Browsing by Author "Paton, Robert, committee member"
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Item Open Access Engineering and evolving helical proteins that improve in vivo stability and inhibit entry of Enfuvirtide-resistant HIV-1(Colorado State University. Libraries, 2019) Walker, Susanne N., author; Kennan, Alan, advisor; Yao, Tingting, committee member; McNally, Andrew, committee member; Paton, Robert, committee memberMethods for the stabilization of well-defined helical peptide drugs and basic research tools have received considerable attention in the last decade. Enfuvirtide is a 36-residue chemically synthesized helical peptide that targets the viral gp41 protein and inhibits viral membrane fusion. Enfuvirtide-resistant HIV, however, has been prolific, and this peptide therapy requires daily injection due to proteolytic degradation. In this dissertation I have developed a method for stabilizing helical peptide therapeutics termed helix-grafted display proteins. These consist of the HIV-1 gp41 C-peptide helix grafted onto Pleckstrin Homology domains. Some of these earlier protein biologics inhibit HIV-1 entry with modest and variable potencies (IC50 190 nM - >1 μM). After optimization of the scaffold and the helix, our designer peptide therapeutic potently inhibited HIV-1 entry in a live-virus assay (IC50 1.9-12.4 nM). Sequence optimization of solvent-exposed helical residues using yeast display as a screening method led to improved biologics with enhanced protein expression in Escherichia coli (E. coli, a common bio-expression host), with no appreciable change in viral membrane fusion suppression. Optimized proteins suppress the viral entry of a clinically-relevant double mutant of HIV-1 that is gp41 C-peptide sensitive and Enfuvirtide-resistant. Protein fusions engineered for serum-stability also potently inhibit HIV-1 entry.Item Open Access Investigating biosynthetic pathways of the Aspergillus genus through biomimetic total synthesis of secondary metabolites(Colorado State University. Libraries, 2022) Benson, Brooke, author; Williams, Robert M., advisor; Kennan, Alan J., advisor; Paton, Robert, committee member; Crans, Debbie, committee member; Crick, Dean, committee memberThe prenylated indole alkaloids are a class of secondary metabolites containing a unique bicyclo[2.2.2]diazaoctane core and a wide range of biological activity. This complex structure has prompted extensive investigation into the biochemical synthesis of these compounds. Currently, three disparate biochemical strategies are known to be used by producing fungi to construct the bicyclic core: (1) NADPH-dependent bifunctional reductase/Diels-Alderase-mediation in formation of the monooxopiperazines; (2) brevianamide assembly through cofactor-independent pinacolase resulting in spontaneous intramolecular Diels-Alder (IMDA) generation of the bicyclo[2.2.2]diazaoctane core; (3) Diels-Alderase mediated enantiodivergent generation of the dioxopiperazines via cytochrome P450 oxidation to achiral azadienes and successive enzyme-mediated stereoselective IMDA reaction. This work aimed to employ biomimetic total synthesis to aid in elucidation of the biosynthetic pathways in the Aspergillus genus, which utilizes the third strategy. This author reports the first total syntheses of 6-epi-Notoamides T10-12 and Notoamide T2, as well as an improved total synthesis of 6-epi-Notoamide T. Also reported are synthetic efforts towards 6-epi-Notoamide T9, Notoamide TI, and Citrinalin C.Item Open Access Oxidative quenching organic photocatalyst design, synthesis and application in dual nickel/photoredox-catalysis(Colorado State University. Libraries, 2023) Chrisman, Cameron Hayes, author; Miyake, Garret, advisor; Paton, Robert, committee member; Zadrozny, Joseph, committee member; Kipper, Matthew, committee memberThe work described in this dissertation focuses on the development of a new class of organic photocatalysts and the application of oxidative quenching photocatalysts in dual nickel/photoredox-catalysis. The design of new organic photocatalysts is crucial for eliminating the need to use rare/expensive ruthenium and iridium that have dominated the field of photoredox catalysis. Additionally, the majority of the catalysts describe here-in operate through an oxidative quenching mechanism that remains underexplored in the field of dual nickel/photoredox catalysis. The first detailed mechanistic study on oxidative quenching in this field is reported and applied in a broad range of couplings.Item Open Access Phosphorus ligand-coupling reactions for the functionalization of pyridine and other azines(Colorado State University. Libraries, 2021) Nottingham, Kyle G., author; McNally, Andrew, advisor; Paton, Robert, committee member; Henry, Chuck, committee member; Cohen, Robert, committee memberPyridines and related azines are ubiquitous in pharmaceuticals, agrochemicals, and materials. The