Chemistry & Biochemistry Doctoral Work

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Influence of Active Site Ligands and Nanoparticle Surfaces on Human Carbonic Anhydrase Isozymes
(North Dakota State University, 2010) Manokaran, Sumathra
Carbonic anhydrase (CA) is an ubiquitously distributed zinc containing metallo enzyme that catalyzes the reversible hydration of carbon dioxide to form bicarbonate and a proton. Existence of 16 isoenzymes of CA in the animal kingdom has been known so far with varying subcellular and tissue distributions. Due to their involvement in many physiological and pathological processes, these isozymes have been the target for drug designing for the past 6 decades. The present study was designed with the aim of understanding the effect of active site ligands and nanoparticle surfaces on human carbonic anhydrase isozymes. In an effort to identify a fluorescent probe for carbonic anhydrases, the quantum yields and binding affinities of a variety of naphthalenesulfonamide derivatives with human carbonic anhydrase isozymes (hCAs) were determined. In this pursuit, a highly sensitive fluorescent probe, JB2-48 was identified. Experiments involving the above flurophore with hCA I unraveled the contributions of the sulfonamide moiety and the hydrophobic regions of the ligand structure on the spectral, kinetic, and thermodynamic properties of the enzyme-ligand complex. The fluorescence data revealed that the deprotonation of the sulfonamide moiety of the enzyme-bound ligand increases the fluorescence emission intensity as well as the lifetime of the ligand. This is manifested via the electrostatic interaction between the active site resident Zn2 + cofactor and the negatively charged sulfonamide group of the ligand. Evidence was provided that the anionic and neutral forms of JB2-48 are stabilized by the complementary microscopic/conformational states of the enzyme. Investigations on the binding of the sulfonamide inhibitor, benzene sulfonamide (BS), with hCA isozymes II and VII, revealed that the binding is stabilized by polar interactions in the former case and hydrophobic interactions in the latter case. In addition, it was found that the binding of BS with hCA II is enthalpically driven at low temperatures, whereas it is entropically driven for its binding with hCA VII. Due to the prevalence of bipolar distribution of charges on hCA XII, the effects of the interaction of differently charged quantum dots, liposomes and polylysine on hCA XII were investigated. These charged particles were found to differently modulate the active site of the enzyme. The data revealed that whereas poly lysine and liposomes exhibited no influence on the binding and catalytic features of the enzyme, quantum dots had significant influence on the above features. Arguments were presented that the above differential feature exhibited by quantum dots, liposomes and poly lysine is encoded in the rigidity versus flexibility of the charged molecules. Studies on the denaturation of hCA isozymes II and XII unraveled their unfolding mechanism. It was found that the unfolding ofhCA XII followed a simple two state model from native to unfolded state; however hCA II unfolded with the formation of a stable intermediate.
Differential Modulation of the Structural and Functional Characteristics of Human Matrix Metalloproteinase Isozymes upon Binding to Different Ligands
(North Dakota State University, 2010) Ganguly, Bratati
Matrix metalloproteinases (MMPs) are a family of Zn2 + -dependent, Ca2 + -containing endoproteinases involved in tissue remodeling and degradation of the extracellular matrix (ECM). Human MMP isozymes are known to be involved in the progression and metastasis of many diseases like cancer, Alzheimer's, and etc. The different nanoparticles (e.g. gold nanoparticles, liposomes, and charged quantum dots) used in this study provides insights into nanoparticle-induced differential modulation in the structural-functional characteristics of MMP 7, 9 and 10 for better therapeutic intervention. To demonstrate the relationship between the rigid and flexible surfaces on the differential modulation of functional and structural characteristics of MMP-7, polylysine (PLL) and cationic gold nanoparticles (Au-CNP) were selected as representative examples. These cationic nano-structures were expected to serve as "soft" (flexible) and ''rigid" (hard) ligands, respectively. Steady-state kinetic analysis demonstrated that PLL induces activation and inhibition of MMP-7 at stoichiometric and super-stoichiometric concentrations respectively. Circular Dichroism spectroscopy was used to confirm that binding of Au-CNP to MMP-7 induces denaturation of the protein. In pursuit of understanding the molecular origin of the intrinsic selectivity in binding of human MMP isozymes to differently charged lipid membranes, steady-state kinetic studies and intrinsic tryptophan quenching studies were carried out. Results demonstrated that differently charged lipid membranes bind to all three MMPs; phosphotidylserine (POPS) liposomes are selective for MMP-7. The bipolar distribution of negative and positive charges on the surface of this enzyme dictates the binding of liposomes and perturbation of catalytic activity. An attempt to explain the molecular rationale for alternative binding modes of differently charged quantum dots (QDs) to the three MMPs, steady-state tryptophan quenching, steady-state kinetics, and time-resolved fluorescence measurements were carried out. Differently charged QDs bind to all the three MMP isozymes. Enzyme activity of these MMPs was perturbed upon binding to cationic and anionic QDs. Binding of MMPs to the differently charged QDs is reversible and is mediated via electrostatic interactions. Analysis of time-resolved fluorescence data indicates that the protein expenences different micro-environments, due to different distribution of intrinsic tryptophan residues (buried and exposed) on MMP isozymes or the existence of two distinct conformations of the protein. Binding to charged QDs perturbs enzyme activity of MMPs either by restricting the access of the substrate to the active-site or through allosteric modulation. In order to develop new isozyme-selective inhibitors, small molecule inhibitors (SMis) were designed, synthesized and screened for MMP-7, 9 and 10. Results indicate that hydroxamates and carboxylates are preferred SMis. Binding preference is based on either the micro-environments of the active-site pockets.
