors. The compounds developed over the course of study may have potential as novel drugs for the relief of multiple important pathologies. Provisional patent protection for this work is currently being pursued.
  • Thumbnail Image
    ItemOpen Access
    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.
  • Thumbnail Image
    ItemOpen Access
    Development of macromolecular phosphorus-containing viologens
    (2018-08-27) Striepe, Laura J.; Baumgartner, Thomas; Sutherland, Todd C.; Derksen, Darren J.; Roesler, Roland; Turner, Raymond Joseph
    This thesis highlights the development and strategy towards larger, macromolecule-based phosphoryl-bridged viologens, or “phosphaviologens”, as an electrode material for application in organic electronics. The general setup of a battery consists of an anode and cathode, separated by an electrolyte. Cathodic materials, or electron-donating p-type materials, have been well established in organic batteries. Their anodic counter-parts, or electron-accepting n-type materials have not seen as much success and require further investigation. The phosphaviologen, developed by the Baumgartner group, has seen significant progress as an n-type material and is investigated in larger systems throughout this thesis. The first research chapter discusses two new “star-shaped” phosphoryl-bridged viologens and their appreciable electron-accepting ability. The three- and four-pendant compounds were fully characterized, and their benefits and drawbacks are examined. The second research chapter discusses the synthetic strategy and attempts of incorporating the phosphaviologen within a larger polymeric material, that is cellulose nanocrystals, and highlights the difficulties associated. Later discussed is an interesting aggregate that is produced between the anionic cellulose nanocrystals and the cationic phosphaviologen molecules. Expanding on the previous chapter, the final research chapter highlights the efforts of developing highly charged phosphaviologen-containing polymers. Initially, various functionalized precursor polymer backbones were utilized with the phosphaviologen. An alternative route was explored with a bottom-up approach, investigating the polymerization of a polymerization-ready phosphaviologen monomer. This chapter closes with a promising outlook with reference to this topic. Lastly, this thesis concludes with the future direction of phosphaviologen aggregates, and the continuation of the development of a polymer-containing phosphaviologen. The overall goal of this thesis was motivated toward developing novel anodic materials for battery applications.
  • Thumbnail Image
    ItemOpen Access
    Elucidating the Interplay Between Lipids and Membrane Proteins Using Multiscale Computer Simulations
    (2020-07-30) Sejdiu, Besian I.; Tieleman, Dirk Peter; Ng, Kenneth Kai Sing; MacCallum, Justin L.; Lyman, Edward; Derksen, Darren J.
    Biological membranes are complex cellular structures formed by a large number of different lipid types, that also contain a variety of bound proteins, carbohydrates, and other molecules. The detailed orchestration of all these elements has been a major focus of scientific research during the last 5 decades. Computer-based methods, such as molecular dynamics (MD) simulations, have proven to be a valuable approach in addressing many of the details of lipid organization and membrane protein activity. I used MD simulations at both atomistic and coarse-grained level of detail to study the number of way lipids and proteins interact and their possible functional ramifications. In part of my work, I studied the interaction of G Protein-Coupled Receptors (GPCRs) with lipids at a family-wide level. Plenty of other computational studies had shown specific lipid-protein interactions for a handful of GPCRs but with quite different outcomes on their number, location, and lipid identity. In my work, I simulated 28 different GPCR structures and showed that they are distinguished by a unique interaction profile with membrane lipids. I provided a comprehensive analysis of simulation results with available crystallographic data. I also studied the lipid-protein interaction profile of AMPA receptors and cyclooxygenases (mainly COX-1), showing that they both form specific interactions with lipids, but do so in a quite different fashion. AMPA receptors interact specifically with diacylglycerol lipids, whereas COX-1 enzymes do so indiscriminately with glycerophospholipids, cholesterol, and fatty acids, but at different levels of interaction strength. Using atomistic simulations, we show the binding pathway of arachidonic acid to COX-1 and identify a series of arginine residues that guide it toward the hydrophobic cavity of the enzyme. As part of my work, I also developed a webserver that automates the analysis and visualization of lipid-protein interactions from MD simulations allowing for the creation of automated pipelines to study lipid-protein interactions in the future. Lastly, I provide a short review of some of the main challenges facing the field along with possible solutions going forward. My work expands our understanding of lipid-protein interactions.
