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- Genre: Doctoral Dissertation
Description
Healthy mitochondria are essential for cell survival. Described herein is the synthesis of a family of novel aminoquinone antioxidants designed to alleviate oxidative stress and prevent the impairment of cellular function. In addition, a library of bleomycin disaccharide analogues has also been synthesized to better probe the tumor targeting properties of bleomycin. The first study involves the synthesis of a benzoquinone natural product and analogues that closely resemble the redox core of the natural product geldanamycin. The synthesized 5-amino-3-tridecyl-1,4-benzoquinone antioxidants were tested for their ability to protect Friedreich's ataxia (FRDA) lymphocytes from induced oxidative stress. Some of the analogues synthesized conferred cytoprotection in a dose-dependent manner in FRDA lymphocytes at micromolar concentrations. The biological assays suggest that the modification of the 2-hydroxyl and N-(3-carboxypropyl) groups in the natural product can improve its antioxidant activity and significantly enhance its ability to protect mitochondrial function under conditions of oxidative stress. The second project focused on the synthesis of a library of bleomycin disaccharide-dye conjugates and monitored their cellular uptake by fluorescence microscopy. The studies reveal that the position of the carbamoyl group plays an important role in modulating the cellular uptake of the disaccharide. It also led to the discovery of novel disaccharides with improved tumor selectivity.
ContributorsMathilakathu Madathil, Manikandadas (Author) / Hecht, Sidney M. (Thesis advisor) / Rose, Seth (Committee member) / Woodbury, Neal (Committee member) / Arizona State University (Publisher)
Created2013
Description
ABSTRACT Manipulation of biological targets using synthetic or naturally occurring organic compounds has been the focal point of medicinal chemistry. The work described herein centers on the synthesis of organic small molecules that are targeted either to cell surface receptors, to the ribosomal catalytic center or to human immunodeficiency virus reverse transcriptase. Bleomycins (BLMs) are a family of naturally occurring glycopeptidic antitumor agents with an inherent selectivity towards cancer cells. DeglycoBLM, which lacks the sugar moiety of bleomycin, has much lower cytotoxicity in cellular assays. A recent study using microbbuble conjugates of BLM and deglycoBLM showed that BLM was able to selectively bind to breast cancer cells, whereas the deglyco analogue was unable to target either the cancer or normal cells. This prompted us to further investigate the role of the carbohydrate moiety in bleomycin. Fluorescent conjugates of BLM, deglycoBLM and the BLM carbohydrate were studied for their ability to target cancer cells. Work presented here describes the synthesis of the fluorescent carbohydrate conjugate. Cell culture assays showed that the sugar moiety was able to selectively target various cancer cells. A second conjugate was prepared to study the importance of the C-3 carbamoyl group present on the mannose residue of the carbohydrate. Three additional fluorescent probes were prepared to improve the uptake of this carbohydrate moiety into cancer cells. Encouraged by the results from the fluorescence experiments, the sugar moiety was conjugated to a cytotoxic molecule to selectively deliver this drug into cancer cells. The nonsense codon suppression technique has enabled researchers to site specifically incorporate noncanonical amino acids into proteins. The amino acids successfully incorporated this way are mostly α-L-amino acids. The non-α-L-amino acids are not utilized as substrates by ribosome catalytic center. Hoping that mutations near the ribosome peptidyltransferase site might alleviate its bias towards α-L-amino acids, a library of modified ribosomes was generated. Analogues of the naturally occurring antibiotic puromycin were used to select promising candidates that would allow incorporation of non-α-L-amino acids into proteins. Syntheses of three different puromycin analogues are described here. The reverse transcriptase enzyme from HIV-1 (HIV-1 RT) has been a popular target of HIV therapeutic agents due to its crucial role in viral replication. The 4-chlorophenyl hydrazone of mesoxalic acid (CPHM) was identified in a screen designed to find inhibitors of strand transfer reactions catalyzed by HIV-1 RT. Our collaborators designed several analogues of CPHM with different substituents on the aromatic ring using molecular docking simulations. Work presented here describes the synthesis of eight different analogues of CPHM.
