Theses and Dissertations from UMD
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Item MOLECULAR RECOGNITION PROPERTIES OF MOLECULAR CONTAINERS IN AQUEOUS SOLUTIONS(2023) King, David; Isaacs, Lyle D; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Supramolecular containers take advantage of non-covalent interactions to do a variety of tasks with high affinity. In particular, water-soluble containers are able to bind biologically relevant molecules to perform useful and interesting tasks. Chapter 1 introduces the field of supramolecular chemistry is introduced and establishes the ability of cucurbit[n]urils (CB[n]) to bind guests with high affinity. It also establishes the uses of water-soluble supramolecular containers, including new-generation pillar[n]arene sulfate (P[n]AS) hosts, in biologically relevant systems. Chapter 2 expands on previous attempts at finding high-affinity host-guest pairings by showing that triamantane amines and triamantane diamines are able to bind CB[8] with femtomolar dissociation constants. It also shows that these ultratight binding complexes can be found in competition measurements with slightly weaker ternary complexes, thus reducing the number of measurements needed and the error of those measurements. Chapter 3 shows the discriminatory power of P6AS towards various amino acids and amino acid amides, as well as their methylated derivatives. This discriminatory power is further explored by showing P6AS shows discriminatory power towards histone 3 peptide sequences that are methylation on either the lysine or arginine. This system was also modeled computationally to investigate the role of water in binding affinity. Chapter 4 expands on the use of P[n]AS in biologically relevant systems by measuring the binding constants and an assay to detect and differentiate various World Anti-Doping Agency (WADA) banned compounds in PBS. The same assay was then used to create a calibration curve in simulated urine for two compounds. In total, the proof-of-concept assay is able to detect Pseudo down to 31.8 μM concentrations.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.Item ACYCLIC CUCURBIT[N]URIL CONGENERS: SYNTHESIS, BINDING PROPERTIES AND MEDICINAL APPLICATIONS(2014) Zhang, Ben; Isaacs, Lyle D; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)An urgent problem for pharmaceutical industry is that the water solubility of an estimated 40-70% of the newly developed active pharmaceutical ingredients (API) are so poor that they cannot be formulated on their own. One interesting topic is to use molecular containers as the solubilizing agents. Supramolecular chemistry has always been an interesting research area and during the past decades, various new supramolecular host*guest systems have been developed. Cucurbit[n]urils (CB[n]) are very promising molecular containers as drug delivery vehicles due to their outstanding recognition properties. In order to discover the most suitable CB[n]-type containers as solubilizing agents, acyclic CB[n]-type containers have been synthesized and their recognition and formulation properties have been studied. In this thesis, three chapters have been included to investigate the possibility of using CB[n]-type containers as solubilizing agents for pharmaceutical agents. Chapter 1 gives an introduction to supramolecular chemistry and formulation techniques using molecular containers. A literature review on the synthesis, functionalization and applications of cucurbit[n]uril is given and the application of cyclodextrins and CB[n] containers in formulation techniques is discussed. Chapter 2 describes a series of acyclic CB[n]-type molecular containers (II-2a - II-2h) with different solubilizing groups bearing different charges for evaluation as potential drug solubilizing agents. The X-ray crystal structures of the negative, positive and neutral hosts (host II-2b, II-2f, and II-2h) are reported. For neutral (II-2h) and positively charged (II-2f) hosts, intramolecular H-bonds and ion-dipole interactions between the solubilizing arms and the ureidyl C=O portals are observed as well as intrahost π−π stacking interactions which results in a self-filling of the cavity. 1H NMR and UV/Vis spectroscopy are used to measure the Ka values of hosts II-2a, II-2h, and II-2f toward guests with different charge and significant decrease is noted in binding affinities of the neutral (II-2h) and positive (II-2f). The pKa of 7H+ alone and in the presence of differently charged hosts II-2a, II-2h, and II-2f are measured and the II-2a induces the largest pKa shift. The poor recognition properties of hosts II-2h and II-2f are reflected in their phase-solubility diagrams with insoluble drugs (tamoxifen, 17-α-ethynylestradiol, and indomethacin). In all cases, the anionic host II-2a functions more efficiently as a solubilizing agent than either neutral II-2h, or cationic host II-2f. In chapter 3, we compare the ability of III-1a - III-1e to solubilize insoluble drugs relative to HP-β-CD. Phase solubility diagrams are created for mixtures of containers III-1a - III-1e and HP- β-CD with 19 drugs. We find that the solubilizing ability of the best container (III-1a - III-1e) is superior to HP-β-CD in all cases. A notable achievement is the solubilization of the developmental anticancer agent PBS-1086. The acyclic CB[n]-type containers display an affinity for the steroid ring system, aromatic moieties of insoluble drugs, and cationic ammonium groups. Compound III-1b is generally the most potent (Ka up to and exceeding 106 M-1) container whereas both III-1a and III-1b display excellent solubility enhancement toward a broad range of insoluble drugs. The broad scope of insoluble drugs that can be formulated with III-1a and III-1b - in many cases where HP- β-CD fails completely - makes acyclic CB[n]-type containers particularly attractive alternatives to cyclodextrins as solubilizing excipients for practical applications.