  • Thumbnail Image
    ItemOpen Access
    An Exploration of Novel Metal-Mediated Vinylcyclopropane Reactivity
    (2020-08) Timmons, Madison Taylor; Derksen, Darren J.; Van Humbeck, Jeffrey Francis; Welch, Gregory C.; Ling, Changchun
    Vinycyclopropanes (VCPs) are an important building block for synthetic and medicinal chemistry as they can undergo a variety of useful cycloaddition reactions to rapidly prepare complex molecular frameworks. Although VCPs contain ring strain, useful energy to drive chemical reactions, they typically still require activation to induce cycloadditions. The activation of vinylcyclopropanes using first row transition metal catalysis is not broadly studied and may offer opportunities for novel reactivity. First row transition metals were used to study the reactivity of three different vinylcyclopropanes toward cycloadditions. This thesis describes the results of screening these unactivated vinylcyclopropanes with Cu, Co, Ni and Fe catalysts. Subsequently, vinycyclopropane-containing natural products were screened for their reactivity toward cycloaddition reactions. Monoterpenes sabinene and 2-carene were utilized as starting materials for these annulations which were tested via rhodium catalysis. Also explored, was the induction of a 1,4-sigmatropic rearrangement reaction with first row transition metal catalysis. The Derksen group has previously reported a photomediated rearrangement in which 6:3:5 and 7:3:5 vinylcyclopropane ring systems were quickly introduced. The synthesis of these materials in good yields and selectivity provides rapid access to polycyclic vinycyclopropanes that offer opportunities for further reactivity. This thesis describes the screening of this transformation via Mn, Ti, Cu, Co, Ni and Fe catalysis rather than photochemical conditions.
  • Thumbnail Image
    ItemEmbargo
    Exploration of Pomalidomide for Heterobifunctional Protein Degraders: From Chemistry to Application
    (2023-04-04) Brownsey, Duncan Keith; Derksen, Darren J.; Van Humbeck, Jeffrey F.; Back, Thomas G.; Ling, Chang-Chun; Williams, Florence J.
    Targeted protein degradation (TPD) has recently come to the forefront of chemical biology and medicinal chemistry as a means to disrupt protein function by selective degradation. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that exemplify TPD technology. One of the most widely used E3 ligase ligands in PROTAC development is pomalidomide which make up 46% of all CRBN-targeting PROTACs. This work explores the chemistry of pomalidomide: first by improving the synthesis of pomalidomide derivatives, second by application in new protein degraders of p300, and then third by characterizing the fluorescent properties of pomalidomide. The improved synthesis of pomalidomide derivatives via an SNAr pathway was began by identification and avoidance of the formation of dimethyl pomalidomide, an undesired byproduct. This led to greatly enhanced yields of compounds that can be used to build new pomalidomide containing PROTACs. As well, differences in the reactivity of amines used to create pomalidomide derivatives were exploited to produce PROTACs in one-pot reactions, which in some instances, exceeded the yields of multistep syntheses used in the literature. Secondly, new degraders of the protein target p300 were prepared using a known p300 ligand A-485, outlining a new strategy to create PROTACs. To verify that linker attachment onto A-485 was amenable to PROTAC function, biotin conjugates were installed and verified using immunoprecipitation blots. A library of A-485-pomalidomide conjugates were then prepared and tested for their p300 degradation capability, which showed a general trend that the PROTACs with longer linkers were more effective degraders. Finally, the fluorescent properties of pomalidomide derivatives were explored. In aqueous solutions, pomalidomide emits visible light with a maximum at ~530 nm upon excitation at 420 nm. This emission was characterized and a library of pomalidomide PROTACs were synthesized and tested in vitro with osteosarcoma cells. In vitro fluorescence microscopy imaging of the pomalidomide library showed trends with linker structure. Relationships between fluorescence, target degradation and calculated partition coefficients were then explored.
  • Thumbnail Image
    ItemOpen Access
    Generation and Transformations of Cationic Heteroaromatic Molecules
    (2019-04-10) Hogan, David Thomas; Sutherland, Todd C.; Heyne, Belinda; Derksen, Darren J.; Shimizu, George K. H.