discovery and development of new purpose-built molecules is contingent on our ability to modify these motifs. Described herein are the development of methods that selectively functionalize pyridine and diazine scaffolds through phosphorus ligand-coupling. Novel phosphine reagents were designed and leveraged to construct C–C, C–O, and C–N bonds on azines from their C–H precursors. Chapter one introduces the history of phosphorus ligand-coupling and defines the reactivity explored throughout this thesis. Both seminal and contemporary examples of phosphorus ligand-coupling reactions are also discussed to provide context for this work. Chapter two focuses on a method to incorporate fluoroalkyl groups onto azines and pharmaceuticals using phosphorus ligand-coupling. This method offers a complementary alternative to widely used radical addition approaches which often produce regiomeric product mixtures on azines. Chapter three presents the investigation of a phosphorus-mediated alkenylation reaction on pyridines and quinolines. Examination of the reaction of pyridylphosphines with alkyne acceptors uncovered divergent reaction pathways from alkenylphosphonium salts. Mechanistic studies provide an explanation for the origin of selectivity obtained in these reactions. Lastly, chapter four expands upon one of these reaction pathways and describes the development of a method for the direct conversion of pyridines into pyridones and aminopyridines.Item Embargo Reductive coupling reactions of organosilanes for the monoselective C–F functionalization of trifluoromethylarenes(Colorado State University. Libraries, 2022) Wright, Shawn E., author; Bandar, Jeffrey, advisor; Paton, Robert, committee member; Borch, Thomas, committee member; Herrera-Alonso, Margarita, committee memberThe mono-selective defluorofunctionalization of trifluoromethylarenes is an emerging strategy to access ⍺,⍺-difluorobenzylic derivatives, which are difficult to access in a divergent manner. Fluorine incorporation is a common strategy employed during the optimization of potential pharmaceuticals in the drug discovery process. Much effort has been spent over the past few decades in developing fluorination methodologies, and the result has been tremendous growth in aryl and alkyl fluorination and trifluoromethylation reactions. On the other hand, methods to install other fluoroalkyl motifs are less developed. Due to the abundant availability of trifluoromethylarenes, mono-selective defluorofunctionalization reactions would be an ideal route to access ⍺,⍺-difluorobenzylic derivatives, which are becoming increasing examined in drug discovery settings. Chapter one will provide the necessary background to understand the context of the work described throughout the following chapters. First, there will be an overview of the importance of fluorine for the development of pharmaceutical compounds. Then there will be a brief summary of the different strategies that have been developed to achieve the trifluoromethylation of arenes as well as the common routes to access ⍺,⍺-difluorobenzylic compounds. Finally, a thorough discussion of the challenges and reported solutions to achieve mono-selective defluorofunctionalization of trifluoromethylarenes will be provided. Chapter two will describe the initial discovery, development, and mechanistic investigation of the defluoroallylation reaction reported by the Bandar group. This discovery led to the identification of a new strategy to achieve reductive coupling through the use of Lewis base activated organosilanes, which provides the basis for the reactions discovered and developed in chapters three and four. Chapter three will describe the discovery, development, and mechanistic investigation of a reductive coupling reaction of trifluoromethylarenes with formamides. This reaction generates a silylated hemiaminal product which is a valuable synthetic intermediate to access a broad scope of ⍺,⍺-difluorobenzylic derivatives. Mechanistic investigations support the generation of a ⍺,⍺-difluorobenzylsilane intermediate in the reaction. Isolated of the ⍺,⍺-difluorobenzylsilane and subsequent derivatizations further broaden the scope of transformations accessible via this reductive coupling process. Chapter four will describe the discovery and preliminary development of the mono-selective hydrodefluorination of trifluoromethylarenes using hydrosilanes activated by a Lewis basic catalyst. Two different catalytic systems are demonstrated that operate via different mechanisms, which provides access to different reaction scopes. A short discussion on the future work of this project will also be provided, where a junior graduate student is developing conditions to enable the mono-selective hydrodefluorination of electron-neutral trifluoromethylarenes.Item Open Access Site-selective functionalization of azines and polyazines via heterocyclic phosphonium salts(Colorado State