Digital Commons Network^™

Part 1: Design, Synthesis, And Evaluation Of Novel Gram-Positive Antibiotics Part 2: Synthesis Of Dihydrobenzofurans Via A New Transition Metal Catalyzed Reaction Part 3: Design, Synthesis, And Evaluation Of Bz/Gabaa Α6 Positive Allosteric Modulators, Christopher Michael Witzigmann

Theses and Dissertations

Part 1. Lead compound SK-03-92 represents a new scaffold for antibiotic drug discovery. Development of a new process for the synthesis of analogs has led to the development of a number of new ligands with even more potent activity against gram-positive bacteria, including drug-resistant strains of S. aureus. Compounds 36 and 38 represent some of the most potent analogs developed thus far, and preliminary results indicate that they are also not cytotoxic. Research into a Heck-mediated transition metal catalyzed pathway towards electron-rich stilbenoid analogs has greatly expanded the scope of future SAR studies. This development has led to 14 new …

Corrosion Of Aluminum Current Collector In Cost Effective Rechargeable Lithium-Ion Batteries, Shengyi Li

Theses and Dissertations

Rechargeable lithium ion batteries (LIB) have been widely used as commercial energy storage systems for portable equipment, electronic devices and high power applications (e.g. electronic vehicles). One issue with the commercialized LIB is that expensive, highly toxic and flammable organic solvents are used in the electrolyte and the fabrication process of electrodes. The toxic organic based solvents increase the production cost and lead to significant safety concerns in the event of a battery overcharge or short circuit. The recent development of “green manufacturing” technology allows manufacturers to replace the organic solvents used in the cathode coating process by aqueous based …

Experimental Methods In Cryogenic Spectroscopy: Stark Effect Measurements In Substituted Myoglobin, Bradley Michael Moran

Theses and Dissertations

Dawning from well-defined tertiary structure, the active regions of enzymatic proteins exist as specifically tailored electrostatic microenvironments capable of facilitating chemical interaction. The specific influence these charge distributions have on ligand binding dynamics, and their impact on specificity, reactivity, and biological functionality, have yet to be fully understood. A quantitative determination of these intrinsic fields would offer insight towards the mechanistic aspects of protein functionality. This work seeks to investigate the internal molecular electric fields that are present at the oxygen binding site of myoglobin.

Experiments are performed at 1 K on samples located within a glassy matrix, using the …

Structural Analysis Of Cell Signaling Complexes, Takuma Aoba

Theses and Dissertations

Bardet-Biedl syndrome (BBS) is a rare genetic disease that causes retinal degradation, obesity, kidney dysfunction, polydactyly, and other cilium-related disorders. To date, more than 20 BBS genes, whose mutants cause BBS phenotypes, have been identified, and eight of those (BBS1-2, 4-5, 7-9, and 18) are known to form the BBSome complex. Recent studies have revealed that the BBSome is closely involved in the trafficking of signaling proteins in the primary cilium. Mutations in BBS genes are highly pathogenic because trafficking in the primary cilium is not fully functional when BBS mutations impair assembly of the BBSome. However, the functional links …

Control Of Matrix Metalloproteinases In A Periodontitis Model: Molecules That Trigger Or Inhibit Mmp Production, Catalina Matias Orozco

Theses and Dissertations

In periodontitis, there is a disruption in the homeostasis of the oral microbiome by peridontopathogenic bacteria. However, while bacteria is essential for periodontitis to occur, the severity, pattern and progression of the disease is not solely determined by the microbial burden, and in fact has a lot to do with the overwhelming host inflammatory response. The response can vary even in two individuals with similar periodontopathogenic profiles. The host response leads to extracellular matrix (ECM) destruction, loss of attachment, alveolar bone resorption and eventually, edentulism. The host's reaction is orchestrated by proinflammatory cytokines and chemokines and matrix metalloproteinases (MMPs). MMPs …

Phytotoxicity Of Silver Species To Egeria Densa And Applications To Phytoremediation, Leonard James Bernas

Theses and Dissertations

Silver species pose a significant threat to aquatic ecosystems because the use of silver nanoparticles (AgNps) for industrial applications is significantly increasing, as are discharges into waterways. The effects have only been studied on select fish and aquatic plants, so more research is needed to understand the risks associated with silver species in the environment. Egeria densa (E. densa, also known as Elodea densa), a common freshwater submerged macrophyte, was exposed to 0-1.25 ppm silver cations and 2 and 15 nm AgNps in an aqueous environment for 7 days. E. densa was chosen for this study because it is a …

