Department of Chemistry & Biochemistry

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High-performance liquid chromatographic methods for quantitative assessment of degradation products and extractives in pretreated lignocellulose.
(Amsterdam : Elsevier B. V., 2006) Chen, Shou-Feng.; Chambliss, C. Kevin.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Long-term economic, national security, and environmental concerns have motivated research into renewable fuels from lignocellulosic biomass. Among energy alternatives, biomass-derived ethanol represents one of the more promising commodities for long-term sustainability of transportation fuels. Herbaceous agricultural residues, such as corn stover, represent a major source of lignocellulosic material with considerable potential for use in biomass-to-ethanol schemes. Currently, the technology for conversion of biomass to ethanol involves dilute acid pretreatment of lignocellulosic materials, followed by enzymatic hydrolysis of cellulose and fermentation of monomeric sugars to produce ethanol. However, a variety of degradation products are produced upon dilute acid pretreatment of lignocellulosic biomass, which exert an inhibitory effect on downstream fermentation processes and reduce bioethanol conversion. Thus there is increased the demand for reliable analytical methods to advance a more understanding of lignocellulose pretreatment. Several liquid chromatographic methods are developed for a systematic analysis of various degradation products. High-performance liquid chromatography is the most widely used analytical separation technique, because of its reproducibility, sensitivity, and suitability for separating nonvolatile species, which makes the method ready for accurate quantitative determinations. A reversed-phase HPLC method with UV detection is developed for simultaneous separation and quantitation of organic acids and neutral degradation products present in the corn stover hydrolysate. On the other hand, inorganic ions and some organic anions which present in water extractive from corn stover are separated and quantitated by the developed ion chromatographic method with conductivity mode. Sugars and alditols are determined using high-performance anion chromatography with pulsed amperometric detection.
Unique fragmentation of pentafluorobenzylic alcohols and the use of modified injection port liners in the gas chromatographic-based screening for catalytic activity.
(2006-02-16T17:04:30Z) Fisher, Henry C.; Garner, Charles M. (Charles Manley), 1957-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
An unprecedented reaction, the base-catalyzed fragmentation of pentafluorobenzylic alcohols, was investigated. Studies on a variety of C6F5-derived alcohols show that a dual reaction pathway occurs in mixed solvent systems such as DMSO and methanol. 19F NMR and GC-MS analyses have been used to examine the mechanism of the fragmenation. Other reaction variables, which involved changing the base and/or solvent conditions, have been studied to determine their effect on fragmentation. The relative rates of reactivity of a variety of pentafluorobenzylic alcohols were determined. A new technique to screen metal catalysts rapidly via GC-MS using modified injection port liners has been developed. A variety of interesting reactions of organic molecules catalyzed by metal salts in the gas phase have been discovered. This technique has also been applied to the fragmentation reactions above.
Modification of fresh tissue surfaces; synthesis of labeled L-dopa analogs; and synthesis of metoclopramide analogs.
