Department of Chemistry & Biochemistry

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A methodology for chemoselective carbonyl ylide formation, total synthesis of (±)-aspergilline A, cyclopiamide A and speradine E and progress toward the total synthesis of (±)-isopalhinine A.
(2018-10-12) Nakhla, Mina Cyril, 1990-; Wood, John L. (John Louis)
In 2001, the total synthesis of (±)-epoxysorbicillinol was completed by Wood and coworkers. This work featured as the key step a Rh(II) catalyzed carbonyl ylide formation and subsequent dipolar cycloaddition of a diazomalonate to yield a highly functionalized oxabicyclic intermediate. In efforts to render the synthesis enantioselective, a method for chemoselective carbonyl ylide formation was devised; this culminated in the formal enantioselective synthesis of (+)-epoxysorbicillinol in 2005. The methodology utilized in this synthesis centered around electronic differentiation of the diazomalonate’s esters to induce chemoselective carbonyl ylide formation. Having established a methodology for chemoselective carbonyl ylide formation the methodology was expanded in scope and steric differentiation of the diazomalonate’s esters explored. Aspergilline A was isolated from Aspergillus versicolor in 2014 by Hu and Gao and was shown to exhibit moderate biological activity against several human cancer cell lines. The compound bears several intriguing structural features including a 6/5/6/5/5/5 fused ring system which contains an oxindole moiety and a substituted tetramic acid. In synthesizing this compound our strategy relied upon two key steps. The first was a single step conversion of a propargyl amine into to a pyrrolinone through the action of an ammonium enolate and the second was a formal [3+2] dipolar cycloaddition between an imidate and a cyclopropenone derived all carbon 1,3 dipole. Ultimately this work resulted in the sixteen step total synthesis of (±)-aspergilline A. Additionally, two other simpler natural products cyclopiamide A and speradine E were synthesized by diverting intermediates accessed during the aspergilline A synthesis. In 2013, the Lycopodium alkaloid isopalhinine A was isolated from Palhinhaea cernua by Zhao and coworkers. To date, the compound has not been shown to exhibit any biological activity. Despite its lack of known biological activity, the compound does possess a variety of synthetically challenging structural features, including a 5/6/6/6/7 fused ring system which contains an isotwistane and a cycloheptane hemiaminal. In devising a synthetic strategy, we settled upon two key synthetic transformations; an allene Nazarov cyclization to construct the central cyclopentanone core and a late stage titanium mediated 6-exo-trig cyclization and subsequent deoxygenation to complete construction of the isotwistane.
Advanced ion mobility - mass spectrometry methods for the analysis of compositionally complex mixtures.
(2016-02-02) Dhungana, Birendra.; Chambliss, C. Kevin.
Enormous analytical challenges are involved in the analysis of compositionally complex samples such as biomass-derived products and crude oils. In this dissertation mass spectrometry (MS)-based novel strategies for the characterization and identification of chemical components in pyrolysis bio-oils are presented. Several techniques including, accurate mass analysis (e.g., Kendrick mass defect analyses, chemical formula determinations, and van Krevelen plots), collision-induced dissociation (CID) and mass – mobility relationships are utilized to support molecular-level investigations. Oily and aqueous fractions of bio-oils produced by slow pyrolysis of two feedstocks, pine shavings (PS) and corn stover (CS), were analyzed by negative-mode electrospray ionization-Orbitrap and ion mobility-time-of-flight (IM-TOF) MS. Oxygenrich species with a high degree of unsaturation were observed, indicating that catalytic upgrading will likely be required if slow-pyrolysis bio-oils are to be utilized as fuel. Additionally, results from analyses of the PS oily fraction subjected to a sequential solvent fractionation demonstrated a partial separation and enrichment of compounds according to oxygen classes, where oxygen classes generally trended with solvent polarities. Generally, higher oxygen classes were preferentially enriched in higher polarity solvents. Mass – mobility correlations were investigated by IM-MS for various structurallyunique homologous series composed of commercially-available compounds. Structural variation involved the inclusion of different repeat units in oligomeric series and different terminal groups in CH2-homologous series. Mass – mobility correlations were also investigated for select CH2-homologous series identified in a bio-oil and compared with results observed for commercial series. A linear mass – mobility correlation (R 2 ≥ 0.996) was established for all series except those in which a substantial change in the gas-phase conformation of ions was probable. Slopes observed for CH2-homologous series with a single terminal group were significantly steeper than slopes observed for series containing two terminal groups. Additionally, a correlation between slope and double bond equivalents suggested that the CH2-homologous series identified in the bio-oil were structurally similar to commercial series containing two terminal groups. Additionally, IM-MS and IM-MS/MS analysis of ions belonging to select CH2-homologous series suggested that mass – mobility correlations and post-ion mobility CID mass spectra may be useful in defining structural relationships among members of a given Kendrick mass defect series.
