M.S. - Chemistry

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https://hdl.handle.net/10125/4358

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Ultrasonic Levitation of Energetic Particles
(2024) Rizzo, Grace Lauren; Kaiser, Ralf I.; Chemistry
Synthesis and Reactivity of a P-Hydrogen Functionalized Benzazaphosphole
(2024) Howard, Miranda P.; Cain, Matthew F.; Chemistry
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.

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