Investigation Of Dynamic Biological Systems Using Direct Injection And Liquid Chromatography Mass Spectrometry, Adam Clayton Swensen

Theses and Dissertations

In biological systems, small changes can have significant impacts. It is, therefore, very important to be able to identify these changes in order to understand what is occurring in the organism. In many cases, this is not an easy task. Mass spectrometry has proven to be a very useful tool in elucidating biological changes even at a very small scale. Several different mass spectrometry based techniques have been developed to discover and investigate complex biological changes. Some of these techniques, such as proteomics, have been through years of development and have advanced to the point that anyone can complete complex …

Synthesis And Characterization Of Polycyclic Aromatic Hydrocarbon ( Pah )-Porphyrin Hybrids, Ruixiao Gao

Theses and Dissertations

Carbaporphyrins are porphyrin analogs where one or more pyrrole units are replaced with a carbocyclic ring. Benziporphyrins are porphyrin analogues with a 1,3-phenylene unit replacing one of the pyrrole subunits. Because of cross-conjugation, benziporphyrins are not aromatic species. However, protonation of benziporphyrins can afford some aromatic characteristics. Although the synthesis of many examples of monocarbaporphyrins have been successfully executed, no examples of porphyrinoids with pyrene subunits have been prepared. Pyrene-containing porphyrinoids, which have been named as pyreniporphyrins, are theoretically significant molecules that provide insights into the aromaticity and reactivity of porphyrinoid systems.

In this thesis, two projects were conducted to …

Development Of An Automated Detection System For Nitrite In Aquatic Environments, Tim Schierenbeck

Theses and Dissertations

The main objective of the project is to develop an automated nitrite sensor for use in aquatic environments, and more specifically for use in recirculating aquaculture systems (RAS), where monitoring can help sustain a controlled environment, protect against nitrite intoxication, and promote fish health. Detecting nitrite manually with semi-quantitative colorimetric test kits, although inexpensive and simple, is prone to inter-user variability and poor sensitivity. An automated nitrite sensor has potential to provide higher resolution measurements at both concentration and time scales and can serve as a research tool for the study of filtration systems essential in maintaining a healthy RAS …

Seasonal And Spatial Variations In Chemical Composition And Fluxes Of Dissolved Organic Matter And Nutrients In The Lower Milwaukee River, Tarek A. Teber

Theses and Dissertations

Physical, chemical and biological processes directly influence the transport, composition, and fluxes of dissolved organic matter (DOM) in river watersheds. Changes in the abundance and composition of DOM and nutrients (P&N) in the watershed should reflect changes in hydrological cycle, effluent discharge, land-use and land-cover, and anthropogenic activities in the river basin, especially in rivers that run through metropolitan areas such as the Milwaukee River. Despite the importance of DOM to ecosystem health and function, a literature search to date finds no comprehensive accounting of DOM in the Milwaukee River. To examine DOM dynamics, monthly water samples were collected between …

Development Of Cellular High Throughput Assays To Determine The Electrophysiological Profile Of Gaba(A) Receptor Modulators For Neurology And Immunology, Nina Yina Yuan

Theses and Dissertations

Gamma (γ) -aminobutyric acid (GABA) is the major inhibitory neurotransmitter found in

the mammalian central nervous system. Its effect stems from its ability to cause the opening of ion channels which causes an influx of negatively charged chloride ions or an efflux of positively charged potassium ions. This hyperpolarization of the neuron lowers the threshold for neuronal firing. This has an overall inhibitory effect on neurotransmission, decreasing the excitability of the neuron and diminishing the likelihood of a successful action potential occurring. There are two classes of GABA receptor: ligand-gated GABAA receptor (GABAAR) and metabotropic GABAB receptor (GABABR). The GABAAR …

Molecular Recognition In Water: Design, Synthesis, And Characterization Of Rigid Molecular Receptors And Enzymatic Mechanistic Probes, Robert William Hoppe

Theses and Dissertations

Molecular recognition can be defined as a selective and reversible binding between two or more molecules through non-covalent interactions. Multiple weakly attractive intermolecular forces work in concert to achieve selectivity in association. Such discrimination is critical to the physiological processes of catalysis, transport, antigen recognition, and storage. To better understand this phenomenon, acyclic synthetic molecular receptors also known as “molecular tweezers” were made to study the inclusion of small molecule guests from water. Three anionic tweezers derivatives with syn¬- cofacial orientation were constructed from a 1,2:4,5-bis-Trӧger’s Base skeleton that differed in the amount and distribution of negative charge about the …