Biochemical and Epidemiological Analysis of Mycobacterium Avium Subspecies Paratuberculosis and Investigation of its Relationship to Crohn's Disease in Humans
(North Dakota State University, 2011) Uzoigwe, Jacinta Chinwe
Background: Crohn's disease is a chronic inflammatory disease of the intestine in humans, with no known cause. Johne's disease is a chronic intestinal disease of ruminants caused by Mycobacterium avium suhspecies paratuberculosis (MAP), and has some features similar to Crohn's disease. Although MAP has been purported to play an etiologic role in Crohn's disease, this causal link is still under debate. Objective: The overall aim of this project is to analyze MAP strains from different hosts (cattle, sheep and humans) and regions in North Dakota by biochemical and epidemiological methods, in order to better understand the pathogenesis and epidemiology of MAP strains and the relationship between MAP and Crohn's disease. The specific aims of this research are the following: Aim 1. Investigate the epidemiological evidence for MAP as a cause of Crohn's disease. Aim 2. Conduct a comparative causality study to investigate whether MAP or other enteric pathogens cause Crohn's disease. Aim 3. Evaluate the occurrence of MAP infections in cattle in North Dakota, 1995-2005. Aim 4. Analyze MAP strains from symptomatic and asymptomatic cattle. Aim 5. Investigate the biochemical variations of rapid and slow growing MAP strains. Aim 6. Evaluate MAP strains from low shedders and high shedders. Methods: MAP isolates were analyzed by biochemical methods of gas chromatography, high performance liquid chromatography and mass spectrometry. In addition, extensive literature review was performed to (1) determine the epidemiologic causal link between MAP and Crohn' s disease and (2) determine whether MAP or other enteric pathogens cause Crohn's disease. Results: Results from our study indicated the availablity of epidemiologic evidence supporting the causal role of MAP in Crohn's disease. It was also demonstrated that MAP is the most implicated organism in the etiology of Crohn's disease when compared to other infectious agents. Investigation of the occurrence of MAP infection in North Dakota showed an increase in number of MAP cases reported, with seasonal trends. Biochemical typing of MAP strains from symptomatic and asymptomatic cattle indicated that the symptoms status of isolates was significantly associated with mass spectra patterns and shedder status (p < 0.05). However, the association between symptoms status and HPLC and GC patterns was not significant (p > 0.05). Investigation of biochemical variations of rapid and slow growing MAP strains showed associations between the biochemical variability of MAP strains and their growth rate and presence of symptoms in the source cattle. Evaluation of MAP strains of different shedding characteristics by univariate logistic regression revealed that the shedder status of isolates was significantly associated with growth rate of isolates, symptom status, and source regions, but not with mass spectra patterns of isolates. Conclusion: Overall, this study strengthens the theories of strain sharing, intraspecies and interspecies transmission, and supports an association between MAP and Crohn's disease. In addition, the understanding of the biochemical variation among MAP isolates will help in the future design of diagnostics, therapeutics and vaccines for Johne's and Crohn's diseases.
Acyl Imidazole : A Promising Template for Asymmetric Lewis and Brønsted Acid Mediated 1,3-Dipolar Cycloadditions
(North Dakota State University, 2011) Rane, Digamber Sadanand
Construction of chiral complex molecules continues to be a challenge for organic chemists all over the world and to address this challenge numerous methodologies have been developed. 1,3-Dipolar cycloaddition reactions is one such simple and elegant method, which can be employed towards the construction of chiral heterocycles. The ability to construct multiple stereocenters in one operation is one of the salient features of dipolar cycloaddition reaction. Asymmetric dipolar cycloaddition via chiral Lewis or Bronsted acid catalyzed processes is aided by the development of various templates, which provide points of attachment for these catalyst. Application of acyl imidazoles as multifunctional templates has been investigated for Lewis and Bronsted acid catalyzed 1,3-dipolar cycloaddition of azomethine imines and nitrones. Chapter 1. A review of 1,3-dipolar cycloaddition towards to construction of chiral nitrogen containing heterocycles is discussed in this chapter. This chapter intends to provide the reader a current state of asymmetric 1,3-dipolar cycloaddition. Chapter 2. Development of exo and enantioselective Cu(II) catalyzed azomethine imine cycloaddition to pyrazolidinone acrylates is discussed in this chapter. The key issues approached in this chapter includes impact of metal geometry on diastereoselectivity as well as effect of N-l and C-5 substitution on enantioselectivity of cycloadducts. Investigation into the scope and limitation of azomethine imines and dipolarophiles has also been discussed. Chapter 3. This chapter introduces acyl imidazoles as multifunctional template for asymmetric azomethine imine cycloaddition. Limitation of substrate scope for azomethine imine cycloaddition encountered in the previous chapter has been resolved by the use of acyl imidazoles as templates. Synthesis of complementary diastereomers of azomethine imine cycloadducts via Lewis acid and Bronsted acid catalyzed reactions has been discussed in this chapter. Chapter 4. This chapter highlights the application of acyl imidazoles as template for first Bronsted acid catalyzed exo and enantioselective nitrone cycloaddition to electron deficient olefins. Study of appropriate chiral Bronsted acid and investigation of breadth and scope of nitrones and dipolarophiles has also been discussed here. Chapter 5. This chapter address one of the most challenging aspect of synthetic organic chemistry namely the construction of chiral quaternary stereocenters. This study highlights chiral Bronsted catalyzed nitrone cycloaddition to p,|3-disubstituted-a,P-unsaturated acyl imidazole leading to the formation of isoxazolidines with chiral quaternary stereocenter. This methodology is useful for the construction of chiral fluorinated heterocycles.