Aggregation of Cu, Zn superoxide dismutase in amyotrophic lateral sclerosis : kinetic, mechanistic, and therapeutic approaches.
(2017-10-31) Abdolvahabi, Alireza, 1985-; Shaw, Bryan Francis, 1976-
Investigating in vitro kinetics of protein aggregation using high-throughput microplate-based assays provides open venues for obtaining valuable information regarding mechanism(s) of pathogenesis of protein aggregates in neurodegenerative diseases, and facilitates development of effective therapies. In this dissertation, I use high-throughput microplate-based assays for studying the real-time kinetics of wild type and ALS-variant Cu, Zn superoxide dismutase (SOD1) aggregation in the context of amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative disease that is hallmarked with selective death of motor neurons, which leads to muscle paralysis, and eventually death. Mutations in SOD1 gene are believed to underlie ~ 3 % of cases of ALS via triggering the misfolding and aggregation of SOD1 protein. These SOD1 aggregates render toxicity in motor neurons via interfering with and disrupting normal functions of cells such as cytoplasmic and axonal transport or membrane integrity. In this dissertation, I first show that aspirin (the quintessential acylating pharmacon) can inhibit the amyloidogenesis of wild-type (WT) and ALS-variant apo-SOD1 by increasing the intrinsic net negative charge of the polypeptide, via acetylation of multiple lysines. In the third chapter, I measure rates of fibrillar and amorphous SOD1 aggregation at high iteration and show that rates of oligomerization were intrinsically irreproducible and populated continuous probability distributions. In the fourth chapter, I used Kaplan-Meier estimators to quantify the probability of apo-SOD1 fibrillization (in vitro) from ~ 103 replicate amyloid assays of WT SOD1 and nine ALS variants, and showed that the probability of apo-SOD1 fibrillization is non-uniformly altered by different mutations. I found a linear correlation between the Hazard ratios of SOD1 fibrillization and those of patient survival in SOD1-linked ALS. The fifth chapter answers a very fundamental question: “how do gyrating beads accelerate amyloid fibrillization?” I found that increasing the mass in beads from non-polymeric materials (e.g., steel) increases the nucleation rate of SOD1 fibrillization, whereas hydrophobicity and surface adhesion affected rate of SOD1 fibrillization in the case of polymeric beads. In chapter six, I study the mechanism behind Hofmeister series in proteins. Chapter seven includes a project dedicated to early detection of leukocoria in children with retinoblastoma, during recreational photography.
Application of ab initio theory to the chemistry of ultrathin films.
(2018-07-11) Brown, Paul A., 1983-; Shuford, Kevin L.
In this work, we investigate a number of important nanosheets, e.g., graphene, haeckelites, and titanium disulfide for the expressed purpose of tuning the electronic ground state properties. We employ condensed matter techniques to interrogate real- ized and theoretically postulated ultrathin films to mine ground state properties that may bolster established, or nascent nanotechnologies. In this regard, a number of ultrathin films are tuned to induce new material properties that are not intrinsic to the original crystal. We show that chemical modification with extrinsic substitutional pnictogen dopants placed within the crystal lattice of graphene can functionalize the basal plane of graphene to obtain potentially catalytic properties. Furthermore, an alternative doping strategy, less intensive than pnictogenic substitutions, including halogen diatomic molecules were introduced as adsorbates on monolayer, bilayer, and multilayer graphenes of different polymorphism to influence the ground state of the graphitic nanosheets. We observed the induction of a band gap of controllable size as a function of halogen and polymorphism. Consequently, the semimetallic graphene sys- tems formed a p-type semiconductor, which enables field-dependent control of Dirac carriers within the ultrathin films. Each of these studies take advantage of the orbital and lattice degrees of freedom enabling tunability of this monoelemental nanosheet. However, the authors postulate theorized ultrathin films dubbed Archimedean ultra- thin films. These nanosheets form a unique semiregular polygonal (4,8)-tessellated configuration. This configuration was extended to bulk crystals where we show the potential for forming ultrathin films that contain this unique symmetry. Two groups were studied: the boron pnictides, and the aluminum pnictides. The ground states featured indirect band gap semiconductors, where it was discovered that the boron- pnictides, in particular the planar configurations, possessed a double band gap. Sub- sequently, the optical response of the boron pnictides were revealed within linear response time-dependent density functional theory, which showed that the planar ul- trathin films displayed strong optical response from the UV to the IR. Finally, the electronic ground state of 1T-TiS2 was mechanically strained to induce phase tran- sitions converting this nanosheet into a direct band gap semiconductor. Hence, we demonstrate the tunability of material properties for a series of ultrathin films, whose material properties could provide or support existing and nascent nanotechnologies for the 21st-century.
