Theses and Dissertations from UMD
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Item High Affinity Host-Guest Pairs Enable In Vitro and In Vivo Sequestration of Drugs of Abuse(2020) Murkli Jr., Steven Louis; Isaacs, Lyle L.I.; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Molecular containers of diverse structure and binding preferences has led to their incorporation in numerous applications such as drug solubilization, drug delivery, and drug sequestration. A detailed understanding of the binding properties of novel molecular containers can both guide future structural refinement and open up new potential applications.Chapter 1 introduces molecular containers and the associated benefits of their use in the pharmacokinetic approach to drug sequestration. Among these containers, CB[n] show the highest promise due to their high affinity and selectivity for their intended drug target while displaying high levels of biocompatibility. Accordingly, innovations to the CB[n] scaffold has led to the development of acyclic CB[n]-type receptors capable of achieving drug reversal in vivo, although further design can yield sequestration agents with higher potency. Chapter 2 provides a thorough investigation of the binding preferences of CB[8] towards a set of biologically relevant drugs. These findings serve as both a blinded experimental dataset for computational chemists to validate their predictive capability on host-guest interactions and to establish a working knowledge of CB[8] binding preferences for future applications. Chapter 3 puts the aforementioned binding preferences of CB[8] to the test versus a panel of drugs of abuse in a continuation of the efforts outlined in Chapter 1. This study is then translated to the successful in vivo sequestration and prevention of phencyclidine (PCP)-induced hyperlocomotion by a water-soluble CB[8] derivative previously studied in the Isaacs group. Chapter 4 presents a new member of the acyclic CB[n]-type receptor class bearing anthracene terminated walls, M3, that by design is capable of increased binding affinity across a large guest library. This increased binding affinity is elucidated versus a comparator host bearing naphthalene walls, M2, that has been previously used as a sequestration agent for Neuromuscular Blocking Agents, (NMBA’s) and is currently the highest potency acyclic CB[n]-type receptor available. Finally, the fluorescent responsiveness of M3 is investigated to create a sensing array capable of distinguishing 22 guests providing basis for future sensing experiments.Item Bioorganic Chemistry of Prodigiosenes: Anion Transport, Basicity, Conformation and G-Quadruplex DNA Binding(2015) Rastogi, Soumya; Davis, Jeffery T; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Naturally occurring prodigiosenes are produced by microorganisms such as Streptomyces and Serratia marcescens. Prodigiosenes are fascinating for their wide range of biological activities in the form of anti-cancer, immunosuppressive, and antimicrobial agents. Some of the analogs, such as prodigiosin, are currently undergoing preclinical and clinical trials. Despite such widespread interest, the origin of prodigiosin's biological activity has not been established unambiguously. Based on biological studies, it is known that prodigiosin plays a physiologically relevant role and has several cellular targets. The work described in this thesis explores some of the chemistry that may help explain prodigiosenes' biological activity. A new series of analogs of prodigiosin bearing an additional methyl and a carbonyl group at the C-ring were evaluated as transmembrane anion transporters. The effect of C-ring modifications in these new prodigiosenes on their basicity, transmembrane anion transport ability and their in vitro anticancer activity was assessed. The ability of prodigiosenes to facilitate co-transport of H⁺Cl⁻ leading to alteration of intracellular pH, and catalyze anion exchange across lipid bilayers has been proposed to be one of the cause of its anti-cancer activity. It has been suggested that the prodigiosenes bind anions in their protonated state at physiological pH. Prodigiosene analogs with modified B-ring demonstrated that the electronic nature of the substituent on the B-ring influences the basicity of these analogs, and consequently, their anion transport efficiency is also affected. A study of the conformations of prodigiosin and its analogs was performed to learn about how the ligands orient in different solvents. This information could potentially link the preferred conformational states of these compounds and their observed biological activities. Lastly, we confirmed that prodigiosin binds at the 3ˈ end of a G-quadruplex DNA. The results from this chapter are significant as they widen the scope of developing prodigiosenes as G-quadruplex binding ligands or telomerase inhibiting agents. Further, they lead the way to revealing another possible mechanism to explain the anti-cancer activity of prodigiosenes.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.Item Discrete and Polymeric Complexes Comprising Bis-nor-seco-CB[10] and Oligoammonium Ions(2009) Nally, Regan; Isaacs, Lyle; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)ABSTRACT Title of Document: DISCRETE AND POLYMERIC COMPLEXES COMPRISING BIS-NOR-SECO-CB[10] AND OLIGOAMMONIUM IONS Regan C. Nally, Ph.D., 2009 Directed By: Professor Lyle D. Isaacs Department of Chemistry and Biochemistry Supramolecular architectures composed of multiple components are challenging to produce, as the enthalpic gain must be greater than the entropic penalty of strict geometrical arrangements. Therefore, it is the goal of supramolecular chemists to strategically design and synthesize molecules that will exhibit selectivity toward formation of a particular complex. This dissertation describes the formation of supramolecular architectures of increasing size and is organized in the following way. Chapter 1 introduces the reader to the field of supramolecular polymer chemistry. Chapter 2 describes the synthesis of a series of monovalent ditopic guests (II-1 - II-6) and their complexation properties toward double cavity cucurbituril host bis-ns-CB[10]. We observed the preferential formation of 1:1, 2:2, and oligomeric complexes rather than the desired n:n supramolecular polymers. Guest II-7 which contains a longer biphenyl spacer successfully precludes the formation of the 1:1 complex but results in the formation of the 2:2 complex (bis-ns-CB[10]2*II-72) rather than supramolecular polymer. Guest II-8 is heterovalent and ditopic and is shown to reversibly form 2:2 and 1:2 complexes (bis-ns-CB[10]2*II-82 and bis-ns-CB[10]*II-82) in response to changes in host:guest stoichiometry. Lastly, this equilibrium can be manipulated by the addition of exogenous CB[6] which selectively targets the hexanediammonium ion binding region of II-8 and delivers the penta-molecular complex bis-ns-CB[10]*II-82*CB[6]2. Chapter 3 describes the formation of a main chain supramolecular polymer from a mixture of poly(diallyldimethylammonium chloride) (III-1) and bis-ns-CB[10]. The bis-ns-CB[10] molecular container behaves as a molecular handcuff, bringing together two ends of individual polymers to form III-1n* bis-ns-CB[10]m, resulting in an extension of the length of polymer. The effect of bis-ns-CB[10] on the physical properties of the polymer was investigated using viscometry in aqueous solution. A decrease in the ηrel was observed upon increasing concentrations of bis-ns-CB[10] to a solution of III-1. Atomic force microscopy (AFM), and diffusion-ordered spectroscopy (DOSY) were performed to probe the mode of interaction between polymer III-1 and bis-ns-CB[10]. Collectively, the data supports the two roles for bis-ns-CB[10]: 1) as a deaggregation agent, and 2) as a molecular handcuff that non-covalently links individual polymer strands resulting in overall extension of the polymer.