Stereoselective Carbon-Carbon Bond Construction Using Indium and Bismuth: New Methods in Green Chemistry
(North Dakota State University, 2012) Balasubramanian, Narayanaganesh
Selective chemical reactions that can be accomplished with minimal waste using non-toxic catalysts and reagents will allow for new greener chemical processes for future environmentally sustainable technologies. This work will present an account on enantioselective nucleophilic addition to carbon-nitrogen and carbon-oxygen double bonds mediated by the environmentally benign indium and bismuth metals. The dissertation entitled “ Stereoselective carbon-carbon bond construction using indium and bismuth: new methods in green chemistry” is divided into three chapters Chapter one outlines a few concepts in green chemistry and background information on the vital role of indium and bismuth in present day organic synthesis. The development of a procedure for using allylic alcohol derivatives for ümpolung type allylation of chiral hydrazones is described in chapter two. This procedure affords homo allylic amines in good yields and excellent diastereoselectivity. An interesting study with respect to the mechanism of the reaction has been conducted. Switching gears towards the end of this chapter, ultrasound-promoted indium-mediated Reformatsky reaction of chiral hydrazones is described. This chapter describes a potential green chemical method for making β-amino acids. In chapter three, indium mediated enantioselective allylation of α-ketoamides is described. The developed procedure is applied in the allylation of linear and cyclic α- ketoamides. Overall, an operationally simple and environmentally benign stratergy development has been explained. The later section of this chapter discusses the Reformatsky reaction in isatin series using the same protocol applied for imines. To fully explore any organometallic reaction, it is important to understand the mechanism with which they operate at molecular level. Chapter three outlines some of our attempts to understand the enantioselective indium and bismuth mediated allylation and the nature of chiral- indium and bismuth Lewis acids. A postive non-linear effect has been observed and studied in bismuth-mediated allylation. Key findings obtained in each chapter and their implications to the future of our research is also discussed in each chapter. The chapters also details on what we understood about the potentials of organoindium and organobismuth chemistry towards developing new green chemical methods.
Biological Effects of Vasoactive Intestinal Peptide/Pituitary Adenylate Cyclase Activating Polypeptide Receptor 1 (VPAC1) and VPAC2 on Chemotaxis and its Regulation of the Tumor Suppressor Ikaros in Leukemic T Cells
(North Dakota State University, 2012) Van der Steen, Travis
One in three children diagnosed with cancer has leukemia. Leukemia patients with mutations in the tumor suppressor transcription factor Ikaros (IK), an anti-leukemic factor that is critical for the development of blood cells; have a poor prognosis despite modern chemotherapy. There is, therefore, a critical need to understand the biology of IK. Research by our laboratory has identified a neurotransmitter, called vasoactive intestinal peptide (VIP), which blocks proliferation through one of its receptors (vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide receptor 1(VPAC1)), but blocks apoptosis through a second inducible receptor (VPAC2), while both receptors have chemotactic properties in primary T cells. Some leukemia patients have reversed VIP receptor expression (low VPAC1; high VPAC2), and we hypothesizes that this contributes to a selective growth advantage. Understanding the biology by which VIP receptors regulate cellular growth (proliferation and apoptosis) and movement (chemotaxis) will be pivotal in establishing their signaling pathways as future drugs target candidates in the fight against leukemia. We hypothesized that VIP/VPAC1 signaling would alter the expression of IK protein and that VIP would direct cellular migration of both VPAC1 and VPAC2 expressing leukemic T cells. To test this hypothesis, we first asked whether VIP/VPAC1 signaling affects the expression and/or the phosphorylation profile of IK a transcription factor that regulates cellular growth. The second question was whether VPAC1 and/or VPAC2 signaling differentially control leukemic cell movement. By one- and two-dimensional polyacrylamide gel electrophoresis followed by Western blot analysis, we showed that VIP signaling suppresses IK expression and changes the isoelectric pools of IK protein in a human leukemia cell line. By using leukemia cells that only express VPAC1 or VPAC2 receptors; we demonstrated that VIP promoted cellular movement, but that this effect was controlled by different pathways elicited by VPAC1 versus VPAC2. Collectively, these data support the notion that the nervous system naturally contributes to normal blood cell function, but after leukemogenesis, the VIP signaling axis may exacerbate the leukemia phenotype.