Approaches to understanding the cumulative effects of stressors on marine mammals.
(2020-12-03) Winfield, Zach C., 1992-; Usenko, Sascha.
In 2017, The National Academy of Sciences reported on the approaches to understanding the cumulative effects of stressors on marine mammals and suggested the use of baleen whale earplugs to evaluate both stress and stressors. The objective of this dissertation is to investigate historic and current organic and inorganic contaminants within the marine ecosystem to better understand the cumulative effects of stressors on marine mammals. Simultaneously, this dissertation also demonstrate links between. The long-term health impact of organic contaminants was assessed in harbor porpoises off the coast of Washington State. This study focused on the POP burden within the blubber of three females (two adults and one juvenile), one of which had a Bcell lymphoma. POP blubber concentrations from different life stages were used to assess the lifetime POPs burden. The juvenile porpoise had the highest contaminant burden followed by the adult female with lymphoma and the nonlymphoma adult. POP life history exposure profiles were reconstructed using baleen whale earplugs. This earplug study expands upon previous earplug studies of both spatial and temporal trends. POPs analysis using earplugs provided contaminant data 30 years prior to the first reports in marine species. Chemical exposure profiles and bioaccumulation rates were reconstructed for a total of six earplugs from the North Pacific and Atlantic Ocean basins. Bioaccumulation rates were found to be 56 times higher in the North Pacific compared to the North Atlantic, suggesting a higher risk of exposure in the North Pacific. Lastly, a single earplug was used to investigate temporal profiles of inorganic elements. The final study used a single fin whale earplug to produce more than 1,600 data points, which were used to reconstruct 48 distinct profiles of toxic, essential, nonessential, rare earth, and other non-biologically relevant elements. This research, in conjunction with concurrent studies, aimed to examine stress profiles and other stressors (e.g., reproduction and whaling; see appendix). Earplug data from this study provides insight into biological and biogeochemical processes as well as preliminary data for further elemental analysis of more earplugs.
Cavity ring down and thermal lens techniques applied to vibrational spectroscopy of gases and liquids.
(2017-06-15) Nyaupane, Parashu Ram, 1980-; Manzanares, Carlos E.
Infrared (IR) and near-infrared (NIR) region gas temperature sensors have been used in the past because of its non-intrusive character and fast time response. In this dissertation cavity ring down (CRD) absorption of oxygen around the region 760 nm has been used to measure the temperature of flowing air in an open optical cavity. This sensor could be a convenient method for measuring the temperature at the input (cold air) and output (hot air) after cooling the blades of a gas turbine. The results could contribute to improvements in turbine blade cooling designs. Additionally, it could be helpful for high temperature measurement in harsh conditions like flames, boilers, and industrial pyrolysis ovens as well as remote sensing. We are interested in experiments that simulate the liquid methane and ethane lakes on Titan which is around the temperature of 94 K. Our specific goal is to quantify the solubility of unsaturated hydrocarbons in liquid ethane and methane. However, it is rather complicated to do so because of the low temperatures, low solubility and solvent effects. So, it is wise to do the experiments at higher temperature and test the suitability of the techniques. In these projects, we were trying to explore if our existing laboratory techniques were sensitive enough to obtain the solubility of unsaturated hydrocarbons in liquid ethane. First, we studied the thermal lens spectroscopy (TLS) of the (Deltav = 6) C-H overtone of benzene and naphthalene in hexane and CCl4 at room temperature.
Characterization of fundamental adsorption behavior of pesticides on polar organic chemical integrative sampler (POCIS).
(2019-04-03) Toteu Djomte, Valerie, 1985-; Chambliss, C. Kevin.
