M.S. - Chemistry

Permanent URI for this collectionhttps://hdl.handle.net/10125/4358

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Progress toward bismuth-based radical initiators and metallopolymers
(University of Hawai'i at Manoa, 2025) La Jeunesse, Jesse Lee; Hyvl, Jakub; Chemistry
Organobismuthanes have long been established as complexes known for it’s accessibility , lowmaterial cost, non-toxicity, as well as the synthetic versatility which has been applied to a growing number of applications. In our synthesis, we utilize previously developed techniques that take advantage of bulkier aryl substituents in diaryl bismuth compounds to prevent scrambling of the products. This has led to the development of affordable materials with highly desirable properties, some of which can be selectively attuned toward specified requirements that have potential applications in polymer and pharmaceutical chemistry. In the first chapter, we examine metallopolymers bearing diarylbismuth substituents and their physical properties. We hypothesized that modifications to these metallopolymers 4 will augment the solubility, allowing for variations in physical properties. First, we explored the copolymerization of diphenyl bismuth styrene (Ph2BiSty) and ditolyl bismuth styrene (Tol2BiSty) with methyl-methacrylate (MMA) to produce p-Ph2BiSty-co-MMA, p-Tol2BiSty-co-MMA, pPh2BiSty, and p-Tol2BiSty. These experiments produced (co)polymers that were found to be insoluble and unsuitable for characterization techniques to be applied. Our second attempt to develop on these systems led to the incorporation of the mesityl aryl group into the bismuth side chain resulting in the synthesis of the dimesityl bismuth styrene (Mes2BiSty) monomer, which was co-polymerized with 4-methyl styrene (MS) and 4-bromostyrene (BS). Similar to the outcomes of the phenyl and tolyl co-MMA co-polymer, the p-Mes2BiSty-co-MS/BS copolymers have similar solubility and homogeneity issues,. In the second chapter, bismuth-based radical promoters are reviewed for their reactivity towards the dehydrocoupling of silanes and TEMPO or PhOH. We also report that a select few of these bismuth-based promoters, in sub-stoichiometric quantities, have the ability to initiate and mediate polymerization of styrene. We report here five non-hypervalent, well-defined, diaryl bismuth radical promoters dimesityl bismuth phenyl thiolate (1-SPh), bis(2,4,6-triisopropylphenyl) bismuth phenyl thiolate (2-SPh), dimesityl bismuth hexamethyl-2,6terphenyl thiolate (1-SHMT), dimesitylbismuth isobutyronitrile (1-IBN), and bis(2,4,6-triisopropylphenyl) bismuth isobutyronitrile (2-IBN). These complexes demonstrate reactivity under thermal and photochemical conditions for the dehydrocoupling of PhSiH3 with PhOH and were found to afford low to moderate reaction turnover. Furthermore, we found two of these complexes (1-SPh and 2- iv SPh) to be somewhat reactive in the dehydrocoupling of PhSiH3 with TEMPO only under photoirradiation conditions, while the other complexes were completely inactive.
Ultrasonic Levitation of Energetic Particles
(University of Hawai'i at Manoa, 2024) Rizzo, Grace Lauren; Kaiser, Ralf I.; Chemistry
It is important to understand the reaction mechanisms and to identify the products formed during the combustion reaction of energetic particles for the development and performance enhancement of hydrocarbon and solid rocket fuels. The utilization of an ultrasonic levitator is of advantage in studying reaction mechanisms considering the experimental advantages of controlling the atmosphere, in avoiding contact surfaces, and in allowing for the study of individual, levitated particles. In this thesis, the decomposition and ignition of two energetic materials, aluminum iodate hexahydrate (AIH) and boron-based hydroxyl-terminated polybutadiene (B/HTPB), are studied utilizing complementary in situ spectroscopic techniques including Raman and infrared spectroscopy, temporally-resolved high-speed optical and infrared imaging, and ultraviolet-visible (UV-Vis) spectroscopy. These studies comprehensively outline the mechanistic details for energy liberation by identifying pivotal reaction steps. Key results highlight the release of oxidizer, the discovery of critical reactive intermediates, and the catalytic role that helps in driving the combustion reactions.