    This thesis contains three chapters, each of which has been published in relevant journals. While the applications of each chapter are unrelated to one-another, the compounds involved fall under the broad class of cationic heteroaromatics either by using such systems directly (chapters one and two) or by forming them during investigation (chapter three). Instead of employing novel methods, the synthetic focus was to use the simplest and shortest possible routes, both to save material and extend the time available for characterization. Investigations in the first two chapters involved reduction electrochemistry, transforming the cationic heteroaromatic compounds into the analogous heteroatomic radicals or anions. How easily this could be accomplished and how long the nascent radicals/anions lived after generation drove the studies. The third chapter is unique because it involves no electrochemistry – instead solely photophysics – and starts with neutral organic compounds, generating the cationic analogues as a method of sensing metal cations.
  • Thumbnail Image
    ItemOpen Access
    Gout Biosensor: Towards the development of a peptide-based diagnostic for crystal arthropathies and Amplifying Graduate Student Perspectives on Supervision and Satisfaction at the University of Calgary
    (2024-09-19) Butler, Tanille Marya; MacCallum, Justin L.; Derksen, Darren J.; Sutherland, Todd C.; Benoit, Wendy L.; Derda, Ratmir
    This thesis primarily investigates the use of fluorescently labelled crystal-targeting peptides to develop a gout biosensor to improve the diagnostics of crystal arthropathies. Additionally, Chapter 7 examines survey responses from a secondary research project exploring graduate student experiences related to supervision and satisfaction within NSERC disciplines at the University of Calgary. With the growing prevalence of gout, there is an increasing need for accurate, cost-effective, and automated diagnostic methods to distinguish between monosodium urate (MSU) crystals, which cause gout, and calcium pyrophosphate dihydrate (CPPD) crystals, responsible for pseudogout. The current gold-standard diagnostic approach, compensated polarized light microscopy, is limited by its dependence on operator skill and lack of automation. To address these challenges, the study employed a multifaceted strategy involving phage display, peptide synthesis, microscopy, flow cytometry, and computational modelling to identify peptides capable of differentiating between MSU and CPPD crystals. Initial phage display efforts were hindered by high background binding of the phage, leading to the unexpected discovery of an interaction between MSU crystals and the major coat protein of the bacteriophage. This finding laid the groundwork for enhancing peptide binding to MSU crystals. While the identified peptides demonstrated strong binding to MSU crystals, specificity remained a challenge due to similar binding observed with CPPD crystals. An Alizarin Red S counterstain was introduced to improve differentiation, distinguishing CPPD crystals without affecting MSU crystals in microscopy studies. However, when flow cytometry was explored as a high-throughput tool, we encountered challenges with dye compatibility. Although 84% accuracy was achieved in classifying individual crystals through logistic regression of peptide-bound crystal data, issues with dye stability and clinical sample complexity indicate further refinement is needed before clinical implementation. The second project focused on graduate students' supervisory and program experiences in NSERC disciplines at the University of Calgary. Data from the 2022 and 2023 Graduate Student Experience Surveys indicated overall satisfaction with supervisory support and communication but highlighted ongoing issues with inadequate funding and mental health challenges despite available institutional resources. These findings highlight areas where enhanced supervisor support and training could better meet evolving student needs.
  • Thumbnail Image
    ItemOpen Access
    Investigating Direct Heteroarylation Reactivity in the Synthesis of π-Conjugated Materials for use in Organic Solar Cells
    (2018-12-12) Payne, Abby-Jo; Welch, Gregory C.; Baumgartner, Thomas; Derksen, Darren J.; Maccallum, Justin L.; Bender, Timothy P.