Determination of accurate time weighted average concentrations (TWACs) of chemicals in water using polar organic chemical integrative sampler (POCIS) is still unsatisfactory, due to the limited understanding of environmental factors impact on POCIS uptake. The objective of this research was to improve understanding of environmental factors effects on POCIS uptake by performing laboratory POCIS exposure experiments. The research mainly focused on 12 pesticides, including common types of pesticides used in the US, with a range of physico-chemical properties. A UPLC-MS/MS method was developed for water and POCIS extract samples analyses of select pesticides. The effects of change in hydrodynamic conditions as well as change in temperature on POCIS sampling rate (Rs) were investigated. Flow velocities at the surface of POCIS devices were determined using a novel method based on the measurement of mass transfer coefficients of the water boundary layer near the surface of POCIS devices. Hydrodynamic conditions effects on POCIS Rs were mainly observed between stagnant flow conditions and 6 cm/s. An Arrhenius model was used to describe the linear relationship between temperature and Rs and the use of temperature-corrected Rs to accurately calculate TWAC was evaluated in field settings. The investigation of suspended sediment effects on POCIS uptake suggested that suspended sediment do not have an effect on POCIS Rs for most compounds, but it may affect transport processes across POCIS membrane for compounds with relatively high hydrophobicity and relatively high affinity to POCIS membrane. The investigation of concentration exposure effects on POCIS uptake demonstrated that concentration exposure has no effect on POCIS Rs or POCIS integrative capability for concentrations ranging from 3 to 60 µg/L over a 21-day exposure period. However, POCIS integrative capabilities may be shortened for POCIS exposures to concentrations higher than 60 µg/L. Additionally, there was an interesting increase in POCIS Rs observed between constant concentration and pulse concentration exposures.
Characterization of human IL-10-producing regulatory B cells.
(2019-08-15) Hasan, Md Mahmudul, 1987-; Oh, SangKon.
Regulatory B cells (Bregs) play a pivotal role in the maintenance of immune tolerance. Such critical roles of Bregs have been demonstrated in multiple disease types, including inflammatory diseases, organ transplantation, allergic asthma, and cancer. However, surface phenotypes and functional characteristics of human Bregs have not been fully investigated. Herein, we report that CD24hiCD38hi transitional B cells (TBs) and CD24hiCD27+ B cells (human equivalent of murine B10 cells) are the major IL-10-producing B cells that are capable of suppressing CD4+ T cell proliferation as well as IFNγ/IL-17 expression. Impaired frequency and function of CD24hiCD38hi TBs and CD24hiCD27+ B10 cells were also found in liver allograft recipient with plasma cell hepatitis (PCH). Further investigation of human Bregs revealed that CD24hiCD27+ B cells consist of two major subsets, CD24hiCD27+CD39hiIgD+IgMhiCD1chi and CD24hiCD27+CD39hiIgD-IgMloCD1c+/lo B cells. These two subsets of Bregs expressed not only IL-10, a major anti-inflammatory cytokine, but also CD39, programmed death-ligand 1 (PD-L1), transforming growth factor beta 1 (TGFβ1), granzyme B, and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). In line with their ability to express such immunosuppressive molecules, they were efficient at suppressing CD4+ T cell proliferation as well as inflammatory cytokine expression. RNA-Seq data further showed that the two CD24hiCD27+ B cell subsets exhibited common as well as distinct transcriptomic signatures. However, they were distinct from TBs and others B cells in many different aspects. Finally, we showed that both frequency and function of CD24hiCD27+CD39hiIgD+IgMhiCD1chi and CD24hiCD27+CD39hiIgD-IgMloCD1c+/lo Bregs were significantly reduced in liver allograft recipients with donor specific alloantibody (DSA+) than DSA- patients and age-sex matched healthy control subjects. Data from this study are fundamental for our understanding of the biology of human Bregs as well as for a rational design of Breg-targeted therapy in future.
Characterization of MCM8/9 in DNA repair.
(May 2023) McKinzey, David Reno, 1995-; Trakselis, Michael A.
MCM8 and MCM9 are recent additions to the minichromosomal maintenance family (MCM) of DNA helicases. While not directly implicated in replication, they show both a protective role in aiding the replication fork and assisting in various aspects of DNA repair. The previously uncharacterized C-terminal extension of MCM9 serves vital roles directing the MCM8/9 complex to the nucleus using a bipartite-like nuclear localization sequence (NLS) and promoting interacts with RAD51 through an identified BRC variant (BRCv) motif. Loss of MCM8/9 slows the overall replication speed resulting from more transient fork reversal, lack of protection of the nascent strand, and ultimately double strand breaks. Finally, enzymatic and structural characterization of MCM8/9 reveals a clear affinity for ssDNA containing substrates, stable protection from nucleases, DNA stimulated ATPase activity, and a preferred unwinding orientation. Using cryo-EM, a Walker B mutant version of the MCM8/9 complex shows the overall hexameric structure with the strong density for the C-terminal ATPase domain bound to nucleotide. Altogether this work shows the structure/function activity of the MCM8/9 complex for a more complete understanding of the importance and impact of this complex to maintain genomic integrity during DNA replication.