Synthesis and Reactivity of a P-Hydrogen Functionalized Benzazaphosphole
(University of Hawai'i at Manoa, 2024) Howard, Miranda P.; Cain, Matthew F.; Chemistry
P–H functionalized benzazaphosphole 3 was synthesized via reduction of chlorophosphine 2 with LiAlH4. Its weak hydridic character was demonstrated via insertion into electrophilic trifluoroacetophenone and dehydrocoupling with fluorinated alcohols. However, 3 readily inserted with difluorocarbene affording 5, which was fully characterized by multinuclear NMR spectroscopy, HRMS, elemental analysis, and X-ray crystallography. The diastereotopic fluorines of the –CF2H group displayed a complex second-order splitting pattern in the 19F NMR spectrum and was successfully simulated using MestReNova. In addition, hydrophosphination between 3 and phenylacetylene generated a mixture of anti- and Markovnikov products 6-6ʺ. Computational modeling of the reaction revealed the anti-Markovnikov E-isomer formed via highly strained phosphirene intermediate, but the major product that crystallized out of solution was the Z-isomer, which was fully characterized by NMR spectroscopy, elemental analysis, and X-ray crystallography.
Temporal and spatial occurrence of oxybenzone and octocrylene in the coastal waters of Oʻahu
(University of Hawaii at Manoa, 2023) Booth, Honour Shore Ai Lin; Williams, Philip G.; Chemistry
Organic ultraviolet filters (UVFs) are gaining increasing attention as contaminants of emerging concern in aquatic and marine ecosystems, entering the environment via plastics and personal care products, such as sunscreens. At heavily used beaches, an important source of UVFs are sunscreens; therefore, the number of people in the water may be an important driver of spatial and temporal variation in UVF concentrations ([UVF]), along with the environmental characteristics of the beach itself, such as the retention time of nearshore waters or flushing due to tide. Presented here are two time series monitoring the temporal and spatial occurrence of the UVFs oxybenzone (BP3) and octocrylene (OC) at popular beaches on Oʻahu in Hawaiʻi. The first time series reports the monthly, diurnal occurrence of BP3 and OC at four beaches on the South Shore of Oʻahu. Samples were collected one Saturday at month in the morning – prior to the arrival of most beachgoers, midday – when beachgoers were most abundant, and sunset – after the accumulated exposure to the days' beachgoers. The second time series reports the bimonthly, diurnal occurrence of BP3 and OC at four sampling locations in the Hanauma Bay Marine Life Conservation District. Hanauma Bay is a protected Bay and popular tourist destination that is open to the public Wednesday through Sunday. Samples were collected on Wednesdays (the first day open each week) and Sunday (the last day open each week) at the time of beach opening, noon, and beach closing every month for seven months. Analytes were extracted via reversed-phase solid phase extraction, extracts were analyzed via LCMS-QQQ in multiple reaction monitoring, and concentrations were calculated using an 11-point standard curve. Using a linear mixed-effects model, I quantified the effects of collection time, sampling location, people, and tide height on [BP3] and [OC]. Both time series occurred during an unprecedented time on Oʻahu, when travel restrictions were being lifted and beaches and parks were being reopened after pandemic closures, which included changes in management practices at Hanauma Bay, as well as when the ban on BP3 went into effect on January 1, 2021. Therefore, additional analyses evaluated whether 1) there are differences in the occurrence of BP3 and OC at South Shore sites before and after the ban on BP3 went into effect; and 2) there are differences in the occurrence of BP3 and OC at Hanauma Bay on the Wednesday morning, on the day the Bay opens, and Sunday morning, on the day the Bay closes. [BP3] and [OC] in surface water from the South Shore sites ranged between 1.00 ng/L to 1,006.99 ng/L and 1.12 ng/L to 7,159.12 ng/L (n = 396). [BP3] and [OC] in surface water at Hanauma Bay ranged from 1.73 ng/L to 1,941.91 ng/L and 2.16 ng/L to 29,986.79 ng/L (n =504). The linear mixed effect model showed that at both the South Shore beaches and Hanauma Bay, interactions between sampling location, collection time, and tide height have the greatest significant effect of [BP3] and [OC]. People density has a main effect on the occurrence of BP3 and OC in waters from the South Shore. Total visitors does not have a main effect on the occurrence of BP3 and OC in waters from Hanauma Bay. The South Shore time series t test results revealed that significant difference in [BP3] and [OC], before and after both the ban on BP3 and the reopening of beaches after pandemic closures, were site dependent. The Hanauma Bay time series t test results showed that there was no significant difference in [BP3] on Wednesday and Sunday mornings; significant difference in [OC] on Wednesday and Sunday mornings varied by month with no distinct seasonal trends. Overall, the occurrence of BP3 and OC in surface waters from the South Shore and Hanauma have high diurnal variation due to anthropogenic activity and grab sampling techniques are limited by sampling frequency. Predicted [BP3] and [OC] generated by the linear mixed effect models can be used for guidance in possible UVF monitoring programs, especially best times to sample given the high diurnal variation.
