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Spellbinding Effects Of The Acidic Cooh-Terminus Of Factor Va Heavy Chain On Prothrombinase Activity And Function, Jamila Hirbawi, Michael Kalafatis

Chemistry Faculty Publications

Human factor Va (hfVa) is the important regulatory subunit of prothrombinase. Recent modeling data have suggested a critical role for amino acid Arg of hfVa for human prothrombin (hPro) activation by prothrombinase. Furthermore, it has also been demonstrated that hfVa has a different effect than that of bovine fVa on prethrombin-1 activation by prothrombinase. The difference between the two cofactor molecules was also found within the Asn-Arg dipeptide in the human factor V (hfV) molecule, which is replaced by the Asp-Glu sequence in bfV. As a consequence, we produced a recombinant hfV (rhfV) molecule with the substitution NR→DE. rhfV together …

Halogen Bonds Formed Between Substituted Imidazoliums And N Bases Of Varying N-Hybridization, Steve Scheiner

Chemistry and Biochemistry Faculty Publications

Heterodimers are constructed containing imidazolium and its halogen-substituted derivatives as Lewis acid. N in its sp³, sp² and sp hybridizations is taken as the electron-donating base. The halogen bond is strengthened in the Cl < Br < I order, with the H-bond generally similar in magnitude to the Br-bond. Methyl substitution on the N electron donor enhances the binding energy. Very little perturbation arises if the imidazolium is attached to a phenyl ring. The energetics are not sensitive to the hybridization of the N atom. More regular patterns appear in the individual phenomena. Charge transfer diminishes uniformly on going from amine to imine to nitrile, a pattern that is echoed by the elongation of the C-Z (Z=H, Cl, Br, I) bond in the Lewis acid. These trends are also evident in the Atoms in Molecules topography of the electron density. Molecular electrostatic potentials are not entirely consistent with energetics. Although I of the Lewis acid engages in a stronger bond than does H, it is the potential of the latter which is much more positive. The minimum on the potential of the base is most negative for the nitrile even though acetonitrile does not form the strongest bonds. Placing the systems in dichloromethane solvent reduces the binding energies but leaves intact most of the trends observed in vacuo; the same can be said of ∆G in solution.

Intramolecular Glycosylation, Alexei Demchenko, Xiao Jia

Chemistry & Biochemistry Faculty Works

Carbohydrate oligomers remain challenging targets for chemists due to the requirement for elaborate protecting and leaving group manipulations, functionalization, tedious purification, and sophisticated characterization. Achieving high stereocontrol in glycosylation reactions is arguably the major hurdle that chemists experience. This review article overviews methods for intramolecular glycosylation reactions wherein the facial stereoselectivity is achieved by tethering of the glycosyl donor and acceptor counterparts.

Controlling Water Exchange Kinetics And Improving Paracest Imaging, Jacqueline R. Slack

Dissertations and Theses

Generating MR image contrast from exogenous contrast media through chemical exchange saturation transfer (CEST) offers several exciting new possibilities, such as multicolored imaging, the interleaving of pre- and post-contrast images, and the potential to perform ratiometric metabolic imaging. The major limitation of the deployment of CEST imaging is the comparatively high detection limits of exogenous agents and particularly at the low B_¹ power levels required to meet SAR requirements. The large chemical shifts afforded by paramagnetic (paraCEST) agents permit more rapid exchange kinetics and therefore potentially more effective contrast agents. Despite comparatively large chemical shifts, many Ln³⁺ DOTA-tetraamide …

Copper(Ii)- And Gold(Iii)-Mediated Cyclization Of A Thiourea To A Substituted 2-Aminobenzothiazole, Zachary W. Schroeder, L. K. Hiscock, Louise N. Dawe