ContributorsPaul, Rakesh (Author) / Hecht, Sidney M. (Thesis advisor) / Moore, Ana L (Committee member) / Rose, Seth D (Committee member) / Arizona State University (Publisher)
Created2013
Description
Chimeric antigen receptor (CAR) T-cell therapies present transformative potentials for progressive and refractory cancer treatment. However, therapy-associated neuronal toxicities, cytokine release syndromes, relapse rates, and the complex responses of patients and medical management have increased the cost of patient care. Prompt point-of-care (POC) quantification of circulating CAR T-cells and associated cytokines could enhance safety, simplify patients' management, and decrease patient care costs. While effective, existing standard detection methods, such as Enzyme-Linked Immunosorbent Assay (ELISA), quantitative Polymerase Chain Reaction(qPCR), and Flow cytometry, are not conducive to quick POC testing due to their complexity and expense. This research introduces a centrifuge-free Rapid Optical Imaging (ROI)-based platform to quantify CAR T-cells and therapy-related cytokine (Interleukin-6) from a single drop of whole blood. Through machine learning, label-free ROI-based CAR T-cell detection has been improved for accuracy compared with fluorescent staining results, and the morphological characteristics of CAR-T cells have been applied to attribute for differentiation and reduce false positives. This multi-layered microfluidic chip integrates cell and cytokines separation, collection, and detection steps, reducing the need for centrifugation or staining procedures. The microfluidic channel system separates white blood cells from whole blood after red blood cell agglutination and membrane filtration. The non-agglutinated samples are then extracted into a subchannel with a functionalized sensor surface for CAR-T-specific detection. Calibration curves were established using blood samples spiked with varying CAR-T cell concentrations. Another subchannel, featuring dual-layer membrane filtration, has been designed for cytokine detection using gold nanoparticle-labeled detection antibodies. Cytokine concentrations are digitally measured by tracking the number of gold nanoparticles in designated zones. This platform aims to offer a rapid and cost-efficient prognostic tool for timely assessment of key molecular and cellular biomarkers of CAR-T therapy patients, facilitating timely and evidence-based treatment adjustments.
ContributorsYu, Nanxi (Author) / Wang, Shaopeng SW (Thesis advisor) / Forzani, Erica EF (Thesis advisor) / Borges, Chad CB (Committee member) / Liu, Yan YL (Committee member) / Arizona State University (Publisher)
Created2023
Description
In this thesis, applications of sparsity, specifically sparse-tensors are motivated in physics.An algorithm is introduced to natively compute sparse-tensor's partial-traces, along with direct implementations in popular python libraries for immediate use. These applications include the infamous exponentially-scaling (with system size) Quantum-Many-Body problems (both Heisenberg/spin-chain-like and Chemical Hamiltonian models). This sparsity aspect is stressed as an important and essential feature in solving many real-world physical problems approximately-and-numerically. These include the original motivation of solving radiation-damage questions for ultrafast light and electron sources.
ContributorsCandanedo, Julio (Author) / Beckstein, Oliver (Thesis advisor) / Arenz, Christian (Thesis advisor) / Keeler, Cynthia (Committee member) / Erten, Onur (Committee member) / Arizona State University (Publisher)
Created2023
Description
Late first row transitional metals have attracted attention for the development of sustainable catalysts due to their low cost and natural abundance. This dissertation discusses the utilization of redox-active ligands to overcome one electron redox processes exhibited by these base metals. Previous advances in carbonyl and carboxylate hydrosilylation using redox active ligand-supported complexes such as (Ph2PPrPDI)Mn and (Ph2PPrDI)Ni have been reviewed in this thesis to set the stage for the experimental work described herein.The synthesis and electronic structure of late first row transition metal complexes featuring the Ph2PPrPDI chelate was pursued. Utilizing these complexes as catalysts for a variety of reactions gave a recurring trend in catalytic activity. DFT calculations suggest that the trend in activity observed for these complexes is associated with the ease of phosphine arm dissociation.