The Role Of Proteome In Cellular Zn2+ Trafficking And In The Ability Of The Fluorescent Zinc Sensors To Image Intracellular Zn2+, Mohammad Rezaul Karim

Theses and Dissertations

Zinc is an essential biological trace metal used in as many as 3000 Zn-proteins, about 10% of the eukaryotic proteome, as either a structural constituent or a catalytic cofactor. These proteins include the zinc fingers, the most prevalent transcription factors that bind a wide range of gene promoters and thus regulate gene expression. A eukaryotic cell contains several hundred micromolar of Zn2+- almost all of it is bound to specific Zn-proteins. Recently, Zn2+ has been reported to serve as a regulatory signal and a neurotransmitter, suggesting that there also exists a dynamic Zn2+ pool in cells. These findings led to …

Structural And Functional Characterization Of Acetoacetate Decarboxylase-Like Enzymes, Lisa Mueller

Theses and Dissertations

The acetatoacetate decarboxylase-like superfamily (ADCSF) is a largely unexplored group of enzymes that may be a potential source of new biocatalysts. Bioinformatic analysis has grouped these approximately 2000 enzymes into seven different families based on comparison of predicted active site residues. To date, only the prototypical ADCs (Family I) that catalyze the decarboxylation of acetoacetate have been studied. Analysis of gene context suggests that Family V contains predominantly enzymes predicted to be involved in secondary metabolism. On average, these share about 20% sequence identity to the true ADCs. To learn more about the diversity of chemistries performed by members of …

The Synthesis Of Fluorescent 3, 6-Dihydroxyxanthones: A Route To Substituted Fluoresceins, Surajudeen Omolabake

Theses and Dissertations

ABSTRACT

THE SYNTHESIS OF FLUORESCENT 3, 6-DIHYDROXYXANTHONES:

A ROUTE TO SUBSTITUTED FLUORESCEIN

by

Surajudeen Omolabake

University of Wisconsin-Milwaukee, 2016

Under the Supervision of Professor Alan W Schwabacher

Xanthones belong to the family of compounds of the dibenzo-γ-pyrone framework. Naturally occurring xanthones have been reported to show a wide range of biological and medicinal activities including antifungal,19 antimalarial,20 antimicrobial,21 antiparasitic,22 anticancer,23 and inhibition of HIV activity in cells.24 Xanthones have also been used as a turn on fluorescent probe for metal ions,32 including use as pH indicators, metal ion sensors, in molecular biology, medicinal chemistry and in the construction of other …

Synthesis Of Subtype Selective Bz/Gabaa Receptor Ligands For The Treatment Of Anxiety, Epilepsy And Neuropathic Pain, As Well As Schizophrenia And Asthma, Michael M. Poe

Theses and Dissertations

The α2/α3 subtype selective Bz/GABAA receptor positive allosteric modulator HZ-166 (3) has been shown to be a nonsedating anxiolytic with anticonvulsant and antihyperalgesic activity. However, instability in vitro and in vivo has hindered its advancement into clinical trials. A series of ligands based off HZ-166 (3) were synthesized. Many of these ligands were designed to increase metabolic stability, while others were synthesized to study the effects that electronics and sterics have on the efficacy exerted when bound to the GABAA receptor. The α3 subtype selective methyl ester MP-III-024 (19) was shown to have increased resistance to metabolism in in vitro …

Electrical Measurements And Attenuated Total Reflection Infrared Spectroscopic Study Of Aromatic Isocyanides And Thiols On Gold, Rasha Khaled Abuflaha

Theses and Dissertations

In 1947, Bell Laboratories produced an amplifier design in which an electric field would enhance the flow of electrons near the surface of a layer of silicon, it was called the “point-contact transistor”, the world’s first semiconductor amplifier. In order to minimize the electronic circuit elements (device miniaturization), the ability to utilize single molecules that function as self-contained electronic devices (molecular electronics) has motivated researchers around the world. Molecular electronics investigates single molecules and collections of molecules assembled into electronic circuits. Currently, semiconductor devices are fabricated using a “top-down” approach that employs lithographic and etch techniques to pattern a substrate, …

The Function Of Renalase, Brett Allen Beaupre

Theses and Dissertations

Renalase was originally reported to be an enzyme secreted into the blood by the kidney to lower blood pressure and slow heart rate. Despite multiple reports claiming to confirm this activity in vivo there has been considerable discord in regards to the reaction catalyzed by renalase. The structural topology of renalase resembles that of known flavoprotein oxidases, monooxygenases and demethylases, but the conserved active site residues are unique to renalase. It has been reported that the catalytic function of renalase is to oxidize circulating catecholamines, however in vitro studies have failed to demonstrate a catalytic activity in the presence of …

