Alumni Dissertations

 

Alumni Dissertations

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  • DESIGN, SYNTHESIS, AND ANTI-TUMOR ACTIVITIES OF BENZOPOLYSULFANE COMPOUNDS THAT MIMICS A TUNICATE-DERIVED NATURAL PRODUCT

    Author:
    Adaikapillai Mahendran
    Year of Dissertation:
    2011
    Program:
    Chemistry
    Advisor:
    ALEXANDER GREER
    Abstract:

    Benzopolysulfanes are untapped potential therapeutic compounds, which possess an impressive array of biological activities. By developing an entirely new class of compounds (polysulfanes) drug resistance can be evaded due to the lack of exposure of organisms to these compounds. However, polysulfanes are challenging compounds to prepare, and usually have very poor water-solubility. New synthetic methods and studies on solubility and cell-directed delivery are needed to explore the range of possibilities of this novel class of compounds. This thesis outlines (1) synthesis and biological activities of benzopolysulfane conjugates namely, PEGylated benzopoylsulfanes; and (2) mechanistic aspects on mode of introduction of sulfur atom to the catechol core; Benzopolysulfanes, 4-CH3(OCH2CH2)3NHC(O)-C6H4-1,2-Sx (x = 3-7, and 9) were synthesized with a PEG group attached through an amide bond and examined for water solubility, antitumor activity, and propensity to equilibrate and desulfurate. LCMS and HPLC data show the PEG pentasulfane ring structure predominates, and the tri-, tetra-, hexa-, hepta-, and nonasulfanes were present at very low concentrations. The presence of the PEG group improved water solubility by 50-fold compared to the unsubstituted benzopolysulfanes, C6H4Sx (x = 3, 5, and 7), based on intrinsic solubility measurements. Polysulfur linkages in the PEG compounds decomposed in the presence of ethanethiol and hydroxide ion. The PEG pentathiepin desulfurated rapidly and an S3 transfer reaction was observed in the presence of norbornene, no S2 transfer reaction was observed with 2,3-dimethylbutadiene. The antitumor activities of the PEG-substituted benzopolysulfane mixtures were analyzed against four human tumor cell lines PC3 (prostate), DU145 (prostate), MDA-MB-231 (breast), and Jurkat (T-cell leukemia). The PEG conjugated polysulfanes had IC50 values 1.2-5.8 times lower than the parent "unsubstituted" benzopolysulfanes. Complete cell killing was observed for the PEG polysulfanes with 4 µM for PC3 and DU145 cells, and with 12 µM for MDA-MB-231 cells. The results suggest that solubilization of the polysulfur linkage is a key parameter to the success of these compounds as drug leads. A mechanism is proposed for the formation of cyclic 5,6,7,8,9-pentathiabenzoc ycloheptene-1,2-diol, 4, from the reaction of o-benzoquinone with reduced elemental sulfur, H2Sx. 1,6-Conjugate addition to the quinone is favored over 1,4-conjugate addition. Hydrogen bonding to the quinone oxygen enhances the nucleophilicity of H2Sx by facilitating the removal of the S-H proton. We propose that initially formed 3-polysulfidobenzene-diol intermediates, 5, are oxidized to their corresponding quinones, 13, and closure of the polysulfur ring subsequently takes place at the C3-C4 bond leading to 4. A possible mechanism for the formation of pentasulfur linkage in 4 is discussed, which the key moiety is found in a number of natural products.

  • Ultra-Large-Pore Ordered Mesoporous Organosilicas and Related Hollow Nanoparticles

    Author:
    Manik Mandal
    Year of Dissertation:
    2010
    Program:
    Chemistry
    Advisor:
    Michal Kruk
    Abstract:

    My dissertation describes the synthesis of ultra-large-pore ordered mesoporous organosilicas and related hollow nanoparticles. In the first part, we developed a versatile approach through which a series of periodic mesoporous organosilicas (PMOs) with 2-dimensional hexagonal structure and different bridging groups can be synthesized. The bridging groups are methylene (-CH2-), ethylene (-CH2CH2-), ethenylene (-CH=CH-), and phenylene (-C6H4-). For this purpose, a combination of a commercially available triblock copolymer Pluronic P123 (EO20PO70EO20) with judiciously chosen micelle swelling agent (cyclohexane, or 1,3,5-triisopropylbenzene) was used as a miceller template, and the initial step of the synthesis was performed at temperature between 10 and 18 oC, followed by hydrothermal treatment at 100-150 oC. The PMOs were characterized using small-angle X-ray scattering (SAXS), nitrogen adsorption, transmission electron microscopy, and solid-state 29Si NMR. For all PMO compositions, the formation of 2-D hexagonal structures with (100) interplanar spacing, d100, up to 21-26 nm was achieved, which is at least seven nanometers larger than d100 reported earlier for any PMO with 2-D hexagonal structure. The nominal (BJH) pore diameters up to 20-27 nm were achieved for the considered compositions of PMOs with with 2-D hexagonal ordering, while even larger pore sizes were sometimes attained for disordered or weakly ordered structures. The mesopores exhibited constrictions or narrow entrances that were widened by increasing the hydrothermal treatment temperature. The pore diameter tended to increase as an initial synthesis temperature decreased, allowing for the pore size adjustment, but the useful temperature range depended on the bridging groups. The present work suggests that the low-temperature micelle-templated synthesis with judicious selected swelling agents is a general pathway to ultra-large-pore 2-D hexagonal PMOs with both aliphatic and aromatic bridging groups. In the second part, we have demonstrated the synthesis of large-pore ethylene-bridged periodic mesoporous organosilica with face-centered-cubic structure. This was achieved by the use of judiciously chosen swelling agents and Pluronic F127 block copolymers at sub-ambient temperature (~ 15 oC). While our work confirmed that 1,3,5-trimethylbenzene (TMB) which was already employed by other researchers, is a facile swelling agent for Pluronic F127-templated ethylene-bridged PMOs with cubic Fm3m structure and our optimization of the synthesis afforded hitherto unreported unit-cell size and pore size for this PMO, it was also demonstrated that swelling agent predicted to have a higher extent of solubilization in Pluronics than TMB provide vast new opportunities. In particular, xylene was found to afford highly ordered materials with large unit-cell size and pore diameter, and a wide range of moderately or weakly ordered materials with very large unit-cell parameters (up to ~ 50 nm) and some with very large pore diameters (up to ~ 20 nm). In this case, the pore size and unit-cell size was tunable by adjusting the amount of inorganic salt (KCl) in the synthesis mixture. The use toluene allowed for the increase in the primary mesopore volume and also afforded large-pore PMOs in the absence of an inorganic salt. The use of the latter was also not required when benzene was used as a swelling agent. The identification of new swelling agents for ethylene-bridged PMO with spherical mesopores is likely to be extendable on PMOs of other framework compositions and for other related materials. In the third part, based on understanding of the condition for the formation of ordered mesoporous organosilicas, we were able to synthesize hollow nanoparticles with different organic bridging groups. Different organic bridging groups such as methylene, ethylene, ethenylene, and phenylene were incorporated in the organosilica walls of the hollow nanoparticles. Further, we were able to synthesize hollow nanotubules comprising of these bridging groups in the walls.

  • Aqueous Solvation of Protein Secondary Structures: Density Functional Theory Study

    Author:
    Mateusz Marianski
    Year of Dissertation:
    2013
    Program:
    Chemistry
    Advisor:
    Joseph Dannenberg
    Abstract:

    In recent years, van der Waals forces have received considerable attention among the scientific community. It is hard to overestimate the significance of dispersion forces which are thought to play important roles in the energetics of biological molecules, such as DNA and peptides. However, the weakest of interactions is also the most difficult to approach by theoretical methods and has been troubling computational chemists for at least last two decades. In my thesis I will answer how well recently developed density functionals deal with the dispersion in the case study of dispersion-enhanced induction complexes, relative stability of pi-stacking and hydrogen bonded dimers, and protein secondary structures. The presented results undermine the belief that recent widely-parametrized and/or dispersion-corrected functionals outperforms older well-established functionals, like famous B3LYP. In the second part of my thesis I will focus on the influence of aqueous solvent on protein structures. Water is present in all biological systems, where it is not only a static medium of the reaction, but also an active part of the process called life, and it requires careful treatment. I compare models of implicit and explicit solvation for beta-turns, alpha-helices, and beta-sheets. I find that solvation by small water clusters can alter the molecular properties of gas phase molecules and continuous methods are not able to model all effects.