(2006-05-27T12:27:47Z) Perera, Aruna B.; Kane, Robert R.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
One of the main goals of the primary project was to develop methods to site specifically immobilize functional proteins on a tissue surface. There are many examples of proteins that have been chemically modified and attached onto solid surfaces such as silica or gold. In those studies, proteins were chemically modified to introduce functional groups, and in most cases, the solid surface was also chemically modified to introduce functional groups onto its surface. The proteins were then immobilized onto the surface using a chemical ligation reaction. However, to the best of our knowledge there are no examples reported in literature where functional proteins have been covalently attached in a site specific fashion onto the surface of a fresh tissue. We hypothesized that the methods used for modifying and immobilizing biomolecules onto solid surfaces could be adapted for use on fresh tissue surfaces. Several different strategies were investigated for the immobilization of the model biomolecules. A direct alkylation method involved reacting a biotin or fluorescent marker (bearing an amine reactive species such as an active ester) directly to the –NH2 groups present on the tissue surface. Reductive methods involved the reduction of the tissue surface with a thiol reducing agent to give free sulfhydryl. The reduced tissue surface was then reacted with a protein or other molecule bearing a thiol reactive species. An oxidative technique used periodiate to oxidize geminal diols (such as those found in proteoglycans in the ECM of tissue) to carbonyl compounds. The oxidation was followed by the reaction of the tissue surface with nucleophilic reagents, such as hydrazides. Aromatic L-amino acid dercarboxylase (AADC) is an enzyme that converts 3, 4-dihydroxyphenylalanine (L-dopa) to dopamine and 5-hydroxytryptophan to serotonin. Inherited deficiency of this enzyme leads to decreased levels of these two neurotransmitters, resulting in severe early onset neurological disorders. In the absence of AADC activity, L-dopa is methylted to 3-0-methyl dopa which is then accumulated in blood, urine and cerebrospinal fluid in infants and children with a deficiency of this enzyme. 3-O-methyl dopa therefore, provides a biochemical marker that can be used to screen for this disease. Thus, the goals of the second project were to synthesize a labeled analog of 3-O-methyldopa for the use in mass spectrometry for the screening of AADC deficiency. The clinical usefulness of high dose MCA as a radio-and chemosensitizer is limited by its central nervous system (CNS) side effects. Primary side effects include drowsiness, acute extrapyramidal reactions, akathisia (generalized motor restlessness) and drug induced Parkinson. MCA has also been shown to increase irritability and anxiety. These CNS side effects are chemically related to the ortho-methoxy group in MCA, which planarizes the molecule and allows it to have a high affinity for dopamine D2 receptors. Since the ortho-methoxy group was suggested to be the cause of the CNS side effects, we hypothesized that modifications at the ortho-methoxy group could decrease the CNS side effects and increase cytotoxicity. Several derivatives of the O-substituted MCA were synthesized and their structure activity relationship (SAR) was studied.
Luminescent supramolecular silver(I) coordination complexes of pyridyl-substituted phosphinites, phosphonites and amines.
(2006-05-28T01:17:15Z) Feazell, Rodney P.; Klausmeyer, Kevin Kenneth, 1969-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Interest in the design and synthesis of supramolecular metal-organic coordination polymers has increased exponentially in the last decade. This attraction comes along with advances in crystallographic instrumentation that has made the collection and processing of crystal data sets faster and more automated than ever. As a result, our understanding of the intra- and intermolecular forces that exist within the confines of the crystalline lattice is at a historic high. In this work we use several new bi- and tridentate pyridyl-substituted phosphinite ligands as well as a series of isomeric aminomethylpyridines to construct discrete, one-, two, and three-dimensional metal-organic coordination architectures with salts of the silver(I) cation. These complexes were then analyzed and discussed in terms of the variables (metal/ligand ratio, anion, temperature, solvent) and forces (donor-metal bonding, hydrogen-bonding, π-stacking, dispersion forces) that cause the structural motifs that are observed. The luminescence of these complexes was also studied and was seen to be variable with changes in structure and metal environment.
Design, synthesis and biological evaluation of new anti-Cancer nitrogen-containing combretastatins and novel cysteine protease inhibitors for the treatment of Chagas.
(2006-05-29T01:54:54Z) Siles, Rogelio.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
In an effort to combat cancer, the development of a relatively new type of anti-cancer drugs known as vascular disrupting agents (VDAs) seems to be a promising clinical approach. VDAs selectively interfere with blood flow in the microvessels that carry nutrients and oxygen to the tumor. Blockage of these vessels will stop tumor growth, produce necrosis, and hence prevent proliferation of cancer cells through the body. The discovery of a group of VDAs known as combretastatins (CA) has sparked an exciting area of anti-cancer drug discovery due to their robust biological activity as evidenced through clinical success, particularly for combretastatin A-4 phosphate (CA-4P) and one nitrogen-based combretastatin CA-4 analogue, AVE8062 which are currently in clinical development. Herein, a small library of seventeen new synthetic oxygen and nitrogen-bearing CA-1 and CA-4 analogues is described. Three of these analogues showed significant inhibition of tubulin assembly (IC50= 2-3 μM) as well as in vitro cytotoxicity against selected human cancer cell lines and in vivo blood flow reduction in SCID mice (23-25% at 10 mg/Kg) suggesting that they have potential for further prodrug modification and development as vascular disrupting agents for the treatment of solid tumor cancers. A separate research project has concentrated on the development of cysteine protease inhibitors, primarily focused toward the inhibition of cruzain, the major cysteine protease of Trypanosoma cruzi which is the agent of the parasitic disease called Chagas’ disease. Currently there is no satisfactory treatment for this disease, and the two accepted drugs, nifurtimox and benznidazole, are associated with significant clinical toxicity. A library of fourteen small non-peptidic thiosemicarbazones has been successfully designed, synthesized and tested against cruzain and cathepsin L from which five compounds showed significant cruzain inhibition in the low namolar range. Although the most active compound synthesized, which is a bromotetrahydronaphthalene thiosemicarbazone, exhibited an IC50=12 nM against cruzain, it also showed activity against cathepsin L (IC50=134 nM). This new pharmacophore introduced may prove useful as a lead compound for further optimization. In addition, this research revealed further insights into the complex structure-activity relationship parameters which may lead to the further development of more selective cruzain inhibitors.