Surface Chemistry Characterization of Hydrodesulfurization and Methanol Synthesis Model Nanocatalysts
(North Dakota State University, 2012) Komarneni, Mallikharjuna Rao
Surface science investigations of model catalysts have contributed significantly to heterogeneous catalysis over the past several decades. The unique properties of nanomaterials are being exploited in catalysis for the development of highly active and selective catalysts. Surface science investigations of model catalysts such as inorganic fullerene-like (IF) nanoparticles (NP), inorganic nanotubes (INT), and the oxide-supported nanoclusters are included in this dissertation. Thermal desorption spectroscopy and molecular beam scattering were respectively utilized to study the adsorption kinetics and dynamics of gas phase molecules on catalyst surfaces. In addition, ambient pressure kinetics experiments were performed to characterize the catalytic activity of hydrodesulfurization (HDS) nanocatalysts. The nanocatalysts were characterized with a variety of techniques, including Auger electron spectroscopy, x-ray photoelectron spectroscopy, electron microscopy, and x-ray diffraction. The adsorption kinetics studies of thiophene on novel HDS catalysts provided the first evidence for the presence of different adsorption sites on INT-WS2. Additionally, the adsorption sites on IF- MoS2 NP and silica-supported Mo clusters (Mo/silica) were characterized. Furthermore, the C-S bond activation energy of thiophene on Mo/silica was determined. These studies finally led to the fabrication of Ni/Co coated INT-WS2, which showed good catalytic activity towards HDS of thiophene. The studies of methanol synthesis catalysts include the adsorption kinetics and dynamics studies of CO and CO2 on Cu/silica and silica-supported EBL-fabricated Cu/CuOx nanoclusters. The adsorption dynamics of CO on Cu/silica are modeled within the frame work of the capture zone model (CZM), and the active sites of the silica-supported Au/Cu catalysts are successfully mapped. Studies on EBL model catalysts identify the rims of the CuOx nanoclusters as catalytically active sites. This observation has implications for new methanol catalyst design.
From Nanocontainer to Nanocatalyst: Mechanistic Studies of [2+2] Photodimerization of Coumarin Derivatives within Cucubit[8]URIL
(North Dakota State University, 2013) Pemberton, Barry Charles
Controlling photoreactions remains a formidable challenge to chemists who have developed several approaches with varying degrees of success to achieve high reactivity/selectivity. Following nature's footprints, chemists have explored the use of confined media for controlling photoreactions. This thesis explores catalytic aspects of a water-soluble supramolecule known as a cucurbituril. Cucurbituril is a macrocyclic oligomer with a large enough cavity to sequester two guest molecules of appropriate size. The guest molecules explored in this thesis is coumarins. The model investigation involves host-guest complexes between cucurbit[8]uril (CB[8]) and coumarin to study the [2+2] photodimerization in water through various spectroscopic techniques. Our initial investigations explored the formation of host-guest complexes with coumarin guests that interacted with CB[8] host. This host guest complexation was used to explore and control photochemical reaction and photophysical properties of encapsulated coumarin guest molecules. The host-guest complexation was found to be dependent on the polarity of the coumarin and the volume constraints imparted by the CB[8] cavity. Observational insights from various coumarins provided insights into formation of host-guest complexes with CB[8]. Some coumarins do not form complexes but if they do they can form 1:1 and 1:2 host guest complexes as well as dynamic host-guest complexes (mixture of 1:1 and 1:2 host-guest complexes). Using dynamic host-guest complexes, we explored the use of CB[8] as a photocatalysts. Photodimerization of 6-methylcoumarin was explored as a model system to understand the supramolecular aspects of photocatalysis. The mechanism for photocatalysis was elucidated using various spectroscopic techniques. Both steady state and time-resolved experiments were carried to ascertain the thermodynamic and kinetic aspects of the supramolecular catalytic process. Spectroscopic investigations provided insights into vital role of dynamic complexes in the catalytic cycle as well as the extrusion of photoproduct from the cavity to enable turnover in the system. Thus this investigation provided an opportunity to build an overall picture of a novel supramolecular photocatalytic process in water. This will undoubtedly foster further development in the area of supramolecular photocatalysis.
Synthesis, Photophysics, and Nonlinear Absorption of Platinum (II) and Iridium (III) Complexes
(North Dakota State University, 2013) Li, Zhongjing
Square planar d8 platinum(II) complexes and octahedral d6 iridium(III) complexes were synthesized. Their photophysics were studied in detail. Structure-property relationship was studied by varying the substitution on the ligands or the π-conjugation extent of the ligands. In Chapter 2, bipyridyl platinum(II) bisstilbenylacetylide complexes (2-1 – 2-6) with different auxiliary substituents on the stilbenylacetylide ligands were synthesized. While the substitution of H on the 4'-position of stilbene by Br and OMe groups does not alter the photophysical properties of the complexes eminently, the photophysical properties are significantly tuned by the CHO, NO2 and NPh2 substituents. In Chapter 3, platinum(II) complexes (3-1 – 3-6) containing 6-[7-R-9,9-di(2-ethylhexyl)-9H-fluoren-2-yl]-2,2'-bipyridine (R = NO2, CHO, benzothiazol-2-yl, n-Bu,carbazol-9-yl, NPh2) ligands were synthesized. It is found that electron-withdrawing substituents (NO2, CHO, BTZ) and electron-donating substituents (n-Bu, CBZ, NPh2) exert distinct effects on the photophysics of the complexes. In chapter 4, platinum(II) complexes (4-1 – 4-6) containing 6-[9,9-di(2-ethylhexyl)-7-R-9H-fluoren-2-yl]-2,2'-bipyridine ligands (R = 4-R'-phenylethynyl with R'= NO2, BTZ, H and OCH3 or R = 4'-BTZ-phen-1-yl or BTZ) were synthesized. The effects of terminal substituents and the different π-conjugated linkages between the BTZ component and the C^N^N core on the photophysics of these ligands and complexes were systematically investigated. In Chapter 5, iridium(III) complexes (5-1 – 5-5) featuring 7-(benzothiazol-2-yl)-9,9-di(2-ethylhexyl)-9H-fluoren-2-yl attachment to the 2-phenylpyridine was synthesized and studied. The effects of the extent of the π conjugation was studied in by the comparison between 5-1 and 5-2, and the effect of the number of the 7-(benzothiazol-2-yl)-9,9-di(2-ethylhexyl)-9H-fluoren-2-yl unit was compared in 5-3 – 5-5. In Chapter 6, bypyridyl iridium(III) complexes (6-1 – 6-7) with different cylometallated arylpyridyl ligands were synthesized. The effects of π-conjugation extension and direction were systematically investigated. Most complexes showed moderate to strong ns transient absorption from visible to near-IR region, indicating stronger excited-state absorption than ground-state absorption in the corresponding region and potential application as reverse saturable absorption materials. Thus, their application as nonlinear absorption materials was demonstrated by reverse saturable absorption (RSA) upon 532 nm ns laser. The RSA trend can be deciphered by the absorption cross section ratio between the excited states and ground states (σex/σ0).