  • The Development Of New Organocatalysts and New Organocatalytic Cascade Reactions

    Author:
    Patrick McGarraugh
    Year of Dissertation:
    2012
    Program:
    Chemistry
    Advisor:
    Stacey Brenner-Moyer
    Abstract:

    Organocatalysis is the use of small organic molecules to catalyze chemical reactions. They are generally cheaper, less toxic, and easier to handle on a laboratory and industrial scale than more traditional metal-based catalysts. This dissertation discusses the development of new organocatalysts and organocatalytic methods for the asymmetric synthesis of useful small molecules. The research conducted has specifically focused on the use of chiral diarylprolinol silyl ether organocatlysts and their ability to catalyze a variety of useful cascade reactions through iminium and enamine catalysis. Cascade reactions are useful in that a great deal of molecular complexity may be generated in a one-pot process using simple, readily available building blocks. Herein, is provided a comprehensive background on the use of diarylprolinol silyl ethers in the catalysis of iminium-initiated cascade reactions. The research conducted has focused on three main topics: 1.) The development of a novel class of bifunctional bissulfonamide organocatalysts for the asymmetric conjugate addition of dicarbonyls to nitroolefins. 2.) The use of diarylprolinol silyl ether organocatalysts to catalyze a novel Michael-Michael cascade reaction which generates fused carbocycles. 3.) The discovery and development of a novel organocascade kinetic resolution reaction using diarylprolinol silyl ether organocatalysts, which can be used for the synthesis of chiral 2,6-disubstituted tetrahydropyrans and chiral 2,5-disubstituted tetrahydrofurans.

  • SPECIATION OF TECHNETIUM-99 INCORPORATED INTO METAL OXIDE MATRICES: A MOLECULAR LEVEL UNDERSTANDING OF Tc-99 REDUCTION AND ITS COMPLEXATION INTO POLYOXOMETALATES

    Author:
    DONNA MCGREGOR
    Year of Dissertation:
    2009
    Program:
    Chemistry
    Advisor:
    Lynn Francesconi
    Abstract:

    Technetium-99 (99Tc) is a long-lived (T1/2 = 2.13 x 105 years) β-emitting (Emax = 294 KeV) radionuclide formed during the fission of 235U and fallout from nuclear weapons testing. It exists in relatively high concentrations in nuclear waste tanks, and the pertechnetate (TcO4-) anion has been shown to leach into surrounding subsurface soils and groundwaters. Due to its long half-life and the high mobility of the pertechnetate (TcO4-) anion, 99) Tc management is an issue for both waste characterization and long-term storage. A better understanding of both its extensive redox chemistry and the parameters that affect the speciation and coordination environment of Tc will promote the development of more appropriate methods for the separation of Tc from nuclear waste tanks as well as more fitting mediums for storage. Polyoxometalates (POMs) are early transition metal oxide clusters that are chemically robust. They have homogeneous crystalline structures and are known to be good model systems for metal oxide solid-state materials such as the glasses and ceramics used to house nuclear waste. The synthesis of pure 99Tc-POM compounds, however, is complicated by both the unwanted hydrolysis of the Tc(V) starting material and difficulties with the separation of the free POM ligand from the desired 99Tc-POM complex. We have developed methods for the clean synthesis of the 99Tc - (α1-P2W17O61)10-) and (α2-P2W17O61)10-) Wells-Dawson POM compounds (as both organic and aqueous soluble complexes) and characterized them using various spectroscopic techniques. POMs also have unique, tunable, electron transfer abilities and can be reduced, both electrochemically and photochemically in the presence of a sacrificial electron donor, by multiple electrons while maintaining their structural integrity. To this end we have investigated a number of POMs; Keggin ions, (XW12O40n-), X=P, n=3; Si, n=4; Al, n=5), the Wells-Dawson lacunary isomer (α2-P2W17O61) 10-), and a "wheel" POM, P8W48O18440-), for their ability to reduce pertechnetate and sequester low valent 99Tc. The resulting low valent Tc species have been characterized by physical methods including multinuclear NMR and electrochemistry.

  • Benzophenone photoprobes for chemical proteomics and drug target identification

    Author:
    Doina Mihai
    Year of Dissertation:
    2011
    Program:
    Chemistry
    Advisor:
    Akira Kawamura
    Abstract:

    Benzophenone photoprobes are widely used in photoaffinity-labeling studies, especially for the characterization of ligand-receptor interaction. Photolabeling studies using benzophenone, however, are by no means routine experiments. It is not uncommon that carefully designed photoligands fail to label target proteins. In order to get insights into the important factors that affect the photolabeling efficiency, we conducted a structure-activity relationship study (SAR) on adenine-benzophenone photoligands. The study suggested that conformational flexibility was the determining factor that controls the photolabeling efficiency by benzophenone photoprobes. In theory, photoaffinity-labeling can also be used for target identification of small molecules. However, the complexity of proteins in biological samples, such as cell lysate, tissue homogenates and serum samples, limits the use of benzophenone photoprobes in drug target identification and chemical proteomics. By using so called "blocking strategy" we were able to systematically classify the list of proteins identified from photoaffinity-labeling studies using benzophenone. The findings of this study enabled us to refine the experimental protocol for drug target identification and chemical proteomics using benzophenone photoprobes. During the affinity purification of phochemically biotinylated proteins, we discovered that monomeric avidin resin can selectively enrich heat shock proteins (Hsps) from complex proteomes. Although such serum Hsps or circulating Hsps, has been linked to various diseases, including cancer and cardiovascular diseases, their characterization have been hampered be the abundant proteins in serum such as albumin and immunoglobulings. The development of simple and reproducible method for Hsp enrichment opens a new opportunity to define the roles of circulating Hsps in various diseases.