Structure-activity relationships and thermodynamics of combretastatin A-4 and A-1 derivatives as potential inhibitors of tubulin polymerization.
(2006-05-29T01:59:46Z) Mugabe, Benon E.; Trawick, Mary Lynn.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Inhibition of tubulin polymerization has been identified as a significant characteristic of potential anticancer agents. Tubulin is a heterodimeric protein of a and b polypepetide chains, each with a molecular weight of 50kDa and is the biochemical target for several clinically used anticancer drugs. Tubulin was purified from calf brain by a method that uses a series of selective polymerizations induced by a temperature jump in the presence of GTP followed by cold depolymerization. Protein purity was determined by SDS-PAGE and the ability of tubulin to polymerize into microtubules. As part of a program to identify vascular disrupting agents (VDAs), we have determined the effect of more than 78 combretastatin A-4 and A-1 analogs on tubulin polymerization. Combretastatin analogs with substitutions in both the trimethoxyphenyl and phenolic rings were analyzed. These included bromo, chloro, fluoro, mono and di-nitro, di-amino and di-amino hydrochloride, serinamides, serinamide hydrochloride salts of CA-4 and CA-1 derivatives many of which showed good antitubulin activities (IC50 = 1.1 – 3.0 µM) which were comparable to those of CA-1 and CA-4. Generally, water soluble combretastatin phosphate salts analyzed did not show significant inhibitory activity on tubulin polymerization. Our research also explored the application of isothermal titration calorimetry in determining the thermodynamic parameters of binding of CA-1, CA-4 and some of their derivatives. Microcalorimetric studies of the interactions between tubulin and combretastatin analogs were designed to directly determine the enthalpy, binding affinity and the number of binding sites involved upon interaction. We have defined the various thermodynamic signatures that characterize interaction of these compounds with tubulin. All tubulin-combretastatin analog interactions were exothermic and showed favorable free energies and binding affinity constants (0.1 – 9.8 x 105 M-1). The binding affinity constants, stoichiometry, and the thermodynamic signatures suggested hydrogen bonding and hydrophobic contacts for the stronger binding interactions between CA-1 and its analogs which were both enthalpy and entropy driven whereas 2,3 di-amino CA-1 and others showed low binding constants, with evidence of conformational changes upon binding.
Discovery and development of unique small molecule chromene based ligands and combretastatin analogs as potential second generation vascular disrupting agents towards cancer chemotherapy.
(2006-05-29T02:07:12Z) Arthasery, Phyllis.; Pinney, Kevin G.; Chemistry and Biochemistry.; Center for Drug Discovery.; Baylor University. Dept. of Chemistry and Biochemistry.; Baylor University. Center for Drug Discovery.
