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
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Item Functionalized Acyclic Cucurbit[n]uril Molecular Containers as Reversal Agents for Drugs(2017) Ganapati, Shweta; Isaacs, Lyle; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The study of molecular containers has a prominent place in the scientific literature with many applications, including drug reversal. The clinical use of the cyclodextrin based reversal agent BridionTM has greatly improved the post-operative safety of patients who undergo surgery aided by NMBAs such as rocuronium. Chapter 1 introduces molecular containers, CB[n], and reports the use of the acyclic CB[n] known as Calabadion 2 as a broad spectrum reversal agent for NMBAs in rats. It also proposes the potential use of molecular containers as reversal agents for the treatment of overdose of illicit drugs in the context of available therapies. Chapter 2 establishes that Calabadion 2 displays good to high levels of selectivity toward the NMBAs rocuronium, vecuronium, and cisatracurium both in vitro and based on simulations designed to capture the essence of the biological system. The excretion profile of Calabadion 2 after NMBA reversal in rats was studied by a 1H NMR assay. It is reported that more than 50% of Calabadion 2 is eliminated intact by the kidneys within 1 hour. Chapter 3 establishes that CB[n] based molecular containers - Calabadion 1, Calabadion 2, and CB[7] display higher affinities than p-sulfocalix[4]arene and HP-β-cyclodextrin toward a panel of illicit drugs for which there are currently no USFDA approved pharmacotherapies. Calabadion 2 but not CB[7] is able to ameliorate the hyperlocomotive activity of rats treated with methamphetamine. The excretion profile of fentanyl and Calabadion 1 post reversal in rats was studied by HPLC and 1HNMR. It is reported that on an average 24 % fentanyl and 40% Calabadion 1 are eliminated by the kidneys within 1 hour. Chapter 4 discusses the synthesis and molecular recognition properties of three new acyclic CB[n] hosts IV-2a – IV-2c which incorporate alkyl linkers of varying lengths- ethyl, hexyl, and decyl; capping one end of Calabadion 1. These hosts were less water soluble than Calabadion 1 due to the loss of two sulfonate groups and did not undergo intermolecular self-association. However, the intramolecular self-inclusion of the alkyl linkers inside the cavity of these hosts led to decreased binding affinities toward guests compared to Calabadion 1.Item Building Block Synthesis and Recognition Properties of Cucurbit[n]uril (n = 7, 8) Derivatives(2015) Vinciguerra, Brittany Marie; Isaacs, Lyle; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Molecular containers have been a topic of interest for chemists since the discovery of crown ethers and their molecular recognition properties in the late 1960’s. Since then, the field of molecular containers has expanded rapidly to include many high affinity and highly selective host molecules. Chapter 1 introduces common molecular containers and goes on to discuss the CB[n] family of molecular containers. The CB[n] family are an exemplary group of hosts because they exhibit extremely high affinities (Ka values up to 1017 M-1) and high selectivity towards their guests which make them excellent candidates for many supramolecular applications. In order to maximize the use of CB[n], it became important to access specialized and functionalized derivatives to cater to various applications and chemistry. Early functionalization routes were limited by a lack of mechanistic understanding, but the mechanistic work of the Isaacs, Kim, and Day groups led to more successful syntheses. Chapter 2 discusses a building block synthesis towards water-soluble CB[7] derivatives Me2CB[7] and CyCB[7]. The recognition properties of Me2CB[7] are investigated as well as its use in drug solubilization. It is found that Me2CB[7], though 10 times more water soluble than CB[7], is able to solubilize drugs only as well as CB[7]. Additionally, a route towards a monofunctionalized CB[7] derivative, Cl-CB[7], bearing a primary chloride which is able to undergo further functionalization to a clickable azide by SN2 chemistry is presented. A click reaction with a small alkyne is performed resulting in a self-associating host whose self-assembly process is further investigated. Chapter 3 discusses a building block synthesis towards the first water-soluble CB[8] hosts Me4CB[8] and Cy2CB[8]. Mechanistic details of the CB[8] formation are elucidated from contrasting experiments and the recognition properties of the CB[8] derivatives are investigated by 1H NMR spectroscopy and X-ray crystallography. The CB[8] derivatives are investigated as potential drug solubilizing agents and it is found that they are able to solubilize several larger pharmaceutical molecules whereas CB[8] is water insoluble.