Stereospecific Photochemical Transformations Involving Axially Chiral Acrylanilides and a-Oxoamides
(North Dakota State University, 2013) Ayitou, Anoklase Jean-Luc
Asymmetric photochemical transformations have been under-explored due to the ineffectiveness of conventional methodologies/reagents/catalysts (point chiral auxiliaries and inductors) that were generally employed for thermal reactions. This limitation to use point chiral auxiliaries for asymmetric photochemistry is partly due to the asynchronous behavior of photo-excitation and chiral transfer/induction processes. This dissertation describes a complementary approach to conventional methodologies involving light induced chirality transfer from atropisomeric viz axially chiral molecular reactants (acrylanilides and α-oxoamides) to enantiopure product(s) with point chirality. The study has revealed the importance of rotamers control in the ground state and how it can impact the stereospecificity during light induced excited state reactions leading to enantiopure product(s). Con-rotatory 6π-photocyclization of axially chiral acrylanilides was explored under various reaction conditions. For example, α,β-unsaturated acrylanilides gave the expected 3,4-dihydroquinolin-2- one photoproduct(s) with enantiomeric excess (ee) values > 90% in both direct and triplet sensitized irradiations. On the other hand, the solution phase direct irradiations of α-substituted acrylanilides yielded racemic photoproduct(s) whereas the triplet sensitized reactions led to ee values > 90% in the expected photoproduct(s). By changing the reaction medium from isotropic media to solid state, α-substituted acrylanilides gave photoproducts with ee values as high as 70%. In addition to the effect of the reaction medium and the reactive spin state on the enantioselectivity, preliminary evaluation of the role of Lewis acid(s) and heavy cations (Na+, K+ and Cs+) were explored. The initial observations were quite promising with ee values up to 90% in the photoproducts upon direct irradiation in isotropic media. The photochemical γ-hydrogen abstraction reaction involving axially chiral α-oxoamides leading to β-Lactam photoproducts was investigated. The enantiomeric ratio (e.r.) > 90:10 in the expected β- Lactam photoproducts was found to be dependent on the temperature under which the irradiation was performed. Furthermore, elevated pressure was employed to counter the effect of elevated temperature and slow the rotation around N-C(aryl) chiral axis leading enantioenriched β-Lactam photoproducts. This dissertation details the overall mechanistic rationales and photophysical control studies during the photochemical transformations of atropisomeric acrylanilides and α-oxoamides leading to chirally enriched products.
Synthesis, Characterization, and Application of Low and Reduced Band Gap Thieno[3,4-b]pyrazine-based Materials
(North Dakota State University, 2013) Mulholland, Michael Edward
Conjugated polymers are a class of materials receiving significant interest due to their unique combination of optical and electronic properties found in inorganics with the flexibility and processability of traditional organic plastics. These materials have become popular in application to electronic devices such as organic photovoltaics (OPVs), organic light-emitting diodes (OLEDs), sensors, electrochromics and field effect transistors (FETs). As the energetic gap between frontier orbitals, the band gap (Eg) is largely responsible for the energetic transitions of these materials and thus tuning of this parameter is of great interest. A popular method to reducing Eg is through the use of fused ring systems such as thieno[3,4-b]pyrazines (TPs). These TP-based materials have been previously applied to solar cells. However, all exhibited limited efficiency (<5% PCE). In an effort to improve the efficacy of TPs in electronic devices, the scope of available TP materials was expanded in an effort to study the effect of changing both side chain and comonomer has on the material properties. In an effort to study the effect of side chains Rasmussen and coworkers introduced a new method in 2008 toward synthesis of 2nd generation TPs with expanded electronic tuning. To further develop this work, preparation of new electron-withdrawing TPs were generated. Application of 1st and 2nd generation TPs in the production of homopolymeric and copolymeric materials was performed, along with characterization of their optical and electronic properties. Select materials with altering side chain and comonomeric unit were then applied to OPV devices and efficiencies were evaluated based on the changed parameter.