Cancer is a devastating disease, which remains one of the leading causes of death worldwide. In our continuing quest to help find a cure for cancer, we have discovered and developed new small molecule vascular disrupting agents also known as VDAs for the treatment of cancer. Vascular disrupting agents, by definition, cause a rapid collapse in tumor blood flow, and an effective agent will cause a prolonged period of vascular shutdown, culminating in extensive tumor cell necrosis. The possibility of targeting a tumor's vasculature using small molecule VDAs is currently under active investigation and lead compounds, like combretastatin-A4P, combretastatin-A1P, AC7700 and ZD6126 are in clinical trials for the treatment of cancer, here in the US and in the UK. In this study, a small library of thirteen unique chromenes have been synthesized and evaluated for their anti-cancer efficacy against a panel of human cancer cell lines, and against the P388 mouse leukemia cell line. The inhibition of tubulin assembly data has also been obtained for some of the compounds. Two of the chromenes synthesized show remarkable cytotoxicity (GI50 values) against prostate, lung, CNS-Giobl, and breast adenocarcinoma cancer cell lines. Their ED50 values against the P388 cancer cell line are better than one of the lead compounds combretastatin-A1 (CA-1). In addition, one of these compounds has an IC50 value of 2-4 µM which is comparable to that of bench lead compounds. This compound, therefore, has the potential for further development as a clinical candidate for the treatment of cancer. Further, combretastatin-A4 (CA-4) and CA-1 analogs have been synthesized and their biological activity has been evaluated. Collaborative research efforts (as a member of a research team of the Pinney laboratory) for the synthesis of a dihydronaphthalene analog, trouble shooting in a project centered on the synthesis of a precursor of CA-1 which would ultimately be suitable for radiolabeling, and a scaling up project of OXi8007 were also undertaken. OXi8007 is now in advanced preclinical development for the treatment of cancer and ophthalmology studies. A significant attempt has also been undertaken for the total synthesis of ZD6126 phenol whose phosphate prodrug was recently evaluated in clinical trials for the treatment of cancer. ZD6126 is currently prepared by semi-synthesis starting from colchicine.
A novel spectropolarimeter for determiation of sucrose and other optically active samples.
(2006-07-25T15:34:19Z) Calleja-Amador, Carlos Enrique.; Busch, Kenneth W.; Busch, Marianna A.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Polarimetry and spectropolarimetry are important tools in the sugar industry and pharmaceutical research. Polarimetric measurements cannot be performed on colored samples because the presence of color interferes with the final reading. To avoid the effect of color in sugar samples, lead subacetate is added. Its use to decolorize sugar is problematic because lead is a pollutant. In this work, a novel spectropolarimeter based on an ordinary spectrophotometer is described for determination of sucrose and other optically active samples. The instrument has no moving parts, and optical rotation is encoded as apparent absorbance which makes it suitable for colored samples. Background correction before apparent absorbance measurements, combined with multivariate statistical analysis over a wide spectral range, proved efficient to avoid chemical pretreatment of the samples. The instrument showed good performance for sucrose predictions and multivariate enantiomeric discrimination.
Design, synthesis and biological evaluation of novel serotonin reuptake inhibitors and novel derivatives of a nitrogen-containing combretastatin analog.
(2006-10-13T16:13:02Z) Miranda, Maria Graciela.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Depression is a common and serious illness that affects one out of every ten Americans each year. Since the 1980's, selective serotonin reuptake inhibitors (SSRIs) have been the pharmaceuticals of choice for the treatment of depression and related disorders. Despite their indisputable efficacy, there is still room for improvement in SSRIs, especially in regard to their onset of action and adverse reaction profile. The research presented herein focused on the design and synthesis of a library of thirty-three novel bivalent molecules that could combine into one molecular entity an enhanced antagonism towards the 5-HT2A receptors while keeping a highly selective inhibition of the serotonin transporter (SERT). These bivalent molecules were constructed by covalently coupling two types of fluoxetine hydrochloride structural homologues (for SERT affinity) with a series of nine functionalized piperazines and piperidines (for 5-HT2A antagonism). Preliminary biological evaluation shows that two of the synthesized molecules, 16b and 17b, exhibit the desired dual activity (Ki = 237 and 195 nM respectively for the 5-HT2A receptor and Ki = 1.2 and 1.8 microM respectively for SERT). The complete set of biological data will outline the potential of the synthesized molecules as a new generation of improved antidepressants. Although remarkable advances have been made in cancer pharmacotherapy, the American Cancer Society declared this disease as the top killer of Americans in January, 2005. Therefore, a second research project presented herein focused on the development of a bivalent drug candidate for the treatment of cancer, which could combine into one molecular entity two distinct forms of cancer treatment, vascular disruption and bioreduction. Although the desired target molecule was not achieved, two unexpected and structurally unique products were obtained, which were fully characterized in regards to their structure. Preliminary biological evaluation indicates that compound 73 shows significant inhibition of tubulin assembly (IC50 = 3.3 microM), while compound 74 shows potent and selective in vitro cytotoxicity towards three human cancer cell lines. Therefore, the continuation of this line of research aimed at an improved treatment option for cancer patients is strongly encouraged.