Chemistry Faculty Publications

Benzothiazole derivatives are a class of privileged molecules due to their biological activity and pharmaceutical applications. One route to these molecules is via intramolecular cyclization of thioureas to form substituted 2-aminobenzothiazoles, but this often requires harsh conditions or employs expensive metal catalysts. Herein, the copper(II)- and gold(III)-mediated cyclizations of thioureas to substituted 2-aminobenzothiazoles are reported. The single-crystal X-ray structures of the thiourea N-(3-methoxyphenyl)-N'- (pyridin-2-yl)thiourea, C₁₃H₁₃N₃OS, and the intermediate metal complexes aquabis[5-methoxy-N-(pyridin-2-yl-κN)-1,3-benzothiazol-2-amine-κN³]copper(II) dinitrate, [Cu(C₁₃H₁₁N₃OS)₂(H₂O)](NO₃) …

Toxicant Formation In Dabbing: The Terpene Story, Jiries Meehan-Attrash, Wentai Luo, Robert M. Strongin

Chemistry Faculty Publications and Presentations

Inhalable, noncombustible cannabis products are playing a central role in the expansion of the medical and recreational use of cannabis. In particular, the practice of “dabbing” with butane hash oil has emerged with great popularity in states that have legalized cannabis. Despite their growing popularity, the degradation product profiles of these new products have not been extensively investigated. The study herein focuses on the chemistry of myrcene and other common terpenes found in cannabis extracts. Methacrolein, benzene, and several other products of concern to human health were formed under the conditions that simulated realworld dabbing. The terpene degradation products observed …

Design, Synthesis, And Biological Activity Of 5'-Phenyl-1,2,5,6-Tetrahydro-3,3'-Bipyridine Analogues As Potential Antagonists Of Nicotinic Acetylcholine Receptors, Yafei Jin, Xiaoqin Huang, Roger L. Papke, Emily M. Jutkiewicz, Hollis D Showalter, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a – 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (K_i = 123 nM) …

Taming Charge Transport In Semiconducting Polymers With Branched Alkyl Side Chains, Bob C. Schroeder, Tadanori Kurosawa, Tianren Fu, Yu-Cheng Chiu, Jaewan Mun, Ging-Ji Nathan Wang, Xiaodan Gu, Leo Shaw, James Kneller, Theo Kreouzis, Michael F. Toney, Zhenan Bao

Faculty Publications

The solid-state packing and polymer orientation relative to the substrate are key properties to control in order to achieve high charge carrier mobilities in organic field effect transistors (OFET). Intuitively, shorter side chains are expected to yield higher charge carrier mobilities because of a denser solid state packing motif and a higher ratio of charge transport moieties. However our findings suggest that the polymer chain orientation plays a crucial role in high-performing diketopyrrolopyrrole-based polymers. By synthesizing a series of DPP-based polymers with different branched alkyl side chain lengths, it is shown that the polymer orientation depends on the branched alkyl …

Global Fire Emissions Estimates During 1997-2016, Guido R. Van Der Werf, James T. Randerson, Louis Giglio, Thijs T. Van Leeuwen, Yang Chen, Brendan M. Rogers, Mingquan Mu, Margreet J.E. Van Marle, Douglas C. Morton, G. James Collatz, Robert J. Yokelson, Prasad S. Kasibhatla

Chemistry and Biochemistry Faculty Publications

Climate, land use, and other anthropogenic and natural drivers have the potential to influence fire dynamics in many regions. To develop a mechanistic understanding of the changing role of these drivers and their impact on atmospheric composition, long-term fire records are needed that fuse information from different satellite and in situ data streams. Here we describe the fourth version of the Global Fire Emissions Database (GFED) and quantify global fire emissions patterns during 1997-2016. The modeling system, based on the Carnegie-Ames-Stanford Approach (CASA) biogeochemical model, has several modifications from the previous version and uses higher quality input datasets. Significant upgrades …

Special Issue: Intramolecular Hydrogen Bonding 2017, Steve Scheiner

Chemistry and Biochemistry Faculty Publications

Even after more than a century of study [1–6], scrutiny, and detailed examination, the H-bond continues [7–12] to evoke a level of fascination that surpasses many other phenomena. Perhaps it is the ability of the simple H atom, with but a single electron, to act as a glue that maintains contact between much more complicated species. Or it might be its geometry, which prefers to hold the bridging proton on a direct line between the two heavy atoms. Not to be ignored are the spectral features of the H-bond: the large red shift of the stretching frequency of the covalent …