Characterization of the metallo-ß-lactamase from Pseudomonas aeruginosa, IMP-1.
(2014-06-11) Solida, Nicole R.; Kim, Sung-Kun, 1968-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
The rate at which pathogenic bacteria are gaining antibiotic resistance has become increasingly alarming. Major contributors of this antibiotic resistance in microbes are a class of enzymes known as β-lactamases. These enzymes are effective in breaking down the most commonly prescribed antibiotics at present. This work investigates two separate metallo-β-lactamase enzymes, first IMP-1, which provides antibiotic resistance to Pseudomonas aeruginosa, and second Bla2, which grants antibiotic resistance to Bacillus anthracis. The main focus of this work was to investigate and characterize IMP-1 according to its activity and stability in temperature and pH. This was done in an effort to increase the general knowledge for potential inhibitors to be designed. The secondary focus of this work was to examine the ability of novel hydroxamate compounds to inhibit the growth of bacterial cells expressing Bla2. In addition to this work, aptamers were investigated as a potential means of future inhibitor design.
Characterization of the single photon initiated dissociative rearrangement reaction (SPIDRR) technique and its application in the study of transition metal cation bound organic cluster reactions.
(2018-07-09) Gutierrez, Michael G., 1992-; Bellert, Darrin Joseph, 1968-
The study of gas-phase ion-molecule reactions has been influential in the investigation of transition metal mediated bond activation and catalysis. This research has recently been advanced by a new method designated the single photon initiated dissociative rearrangement reaction (SPIDRR) technique. SPIDRR measures the microcanonical kinetics for reactions between transition metal cations and neutral organic molecules. By assessing the energy dependence of the microcanonical rate constant, as well as determining product branching fractions and kinetic isotope effects, SPIDRR can establish unique mechanistic and dynamic information. This dissertation will provide a detailed overview of the SPIDRR technique and demonstrate its application in the study of transition metal cation bound organic cluster reactions.
Chemical kinetics and dynamics of M+(organic) molecules using single photon initiated dissociative rearrangement reactions (SPIDRR) measurements.
(2018-07-17) Theis, Zachry C., 1988-; Bellert, Darrin Joseph, 1968-
Gas-phase studies are important to many areas of science and technology. The ability to prepare molecular species in an environment devoid of complexities present in the condensed phase allows for high resolution measurement of molecular level details. This is particularly important when studying ion-molecule reactions where transition metals are involved. The open-shell, radical nature of the transition metal in combination with its charge promotes a host of low-energy chemical transformations with multiple reactive pathways open within a few eV of the zero point level of the encounter complex ground state. Moreover, barriers along these pathways are often submerged with respect to the separated reactant limit making both temporal and energetically resolved kinetic measurement challenging. However, it is precisely these qualities of a transition metal cation (a chemically reactive center that mediates low energy chemical transformations) that make it a desired catalytic active site and thus demands high resolution study. To this end, the single photon initiated dissociative rearrangement reaction (SPIDRR) technique was developed. This dissertation details the use of this novel tool toward measurement of the kinetics and dynamics of the Ni+ and Co+ mediated decomposition of several organic molecules. Ab initio quantum chemical calculations were performed to compliment these experimental studies. The potential energy surface has been determined at the DFT level to suggest the mechanistic features that occur during the metal mediated decomposition of an organic molecule. The combination of experiment and theory has permitted a far deeper understanding of the reaction dynamics and has proven integral towards explaining experimental observation. For example, emerging concepts that guide hydrogen transfers on Ni+ centered catalytic reactions have evolved from this synergistic combination.
Chemistry, electrochemistry and electron transfer induced reactions of cobalt complexes with fluorinated ligands.
