Theses and Dissertations from UMD

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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM

More information is available at Theses and Dissertations at University of Maryland Libraries.

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    Tailoring Guanosine Hydrogels for Various Applications
    (2018) Plank, Taylor Nicole; Davis, Jeffery T; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Supramolecular hydrogels are of current interest for their ease of use, potential biocompatibility, and reactivity to stimuli. These gel materials have found use in a number of fields ranging from drug delivery and tissue engineering to sensing and environmental remediation. For over a century, guanosine (G 1) and its derivatives have been known to form hydrogels based on self-assembled G4-quartet structures. Recent research has focused on extending the lifetime stability of these hydrogels and modifying their properties to better suit the gels for applications in multiple fields. One such method involves the mixing of G 1 (or G-derivatives) with 0.5 eq of KB(OH)4, which results in the formation of guanosine-borate (GB) diesters. The GB-diesters self-assemble into G4-quartets stabilized by K+, the G4-quartets then stack to form wires that entangle to make a fibrous hydrogel network. This thesis details modifications of this GB-hydrogel system and explores applications of the resulting hydrogels. Modification of the 5ʹ-OH group of G 1 to form 5ʹ-deoxy-5ʹ-iodoguanosine (5ʹ-IG 2) results in a hydrogel that self-destructs via intramolecular cyclization to 5ʹ-deoxy-N3,5ʹ-cycloguanosine (5ʹ-cG 3). Guanine analog drugs can be incorporated into this hydrogel network and then released upon self-destruction of the gel. Substitution of boric acid with benzene-1,4-diboronic acid (BDBA 4) to form hydrogels with G 1 and K+ results in hydrogels that can be crosslinked with Mg2+. These G-BDBA-Mg hydrogels have a lower critical gelator concentration (cgc) than their non-crosslinked counterparts and can be used for cell growth applications. Utilizing binary mixtures of 8-aminoguanosine (8AmG 5) with G 1 allows for the formation of hydrogels with various salts. Hydrogels made of different salts preferentially absorb either cationic or anionic dyes from water, making them candidates for use in environmental remediation. Other 8-substituted G-analogs, including, 8-bromoguanosine (8BrG 6), 8-iodoguanosine (8IG 7), and 8-morpholinoguanosine (8morphG 8) can be used in binary mixtures with G 1 to form gels at room temperature upon mixing with KB(OH)4. Room temperature hydrogels have potential applications in enzyme immobilization, drug encapsulation, and environmental cleanup.
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    Guanosine-borate hydrogels- Form and function
    (2015) Peters, Gretchen Marie; Davis, Jeffery T; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Due to their biocompatibility and stimuli-responsive nature, supramolecular hydrogels derived from natural products are attractive for a number of biomedical applications, including diagnostics, targeted drug delivery and tissue engineering. Nucleosides, the building blocks of nucleic acids, are desirable candidates for forming supramolecular gels as they readily engage in reversible, noncovalent interactions. Guanosine (G 1), in particular, is unique in that it has multiple faces for noncovalent interactions and can self-associate into stable higher-order assemblies, such as G4-quartets and G-quadruplexes. This self-assembly of G 1 and its derivatives into G4-quartets has long been known to induce hydrogelation. However, the requirement of excess salt and the propensity of G 1 to crystallize persist as limitations for G4-hydrogels. Thus, recent interest has focused on developing G4-hydrogels with improved lifetime stabilities and lower salt concentrations. The work described here focuses on a long-lived G4-hydrogel made from G 1 and 0.5 equiv. of KB(OH)4. Gelation occurs through the formation of guanosine-borate (GB) diesters and subsequent assembly into cation-templated G4•K+-quartets. The physical properties and stability of the GB hydrogel can be readily manipulated by varying the gelation components. For example, merely altering the identity of the cation drastically alters the gel’s physical properties. Namely, while GB hydrogels formed with K+ are self-supporting and robust, mixing G 1 with LiB(OH)4 results in a weak gel that readily dissociates upon physical agitation. Small