Synthesis Of Small Molecule Heterocycles As Antimicrobial And Anticancer Agents, Zakeyah Ali Alsharif

Student Theses and Dissertations

This thesis contains three chapters. In chapter one, the synthesis of dihydropyrido-pyrimidones derivatives by using hexafluoroisopropanol (HFIP) as a solvent was reported and the synthesized compounds were tested against different bacteria but no activity was observed. In the second chapter, the syntheses of thiazoline and thiazole derivatives were reported. In this methodology, HFIP was used to promote for the reaction and sixty new molecules were synthesized. Two of these compounds showed promising activity as a potent anti-cancer agent against several cell lines. In the third chapter, pyrazole derivatives were synthesized and tested against different types of bacteria. Among these compounds, …

Fatty Acid Concentration And Phase Transitions Modulate Aβ Aggregation Pathways, Pratip Rana, Dexter Dean, Edward Steen, Ashwin Vaidya, Vijayaraghavan Rangachari, Preetam Ghosh

Faculty Publications

Aggregation of amyloid β (Aβ) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD and hence, there is increasing interest in understanding their formation and behavior. Aggregation is a nucleation-dependent process in which the pre-nucleation events are dominated by Aβ homotypic interactions. Dynamic flux and stochasticity during pre-nucleation renders the reactions susceptible to perturbations by other molecules. In this context, we investigate the heterotypic interactions between Aβ and fatty acids (FAs) by two independent tool-sets such as …

Development And Validation Of A Novel Lc–Ms/Ms Method For Simultaneous Determination Of Abiraterone And Its Seven Steroidal Metabolites In Human Serum: Innovation In Separation Of Diastereoisomers Without Use Of A Chiral Column, Mohammad Alyamani, Zhenfei Li, Sunil K. Upadhyay, David J. Anderson, Richard J. Auchus, Nima Sharifi

Chemistry Faculty Publications

Abiraterone acetate (AA), the prodrug of abiraterone, is FDA-approved for the treatment of castration-resistant prostate cancer. Abiraterone is metabolized in patients to a more potent analogue, D4A. However, we have recently reported that this analogue is further metabolized to additional metabolites in patients treated with AA. Here, we present a liquid chromatography-tandem mass spectrometry method developed to resolve and detect abiraterone and its seven metabolites in human serum using an AB Sciex Qtrap 5500 mass analyzer coupled with a Shimadzu Nexera UPLC station. Analytes and the internal standard (abiraterone-d4) were extracted from human serum using the liquid–liquid extraction procedure. The …

Dietary Guidelines And Its Implications For Coconut Oil, Fabian M. Dayrit

Chemistry Faculty Publications

The dietary advice that is generally followed nationally and internationally closely follows the Dietary Guidelines for Americans which was first published in 1980 and which has been through eight editions. All of the editions of the Dietary Guidelines recommend a diet that is low in fat, and most editions recommend the replacement of saturated fat with polyunsaturated fat. This recommendation is based on the saturated fat-cholesterol-heart disease hypothesis that was first proposed by Ancel Keys in the 1950s. Coconut oil was labeled as unhealthy because of its high saturated fat composition. However, this label is unwarranted. Re-analysis of the work …

Synthesis And Evaluation Of Tetrahydroprotoberberines As Dopamine Receptor Ligands, Satishkumar V. Gadhiya

Dissertations, Theses, and Capstone Projects

Dopamine (DA) receptors belong to the G-protein coupled receptors (GPCRs) family, divided in to two groups based on their high homology transmembrane domains; D1-like DA receptors (D1, D5) and D2-like DA receptors (D2-D4). DA receptor specific ligands have been exploited as a means for studying the prognosis and curing several CNS disorders. Though several efforts have been devoted to discover selective and potent DA receptor ligands, complete selectivity within the DA receptor subtypes remains a challenge.