Gas Phase Structure Characterization Using Fourier Transform Ion Cyclotron Resonance Mass Spectrometry, Anupriya Anupriya

Theses and Dissertations

This dissertation investigates Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) based techniques to study the impact of molecular structure on conformation and binding energetics. A novel method to determine collison cross sectional areas using FTICR (CRAFTI), initially developed by the Dearden lab, was applied to study the conformations of molecular systems with unique structural attributes in an attempt to explore the molecular range of CRAFTI. The systems chosen for CRAFTI studies include crown-ether alkylammonium complexes and biogenic amino acids. The results were found to be consistent with expected behavior, and strongly correlated with experimental measurements made using ion mobility …

Computational Studies On Mechanisms And Reactivity Of Mercury And Cobalt Organometallic Reactions, Jack Terrell Fuller

Theses and Dissertations

Density Functional Theory (DFT) is a powerful tool for treating large organometallic structures efficiently and accurately. DFT calculations on the Hg-catalyzed oxidation of methane to methyl bisulfate in sulfuric acid suggest the lowest energy pathway involves a closed-shell electrophilic C–H activation mechanism coupled with metal alkyl reductive functionalization and oxidation by SO3. Comparison to Tl, Zn, and Cd suggests that Hg is unique in its ability to catalyze this set of reaction steps. Comparison to K2S2O8 highlights the selectivity of this C–H activation reaction as opposed to radical conditions. In contrast, DFT calculations indicate that CoIII(TFA)3 oxidizes methane through a …

Synthesis And Biological Evaluation Of Small Molecule Inhibitors Of Bmpr1b, Paulo Andre Machicao Tello

Theses and Dissertations

Methods for preparing an array of potential small molecule inhibitors of Bone Morphogenetic Protein Receptor 1b (BMPR1b) are described. Target molecules were prepared from two general classes: (1) N9-aryl-N6-ureidoadenines, and (2) dicarbamyl iodoacetamides. Recent data from the Peterson lab indicated that both classes might bind to BMPR1b and thus inhibit this key receptor. Docking studies performed using Sureflex Dock suggested the N9-aryl-N6-ureidoadenines would bind to the active site of BMPR1b. In addition antiproliferative activities of dicarbamyl iodoacetamides previously synthesized in the Peterson lab pointed to this moiety as an attractive target for structure activity relationship (SAR) development. Compounds were prepared …

Computational Studies Of Alkane C-H Functionalization By Main-Group Metals, Samantha Jane Gustafson

Theses and Dissertations

The most efficient homogeneous catalysts for hydroxylation of light alkanes utilize transition metals in superacid solvent and operate by tandem electrophilic C-H activation/metal-alkyl (M-R) functionalization. An emerging alternative strategy to transition metals is the use of high-oxidation state main-group metals (e.g. TlIII, PbIV, IIII) that hydroxylate light alkanes. This dissertation reports density-functional theory calculations that reveal the mechanisms, reactivity, and selectivity of TlIII promoted alkane C-H functionalization in trifluoroacetic acid and TlIII-dialkyl functionalization in water. Calculations reveal that TlIII oxidizes alkanes via a closed-shell C-H activation and M-R functionalization mechanism that is similar to transition-metal C-H functionalization mechanisms. Comparison of …

Studies Toward Yaku'amide A And Synthesis And Applications Of Bulky Α,Β-Dehydroamino Acids, Jintao Jiang

Theses and Dissertations

Yaku'amide A shows a unique inhibitory profile against a series of 39 human cancer cell lines (JFCR39). In our efforts to synthesize yaku'amide A, we have optimized our regioselective base-free aminohydroxylation method with a series of nitrogen sources, developed a chiral reagent-mediated aminohydroxylation strategy and chemoselective deprotections of the resulting aminohydroxylation product, and explored a stereospecific E2 dehydration and O-N acyl transfer sequence. In addition, we have prepared the right-hand tetrapeptide and the NTA subunit. For our bulky α,β-dehydroamino acids project, we have developed strategies to incorporate α,β-dehydroamino acids such as ΔVal and ΔEnv into small synthetic peptides via Solid …

Iron Uptake And Accumulation Is A Target Of Nickel Toxicity During The Lag Phase In Escherichia Coli, Geoffrey Tuttle Ford