molecules, such as cationic dyes and nucleosides, could be selectively incorporated into the GB hydrogel through reversible noncovalent and covalent interactions. One such dye and known G4-quartet binding ligand, thioflavin T (ThT) fluoresces in the presence of the GB hydrogel. The ThT fluorescence increases as a function of gelator concentration with a sharp increase correlating to the gel point. Thus, this ThT fluorescence assay is a new method for probing the formation of G4-hydrogels. Additionally, ThT acts as a molecular chaperone for Li+ GB hydrogelation. Substoichiometric amounts of ThT results in faster hydrogelation, increased gel strength and improved recovery of a hydrogel destroyed by external stress. Insights gained from this research have implications towards development of biomaterials, biomolecule sensing, and drug delivery.
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    Synthetic Ion Channels From Lipophilic Guanosine Derivatives
    (2009) Ma, Ling; Davis, Jeffery T; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Synthetic ion channels and pores not only represent models of natural transmembrane ion channels, but also demonstrate their potential applications in the areas of drug delivery, biosensors, antimicrobial agents and other molecular devices. In this thesis, lipophilic guanosine derivatives that combine both "molecular recognition" and "membrane soluble" features are utilized for the development of the self-assembled synthetic ion channels. The potential of lipophilic G-quadruplexes to function as synthetic ion channels has been investigated by tracing the cation exchange process between free cations and G-quadruplex bound cations. Cation exchange between bulk cations (K+, NH4+) in solution and the bound cations in G-quadruplexes (G 1)16*4Na+*4DNP- was investigated by electrospray ionization mass spectrometry and by 1H , 15N NMR spectroscopy. The ESI-MS and 1H NMR data showed that G-quadruplexes containing "mixed cations" formed through a sequential ion exchange process. The use of NMR-"visible" 15NH4+ cations in the NMR titration experiments allowed the determination of two "mixed-cation" intermediates by 15N-filtered 1H NMR and selective NOE spectroscopy. A "central insertion" pathway was proposed for the cation exchange process from (G 1)16* 4Na+* 4DNP- to (G 1)16* 4NH4+* 4DNP-. In the lipophilic G-quadruplex, the "central" Na+, bound between the 2 symmetry related G8-Na+ octamers, is bound less strongly than are the 2 "outer" Na+ ions sandwiched within the G8-octamers. These results demonstrated the dynamic nature of lipophilic G-quadruplex in solution and directed the design of a ditopic guanosine-sterol conjugate as an approach toward making synthetic ion channels. Guanosine-sterol conjugate 3-1 was prepared by coupling 2', 3'-bis-TBDMS, 5'-amino guanosine with a bis-lithocholic acid derivative. Voltage clamp experiments demonstrated a series of stable, single ion channel conductances when compound 3-1 was incorporated into a planar phospholipid membrane. These channels are large; with nanoSiemens conductance values and they last for seconds of "open" time. This feature distinguishes them from most synthetic channels, which typically conduct in the picosiemens range with millisecond lifetimes. The structural studies using the bis-lithocholamide linker demonstrated that the guanosine moiety plays an essential role in the self-assembly of the transmembrane ion channels. The sizes of the most prevalent single channels calculated by Hille's equation are much larger than the diameter of a G-quartet, which suggested that the ion transport proceeded through larger pore(s) that form upon self-assembly of lipophilic guanosine-lithocholate 3-1 within the phospholipid membrane. The large transmembrane pore(s) could be envisioned as a supramolecular structure with hydrophobic walls of bis-lithocholate linker and a central pillar of a cation-filled G-quadruplex. The use of a bis-urea functionality in the bis-lithocholic acid linker generated guanosine-sterol conjugate 4-1. The ion channel activity of 4-1 was demonstrated by voltage clamp experiment. Large ion channels formed from 4-1 had longer life-times than those formed from compound 3-1. The extra stabilization of self-assembled ion channels attributed to the bisurea hydrogen bonding is consistent with the structural hypothesis of ion channels. The stable large transmembrane ion channels self-assembled by lipophilic guanosine derivatives have potential for delivery of drugs or biomolecules.