Studies on regression modeling of spectral data as a means of chiral analysis.
(2006-10-13T16:32:15Z) Ingle, Jemima Rose.; Busch, Kenneth W.; Busch, Marianna A.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
The enantiomeric composition of samples was determined using spectroscopy and multivariate regression modeling. Partial least-squares (PLS-1) regression models were developed from the spectral data of solutions containing both enantiomers in varying ratios. The developed regression models were used to predict the enantiomeric composition of unknown validation samples. The predictive ability of the models was evaluated in terms of the root mean square absolute error and the root mean square percent relative error. To address the issue of enantiomeric compositions higher than 0.9, a study was conducted using a large number of samples of phenylalanine and [beta]-cyclodextrin in the upper percentile range, varying from 90-100%. Validation studies with these samples gave absolute errors of 0.0217. In order to study the effects of varying the analyte concentration, two compounds were studied at five concentration levels. Three analyses were performed for each compound. One analysis used only the raw spectral data, one analysis included the concentration as a variable, and one analysis utilized the normalized spectra. Solutions of phenylalanine and [beta]-cyclodextrin resulted in a best absolute error of 0.0316 for the normalized spectral data. Solutions of norephedrine and [beta]-cyclodextrin resulted in a best absolute error of 0.0367 for the raw data. Finally, the spectral data can be used to predict the concentration, the predicted concentration used to normalize the data, and the new normalized data used to predict the enantiomeric composition with an absolute error of less than 0.06 for both compounds. Two simple sugars were tested for their use as chiral auxiliaries. Validation studies with fructose gave absolute errors of 0.0211 (2-octanol) and 0.0308 (phenylalanine); validation studies with glucose gave an absolute error of 0.0184. A comparison study between NIR and UV-visible spectral ranges yielded much poorer results in the NIR (absolute error 0.298) than in the UV-visible (absolute error 0.0308). Finally, a comparison study of 2-octanol and [alpha]-methylbenzylamine with and without a chiral auxiliary was completed. These results varied widely based on solvent and concentration. Modeling studies with impurities did not resemble the spectral behavior of real samples.
Electrochemistry and electron transfer induced substitution reactions of methylcyclopentadienylmolybdenum tricarbonyl complexes and electrospray ionization mass spectrometry and x-ray crystallographic characterization of related molybdenum complexes.