Mechanistic Studies on the Methionine Aminopeptidase and Peptide Deformylase Catalyzed Reactions
(North Dakota State University, 2013) Sule, Nitesh
In the search for novel antibiotic and therapeutic targets, methionine aminopeptidase (MetAP) and peptide deformylase (PDF) have recently been identified as eminently compelling. These enzymes are involved in the co-translational modification of nascent polypeptides, affecting majority of the cellular proteome across all the kingdoms of living organisms. As a result, the various isoforms of MetAP and PDF have been successfully targeted by antimalarial and anti-cancer drugs. However, in spite of great interest in the bacterial forms of these enzymes as potent antibiotic targets, efforts to develop such agents have failed. This investigation is a study of the biochemical and biophysical features of the E. coli isoforms of MetAP and PDF in order to understand the unique characteristics of these bacterial enzymes. The catalytic properties of these enzymes were studied using a combination of direct and coupled spectrometric assays. Potent inhibitors of MetAP were identified by screening a focused library of compounds and potential pharmacophores were determined. The inhibitor-enzyme interactions were further studied via steady-state and transient kinetic methods. While attempting to enhance the solubility of the tight-binding inhibitors using cyclodextrins, a novel substrate-driven mode of enzyme inhibition by 2-hydroxypropyl-β-cyclodextrin was discovered. The metal-ion binding properties of MetAP were studied and in this effort, the luminescence of the trivalent lanthanide ion europium was identified as a convenient signal for monitoring metal- ion binding to the enzyme. Moreover, europium was found to catalytically activate MetAP. These properties allowed the characterization of MetAP—metal-ion binding with various metals, and this represents the most comprehensive study of the MetAP metal-ion interactions. The C-terminal domain of PDF is implicated in imparting highly unusual properties to PDF, hence the stability of PDF was characterized with respect to this domain. The truncated form of PDF lacking the C-terminal domain was found to be remarkably robust with the secondary structure as well as catalytic activity being very resistant to loss by heat. The evidence suggests additional roles for the C-terminal domain in regulating PDF. Overall, the work described here provides new understanding and avenues for enzymological pursuits of MetAP, PDF and similar valuable targets.
Exciton Diffusion, Transport, and Localization in Conjugated Polymers
(North Dakota State University, 2013) Bjorgaard, Josiah August
Conjugated polymers are wide bandgap semiconductors which have a series of conjugated π-orbitals that extend along the polymer ‘backbone’. The π-orbital conjugation can be disrupted by twisting of the polymer, affecting their optical properties. These materials are very useful for devices, where they are frequently found in semicrystalline thin films. In thin films, Frenkel excitons diffuse on a nanometer scale. However, measurement of the diffusion length of excitons in conjugated polymer films is currently very difficult. Disordered packing and twisting of polymers plays a significant role, but has not been examined in detail. This dissertation presents methods of measuring exciton diffusion length in polymer films and nanoparticles and explains the effect of nuclear disorder on the optical spectra and exciton diffusion in semicrystalline polymer films.
Attempted Total Syntheses of a Novel Lycopodine-Class Alkaloid and (R)-Myricanol, Compounds for the Treatment of Alzheimer's Disease
(North Dakota State University, 2013) Ostlund, Anthony John
Alzheimer's Disease (AD) is a significant challenge to both the pharmaceutical world as well as the synthetic organic chemistry world. One of the most important problems in this field is the lack of a unified approach to the most biologically active class of natural products for the treatment of AD, the lycopodine alkaloids. Presented herein is an attempt at the total synthesis of a novel member of this family. The synthesis spans three complete generations of retrosynthesis and forward progress. In the ultimate effort, the carbon backbone of the entire lycopodine class was successfully synthesized using a 6 step process in 44% overall yield. Features of this synthesis are the formation of an intermediate aldehyde by tandem Horner-Wadsworth-Emmons olefination/Baylis-Hillman reaction, quantitative reduction resulting in a monoprotected diol, cationic Au(I) O-vinylation, and microwave assisted Claisen rearrangement. The final step towards the backbone was realized using a hydrozirconation/transmetalation sequence with addition to the aldehyde to make the penultimate allylic alcohol in 54% yield. Final studies on the elimation of the allylic alcohol to create the desired 1,3-diene functionality show limited access to this important precursor. Simultaneous model system studies have shown that an intramolecular, cationic Rh(I)-catalyzed ynamide Diels-Alder reaction is feasible to set the B and D rings of the final lycopodine core, although the reaction requires optimization. Model systems for the unique intramolecular allylation proposed in the retrosynthesis also show feasibility, however the intramolecular variant has not been fully explored. Additional studies towards the total synthesis (R)-myricanol are also presented as a continuance of efforts towards general approaches to AD combative compounds. Featured are straightforward methods to the two main segments of the natural product, including a three-step process to synthesize the southern half. Finally, a successful 2-step synthesis of (R)-convolutamydine E is used to showcase an In(0)-mediated allylation methodology.