The Novel Purification and Biophysical Characterization of CXC Chemokines
(University of Hawaii at Manoa, 2022) Martin, Patrick; Haglund, Ellinor; Chemistry
The chemokines are small, signaling proteins responsible for leukocyte recruitment through concentration gradient driven responses for inflammatory diseases such as tissue damage or sun burn, tumor suppression and regulation, and obesity from insulin resistance. In particular, the CXC family of chemokines are active as monomers, homodimers, and heterodimers, with binding affinities for multiple CXC G-protein-coupled receptors. This intricate network has been linked to many cell signaling pathways, but the overall protein folding mechanisms as a concentration driven monomer-dimer equilibrium have yet to be established. In this work, a novel, inclusion body purification is developed to express and purify biologically active CXCL chemokines in milligram quantities for thermodynamic and kinetic biophysical characterization experiments. The results show, that the CXCL chemokines folds and self-associates into homodimers that can activate a membrane bound CXC Receptor, at concentrations above 20 M. Interestingly, the tested CXC ligands display different native circular dichroism spectrum and have stability DG values from 5 to 20 kcal/mol. This indicates the chemokine network has evolved both its specificity and promiscuity to finetune the delicate interplay between ligands and receptors. Thus, these initial studies of the CXC chemokines establishes the foundation for further characterization of chemokines to define fundamental principles governing protein-protein interaction. These principles will help to elucidate molecular details of chemokine-signaling with a long-term goal of finding new drug targets to enhance or suppress signaling.
Identification of a Rubredoxin-like Protein Required for Biotin Synthesis in Mycobacteria
(University of Hawaii at Manoa, 2022) Omolo, Kenneth; Jarrett, Joseph J.; Chemistry
In Mycobacterium tuberculosis (TB), biotin is crucial for synthesizing glucose, fatty acids, and mycolic acid components of the bacterial cell wall essential for survival and pathogenesis. TB grows in a biotin-deficient environment during infection and must synthesize its own biotin de novo. Biotin synthase catalyzes the final step in biotin synthesis, in which S-adenosylmethionine (SAM) is used to oxidize C-H bonds and a sulfur atom from an iron-sulfur cluster is inserted between two carbon atoms in the biotin precursor, dethiobiotin. In E. coli, biotin synthase also requires the exogenous electron donor flavodoxin, but this protein will not support the activity of the TB enzyme. In mycobacterial genomes, the biotin synthase gene (BioB or Rv1589 in TB) is found adjacent to two uncharacterized genes that code for small proteins with unknown functions (Rv1590 and Rv1591 in TB). Rv1590 codes for a metal-binding protein homologous to rubredoxin domains, suggesting Rv1590 could be involved in electron transfer reactions. This research project focuses on cloning the Rv1590 gene, heterologous expression in E. coli, purification of the resulting metalloprotein, and investigation of the secondary structure, thermal stability, metal content, and redox activity of the purified protein.