    This thesis is focused on applying direct heteroarylation as an efficient synthetic route to access new π-conjugated molecular materials for use in organic solar cells. Chapter one introduces π-conjugated materials, organic solar cells, and design considerations in the development of sustainable and efficient methods towards accessing high-performance materials. Chapter two introduces a novel π-conjugated building block, indoloquinoxaline, which is available from inexpensive starting materials and can be accessed from a modular and high yielding synthesis. Its materials’ properties are investigated through its incorporation as a terminal unit in three different molecular constructs (1-3) using Stille couplings and the more economical direct heteroarylation coupling. Building directly from this work, chapter three focuses on the use of the indoloquinoxaline building block and its fluorinated derivative to access a series of π-extended squaraine dyes (4-7) via Sonogashira and direct heteroarylation couplings expanding the substrate scope of the latter more versatile and atom-economical cross-coupling. Chapter four applies the synthetic methods developed in chapters two and three and extends these principles to the design and synthesis of an asymmetric π-conjugated molecular structure combining the organic dyes, perylene diimide, diketopyrrolopyrrole, and indoloquinoxaline in a linear fashion via direct heteroarylation (8). The asymmetric compound 8 is exploited for its low energy absorption as a non-fullerene acceptor in organic solar devices. Adapting the synthetic protocols from chapter four, chapter five explores the incorporation and effect of a rylene building block new to organic electronics, N-(alkyl)benzothioxanthene- 3,4-dicarboximide (BTXI), on materials properties in order to learn more about its potential use in organic electronic applications (9-11). The three molecular semiconductors (9-11) are compared and evaluated in organic thin-film transistors and organic solar cells. Chapter six concludes this thesis detailing unprecedented direct heteroarylation reactivity which is uncovered and exploited in order to access a novel tetrameric perylene diimide (12) non-fullerene acceptor for organic solar cell applications.
  • Thumbnail Image
    ItemOpen Access
    Synthesis and Biological Evaluation of Heterobifunctional Small Molecules for Proteasome-Mediated Protein Degradation of Myeloid Cell Leukemia 1 (MCL1)
    (2020-09-14) Papatzimas, James W; Derksen, Darren J.; Ling, Chang-Chun; Bahlis, Nizar J.; MacCallum, Justin L.; Pierce, Joshua G.
    Protein–protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. However, these kinds of protein interactions are difficult to perturb using traditional medicinal chemistry strategies. This has given rise to the development of a new method of addressing disease related proteins known as targeted protein degradation (TPD). TPD employs heterobifunctional small molecules which are capable of recruiting the cell’s natural recycling machinery, the ubiquitin proteasome system (UPS), and inducing proximity between this natural degradation machinery and a protein of interest (POI) to promote proteasomal degradation of the protein into its amino acid subunits. An ideal PPI-based target is the anti-apoptotic protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma (MM) where MCL1 levels directly correlate to disease progression. Current strategies for halting the antiapoptotic properties of MCL1 revolve around inhibiting its sequestration of proapoptotic factors. Existing inhibitors disrupt endogenous regulatory proteins; however, this strategy leads to an increase of MCL1 protein expression, a detrimental effect for several diseases. MCL1 has also been a challenging biological target to inhibit due to the prolific on-target cardiotoxicity associated with global MCL1 inhibition or knockdown.This work showcases the development of the first in class heterobifunctional small molecules capable of selectively targeting MCL1 through TPD methodology, leading to successful degradation. A synthesis program was embarked upon where chemical probes and cellular assay-guided structure activity relationship (SAR) studies motivated the optimization of these degrader compounds. We have confirmed the involvement of the E3 ubiquitin ligase CUL4A–DDB1 cereblon (CRBN) ubiquitination pathway through rigorous UPS checkpoint validation, making these MCL1 degraders a first step toward a new class of antiapoptotic B-cell lymphoma 2 (BCL2) family protein degraders.
  • Thumbnail Image
    ItemOpen Access
    Waterfall: An Online Sequential Monte Carlo Strategy for Conformational Sampling
    (2020-05-08) Muniyat, Mir Ishruna; MacCallum, Justin L.; Derksen, Darren J.; Noskov, Sergei Yu; Kusalik, Peter G.
    Conformational sampling of physical systems, such as biomolecules, remains challenging since their energy landscapes are rugged with energetic and entropic barriers. Metastable states on a landscape are often separated by substantial energetic barriers and numerous local minima where a system can easily get trapped. Entropic barriers, arising from many possible conformations of a system, make finding the important states a needle-in-a-haystack problem. Enhanced sampling algorithms can potentially overcome both barriers, making it possible to sample the important states efficiently. However, existing algorithms come with certain limitations. We developed ``Waterfall Sampling” to overcome some of the limitations of existing algorithms. The algorithm employs a Sequential Monte Carlo strategy where it promotes exploration of the high-probability regions on the conformational landscape. It is an online method, that is, we can keep adding states indefinitely to improve statistics. We successfully tested Waterfall on a data-guided integrative structural biology problem and compared its efficiency with the existing algorithms.