(2008-03-03T17:20:55Z) Gunawardhana, Kihanduwage N.; Gipson, Stephen L. (Stephen Lloyd); Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
The chemical or electrochemical reduction of the trifluoroacetyl complex CF3COCo(CO)3PPh3 involves a single electron transfer yielding trifluoromethyl radical and an anionic cobalt carbonyl complex. The mechanism is proposed to involve electron transfer followed by initial dissociation of either a carbonyl or phosphine ligand from the 19-electron [CF3COCo(CO)3PPh3 ]- anion. The resulting 17-electron intermediate undergoes subsequent one-electron reductive elimination of trifluoromethyl radical by homolytic cleavage of the carbon-carbon bond of the trifluoroacetyl group. The CF3· radical can be trapped by either benzophenone anion, forming the anion of [a]-(trifluoromethyl)benzhydrol, or Bu3SnH, yielding CF3H. The final organometallic product is an 18-electron anion, either [Co(CO)4]- or [Co(CO)3(PPh3)]-, depending upon which ligand is initially lost. The chemical or electrochemical reduction CF3Co(CO)3PPh3 is a two-electron process involving heterolytic cobalt-carbon bond cleavage to yield trifluoromethyl anion and cobalt carbonyl anions. The trifluoromethyl anion rapidly decomposes to fluoride and difluorocarbene. This carbene may dimerize to form C2F4. The unstable fluoro carbene can also be trapped by cyclohexene. The mechanism proposed for the reduction of C6F5Co(CO)3PPh3 involves a homolytic cobalt-carbon bond cleavage to form C6F5[bullet] radical. The resultant C6F5[bullet] radical abstracts hydrogen or deuterium from the solvent or trace amounts of water to produce C6F5H or C6F5D. With an excess of reducing agent this C6F5[bullet] radical can be further reduced to C6F5- anion before forming pentafluorobenzene by protonation. The inorganic fragment, the 18-electron [Co(CO)3PPh3]- anion, may participate in a ligand exchange reaction to form [Co(CO)4]-. In addition, interesting reactivity was observed between C6F5Co(CO)3PPh3 and tin hydrides, deuterides and chlorides without any reducing agents. We have demonstrated that ligand replacement reactions can be used for the synthesis of new cobalt-NHC complexes with fluorinated alkyl, acyl and aryl ligands. In addition, the X-ray crystal structure of CF3COCo(CO)3PPh3 was obtained to compare the bond lengths and bond angles with other related compounds. An unusual Co-C(acyl) bond length was observed for CF3COCo(CO)3PPh3. Considering the bond lengths of other alkyl and acyl complexes, it can generally be argued that the position of the alkyl/acyl equilibrium varies with the Co-C(alkyl/acyl) bond length.
Chemometric modeling of UV-visible and LC-UV data for prediction of hydrolysate fermentability and identification of inhibitory degradation products.
(2011-12-19) Hedayatifar, Negar.; Chambliss, C. Kevin.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Production of ethanol from lignocellulosic biomass requires a pretreatment step to liberate fermentable sugars trapped within the plant. During pretreatment, lignin and some sugars undergo degradation to form compounds which have shown inhibitory effects to fermentative microorganisms. Accordingly, development of a rapid and accurate method for assessment of microbial inhibition and identification of inhibitory compounds is essential for gaining a better understanding of pretreatment and its downstream effects on fermentation processes. Traditional methods for identification of inhibitory compounds involve a “bottom-up” approach. Using this approach, one or more known degradation compounds are added to fermentation media and their effects on batch fermentation of ethanol are observed. These methods are extremely time-consuming and labor-intensive which makes them unattractive to researchers. Furthermore, they are carried out on degradation compounds that have already been identified. Given that biomass hydrolysates contain many unidentified constituents, identification of inhibitory compounds by traditional means is unlikely to occur on a timescale that is consistent with current mandates for commercial production of cellulosic ethanol. To address these limitations, we have developed a chemometric model that correlates ultraviolet (UV)-visible spectroscopic data of 21 different biomass hydrolysates with their fermentability (percent inhibition of ethanol production). This novel approach enables rapid prediction of hydrolysate fermentability using UV-visible spectroscopic data alone and offers significant improvements in throughput and labor when compared to traditional batch fermentation methods. The model was subsequently used to predict percent inhibition for five hydrolysate samples, with a root-mean-square error of prediction of 6%. To evaluate the use of chemometric modeling for identification of inhibitory compounds in biomass hydrolysate, a second model was developed to correlate HPLC-UV chromatographic data of the 21 hydrolysates with their percent inhibition. Detection was monitored at four specific wavelengths identified by the UV-visible model as significant spectral regions. Once constructed, the HPLC-UV model was used to identify retention times that had the highest correlation with inhibition. To determine whether better resolution or more universal detectability of sample constituents may lead to identification of additional retention times, a third chemometric model was developed with chromatographic data of hydrolysates obtained via ion chromatography with conductivity detection.
Computational study of glycopeptide antibiotics interactions with Staphylococcus aureus peptidoglycan.
(2021-08-04) Olademehin, Olatunde P., 1985-; Shuford, Kevin L.