  • Chiral Sulfurization For Synthesis Of Antisense Oligonucleotides

    Author:
    Joshua Mukhlall
    Year of Dissertation:
    2010
    Program:
    Chemistry
    Advisor:
    William Hersh
    Abstract:

    Chapter 1: Antisense and RNA interference (RNAi) reagents are two of the most widely studied oligonucleotide-based therapeutics. Phosphorothioate oligonucleotide, an antisense reagent, has a stereogenic center at the phosphorothioate linkage and in the absence of enantioselective synthesis, a mixture of diastereomers results. Stereodefined phosphorothioates have shown greater antisense activity; however, only a few research groups have successfully designed methods for enantioselective synthesis of phosphorothioates with >98% de, albeit in low yields. This dissertation presents a conceptually different method for enantioselective synthesis of phosphorothioate oligonucleotides via a Curtin-Hammett system that requires epimerization of the phosphite triester on the reaction time scale and selective sulfurization of one of the equilibrating epimers with a chiral sulfurizing reagent. Chapter 2: 2-Cyanoethyl[5'-O-acetyl-2'-deoxythymylyl]-(3',5')-3'-O-(acetyl)-2'-deoxythymidine phosphite triester was found to invert at 150 ºC with ΔG = 33.0 ± 0.2 kcal/mol. Separation of the two diastereomers of the phosphite triester was successfully achieved via its 2-cyanoethyl[5'-O-(p,p'-dimethoxytrityl)-2'-deoxythymylyl]-(3',5')-3'-O-(tert-butyldimethylsilyl)-2'-deoxythymidine boranophosphate analogue. For the inversion study the p,p'-dimethoxytrityl and tert-butyldimethylsilyl groups were substituted with acetyl groups to reduce decomposition during heating. Attempts to induce inversion at lower temperature with acidic and radical species failed. Chapter 3: Chiral analogues of phenylacetyl disulfide (PADS) and 5-methyl-3H-1,2,4-dithiazol-3-one (MEDITH) were synthesized from the same α-alkylated carboxylic acids to give products with enantiomeric purities of 99.0 to >99.9% and 86.1-99.4%, respectively. X-ray diffraction results for one pair of enantiomers unequivocally establish the absolute configurations of two disulfides, and density functional theory (DFT) calculations suggest that the observed high specific rotations could be due to preferred retention of helicity about the S-S bond in solution. Chapter 4: Phosphite triesters with varying degrees of steric hindrance around the phosphorus atom (β-cyanoethyl, TMS, TBDMS, and TPS derivatives) were screened against chiral analogues of PADS and MEDITH. The RPS:SPS diastereomeric ratios of the resulting phosphite sulfides or phosphorothioates were determined by reverse-phase HPLC, and a numerical procedure was developed to express the diastereoselectivity of the reactions. The best selectivities to give RPS enriched and SPS enriched phosphorothioates were achieved with MEDITH analogues (S)-6d (naproxen derivative) (14.7% de) and (S)-6c (isopropyl group at the α position) (-7.9% de), respectively, when reacted with the phosphite triester bearing the TMS group.

  • SYNTHESIS, CHARACTERIZATION, RAMAN, AND SURFACE ENHANCED RAMAN STUDIES OF SEMICONDUCTOR QUANTUM DOTS

    Author:
    Yi Pan
    Year of Dissertation:
    2012
    Program:
    Chemistry
    Advisor:
    John Lombardi
    Abstract:

    The major contributions and discoveries of the dissertation include: (1) Homogeneous nucleation processes for the formation of nanocrystals can occur at low temperature and do not need to proceed at high temperature to overcome a high energy barrier. Monodisperse PbS quantum dots (QDs) obtained with nucleation and growth at 45°C support this finding. (2) Monodisperse single elemental Se QDs can be produced by simple solution crystallization from TDE (1-tetradecene) or ODE (1-octadecene). (3) TDE is a better non-coordinating solvent compare to ODE. STDE (S dissolved in TDE) and SeTDE (Se dissolved in TDE) are stable reagents with long storage time. They can be used as universal precursors for S-containing and Se-containing QDs. (4) QDs synthesis can be carried out at low temperature and relatively short reaction time using the simple, non-injection, one-pot synthetic method. (5) The one-pot method can be extended for the synthesis of QDs and graphene oxide nanocomposites and metal and graphene oxide nanocomposites. (6) PbCl2-OLA (oleylamine) is a universal system for the synthesis of Pb-chaclogenides QDs. (7) Surface enhanced Raman spectroscopy (SERS) is used to probe both size and wave length dependent quantum confinement effects (QCEs) of PbS QDs. (8) Raman spectroscopy is a powerful tool to elucidate crystal structure of Se nanoclusters with size of 1-2 nm. Semiconductor QDs have attracted considerable attention due to their potential for energy-efficient materials in optoelectronic and solar cell applications. When the radius of a QD is decreased to that of the exciton Bohr radius, the valence and conduction bands are known to split into narrower bands due to QCEs. QCEs are both size and wave length dependent. We have developed, synthesized and characterized a series of Pb-chaclogenide QDs, which all the sizes of the QDs are monodisperse and smaller than their respective exciton Bohr radius, to study the QCEs of these QDs. SERS is used as a crucial tool to investigate these QCEs. The QCEs are due to any of the following three resonances or a combination among them: interband resonance, molecular state resonance, and charge-transfer resonance.

  • Applications of Bionanotechnology

    Author:
    Christophe Pejoux
    Year of Dissertation:
    2011
    Program:
    Chemistry
    Advisor:
    Hiroshi Matsui
    Abstract:

    The aim of nanotechnology is to devise technologies at the crossroads of chemistry, physics and biology to shape matter at the atomic scale to form nanosized functional objects and to arrange them into intricate assemblies to elaborate new devices. Today, its biological aspect is largely emphasized to tackle biomedical issues such as pathogen identification, disease diagnosis and treatment. In this respect, interdigitated electrodes were employed to monitor the presence of harmful bacteria, then to attempt to detect human PC3 carcinoma prostate cells as well as the size variation of stimulus-responsive hydrogel beads designed for drug delivery. Our second project aimed at demonstrating the potential use of TiO2-labeled antibodies as substitute for horse-radish peroxidase-labeled antibodies for Enzyme-Linked ImmunoSorbent Assays (ELISA). Our last project revolved around harnessing the enzymatic activity of urease to grow silver-sulfide nanoparticles.

  • FACTORS AFFECTING THE REMOVAL OF AMMONIA FROM AIR ON CARBONACEOUS ADSORBENTS: INVESTIGATION OF REACTIVE ADSORPTION MECHANISM

    Author:
    Camille Petit
    Year of Dissertation:
    2011
    Program:
    Chemistry
    Advisor:
    Teresa Bandosz
    Abstract:

    Air pollution related to the release of industrial toxic gases, represents one of the main concerns of our modern world owing to its detrimental effect on the environment. To tackle this growing issue, efficient ways to reduce/control the release of pollutants are required. Adsorption of gases on porous materials appears as a potential solution. However, the physisorption of small molecules of gases such as ammonia is limited at ambient conditions. For their removal, adsorbents providing strong adsorption forces must be used/developed. In this study, new carbon-based materials are prepared and tested for ammonia adsorption at ambient conditions. Characterization of the adsorbents' texture and surface chemistry is performed before and after exposure to ammonia to identify the features responsible for high adsorption capacity and for controlling the mechanisms of retention. The characterization techniques include: nitrogen adsorption, thermal analysis, potentiometric titration, FT-IR spectroscopy, X-ray diffraction, Energy Dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy and Electron Microscopy. The results obtained indicate that ammonia removal is governed by the adsorbent's surface chemistry. On the contrary, porosity (and thus physisorption) plays a secondary role in this process, unless strong dispersive forces are provided by the adsorbent. The surface chemistry features responsible for the enhanced ammonia adsorption include the presence of oxygen- (carboxyl, hydroxyl, epoxy) and sulfur- (sulfonic) containing groups. Metallic species improve the breakthrough capacity as well as they lead to the formation of Lewis acid-base interactions, hydrogen-bonding or complexation. In addition to the latter three mechanisms, ammonia is retained on the adsorbent surface via Brønsted acid-base interactions or via specific reactions with the adsorbent's functionalities leading to the incorporation of ammonia into the adsorbent's matrix. Another mechanism involves dissolution of ammonia in water when moisture is present in the system. Even though this process increases the breakthrough capacity of a material, it provides rather weak retention forces since ammonia dissolved in water is easily desorbed from the adsorbent's surface.