Furthermore, the synthesis and characterization of a phosphine-substituted aryl diimine ligand, Ph2PPrADI-H was explored. Addition of Ph2PPrADI-H to CoCl2 resulted in C-H activation of the ligand backbone and formation of [(Ph2PPrADI)CoCl][Co2Cl6]0.5. Reduction of [(Ph2PPrADI)CoCl][Co2Cl6]0.5 afforded the precatalyst, (Ph2PPrADI)Co, that was found to effectively catalyze carbonyl hydrosilylation. At low catalyst loading, TOFs of up to 330 s-1 could be achieved, the highest ever reported for metal-catalyzed carbonyl hydrosilylation.
This dissertation also reports the first cobalt catalyzed pathway for dehydrocoupling diamines or polyamines with polymethylhydrosiloxanes to form crosslinked copolymers. At low catalyst loading, (Ph2PPrADI)Co was found to catalyze the dehydrocoupling of 1,3-diaminopropane and TMS-terminated PMHS with TOFs of up to 157 s-1, the highest TOF ever reported for a Si-N dehydrocoupling reaction. Dehydrocoupling of diamines with hydride-terminated polydimethylsiloxane yielded linear diamine siloxane copolymers as oils.
Finally, dehydrocoupling between diamines and organosilanes catalyzed by a manganese dimer complex, [(2,6-iPr2PhBDI)Mn(μ-H)]2, has allowed for the preparation of silane diamine copolymers. Exceptional solvent absorption capacity was demonstrated by the solid networks, which were found to absorb up to 7 times their own weight. Furthermore, degradation of these networks revealed that their Si-N backbones are easily hydrolysable when exposed to air. The use of lightly crosslinked copolymers as coatings was also studied using SEM analysis.
ContributorsSharma, Anuja (Author) / Trovitch, Ryan J. (Thesis advisor) / Seo, Dong-Kyun (Committee member) / Moore, Gary F. (Committee member) / Arizona State University (Publisher)
Created2024
Description
Microplastics, plastics smaller than 5 mm, are an emerging concern worldwide due to their potential adverse effects on the environment and human health. Microplastics have the potential to biomagnify through the food chain, and are prone to adsorbing organic pollutants and heavy metals. Therefore, there is an urgent need to assess the extent of microplastic contamination in different environments. The occurrence of microplastics in the atmosphere of Tempe, AZ was investigated and results show concentrations as high as 1.1 microplastics/m3. The most abundant identified polymer was polyvinyl chloride. However, chemical characterization is fraught with challenges, with a majority of microplastics remaining chemically unidentified. Laboratory experiments simulating weathering of microplastics revealed that Raman spectra of microplastics change over time due to weathering processes. This work also studied the spatial variation of microplastics in soil in Phoenix and the surrounding areas of the Sonoran Desert, and microplastic abundances ranged from 122 to 1299 microplastics/kg with no clear trends between different locations, and substantial total deposition of microplastics occurring in the same location with resuspension and redistribution of deposited microplastics likely contributing to unclear spatial trends. Temporal variation of soil microplastics from 2005 to 2015 show a systematic increase in the abundance of microplastics. Polyethylene was prominent in all soil samples.
Further, recreational surface waters were investigated as a potential source of microplastics in aquatic environments. The temporal variation of microplastics in the Salt River, AZ over the course of one day depicted an increase of 8 times in microplastic concentration at peak activity time of 16:00 hr compared to 8:00 hr. Concurrently, microplastic concentrations in surface water samples from apartment community swimming pools in Tempe, AZ depicted substantial variability with concentrations as high as 254,574 MPs/m3. Polyester and Polyamide fibers were prevalent in surface water samples, indicating a release from synthetic fabrics. Finally, a method for distinguishing tire wear microplastics from soot in ambient aerosol samples was developed using Programmed Thermal Analysis, that allows for the quantification of Elemental Carbon. The method was successfully applied on urban aerosol samples with results depicting substantial fractions of tire wear in urban atmospheric environments.
ContributorsChandrakanthan, Kanchana (Author) / Herckes, Pierre (Thesis advisor) / Fraser, Matthew (Committee member) / Shock, Everett (Committee member) / Arizona State University (Publisher)
Created2024