(Oxford, UK : Elsevier, 2007) Munisamy, Thiruvengadam.; Gipson, Stephen L. (Stephen Lloyd); Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
The complexes Cp'Mo(CO)3X (X = Cl, Br, I; Cp' = C5H4CH3) and [Cp'Mo(CO)3(L)]+ (L = CH3CN, CH3COCH3) were synthesized and their electrochemistry and electron transfer induced substitution reactions were studied. Electrochemical studies of Cp'Mo(CO)3X showed that it is reduced via a DISP-type mechanism. The mechanism was confirmed both chemically and electrochemically. Attempts to perform electron transfer induced substitution reactions in the presence of 2eligands formed [Cp'Mo(CO)3]- as the major product, in addition to Cp'Mo(CO)2(L)X, which was formed in greater amounts when the reducing agent was added in aliquots. [Cp'Mo(CO)3]- is proposed to form via the disproportionation pathway while Cp'Mo(CO)2(L)X is formed via a self-exchange substitution pathway. The disproportionation reaction occurs because of the large formation constants of the 19e- [Cp'Mo(CO)3X]- intermediates. The large formation constants of the 19e-[Cp'Mo(CO)3X]- complexes also prevent the electron transfer chain reaction pathway which has been observed for the isoelectronic CpFe(CO)2X (Cp = C5H5) complexes. The self-exchange substitution reaction occurs between the [Cp'Mo(CO)3]- formed from the disproportionation reaction and Cp'Mo(CO)3X and L. 31P NMR was used to confirm the reaction mechanism. The self-exchange substitution reaction is inhibited at low temperature and under a CO atmosphere. Complexes of the type [Cp'Mo(CO)3(L)]+ (L = CH3CN, CH3COCH3) showed an ECE-type reduction mechanism when studied using cyclic voltammetry and the electron transfer induced substitution formed [Cp'Mo(CO)3(PPh3)]+ and [Cp'Mo(CO)2(PPh3)2]+ as major products via an electron transfer chain pathway. These results confirm that cyclopentadienylmolybdenum carbonyl complexes can undergo an electron transfer chain reaction like the isoelectronic CpFe(CO)2X when unhindered by factors such as large formation constants. Electrospray mass spectrometry was used to characterize the complexes [Cp'Mo(CO)3(CH3CN)]PF6 and [{Cp'Mo(CO)3}2(μ-I)]BPh4. The mass spectra showed the molecular ion peaks in addition to fragment ion peaks for [M-nCO]+. Finally, X-ray crystal structures of cis-Cp'Mo(CO)2(PPh3)I, [{Cp'Mo(CO)3}2(μ-I)]BPh4, [Cp'Mo(CO)3(CH3CN)]BF4, [Cp'Mo(CO)3(C5H5N)]BPh4 and cis-[Cp'Mo(CO)2(C5H5N)2]BPh4 were obtained and their bond lengths and bond angles were found to be in good agreement with those in related molybdenum complexes.
Determination of pharmaceuticals and personal care products in fish using high performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry.
(Washington, DC : American Chemical Society Publications., 2007) Ramirez, Alejandro Javier.; Chambliss, C. Kevin.; Brooks, Bryan W.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Labeled as emerging organic contaminants, pharmaceuticals and personal care products (PPCPs) have been the focus of global environmental research for over a decade. PPCPs have caused widespread concern due to their extensive use. As PPCPs were designed to correct, enhance, or protect a specific physiological or endocrine condition, their target effects in humans and/or farm stocks are relatively well understood and documented. However, there is limited knowledge about their unintended effects in the environment. To address the occurrence, distribution and fate of PPCPs in the environment, efficient and reliable analytical methods are needed. The relatively low concentration, high polarity, and thermal lability of some PPCPs, together with their interaction with complex environmental matrices, makes their analysis challenging. Sample preparation followed by GC or HPLC separation and mass spectrometry (MS) detection has become the standard approach for evaluating PPCPs in environmental samples. PPCPs have been widely reported in water, sediment and biosolids, but reports of their occurrence in aquatic organisms have been limited by the difficulty of analysis. Herein, we report the first HPLC-MS/MS screening method for the analysis of 23 pharmaceuticals and 2 metabolites representing multiple therapeutic classes in fish tissues. The developed methodology was successfully applied to assess the occurrence of target analytes in fish collected from 8 locations throughout the United States (6 effluent-dominated rivers and two reference sites). A complementary GC-MS method was developed for the analysis of 12 additional compounds belonging to either personal care product or industrial use compound classes in fish muscle. This approach was also applied to screen for target analytes in fish collected from a regional effluent-dominated stream.
Synthetic coenzymes for in vitro selection of DNA enzymes.