Tetrahydroprotoberberines (THPBs) are a group of naturally occurring tetracyclic alkaloids that belong to the tetrahydroisoquinoline family. A wide range of biological activities are associated …

Α-Conotoxin Decontamination Protocol Evaluation: What Works And What Doesn’T, Matthew W. Turner, John R. Cort, Owen M. Mcdougal

Chemistry and Biochemistry Faculty Publications and Presentations

Nine publically available biosafety protocols for safely handling conotoxin peptides were tested to evaluate their decontamination efficacy. Circular dichroism (CD) spectroscopy and mass spectrometry (MS) were used to assess the effect of each chemical treatment on the secondary and primary structure of α-CTx MII (L10V, E11A). Of the nine decontamination methods tested, treatment with 1% (m/v) solution of the enzymatic detergent Contrex™ EZ resulted in a 76.8% decrease in α-helical content as assessed by the mean residue ellipticity at 222 nm, and partial peptide digestion was demonstrated using high performance liquid chromatography mass spectrometry (HPLC-MS). Additionally, …

Computational Investigation Of The Pore Formation Mechanism Of Beta-Hairpin Antimicrobial Peptides, Richard Lipkin

Dissertations, Theses, and Capstone Projects

β-hairpin antimicrobial peptides (AMPs) are small, usually cationic peptides that provide innate biological defenses against multiple agents. They have been proposed as the basis for novel antibiotics, but their pore formation has not been directly observed on a molecular level. We review previous computational studies of peptide-induced membrane pore formation and report several new molecular dynamics simulations of β-hairpin AMPs to elucidate their pore formation mechanism. We simulated β-barrels of various AMPs in anionic implicit membranes, finding that most of the AMPs’ β-barrels were not as stable as those of protegrin. We also performed an optimization study of protegrin β-barrels …

Stereospecific Electrophilic Fluorination Of Alkylcarbastannatrane Reagents, Xinghua Ma

Dissertations, Theses, and Capstone Projects

The introduction of fluorine atoms into organic molecules significantly changes their physical, chemical, and biological properties. Fluorinated organic compounds are used as pharmaceuticals, agrochemicals, materials, and tracers for positron emission tomography (PET). For example, the site-specific fluorination of drugs can block sites of phase I metabolism by cytochrome P450 enzymes as well as improve target-binding affinities. In view of the unique features of fluorine-containing compounds, there has been increasing interest in the development of novel methods for the synthesis of fluorinated molecules, especially the site-specific monofluorination of complex molecules. Herein, we present the enantiospecific conversion of chiral secondary alkylcarbastannatranes into …

Electrostatic Interactions Of Water In External Electric Field: Molecular Dynamics Simulations, Qiang Zhu, Zigui Kan, Jing Ma

Journal of Electrochemistry

A series of molecular dynamics simulations with or without external electric field have been carried out for a bulk water with periodic boundary condition. The difference in radial distribution function of interatomic O…O distance is subtle, with and without external electric field, except for the orientation of dipole moments of water molecules. Without the applied external electric field, distribution of the orientation angle of dipole moments is rather broad. The induced local electric field is analyzed as a function of altitude in direction of electric field. The variation of the local induced electric field is increased as the increase of …

Identification Of Hydrated And Dehydrated Lipids And Protein Secondary Structures In Seeds Of Cotton (Gossypium Hirsutum) Line, Diwas Kumar Silwal, Nsoki Phambu, Bharat Pokharel, Ahmad Naseer Aziz

Chemistry Faculty Research

Cottonseeds from two parents (TM-1 and 3-79) and their 17 progeny (chromosomal substitution) lines were analyzed for various secondary structures of proteins and moisture content of lipids, separately in hulls and kernels. Fourier transform infrared spectroscopy (FTIR) was used on mature seeds from Upland cotton (G. hirsutum) progeny lines and parents. Based on secondary structures of proteins and hydration levels of lipids, differences were observed among the cottonseeds. The two progeny lines – CS-B12sh and CS-B22sh retained lipid moisture content and protein secondary structures similar to both parents, while CS-B06, CS-B15sh and CS-B16 remained distinct from either parent. On the …