Assessing The Intestinal Permeability Of Small Molecule Drugs
(University of Hawaii at Manoa, 2022) Shoji, Alyson Taylor; Sun, Rui; Chemistry
A protocol that accurately assesses the intestinal permeability of small molecule compounds plays an essential role in decreasing the cost and time in inventing a new drug. This manuscript presents a novel computational method to study the passive permeation of small molecule drugs based on the inhomogeneous solubility-diffusion model. The multidimensional free energy surface of the drug transiting through a lipid bilayer is computed with transition-tempered metadynamics that accurately captures the mechanisms of passive permeation. The permeability is computed by following the diffusion motion of the drug molecules along the minimal free energy path found on the multidimensional free energy surface. This computational method is assessed by studying the permeability of five small molecule drugs (ketoprofen, naproxen, metoprolol, propranolol, and salicylic acid). The results demonstrate a remarkable agreement between the computed permeabilities and those measured with the intestinal assay. The \textit{in silico} method reported in this manuscript also reproduces the permeability measured from the intestinal assay (\textit{in vivo}) better than the cell-based assays (e.g., PAMPA and Caco-2) do. In addition, the multidimensional free energy surface reveals the interplay between the structure of the small molecule and its permeability, shedding light on strategies of drug optimization. This new model was developed based on the inhomogeneous-solubility diffusion model. Our current model, although exceptional at predicting permeabilities, differs from the original theory derivation of the inhomogeneous-solubility diffusion model. This brings attention, through the study of ten small molecule drugs, that our new model and the original model need to be updated. The permeability shown by these ten small molecule drugs will touch on the issues of minimizing error in transition-tempered metadynamics simulations, and the importance of anchoring different points at zero when calculating permeability with the inhomogeneous-solubility diffusion model.
S-Adenosyl-L-Methionine Radical Enzymes: (I) Metabolism of the Product 5’-Deoxyadenosine (II) Investigation of the Mechanism of Biotin Synthase
(University of Hawaii at Manoa, 2022) Lam, Matthew J.; Jarrett, Joseph T.; Chemistry
5’-Deoxyadenosyl radicals are formed when the S-C5’ bond of S-adenosyl-L-methionine (SAM) undergoes a one-electron reductive cleavage. The 5’-deoxyadenosyl radical then abstracts a hydrogen atom from the substrate, RH, forming a substrate-centered radical and 5’-deoxyadenosine (5’-dAH). Radical SAM enzymes are present in many biochemical pathways, and most of these enzymes generate 5’-dAH as a product. Buildup of 5’-dAH would be detrimental due to product inhibition of Radical SAM enzymes and potentially other SAM-dependent enzymes. The metabolic fate of 5’-dAH is unknown. Notably, 5’-methylthioadenosine (MTA), which is structurally similar to 5’-dAH, is also a byproduct of several SAM-dependent enzymes. The MTA pathway, commonly known as the methionine salvage pathway, has been partially biochemically characterized in Bacillus subtilis and Klebsiella pneumoniae. We propose that some of the enzymes in this pathway may be promiscuous for 5’-dAH. This thesis will first consist of work on the synthesis of 5-deoxyribose (5dr) and 5-methylthioribose (MTR), the products of the first enzyme in the bacterial MTA pathway, MTA nucleosidase (MtnN). In this work, we will show that the subsequent enzyme in the MTA pathway, methylthioribose kinase (MtnK) is also promiscuous and phosphorylates both 5dr and MTA. The product of the enzyme reaction with 5dr is 5-deoxyribose-1-phosphate (5-dR1P). A complete structural characterization of this molecule will be described. Biotin is biosynthesized by the radical SAM enzyme biotin synthase. Biotin is a water-soluble enzyme cofactor that is not biosynthesized by mammals and is therefore an essential vitamin in humans. This cofactor is involved in the biosynthesis of fats and carbohydrates and the metabolism of amino acids. A mechanistic understanding of the chemistry that biotin synthase catalyzes in its active site may be useful in the discovery of drugs that can treat infections caused by microbes like E. coli and Mycobacterium Tuberculosis. One useful tool in probing the mechanism of this enzyme is to examine the kinetic isotope effect (KIE) that occurs when deuterium is incorporated into the substrate dethiobiotin. The biotin biosynthetic pathway transforms the C3 methyl group of L-alanine into the C9 methyl group of dethiobiotin. The second part of my thesis work will focus on the synthesis of mono- or di-deuterated alanine, which would then be used to biosynthesize mono- or di-deuterated dethiobiotin. Finally, a novel method for the chemical synthesis of dethiobiotin that begins with a syn-diamination across an alkene will be described.