University. Libraries, 2020) Dolewski, Ryan D., author; McNally, Andrew, advisor; Paton, Robert, committee member; Henry, Chuck, committee member; Kanatous, Shane, committee memberPyridine and diazines are frequently found in FDA approved drugs, biologically active compounds, agrochemicals, and materials. Given the importance of these structural motifs, direct methods that selectively functionalize pyridine and diazine scaffolds have been developed. These methods and their associated challenges are discussed in chapter one. In chapter two, a strategy to directly and selectively functionalize pyridines and diazines via heterocyclic phosphonium salts is presented. The process is broadly applicable for pyridines and diazines and the late-stage functionalization of pharmaceuticals. Four reaction manifolds are amenable to transforming heterocyclic phosphonium salts into valuable derivatives. In chapter three, inherent factors that control site-selectivity in polyazine systems are described along with mechanistically driven approaches for site-selective switching, where the phosphonium ion can be predictably installed at other positions in a polyazine system. The fourth chapter focuses on a new strategy to selectively alkylate pyridines via a traceless dearomatized phosphonium salt intermediate. Preliminary studies show this protocol is amenable to building-block pyridines, drug-like fragments and pharmaceuticals. A late-stage methylation strategy is also presented.Item Open Access Sustainable polymer synthesis through the design of organic photoredox catalysts and development of poly(norbornane trithiolanes)(Colorado State University. Libraries, 2023) Price, Mariel Jene, author; Miyake, Garret, advisor; Paton, Robert, committee member; Zadrozny, Joseph, committee member; Herrera-Alonso, Margarita, committee memberThere are many avenues through which the sustainability synthesis, use, and disposal of polymeric materials can be approached. One of the two approaches explored in this work is the sustainable design and use of polymerization catalysts. Proper employment of catalysis can greatly decrease the energy input required to synthesize polymers and intentional design of those catalysts can enable their use in small quantities without compromising their effectiveness or the sustainability with which they are made and used. Herein, the development of a new class of metal-free photoredox catalysts (made from abundant elements) which can use visible wavelengths of light (a readily available, replenishable, and mild source of energy) to control the polymerization acrylate monomers is reported. Through this work we provide insight into how catalyst structure can be tuned to achieve desired properties and what properties might render certain catalysts more effective at lower loadings. The second approach explored herein towards improving the sustainability of polymer synthesis, use, and disposal is related to the recyclability of the polymeric materials. In addition to sustainable synthesis through catalysis, one way to improve the sustainability of polymeric materials is to increase their viable economic lifetime. Polymeric materials that are readily recyclable prevent the loss of materials through disposal. In the work reported herein methods for the synthesis and polymerization of sulfur-containing monomers to generate polymeric materials with intrinsic recyclability are investigated, approaches for efficient depolymerization of such polymers improved, and the scope of these materials expanded.Item Embargo Synthesis and characterization of biologically relevant redox-active molecules(Colorado State University. Libraries, 2023) Kostenkova, Kateryna, author; Crans, Debbie, advisor; Zadrozny, Joseph, committee member; Paton, Robert, committee member; Worley, Deanna, committee memberRedox chemistry is fundamental to several essential life processes, such as energy metabolism, respiration, and free radical formation. Many redox-active inorganic and organic molecules are promising agents to combat difficult-to-treat diseases, including cancer and tuberculosis. This dissertation covers the syntheses, studies of the fundamental chemical and biological properties of two vastly different classes of redox-active molecules, inorganic and organic molecules. Most of this work has investigated the fundamental development of hydrophilic, hydrophobic and amphiphilic redox-active vanadium complexes for the treatment of different types of cancer. The last chapter of this dissertation describes the studies of the fundamental properties of demethylmenaquinones which are biosynthetic precursors to menaquinones, lipid electron carriers essential for anaerobic bacterial respiration of several types of bacteria, including Escherichia coli, Actinomadura madurae and pathogenic Mycobacterium tuberculosis. Targeting bacterial electron transport chain disrupts respiration of pathogenic Mycobacterium