New Strategies for Ruthenium Catalyzed C-C Bond Formation
(North Dakota State University, 2014) Zhang, Jing
Transition metal-catalyzed C-H bond activation allows direct functionalization of the ubiquitous C-H bonds in organic molecules to increase the molecular complexity. Since Murai's pioneering work in ruthenium catalyzed regioselective arene-alkene coupling reaction, a number of transition metal catalysts have been developed for C-C bond formation via C-H bond activation. However, metal-catalyzed C-H functionalization faces a number of long-standing challenges such as the control over regio- and stereoselectivity and harsh reaction conditions. Presented herein is our research on the development of ruthenium(II)-based catalysts for new and improved methods in C-C bond formations by formal activation of sp2 C-H bonds and subsequent coupling with alkyne substrates. Chapter 1 introduces the background of alkyne hydroarylation initiated by transition metal-catalyzed C-H bond activation and the significance to develop new strategies to overcome the limitations of current methods. In Chapter 2 and Chapter 3, ruthenium(II)-N-heterocyclic carbene (NHC) catalyst systems were developed for efficient [3+2] carbocyclization between N-H aromatic ketimines or aromatic ketones and internal alkynes under very mild conditions. This process incorporates the ortho-directing imine and ketone groups for C-H bond activation into the overall transformation in a tandem manner and enables efficient access to indenyl amines and alcohols in high yields. Chapter 4 describes the development of bis-cyclometalated ruthenium(II) complexes with readily available N-H aromatic ketimine and ketone ligands as a new class of catalyst precursors for C-C coupling reactions. The catalytic activity of the bis(imine) complex is evaluated in several catalytic coupling reactions of alkene and alkyne substrates. The coupling reactions are proposed to proceed by Ru(II)/Ru(IV) catalytic cycles involving C-C bond formation by oxidative cyclization. Chapter 5 details the development of a decarboxylative alkyne hydroarylation process to synthesize arylalkenes with controlled and versatile regiochemistry of aromatic substituents. Following a tandem sequence of C-H bond activation and alkyne coupling, the subsequent decarboxylation is facilitated by the newly installed ortho-alkenyl moiety and is compatible with various aromatic substituents at para-, meta- and ortho-positions. This new decarboxylation strategy eliminates the prerequisite of substrate activation by ortho-substitution and allows a broad scope of substituted benzoic acids to serve as aromatic building blocks for alkyne hydroarylation.
Stereospecific Phototransformations of Atropisomeric Chromophores
(North Dakota State University, 2014) Kumarasamy, Elango
Photochemical transformations are unique strategy in synthesis that enables us to access complex and structurally diverse organic scaffolds. However, the challenges in controlling the excited-state to perform stereoselective reactions left this method under-utilized. This dissertation describes a novel strategy that employs atropisomeric chromophores to perform stereospecific phototransformations. The success of this strategy is well established in thermal chemistry but not comprehensively investigated in photochemical transformations. This research largely relies on rotamer control in the ground state (NEER principle) wherein the axial chirality in the starting material was transferred to point chirality in the products upon excitation. The chapter 1 describes the principle differences between the asymmetric thermal and asymmetric photochemical reactions. Further, a survey of methodologies developed towards asymmetric phototransformations and their outcomes are described. A brief introduction about the atropisomeric systems in thermal chemistry and the preliminary investigations in phototransformations are also provided. In chapter 2, enantiospecific disrotatory 4π-ring closure of atropisomeric 2-pyridones were investigated. The differential axial chirality designed (sterics and H-bonding units) displayed distinct temperature and solvent dependency on the enantiospecificity of the reaction. Eyring plot was computed to calculate the differential activation enthalpy and entropy for the reaction. Also, the course of phototransformation was followed through single-crystal XRD to decipher the preferred mode of cyclization for a given isomer of 2-pyridones. The high-pressure racemization and photoreaction study revealed that pressure provided stable chiral axis even at elevated temperature resulting in higher enantiomeric excess (ee) in the photoproduct. The chapters 3-5 describe the [2+2]-photocycloaddition of atropisomeric enamide, maleimide and imine derivatives. The design features on these molecules allowed us to perform complementary reactions that are not observed in the literature. These modifications were significant improvement to “axial to point chiral” strategy that improves the versatility of the photoreactions. For example switching of the excited state in enamides, continuous flow visibleiv light photocatalysis of maleimides and unusual photocycloaddition of stabilized imines are notable features. This dissertation encompasses detailed studies on the mechanism, scope and photophysical studies on new atropisomeric chromophores such as 2-pyridones, enamides, maleimides and imine derivatives that provides excellent avenue to access chirally enriched building blocks.
Enhanced Sensitivity of Lateral Flow Strip Biosensors Based on Enyzmatic Reaction and Nanomaterials
(North Dakota State University, 2014) Xu, Hui
Ultrasensitive detection for trace amount of proteins plays pivotal role in the diagnosis of specific diseases in clinical application, basic discovery research and the improvement of proteomics. Recently, lateral flow strip biosensor (LFSB) has gained considerable attention for protein analysis. Compared with the traditional immunoassays, LFSB has several advantages: user-friendly format, short assay time (generally several minutes), less interference due to chromatographic separation, a relatively low cost, and no requirements for skilled technicians. This ideal technique is suitable for on-site testing by people who are untrained. Traditional gold nanoparticles (GNPs) based LFSB have been used for qualitative and semiquantitative analysis, the application of GNP-based LFSB is limited by its low sensitivity. In this dissertation, different nanomaterials and advanced detection technologies have been used to enhance the LFSB sensitivities. An ultrasensitive LFSB based on horseradish peroxidase (HRP)/GNP dual labels was developed for qualitative (Yes/No) and quantitative detection of protein. The LFSB signal was enhanced dramatically by introducing the second tracer (enzyme) on the GNP surface. The detection limit of LFSB was 100 times lower than that of GNP-based LFSB. A fluorescent LFSB based on enzyme tracers was developed for sensitive detection of proteins. Alkaline Phosphatase (ALP) was selected as a label to prepare the LFSB. The signal was from the fluorescent emission of the ELF-97 alcohol precipitate which was the product of ALP catalyzed dephosphorylation of ELF-97 phosphate. ALP-conjugated antibody (ALP-Ab) functionalized gold nanoparticles (GNPs) were used as labels for the development of a chemiluminescence-based quantitative LFSB. The use of detection and GNPs as enzyme carriers allowed accurate and sensitive analyte detection. GNP-decorated silica nanorods (GNP-SiNRs) were synthesized and employed as the labels for ultrasensitive detection of proteins on the LFSB. Owing to its biocompatibility and convenient surface modification, SiNRs were used as carriers to load numerous GNPs. The signal of the GNP-SiNR based LFSB was enhanced significantly compared to the GNP-based LFSB since more GNPs were captured through the sandwich-type immunoreactions.