(2007-01-22T20:37:20Z) Carranza, Dorn L.; Kane, Robert R.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Over the past 10 years a number of catalytically active single-stranded DNA molecules (deoxyribozymes) have been isolated from combinatorial libraries (pools) of randomized oligonucleotides. These enzyme-like DNAs customarily utilize divalent metal ions as cofactors in their catalysis. The metal ion cofactors are important because they can participate in both the correct folding of the deoxyribozymes and in the acid/base catalysis. In a new approach, we have designed and synthesized a group of potential small molecule coenzymes, designated as the IDA-oligonucleotide coenzyme, the bis-histidine aromatic coenzymes and the bis-imidazole peptide coenzymes, which could be used by deoxyribozymes in the hydrolysis of a target RNA phosphoester. It was hoped that careful design would provide these molecules with a balance of solubility, binding, and catalytic power. These synthetic coenzymes were included in combinatorial selection experiments aimed at isolating coenzyme-dependent deoxyribozymes from a randomized pool of DNA. Kinetic analysis of deoxyribozymes obtained in these experiments showed a rate enhancements that were dependent on the coenzyme used in the selection. Results of pH-dependent activity profiles of several deoxyribozymes/coenzyme systems suggest a catalytic role for the coenzyme imidazoles. In conclusion, we have demonstrated that combinatorial selection techniques can be used to select for coenzyme-dependent deoxyribozymes. This convenient methodology provides the opportunity to utilize the power of synthetic organic chemistry for the invention of novel coenzymes optimized for desired transformations. In addition, the methodology described in this dissertation complements rational design approaches, and provides a unique opportunity for the study of various aspects of enzyme/coenzyme design.
Vibrational spectroscopy in cryogenic solutions: application of thermal lensing and Fourier transform techniques to the study of molecular C-H overtone transitions.
(2007-01-22T21:58:23Z) Lopez-Calvo, Alfredo.; Manzanares, Carlos E.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
This dissertation explores the application of thermal lensing to vibrational overtone spectroscopy in cryosolutions. Specifically, C-H (delta v = 6) overtone spectra of hydrocarbons dissolved in liquefied rare gases are presented. In addition, Fourier transform (IR, NIR, VIS) spectra between 5000 and 15000 cm-1 are provided for each sample. Main contents were organized in five chapters. First, an introduction on the thermal lens effect, covering principles, theoretical modeling, and general applications. Second, delineation of experimental procedures and instrumental setups. Third, a thorough analysis of thermal lens intensities in methane-argon and methane-nitrogen solutions. Particular topics include concentration and solvent dependency, detection limits, and time-profiles in single and dual-beam experiments. Fourth, description of overtone spectra of saturated hydrocarbons (ethane, propane, butane, isobutane) and calculation of local-mode parameters. And fifth, a similar analysis as before for alkene (ethylene, propylene, isobutylene, cis-2-butene, trans-2-butene) solutions. The main conclusion of the project is the successful applicability of thermal lensing to cryogenic samples, showing comparable performance to room-temperature studies.
Studies on the application of laser photoionization in supersonic-jets for the generation of intense ionic clusters.
(2007-02-07T18:55:55Z) Navea, Juan G.; Manzanares, Carlos E.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Pulsed photoionization in a supersonic expansion was investigated for the production of intense ionic cluster beams from seeded organic molecules. Neutral clusters were photoionized in a pulsed system and studied by means of an optic ion array; the molecular beam design was optimized and is described as a mean to investigate ionic clusters. Neutral clusters were generated and directed to an acceleration region where ionization occurred via a focused 266 nm pulsed laser beam. A set of static voltage plates in the acceleration region provide the ionic clusters with the kinetic energy required for mass separation and detection. Optimization of the parameters involved in the molecular beam apparatus are discussed as well as the calibration of the Time of Flight-Mass Spectrometer (TOF-MS). Low order clusters were recorded and cluster cations of (C6H5CH3)n+, (n-C6H14)n+, (ClC6H5)n+ were produced by a multiple photon photoionization process in the acceleration region. The observed cluster mass spectra for (C6H5CH3)n+,(n-C6H14)n+, (ClC6H5)n+ presented characteristic features that are discussed. Cationic and neutral toluene clusters were computationally minimized by Density Functional Theory (DFT) and Hartree-Fock (HF) Theory. The geometry and potential energy of observed toluene clusters was calculated using Gaussian 98 system of programs by the method DFT B3LYP 6-31 (G)*. Conformational switching was found to have a predominant role in the stability of ionic clusters as well as favored the frontier orbital interaction of the toluene ionic dimer. The photoionization potential energy surface was calculated, involving the conformation switching for toluene dimer and trimer. Chlorobenzene dimer was also minimized and its conformational switching is presented. A perpendicular conformation structure (T-shaped) is favored for the chlorobenzene neutral dimer, instead of the antiparallel structure observed for toluene neutral dimer.