Staphylococcus aureus is generally known for its ability to acquire resistance to any antibiotic. Methicillin-resistant S. aureus is one of the leading etiological agents responsible for the hospital- and community-acquired infections. Due to the rise of multidrug resistant bacteria, there is a great need for continuous discovery and development of new antibiotics to overcome the inevitable emergence of antibiotic resistance in pathogens. Numerous classes of antibiotics, including glycopeptide antibiotics, target bacterial cell wall biosynthesis, where the cell wall plays an essential role in maintaining the structural integrity and morphology of bacteria. The major component of the cell wall is peptidoglycan (PG), a unique feature found in all bacteria. Inhibition of PG biosynthesis during cell growth results in bacterial cell lysis. This dissertation examines the glycopeptide antibiotics interactions with PG by molecular dynamics simulations to provide insight into modifying existing therapeutics or developing novel pharmacological therapeutics. Steered molecular dynamics simulations and umbrella sampling were also applied, when necessary, to characterize the thermodynamic properties and the dynamics of select glycopeptide-PG complexes. Our simulations provide insights into the role of amino acid residues, which are not directly involved in the dipeptide binding of glycopeptides, in improving the binding of the glycopeptides to PG. We also reveal computational evidence of a secondary-binding site contributing to the enhancement in the binding of oritavancin to PG compared to other glycopeptide antibiotics lacking the additional binding interactions.
Construction and calibration of a custom time-of-flight mass spectrometer and its use in measuring the reaction kinetics of transition metal ion-organic interactions.
(2009-09-03) Castleberry, Vanessa A.; Bellert, Darrin Joseph, 1968-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
A unique instrument was constructed and used to generate and interrogate jet cooled neutrals, ions and their respective clusters. The instrument is a result of the artful marriage of supersonic expansions combined with time of flight spectroscopy. Ionization occurs in a large main chamber. The ions are separated via a kinetic energy pulse from a custom built linear particle accelerator. The revelatory hardware for our instrument is a microchannel plate detector (MCP). The MCP is mounted on the exit of a custom designed and built hemispherical energy analyzer (sector), which acts as an energy filter. This filtering characteristic of the sector permits study of selected ionized fragments. To test the instrument, the 2-photon resonant, 3-photon ionization spectrum of gaseous atomic copper was measured. The (n = 9 – 21) Rydberg series was observed in 2-photon excitation. The term energies of this series converged to copper's lowest ionization threshold with an apparent quantum defect of 0.92. The state which couples the ground state of copper to the Rydberg series is a non-stationary state composed primarily of the spin-orbit components of the lowest 2P° atomic states. Additionally, the time dependence of the gaseous unimolecular decomposition of the jet-cooled adduct ion, Ni⁺•Acetone was monitored by selective detection of the daughter fragment, Ni⁺CO. Various photon energies were supplied to initiate dissociation of the adduction. The energies employed in this reaction were well below that required to fragment C-C ς-bonds. First-order unimolecular decomposition rate constants, k(E) ranged from 55000 – 113000 s⁻¹. The rate constants decreased with decreasing amounts of internal excitation. Ni⁺ cation is implicated as a catalytic necessity to activate the bond and cause molecular fragmentation. These experiments represent the first direct kinetic study of such catalytic type reactions.
Coordination chemistry of novel multifunctional pyridylphosphine ligands.
(2015-07-29) Smith, Marissa Kay Penney.; Klausmeyer, Kevin Kenneth, 1969-
Coordination complexes with ligands that incorporate multiple donor moieties have been of particular interest due to the unique and diverse characteristics they can possess. In particular, phosphine- and/or nitrogen-based ligands that are designed to be geometrically flexible have been shown to demonstrate coordination modes that favor the formation of complexes that range from small discrete molecules to extended polymeric networks. The purposeful design of these architectures is often complicated by the unpredictable influence of factors such as crystallization solvent, interaction of counterion, metal-to-ligand reaction ratio, and presence of auxiliary ligands. However, these same factors aid in the isolation of novel metal complexes and lend a better understanding of the nature of the ligand. In this work, a new family of pyridylphosphine ligands are featured with various metal salts and select bipyridine derivatives. The coordination complexes range from smaller discrete molecules to 1-dimensional polymers depending heavily on the preference of the ligand: the ability or inability to chelate. Ligands that do not have the ability to chelate are limited to bridging as a sole mode of coordination and often result in the formation of polymers, while ligands that are capable of chelation often result in the formation of simple to complex discrete molecules. In addition to single crystal X-ray crystallography, all complexes were characterized via ¹H and ³¹P NMR spectroscopy, elemental analysis, as well as photoluminescence spectroscopy when applicable.
Copper ionophores induce autophagy in melanoma cells.