tuberculosis, thus, studying the properties of demethylmenaquinone analogs is of great interest. Chapter one, an introductory chapter, presents a comprehensive review of the developments in vanadium anticancer therapeutics over the last five years. The structural diversity of the vanadium-containing anticancer compounds, potential applications to various cancer cell lines, and different modes of delivery of highly cytotoxic vanadium species are described in detail. Vanadium gained interest for its anticancer applications after bis(maltolato)oxovanadium(IV), an antidiabetic complexes studied in Phase II clinical trials, went off patent in September 2011. Previous studies with vanadium antidiabetic complexes, however, provided valuable information to understand the action of novel vanadium anticancer complexes, as cancer and diabetes target the same metabolic pathways. Chapters two and three describe the syntheses, spectroscopic characterization, and cytotoxic studies of novel vanadium(V) catecholate complexes with pyridine-containing Schiff base ligands. According to previous reports, vanadium(V) Schiff base catecholate complexes are promising agents for glioblastoma treatment, and herein we investigated whether the presence of the pyridine ring on the Schiff base scaffold improves cytotoxicity and hydrolytic stability of the vanadium catecholato complexes. The studies showed that the presence of the pyridine ring improves hydrolytic stability of the V(V) catecholate complexes, yet it decreases their uptake into glioblastoma cells which result in the decrease of cytotoxicity of the complexes. Even though the stability increased and the compounds have enough time to get into cells, the efficacy of these complexes decreased. Chapter three further explores the redox properties and the redox reaction mechanism of vanadium(V) Schiff base catecholate complexes with pyridine-scaffolds and tert- butyl substituted catecholate ligands. Chapter four describes the speciation studies and testing of vanadium(V) dipicolinate that enhance the effects of oncolytic viruses, non-pathogenic viruses that can infect and kill cancer cells. Additionally, the chapter describes 1H and 51V NMR studies carried out in model membrane interfaces. The data show that V(V) dipicolinates hydrolyze under physiological conditions and generate vanadate which ultimately enhances the spread of the oncolytic viruses. V(V) dipicolinates are located on the interface of the aqueous pool and hydrophobic region of model membranes which also contributes to their hydrolysis. Chapter five describes PtIV and MoVI monosubstituted decavanadates, monoplatino(IV)nonavanadate(V) ([H2PtIVVV9O28]5-, V9Pt), and monomolybdo(VI)-nonavanadate(V) ([MoVIVV9O28]5-, V9Mo), and their ability to initiate signal transduction on the luteinizing hormone receptor (LHR) in CHO cells and their speciation chemistry under the biological experiments. The PtIV and MoVI monosubstituted decavanadates are large vanadium- oxo clusters that are structurally similar to decavanadate but have different charges. The results showed that both V9Mo and V9Pt affect LHR expression and do not inhibit cell growth which is different than the decavanadate ([V10O28]6−, abbreviated V10). Although all the clusters hydrolyze under the assay conditions lifetimes are different, and this was characterized using spectroscopic methods. Using the washing experiments, we were able to show that the V9Pt and V9Mo monosubstituted decavanadates do not associate with the cells and, hence, do not negatively affect cell growth, however, they are more effective in initiating signaling. Chapter six describes initial efforts to study the fundamental properties of two truncated demethylmenaquinones, biosynthetic precursors for menaquinones. The studies are important to understand the fundamental differences between the chemical properties of menaquinones and demethylmenaquines which include 3D conformation and redox potential. Indeed, the development of inhibitors of MenG, a methyltransferase enzyme that coverts demethylmenaquines to form menaquinones, is a known target for drug development for antitubercular applications. Therefore, we investigated whether non-native demethylmenaquines would convert to menaquinones by the relevant enzymes present in the membrane preparations. In summary, the first five chapters demonstrate 1) the diversity of applications of vanadium compounds for treatment of different types of cancer and 2) the efforts to develop vanadium- based anticancer therapeutics to treat different types of cancer. The final chapter describes efforts in fundamental studies preparing and characterizing the chemical properties the truncated demethylmenaquinones. In addition, we demonstrated that the membrane preparations of mycobacteria concerted the synthesized truncated demethylmenaquinone-2 and demethylmenaquinone-3 are processed to form menquinone-2 and menaquinone-3.