Differential Uptake Of Gold Nanoparticles By 2 Species Of Tadpole, The Wood Frog (Lithobates Sylvaticus) And The Bullfrog (Lithobates Catesbeianus), Lucas B. Thompson, Gerardo L.F. Carfagno, Kurt Andresen, Andrea J. Sitton, Taylor B. Bury, Laura L. Lee, Kevin T. Lerner, Peter P. Fong

Biology Faculty Publications

Engineered nanoparticles are aquatic contaminants of emerging concern that exert ecotoxicological effects on a wide variety of organisms. We exposed cetyltrimethylammonium bromide–capped spherical gold nanoparticles to wood frog and bullfrog tadpoles with conspecifics and in combination with the other species continuously for 21 d, then measured uptake and localization of gold. Wood frog tadpoles alone and in combination with bullfrog tadpoles took up significantly more gold than bullfrogs. Bullfrog tadpoles in combination with wood frogs took up significantly more gold than controls. The rank order of weight-normalized gold uptake was wood frogs in combination > wood frogs alone > bullfrogs in combination …

Life’S Late Digital Revolution And Why It Matters For The Study Of The Origins Of Life, David A. Baum, Niles Lehman

Chemistry Faculty Publications and Presentations

The information contained in life exists in two forms, analog and digital. Analog information is manifest mainly in the differing concentrations of chemicals that get passed from generation to generation and can vary from cell to cell. Digital information is encoded in linear polymers such as DNA and RNA, whose side chains come in discrete chemical forms. Here, we argue that the analog form of information preceded the digital. Acceptance of this dichotomy, and this progression, can help direct future studies on how life originated and initially complexified on the primordial Earth, as well as expected trajectories for other, independent …

Optical Sensing And Separation Based On Ordered Three-Dimensional Nanostructured Surfaces, Mathias Schubert, Tino Hofmann, Daniel Schmidt, Patrick H. Dussault, Andrea Homes, Rebecca Lai

Patrick Dussault Publications

A sensor having a substrate is provided in which structures are disposed on a surface of the substrate . The structures can be , e . g . , nanostructures . Polarized light is directed toward the sensor , and birefringence of the structures with respect to the light is measured . Target particles that interact with the structures are detected based on changes in the measured birefringence .

Molecular Basis For The Substrate Specificity Of Quorum Signal Synthases, Shi-Hui Dong, Nicole D. Frane, Quin H. Christensen, E. Peter Greenberg, Rajesh Nagarajan, Satish K. Nair

Chemistry and Biochemistry Faculty Publications and Presentations

In several Proteobacteria, LuxI-type enzymes catalyze the biosynthesis of acyl–homoserine lactones (AHL) signals using S-adenosyl– L-methionine and either cellular acyl carrier protein (ACP)-coupled fatty acids or CoA–aryl/acyl moieties as progenitors. Little is known about the molecular mechanism of signal biosynthesis, the basis for substrate specificity, or the rationale for donor specificity for any LuxI member. Here, we present several cocrystal structures of BjaI, a CoAdependent LuxI homolog that represent views of enzyme complexes that exist along the reaction coordinate of signal synthesis. Complementary biophysical, structure–function, and kinetic analysis define the features that facilitate the unusual acyl conjugation with S-adenosylmethionine …

Neurological Impact Of Zinc Excess And Deficiency In Vivo, Ronald Bartzatt

Chemistry Faculty Publications

Zinc is an essential mineral that can cause pathological effects whether in excess or deficiency. Zinc is a component for over 250 enzymes and is required for cell growth, cell division, and cell function. Zinc is found in muscle and bones, with the prostrate, liver, skin, and kidney having detectable levels of zinc. However, zinc present in excess or deficiency can cause significant pathology in patients that include deleterious effects neurologically. Zinc in excess in vivo can cause focal neuronal pathology, while zinc deficiency can bring about mental lethargy, neuropsychiatric disorders, and reduced nerve conduction. Zinc is assimilated within the …