(2013-09-16) Dao, Long, 1988-; Farmer, Patrick Joseph, 1957-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Malignant melanoma is a particularly aggressive form of skin cancer, for which the only current treatment option is excision. As melanoma is an inherently antiapoptotic model of cancer, other avenues of cell death were pursued, namely autophagy, a mechanism in which a cell devours itself in times of stress. In this study, two copper ionophores, disulfiram and thiomaltol, were investigated against melanoma. By using immunocytochemistry, Western Blotting and supravital staining, it was confirmed that both ionophores induce autophagy, and furthermore, drive the process to completion. In addition, when tested for viability with the autophagy inhibitor hydroxychloroquine, both ionophores showed evidence of synergism. To further study the migration of copper, STEM-EDX was used on thiomaltol treated melanoma cells.
Decarbonylation, reductive electrochemistry and x-ray crystal structures of some rhodium diphosphine acyl complexes.
(2011-01-05T19:43:44Z) Panthi, Basu Dev.; Gipson, Stephen L. (Stephen Lloyd); Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Acyl complexes of rhodium(III) with chelating diphosphine ligands (P-P = 1,3- bis(diphenylphosphino)propane and others) are well known for their stability toward decarbonylation. Various rhodium diphosphine acyl complexes were synthesized and characterized by IR, NMR (¹H, ¹⁹F, and ³¹P), cyclic voltammetry, elemental analysis and X-ray crystallography. The chemical and electrochemical reduction of the rhodium diphosphine acyl complexes Rh(P-P)(COR)I₂ involves a net two-electron transfer yielding Rh(P-P)(CO)I, alkyl anion and iodide. The mechanism involves an initial one-electron transfer followed by the liberation of one of the iodides. Then a second electron transfer with the migration of alkyl group takes place yielding the 18-electron complex [Rh(P-P)(CO)(R)I]⁻. This 18-electron complex loses the alkyl group as the anion, producing Rh(P-P)(CO)I as the final product. We observed a difference in thermal stability between the acetyl and trifluoroacetyl complexes. Others have found that the acetyl complex is very stable in terms of alkyl migration while the monodentate phosphine analog of this complex undergo alkyl migration followed by the loss of alkyl halide. We discovered that when the acetyl group is replaced by a trifluoroacetyl group the resulting complex is unstable in terms of alkyl migration. It slowly changes from the acyl complex to the alkyl complex in solution at room temperature. If the resulting solution is allowed to stand for a long period of time, ca. 20 days or more, it gives the decarbonylated product Rh(P-P)(CF₃)I₂. When the trifluoroacetyl group is replaced by a difluoroacetyl group the complex does not undergo alkyl migration while replacing it with a chlorodifluoroacetyl group increases the rate of alkyl migration. The pentafluoropropionyl complex also undergoes alkyl migration. X-ray crystal structures of 19 rhodium diphosphine complexes were measured and their geometric parameters are compared with related structures. All five-coordinate complexes have square pyramidal geometries with the acyl group occupying the apical position.
Decontamination of metals from firefighter turnout gear and solubility determination of auranofin.
(August 2022) Stolpman, Drew, 1995-; Solouki, Touradj, 1963-
Heavy metals are one of the types of contaminants that firefighters are potentially repeatedly exposed to from prior fires when doffing gear if the gear is not effectively decontaminated. Some heavy metals can be acutely toxic, such as arsenic. Decontamination of gear is essential to reduce and stop continued exposure. Laundering methods can remove heavy metals from firefighter gear and minimize re-exposure. A nitric acid digest was used to extract heavy metals of samples of gear sections before and after laundering with a standard detergent and the Decon7 cleaning solution. Concentrations of arsenic (As), cadmium (Cd), chromium (Cr), lead (Pb), and antimony (Sb) in the acid digests were measured using inductively coupled plasma mass spectrometry (ICP MS). Chapter TWO presents the findings from multiplicate gear samples that showed that, on average, the standard detergent was less effective than Decon7 in removal of the studied metals. Metal-based drugs are increasingly developed for use in cancer treatment regimens. New compounds are typically characterized using mass spectrometry, x-ray crystallography, and nuclear magnetic resonance. A shake flask method uses partitioning to determine the polarity and estimate the solubility in water. However, this estimation is not a measurement of solubility and does not report the solubility of the compound in solutions that efficacy testing is done in, such as cell medium. Thus, dosages may be assigned above the solubility limit. The known metal to drug stoichiometry and concentrations of metal in solutions saturated with the compound can be used to determine the drug solubility in complex solutions, such as cell medium. Chapter THREE reports the solubility of auranofin, a well characterized drug, in water and cell medium. Chapter FIVE reports the solubility of synthesized gold(I) complexes in cell medium.

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