Formal Synthesis Of (±)-rocaglamide
(University of Hawaii at Manoa, 2022) Kim, Duk Hwan; Tius, Marcus A.; Chemistry
The formal synthesis of the (±)-rocaglamide precursor was accomplished in six steps in 13% overall yield.
Molecular Dynamics Simulations In The Study Of Biological Lipid Membranes
(University of Hawaii at Manoa, 2021) Kang, Christopher Alan; Sun, Rui; Chemistry
Molecular dynamics simulations solve Newton’s equations of motion for a system of interactingatoms using the energy gradient calculated from a potential function which describes the system of atoms. Subsequently, the trajectories generated from the classical mechanical calculations are used to gain molecular-level insight into varying problems of biological interest. More specifically, we may link important macroscopic properties of proteins or membranes (composition, organization, folding, etc.) derived from experiments to properties at the molecular level arising from interactions between individual amino acids or lipids. The simulations in this thesis investigate the dynamics of lipid monolayers involved in the tear film lipid layer (eyes), where a new class of lipid is under investigation, and in pulmonary sufactant (lungs), which has been hypothesized to be inhibited by the presence of organic compounds in the vapors of electronic cigarettes. A preliminary analysis of a novel iso-area phase transition is also provided. In addition, α-synuclein, thought to be the primary purveyor of Parkinson’s disease is investigated and its mechanism of binding is elucidated.
Attempted Synthesis of a 10-P-3 Species: Cyclization Interrupts the Pathway
(University of Hawaii at Manoa, 2021) Chinen, Beatrice; Cain, Matthew F.; Chemistry
Main group (MG) element-based catalysis provides an enticing solution to the health and environmental problems associated with traditional transition metal catalysis. However, a major obstacle is the large HOMO-LUMO gap present in MG compounds. Confining the active center in a geometrically-distorted rigid chelated structure has shown promise by lowering this barrier and enabling fundamental organometallic-type processes like oxidative addition, insertion, and reductive elimination, leading us to pursue the synthesis of 10-P-3 species 8. To that end, a modified procedure was developed to generate Martin ligand 7-Br, an electron-deficient diol. The ligand was methylated with MeI in the presence of K2CO3 affording diether 9, which was characterized by NMR spectroscopy, elemental analysis, and X-ray crystallography. We hypothesized that exposure of 9 to a three-step metal-halogen exchange/phosphination/reduction sequence would generate target 8, a hypervalent 10–P–3 species stabilized within a rigid pincer framework by electron-withdrawing axial O-donors. Instead, after phosphination, the presumed PCl2-substituted intermediate underwent cyclization to monochlorinated 10, which was functionalized to p-tolyl-substituted 11 and characterized by NMR spectroscopy, elemental analysis, and X-ray crystallography. This work provides insights into cyclization chemistry in fluorinated OCO pincer compounds that will guide future attempts at generating hypervalent 10-P-3 species.
Emblide and trochelin: two novel diterpenoid constituents of Pacific soft corals, Sarcophyton spp
(University of Hawaii at Manoa, 1978) Toth, John Andras; Chemistry
The discovery of prostoglandins from the gorgonian, Plexaura homomalla, rendered recognition in the cbenical community of a previously obscure subclass of coelenterates, the Alcyonaria or Octocorallia, to which the gorgonians belong (Chapter I). Since the
A computer interfaced high temperature/Knudsen cell quadrupole mass spectrometer data acquisition system: application to the investigation of the volatile abundance of submarine basalts from the Mariana Island-arc and trough
(University of Hawaii at Manoa, 1978) Liu, Norman Wai Kwong; Chemistry
A method for the controlled heating of a high temperature Knudsen-cell effusion source and an automatic data acquisition system for an interfaced quadrupole mass spectrometer are described. The method of controlled heating (with variable heating rates, 1.