Identification of Active Sites in Heterogeneous Catalysis and Surface Chemistry Study of Alkanes Adsorption
(North Dakota State University, 2014) Chakradhar, Ashish
Heterogeneous catalysis is considered the basis of the chemical industry. Surface science investigations on model catalysts have made significant contributions in gaining molecular level understanding of heterogeneously catalyzed reactions. Surface science studies involving the interactions of coal combustion gases such as CO and CO2 on electron beam lithography (EBL)-fabricated CuOx/SiO2 nanoclusters to identify active sites and kinetics data characterizing the alkane adsorption on surfaces of alkaline earth metal oxides, metalloids, and metals are investigated in this dissertation. Diverse surface phenomena such as surface-adsorbate interactions, adsorbate-adsorbate interactions, chemical rearrangements of adsorbed reaction intermediates, identification of active sites, and formation of products have been studied utilizing surface science techniques. Thermal desorption spectroscopy (TDS) and molecular beam scattering (MBS) were utilized to study the adsorption kinetics and dynamics, respectively, of probe molecules on catalyst surfaces. The catalyst surfaces were characterized by various surface science techniques such as Auger electron spectroscopy (AES), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), low energy electron diffraction (LEED), and scanning electron microscopy (SEM). Active sites on the catalyst surface of EBL-fabricated Cu/CuOx nanoclusters (methanol synthesis model catalyst) were identified for CO and CO2 adsorption. Experimentally, it was proven that CO2 adsorbs preferentially along the clusters' rim site and CO on both the rim and terrace sites. Identifying the active sites on a catalyst surface forms the basis of systematic catalyst design strategies. Bond activation in alkanes is a crucial step in the catalytic processing of alkanes in application such as the catalytic combustion of natural gas, exhaust gas remediation, and the selective oxidation of alkanes to high demand products. Adsorption of small chain alkanes such as n-butane, n-pentane, and n-hexane on CaO(100) surface resulted in bond activation to form mostly methane and ethylene via hydrogen abstraction. This production of hydrogen gas has significant economic and environmental benefits. Whereas, the adsorption of n-butane on Sb(111) and silica-supported Mo clusters was found to be molecular and non-activated. However, a strong hydrophobic property of Sb(111) surface was characterized by studying co-adsorption of n-butane and water. In addition, the adsorption sites for n-butane on Sb(111) and Mo nanoclusters were characterized.
Stereospecitic Phototransformations of Axially Chiral Chromaphores
(North Dakota State University, 2014) Kumarasamy, Elango
Video summarizing Ph.D. dissertation for a non-specialist audience.
Biophysical Studies of Ligand Binding to Human Histone Deacetylase-8
(North Dakota State University, 2014) Singh, Raushan Kumar
Due to an involvement in various patho-physiological conditions, human histone deacetylases (HDACs) are high priority drug targets for the treatment of several diseases, such as cancer, heart failure, neurodegeneration, etc. An effector (inhibitor/activator) of these enzymes has a great potential to alleviate the above disease conditions. In this regard, HDAC inhibitors – Zolinza and Istodax - have already been approved by the FDA for the treatment of T-cell lymphoma, aside from several other inhibitors which are in the advanced level of clinical trials. HDAC8 serves as a prototype to study structural-functional and catalytic features of human HDACs. In order to pursue the biophysical studies of the ligand-binding, HDAC8 was cloned, expressed, and purified from E. coli. A high-throughput screening (HTS) of an in-house library of small molecules was performed utilizing a trypsin-coupled in vitro HDAC8 assay to discover novel effectors of HDAC8, and the N-acetylthiourea and the thiopyridine derivatives were discovered as the isozyme-selective inhibitors and activators of HDAC8, respectively. In vitro HDAC8 assay utilizing a fluorogenic peptide as a substrate often produces artifactual results. Therefore, a substrate-independent HDAC8 assay was developed utilizing a fluorescent analog of a pan-HDAC-inhibitor. In view of the fact that the downstream cellular response of a drug is often dictated by the transient kinetic and thermodynamic parameters of its interaction with the target, the transient kinetics and thermodynamics of interaction of the selected HDAC8 inhibitor with the enzyme were thoroughly investigated. It was observed that the dissociation off-rate and/or the enthalpy of binding of an HDAC8 inhibitor to the enzyme could play a crucial role in determining its in vivo efficacy. A rationale has been presented that the above parameters of the ligand-protein interaction could be utilized for optimizing a drug candidate (HDAC8 inhibitor) in order to enhance its in vivo potency.

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