Biophysical And Computational Studies Of The Vcci:Vmip-Ii Complex, Anna Nguyen, Nai-Wei Kuo, Laura Showalter, Ricardo Ramos, Cynthia Dupureur, Michael Colvin, Patricia Liwang

Chemistry & Biochemistry Faculty Works

Certain viruses have the ability to subvert the mammalian immune response, including interference in the chemokine system. Poxviruses produce the chemokine binding protein vCCI (viral CC chemokine inhibitor; also called 35K), which tightly binds to CC chemokines. To facilitate the study of vCCI, we first provide a protocol to produce folded vCCI from Escherichia coli (E. coli.) It is shown here that vCCI binds with unusually high affinity to viral Macrophage Inflammatory Protein-II (vMIP-II), a chemokine analog produced by the virus, human herpesvirus 8 (HHV-8). Fluorescence anisotropy was used to investigate the vCCI:vMIP-II complex and shows that vCCI binds to …

Selective Inhibitors Of Human Mpges-1 From Structure-Based Computational Screening, Ziyuan Zhou, Yaxia Yuan, Shuo Zhou, Kai Ding, Fang Zheng, Chang-Guo Zhan

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs. Although various mPGES-1 inhibitors have been reported in literature, few have entered clinical trials and none has been proven clinically useful so far. It is highly desired for developing the next generation of therapeutics for inflammation-related diseases to design and discover novel inhibitors of mPGES-1 with new scaffolds. Here, we report the identification of a series of new, potent and selective inhibitors of human mPGES-1 with diverse scaffolds through combined computational and experimental studies. The computationally modeled binding structures of these new inhibitors with mPGES-1 provide …

Mri In Cancer: Improving Methodology For Measuring Vascular Properties And Assessing Radiation Treatment Effects In Brain, Chong Duan

Arts & Sciences Graduate Student Theses and Dissertations

Tumors cannot survive, progress and metastasize without recruiting new blood vessels. Vascular properties, including perfusion and permeability, provide valuable information for characterizing cancers and assessing therapeutic outcomes. Dynamic contrast-enhanced (DCE) MRI is a non-invasive imaging technique that affords quantitative parameters describing the underlying vascular structure of tissue. To date, the clinical application of DCE-MRI has been hampered by the lack of standardized and validated quantitative modeling approaches for data analysis.From a therapeutic perspective, radiation therapy is a central component of the standard treatment for patients with cancer. Besides killing cancer cells, radiation also induces parenchymal and stromal changes in normal …

Effects Of Nucleosome Structure On Dna Photoproduct Formation And Deamination, Kesai Wang

Arts & Sciences Graduate Student Theses and Dissertations

Cyclobutane pyrimidine dimers (CPDs) are DNA photoproducts linked to skin cancer, whose mutagenicity depends in part on their frequency of formation and deamination. Nucleosomes modulate CPD formation, favoring outside facing sites, and disfavoring inward facing sites. A similar pattern of CPD formation in protein-free DNA loops suggest that DNA bending causes the modulation of photoproduct formation in nucleosomes. To systematically study the cause and effect of nucleosome structure on CPD formation and deamination, we had developed a circular permutation synthesis strategy for positioning a target sequence at different superhelix locations (SHLs) across a nucleosome in which the DNA has been …

Mass Spectrometry-Based Structural Proteomics: Methodology And Application Of Fast Photochemical Oxidation Of Proteins (Fpop), Ben Niu

Arts & Sciences Graduate Student Theses and Dissertations

The dissertation will be solely focused on using mass spectrometry to characterize protein high order structures (HOS), it emphasizes the use of hydroxyl radical footprinting (FPOP) coupled to bottom-up MS approach. A detailed background information about FPOP, and the corresponding method developments as well as applications will be covered.The first chapter will be a comprehensive review regarding the FPOP. Following this, chapter 2, 3, and 4 will be focused on the method developments. Chapter 2 describes an isotope dilution GC-MS method to quantitate OH radicals in FPOP; chapter 3 describes the incorporation of Leu-enkephalin as reporter peptide for a more …