Investigation of Small Molecule STAT3 Inhibitors
(University of Hawaii at Manoa, 2021) Napier, Patrick; Tius, Marcus A.; Chemistry
STAT3 protein is crucial in cell proliferation, apoptosis, and host immune responses. In normal cell cycles STAT3’s activation is fleeting, but in many cancer cell lines aberrantly activated STAT3 promotes cancer progression. The inhibition of STAT3 protein’s ability to bind to DNA is an attractive treatment for aggressive carcinomas. The Tius Group has designed and synthesized a promising line of STAT3 inhibitors. The high activity of these inhibitors is attributable to the inclusion of a pentafluorobenzenesulfonamide or difluorocyanobenzesulfonamide moiety. A crucial fluorine atom in these inhibitors undergoes SNAr with a cysteine residue in the protein.In this thesis a small library of thirteen compounds and their SAR is reported. The difluorocyanobenzenesulfonamide “warhead” that was often included in inhibitors due to its potency, was found to be unstable in plasma due to reaction with native nucleophiles such as glutathione and plasma proteins. This provided the impetus to explore other scaffolds to attenuate the reactivity of the difluorocyanobenzenesulfonamide that would have desirable reactivity and pharmacokinetics. The SAR analysis of the “warhead” of the inhibitors is the focus of the work done. To attenuate the reactivity of the difluorocyanobenzenesulfonamide, inhibitors that incorporated constitutional isomers of the difluorocyanobenzesulfonamide: S3I-H265, S3I- H270, S3I-H275, and S3I-H289 were made. They indicated through their potency and lack of plasma stability that they would be unsuitable for further study. Inhibitors S3I-H254, S3I-H261 replaced the fluorines in the difluorocyanobenzenesulfonamide motif with a chlorine one at a time. Inhibitors S3I-H296, S3I-H299, and S3I-H308 were made in order to determine whether the substitution of an amide for the nitrile group would lead to higher potency and stability, however, the potency of these inhibitors was low. To explore whether alkyl substitution would improve the qualities of the pentafluorobenzenesulfonamide S3I-H287 was made. The activity of this compound was only slightly higher than that of S3I-H247 its parent. The activity of the inhibitors synthesized for this thesis indicate that novel reactive scaffolds need to be explored in order to provide a candidate for clinical trials.
Stereoselective Synthesis Of Trisubstituted (Z)-trifluoromethyl Alkenes
(University of Hawaii at Manoa, 2020) Liu, Chaolun; Tius, Marcus A.; Chemistry
A stereoselective synthesis of trisubstituted (Z)-trifluoromethyl alkenes has been developed. Treating allenes bearing a trifluoromethyl substituent with trifluoroacetic acid leads to the highly stereoselective formation of trisubstituted (Z)-trifluoromethyl alkenes. Treating trifluoromethyl allenes with Hg(OCOCF3)2 or iodine leads to fully substituted dienes. A novel synthesis of 3-trifluoromethyl-4-isoxazolines has developed. We demonstrated the synthesis of seven trifluoromethyl 4-isoxazolines, one heptafluoro-1-propyl 4-isoxazoline and one example of a non-fluorinated 4-isoxazoline.