Theses and Dissertations

Various transition metals are essential to all forms of life, and are only required in trace amounts. But this dependence comes as a double-edged sword. All organisms must maintain a careful intracellular quota that does not traverse outside an acceptable range. One transition metal in particular is nickel. The importance of this transition metal has been debated widely and its function varies greatly between organisms, including bacteria. However, the adverse effects caused by over exposure to this metal have been the center of much experimentation in recent years. Still, the mechanisms of nickel toxicity and the subsequent effects on cellular …

Quantum Dot Metrics For Preparative Chemistry And Fluorescence Applications, Yi Shen

Theses and Dissertations

Colloidal semiconductor quantum dots (QDs) are considered to be a promising candidate for bio-imaging and solar cells because of their extraordinary photo-physical properties. The ultimate goal of this dissertation is to design a reliable matrix and a reproducible method to prepare QDs-based biocompatible probe for fluorescence applications. Synthesis of quantum dots requires a large amount of ligands to improve the stability at high temperature. However, for further application and surface modification of QDs, excess ligands must be removed. In this dissertation, I will first describe using gel permeation chromatography (GPC) as a media to purify different types of QDs. A …

Ligand-Induced Magnetic Changes In Metal Thin Films, Fiona Senta Oberbeck-Oxsher

Theses and Dissertations

The investigation of magnetic properties of thin films whose surfaces were modified by organic molecules shows that the addition of any functional group to the surface measurably changes the magnetic properties. The effect often scales with ligand strength and is not limited to surfaces with ferromagnetic properties. Improving upon the technique developed by Knaus et al. [1], a stable and sensitive device was developed to measure this magnetic effect using the planar Hall effect (PHE) in order to shed light onto controversial questions of purported paramagnetism of thiolated gold. There is a measureable non-diamagnetic response of thin gold layers when …

The Development Of A High Resolution Deep-Uv Spatial Heterodyne Raman Spectrometer, Nirmal Lamsal

Theses and Dissertations

Raman spectroscopy is a light scattering technique that has a huge potential for standoff measurements in applications such as planetary exploration because a Raman spectrum provides a unique molecular fingerprint that can be used for unambiguous identification of target molecules. For this reason, NASA has selected a Raman spectrometer as one of the major instruments for its new Mars lander mission, Mars 2020, in the search for biomarkers that would be the indicators of past or present life. Raman scattering is strongest at UV wavelengths because of the inherent increase in the Raman cross section at shorter wavelengths and because …

Structural And Functional Studies Of Nicotinamide Adenine Dinucleotide And Streptolysin S Biosynthesis Proteins From Streptococcus Pyogenes, William T. Booth

Theses and Dissertations

Invasive infections caused by Streptococcus pyogenes, also known as Group A Strep (GAS), results in approximately 600,000 deaths annually. With evidence of antibiotic-resistant strains of this bacterium on the rise, there is a need for the identification of new drug targets to control these infections. In our approach we target the quinolinate-salvage pathway (QSP) and the streptolysin S (SLS) biosynthesis pathway. The QSP provides a secondary pathway for NAD+ biosynthesis within this organism; the SLS pathway leads to the formation of a quorum sensing molecule (SLS). We hypothesize that inhibition of the pathways will lead to GAS cell death or …

Synthesis And Biological Activity Of Novel Quorum Sensing Compounds, Joseph Nicholas Capilato

Theses and Dissertations

Bacteria communicate with chemical signals in a process known as quorum sensing. This population density-dependent process involves the bacterial production, release and detection of structurally specific small molecules and enables the bacterial pathogen to regulate its virulence on a population-wide level. Using a variety of chemical and biological techniques, I have studied various quorum sensing systems in several bacteria, including Vibrio cholera and Pseudomonas aeruginosa. A key principle of this research involves the design, synthesis and testing of novel compounds for their biological activity. These molecules are typically based off of an initial lead target, which is often identified …

Criteria For Selecting Pegylation Sites On Proteins For Higher Thermodynamic Stability, Paul B. Lawrence

Theses and Dissertations

PEGylation of protein side-chains has been used for more than 30 years to enhance the pharmacokinetic properties of protein drugs, and has been enabled by the recent development of many chemoselective reactions for protein side-chain modification. However, there are no structure- or sequence-based guidelines for selecting sites that provide optimal PEG-based pharmacokinetic enhancement with minimal loss to biological activity. Chapter 1 is a brief introduction to protein PEGylation. In chapter 2 we use the WW domain of the human protein Pin 1 (WW) as a model system to probe the impact of PEG on protein conformational stability. Using a combination …