Browsing by Author "Zadrozny, Joseph, committee member"
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Item Open Access Exploration of nitric oxide generation from S-nitrosoglutathione for the advancement of anti-fouling glucose biosensor membrane materials(Colorado State University. Libraries, 2022) Melvin, Alyssa C., author; Reynolds, Melissa M., advisor; Zadrozny, Joseph, committee member; Farmer, Delphine, committee member; Chen, Thomas, committee memberBlood-contacting medical devices such as implantable glucose sensors suffer from biofouling which limits the lifetime of the device and puts the patient at risk of arterial embolism and infection. Researchers have been developing medical device coatings to address the two causes of surface biofouling: thrombus and biofilm formation. One promising strategy is surface-localized production of nitric oxide (NO), a biomolecule with antithrombotic and antibacterial physiological functions, as a multifunctional therapeutic for biofouling prevention. Because NO is a gaseous free radial with a very short physiological half-life, achieving localized NO generation presents a clear challenge. An innovative approach that will be explored herein is incorporating catalysts on the medical device surface that release NO from endogenous NO sources, S-nitrosothiols (RSNOs). A water stable copper-based metal–organic framework (MOF) CuBTTri, Cu(II) benzene-1,3,5-tris(1H-1,2,3-triazoy-5-yl), has been shown to be an effective catalyst for the generation of NO from RSNOs. Two RSNOs, S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylpenicillamine (SNAP), are commonly used in the development of new NO-generating materials. It is known that RSNOs are susceptible to decomposition by stimuli including heat, light, and trace metal ions which can inadvertently be introduced through basic handling, storage conditions, and experimental setups. Despite their frequent use, there is limited and conflicting literature examining the comparative stability of GSNO and SNAP. In order to accurately characterize and quantify the behavior of NO-generating materials, reliable and robust methods must be developed to prevent spontaneous RSNO decomposition under the desired experimental conditions. In Chapter 2, the comparative stability of GSNO and SNAP was thoroughly examined to inform subsequent experiments in the development of CuBTTri-based anti-fouling materials with RSNOs as the NO source. Though CuBTTri is an effective catalyst for this reaction, solid state material must be immobilized into a flexible, processable scaffold for coating devices. In Chapter 3, the effects of incorporating CuBTTri into a medical grade polyurethane composite material on NO generation is explored. In Chapter 4, the effects of three key parameters of CuBTTri composite materials, MOF particle size, MOF loading, and polymer concentration, on NO generation are evaluated to assess the tunability of these next-generation materials. In Chapter 5, the effects of the CuBTTri/polyurethane composite material on the enzyme function and analytical performance of a glucose biosensor are examined. Though metal ion-promoted NO release from RSNOs is promising strategy for the development of NO-generating materials, the majority of studies focus on copper, and few have surveyed the ability of other common metal ions to produce this effect. Finally, in Chapter 6, NO generation from GSNO by Cu2+ and twenty transition and post-transition metal ions was monitored using NO-selective chemiluminescence-based detection to expand the range of potential metals for the development of NO-based anti-fouling materials.Item Open Access Investigation of the extraction of stable ⁴⁵Sc and carrier free ⁴⁴Sc for theranostic applications(Colorado State University. Libraries, 2022) Brown, Morgan L., author; Sudowe, Ralf, advisor; Brandl, Alexander, committee member; Zadrozny, Joseph, committee memberScandium is an element of major interest when it comes to theranostic applications. There are mainly two isotopes of scandium utilized in medical applications, Sc-44 and Sc-47. Sc-44 is a positron emitter and is used for imaging, while Sc-47 is utilized as a beta emitter for targeting tumors. Together, the pair make up a theranostic agent. This research mainly focuses on Sc-44. To utilize the isotope after production, it must first be separated and purified from target material, in this case titanium. One of the quickest and most efficient way to separate radioisotopes, especially for medical purposes, is extraction chromatography. The goal of this research is to understand and possibly improve the separation of scandium from titanium by employing a variety of different chromatographic resins in a fast manner. Previous studies in the literature yielded data from several groups that examined the uptake of scandium and titanium on an extraction chromatographic resin based on a tetraoctyl diglycolamide, DGA. These groups employed either stable or radioactive scandium for their experiments. While the uptake of titanium was consistent between the studies, all groups have reported different values for the uptake of scandium. The aim of this part of the work is to compare both the uptake of stable and radioactive scandium to further elucidate the discrepancies between the studies reported in the literature. Radioactive Sc-44 for tracer studies will be obtained by "milking" a Ti-44 generator in regular intervals. Both stable and radioactive results obtained in this research will be compared.Item Open Access New base-catalyzed processes enable new approaches to C–H functionalization reactions(Colorado State University. Libraries, 2022) Puleo, Thomas R., author; Bandar, Jeffrey, advisor; McNally, Andy, committee member; Zadrozny, Joseph, committee member; Chatterjee, Delphi, committee memberBrønsted bases are ubiquitous, inexpensive, and widely available reagents used in synthetic chemistry due to their well-studied and predictable activation mode. This thesis details the discovery and incorporation of new Brønsted base-catalyzed processes into fundamental proton transfer equilibria to enable new approaches to C–H functionalization reactions. The direct functionalization of C–H bonds represents a streamlined and attractive approach to access valuable synthetic targets, and this utility will be highlighted throughout the discussion of each method.Chapter one describes the discovery and development of a base-catalyzed α-selective styrene deuteration reaction. The mechanistic studies that led to the conceptualization and optimization of this reaction will be highlighted. α-Deuterated styrenes are compounds frequently utilized in the mechanistic studies of alkene functionalization reactions and this work represents the first method to achieve α-selective hydrogen isotope exchange on styrene derivatives. Chapter two provides an overview of existing approaches to catalytic aryl halide isomerization reactions. A particular focus on base-catalyzed aryl halide isomerization reactions will be provided, as these reports serve as the mechanistic foundation for the reactions developed throughout the remainder of the thesis. Chapter three describes our discovery and application of a general approach to base-catalyzed aryl halide isomerization. Aryl halides are valuable compounds in synthetic chemistry, and this new catalytic isomerization process unlocks a new mode of reactivity for these compounds. The scope of this process is demonstrated on several simple aryl bromides and iodides. The second part of this chapter will highlight an application of this process to enable the 4-selective nucleophilic substitution of 3-bromopyridines. Chapter four describes our approach to achieve nucleophilic C–H etherification of electron-deficient N-heteroarenes via a base-catalyzed halogen transfer mechanism. 2-Halogenated thiophenes efficiently transfer halogens to N-heteroaryl anions to generate N-heteroaryl halide intermediates that undergo nucleophilic aromatic substitution with alkoxide nucleophiles. Additionally, C–H etherification can be sequenced with a cascade base-promoted elimination to enable N-heteroarene C–H hydroxylation. The scope of process is highly general, and regioselective C–H etherification and hydroxylation is demonstrated on thiazoles, oxazoles, imidazoles, pyridines, pyrimidines, pyridazines, and polyazines. Chapter five briefly highlights two new C–H functionalization reactions currently being developed that are enabled by base-catalyzed halogen transfer. First, use of this approach to enable the C–H hydroxylation of benzenes will be described. Second, the monoselective and site-selective benzylic C–H etherification of toluenes and polyalkyl benzenes will be detailed. In the final part of the chapter, I will summarize my contributions and discuss the future outlooks on this chemistry.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 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.