Synthesis and SAR Analysis of a Family of STAT3 Inhibitors
(University of Hawaii at Manoa, 2019) Shonkwiler, Airlia Marie; Tius, Marcus A.; Lopez-Tapia, Francisco; Chemistry
Inhibiting STAT3 dimerization and the interaction of STAT3 with the DNA-binding domain is important for preventing the progression of malignant transformations in glioma, breast, prostate, ovarian and other cancers. The Tius group has designed STAT3 inhibitors that disrupt STAT3 dimerization/DNA-binding. However, for these STAT3 inhibitors to be developed into effective anti-cancer drugs, the potency and physicochemical properties of these molecules needs to be improved. Previous SAR analysis was performed to improve the potency and physicochemical properties of the STAT3 inhibitors and from this analysis a general scaffold was developed (Chapter 1, Figure 7). It was determined that pyridine or pyrazine structural motifs in region 2 (R2) produced the most potent compounds compared to analogs with different heterocycles. To resolve which heteroarene, pyridine or pyrazine, produces the most potent compounds more analogs containing these functional groups were needed for comparison. It was also shown that one compound with difluorocyanobenzenesulfonamide in region 3 (R3) had improved potency over its pentafluorobenzenesulfonamide analog. To confirm that the difluorocyanobenzenesulfonamide fragment generally improves compound potency, more analogs needed to be examined. Furthermore, it was discovered that compounds containing a carboxyl or hydroxamic acid functional group in region 4 (R4) have good potency, but poor permeability. Functionalities in R4 needed to be varied to improve both potency and permeability. In an attempt to optimize R2, R3, and R4 in terms of potency and physicochemical properties 12 small molecule STAT3 inhibitors were prepared. These compounds were designed and synthesized using convergent routes containing 7-15 synthetic steps. The synthetic route employed had broad functional group tolerance that easily enabled the development of a small molecule library for biological screening. Each molecule prepared was tested for STAT3 DNA-binding inhibitory activity using the EMSA assay. The physicochemical properties of lead inhibitory agents will be tested in the near future. SAR analysis on R2 was inconclusive; more analogs comparing pyridine and pyrazine need to be explored to resolve which heterocycle leads to the most potent compounds. Replacing the pentafluorobenzenesulfonamide functional group with difluorocyanobenzenesulfonamide increased potency in three out of the four analog comparisons suggesting that compounds with R3 = difluorocyanobenzenesulfonamide have better potency compared to analogs with R3 = pentafluorobenzenesulfonamide. Compounds with R4 = N-methylsalicylamide, N,N-dimethylsalicylamide, meta-difluoromethylbenzene, or meta-fluorobenzene had similar or lower STAT3 inhibitory activity than the parent compounds with R4 = salicylic acid. However, replacing the salicylic acid functionality with benzene enhanced potency. This suggests that functional groups on the benzene ring in R4 are not necessary for enhancing potency.
Investigations of lysine and lysine-derived crosslinks in elastin via solid-state NMR spectroscopy
(University of Hawaii at Manoa, 2019) Panek, Paulina; Kumashiro, Kristin K.; Chemistry
Elastin is responsible for elasticity and resiliency of force-bearing tissues in vertebrates. This polymeric protein is produced from a ~70 kDa precursor, tropoelastin, During the post-translational modification, a network of inter- and intramolecular covalent crosslinks is formed from lysine residues. As many as eleven different bi-, tri-, and tetrafunctional modifications are present in mature elastin, which are critical for normal tissue function. These products have only been characterized in hydrolysates and enzymatically-cleaved peptides, but never observed directly in the intact protein. Two isotopes of lysine, [U-13C,15N-Lys] and [13Cε-Lys], were independently incorporated into the neonatal rat smooth muscle cell (NRSMC) elastin. Samples with high levels of enrichment (~90%) were used for high-resolution solid-state nuclear magnetic resonance (ssNMR) studies. One- and two-dimensional measurements allowed for analysis of the secondary structures of lysines. Random coil and α-helices were the predominant conformations. The helical content is higher in a frozen sample than at the physiological temperature. Experiments based on cross-polarization allowed for quantification of unmodified lysine as well as desmosine and isodesmosine, crosslinks unique to elastin. The presence of rare bi- and trifunctional crosslinks was confirmed.
Thuricin CD Biosynthetic Pathway: Isolation and Characterization of the Precursor Peptides and Sactisynthases Trnα and Trnβ
(University of Hawaii at Manoa, 2018-12) Mazzotti, Giacomo; Jarrett, Joseph T.; Chemistry
Thuricin CD is the most potent antibiotic against C. difficile known to date. Metronidazole and other drugs currently in use strongly alter the microbiota balance in the gut, with dangerous side effects. Thuricin CD has been shown to have a potency equivalent to those antibiotics, but with far less unspecific activity. It has only been isolated in low amounts from B. thuringiensis, and now a larger scale production and advances in clinical trials are needed. Understanding of its biosynthetic pathway is fundamental in order to accomplish such goals. To date, the mature bioactive peptide has been thoroughly characterized, but none of the enzymes responsible for the post-translational modifications have been studied at all. The two subunits forming the active peptide thuricin CD, Trnα and Trnβ, each feature three cysteine to α-carbon crosslinks. This unique structure is the hallmark of the sactipeptides family, a class of ribosomal synthesized and post-translationally modified natural products counting only a few known members. These thioether crosslinks are known to be formed by radical S-adenosyl-L-methionine (SAM) enzymes, and while several mechanisms for installation of these bonds have been proposed, little enzymology data exists to support them. Usually, the sactipeptide operons contain one of these enzymes, which is responsible for one or multiple crosslinks. Thuricin CD is comprised of two different peptide subunits that works in synergy, and the gene cluster shows the presence of two radical SAM enzymes, whose specific functions are unknown. Heterologous expression in Escherichia coli, purification and initial characterization of TrnC and TrnD will be presented, in addition to methodology for the expression and purification of their substrates TrnA and TrnB, by way of a fusion protein system. Attempts to the understanding of the system will also be discussed, laying the groundwork for further investigations.
Simulated Space Weathering Of Planetary Surfaces
(University of Hawaii at Manoa, 2018-12) Crandall, Parker Brian; Kaiser, Ralf I.; Chemistry
Remote sensing data and laboratory simulation experiments have demonstrated the dramatic effects space weathering of planetary bodies can have to alter the chemical makeup of planetary surfaces. The dominant weathering processes are affected by the presence of an atmosphere, which effectively shields ionizing radiation in the form of solar wind and micrometeorite impacts. Here, novel laboratory experiments simulating the effects of space weathering agents on the surface of Mars and the Moon are presented. The results aim to assist in the ongoing investigations of three important discoveries made over the last few decades: First, the apparent lack of exogenic organic molecules on Mars, second, the generation of H2 molecules in the lunar exosphere, and third, the presence of surficial hydroxyl (–OH) groups bound in lunar minerals and exposed water ice deposits at the lunar poles. The systematic approach of these experiments provides important mechanistic details towards the formation of radiogenic molecules on these planetary bodies. In addition, they can be extended to similar environments throughout the Solar System.
Physisorption Processes on Graphene Related Surfaces with Applications to Solid State Hydrogen Storage
(University of Hawaii at Manoa, 2017-12) Squire, Christian; Chemistry
This thesis investigates physisorption interactions of molecular hydrogen on graphene surfaces. The structure of graphene is outlined, followed by an overview of hydrogen storage materials. Focusing on hydrogen storage in a lightweight solid state material, molecular hydrogen is rst adsorbed onto a pure graphene surface and the binding energy of the physically adsorbed molecule is calculated using two di erent computational methods. In a primary cluster approach, polycyclic aromatic hydrocarbons (PAHs) are used as approximations to graphene. In the SLAB approach, periodic boundary conditions are used to represent an in nite graphene sheet in repeating units. A series of small molecules, including H2, are adsorbed on graphene and their corresponding physisorption energies are calculated. The results of the two methods are compared to develop a reliable yet e cient computational approach to lightweight physisorption systems. Then, lightweight alkali metals, halogens, and corresponding alkali halides are adsorbed onto graphene and their physisorption energies are calculated. Molecular hydrogen is then adsorbed to these structures and its physisorbed energy is reevaluated. LiF is shown to increase the magnitude of the H2 PSE to -15.3 kJ/mol as a result of 2 adsorbed H2 molecules, NaF is shown to increase the magnitude of the H2 PSE to -17.8 kJ/mol as a result of 3 adsorbed H2 molecules, LiCl is shown to increase the magnitude of the H2 PSE to -11.7 kJ/mol as a result of 4 adsorbed H2 molecules, and NaCl is shown to increase the magnitude of the H2 PSE to -10.3 kJ/mol as a result of 6 adsorbed H2 molecules. To our knowledge, this series of calculations has not been performed. These results provide potential novel coadsorbants that will increase the binding energy of the intact hydrogen molecule. The results can be used to propose a novel lightweight solidstate hydrogen storage system.

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