Studies on bovine γ-glutamylamine cyclotransferase.
(2007-02-14T21:44:02Z) Roca, Maryuri.; Trawick, Mary Lynn.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
The purification and study of proteins are cooperative processes because at least partially purified protein is needed in order to study its properties, and certain information about the protein's properties is required in order to design its purification. Particularly difficult to purify is γ-glutamylamine cyclotransferase (γGACT ) which catalyzes the cyclization of the γ-glutamyl moiety in L-γ-glutamylamines, notably Nε−(γ-glutamyl)lysine. From this last activity the function of the enzyme is speculated to be related to the catabolism of transglutaminase products; although, there is no direct evidence of this. Electrophoretically pure bovine γGACT was obtained using preparative ultracentrifugation, anion exchange chromatography on DEAE-Sepharose, ammonium sulfate fractionation and precipitation, size exclusion chromatography on Sephacryl S100, anion exchange chromatography on Mono-Q under reducing conditions, isoelectric focusing of the alkylated sample, electroelution, electrophoresis, ultrafiltration, and lyophilization. The enzyme was purified more than 2,000 fold to a specific activity of more than 1,300U/mg of enzyme. A monomeric enzyme of molecular mass of 22,000 Daltons was observed. Anion exchange chromatography on a Mono Q GL column revealed two forms of the enzyme with pIs of 6.86 and 6.62 under non-reducing conditions, and a single form of pI 6.62 under reducing conditions. γGACT was then subjected to analytical isoelectric focusing and the active fraction appeared as a single band on SDS-PAGE. Amino acid sequencing of the tryptic digest of the band from SDS-PAGE corresponding to the enzyme was carried out by microcapillary reverse-phase HPLC nano-eletrospray tandem mass spectrometry; 42 proteins and protein fragments of similar mass and pI as that of γGACT were obtained. Analysis of their properties indicates that the unknown protein for MGC:134378 is the most likely protein to be the bovine γGACT enzyme. However, expression of the active enzyme from the cloned gene has to be done in order to assure that this is indeed the γGACT enzyme. An affinity column based on the inhibitor glutarylhexylamine showed binding of the enzyme when loaded at low ionic strength and elution when salt was increased.
Design and synthesis of dihydronaphthalene vascular disrupting agents and indolequinone-based bioreductives.
(2007-03-08T15:41:24Z) Dogra, Abhishek.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Cancer remains a deadly affliction for millions across the United States, and the number of new cases is only expected to rise in the years to come. In the field of anticancer research, vascular disrupting agents (VDAs) that preferentially target the tumor vasculature show great promise. The naturally occurring combretastatins, especially combretastatin A-4 (CA4) and combretastatin A-1 (CA1), in suitable prodrug form, have proven to be highly effective VDAs. In this study, efforts were directed towards the synthesis of two combretastatin analogs bearing key features of CA4 on a dihydronaphthalene framework: Oxi 6196 and a beta-dihydronaphthalene analog. In addition to VDAs, another class of exciting anticancer drugs is bioreductive agents that are selectively targeted towards the hypoxic region of tumors. These compounds are chemically reduced selectively and intracellularly to form active cytotoxic compounds. This study also presents the design and synthesis of two analogs of indolequinone-based prodrugs, which can be triggered to release an attached VDA upon bioreductive activation from the 3- or the 2-position, as well as the attempted synthesis of a CA4-tirapazamine bioconjugate drug.
Synthesis, characterization, and applications of redox-mediated ion exchangers.
(2007-12-04T19:51:40Z) Feazell, Monica N.; Chambliss, C. Kevin.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
The technology for conversion of lignocellulosic biomass resources to fuels and chemicals has been under development for decades. There are many process configurations for conversion of biomass to ethanol, one of the well-studied technologies is to use a dilute-acid-catalyzed pretreatment followed by enzymatic hydrolysis and fermentation to produce the ethanol. However, the pretreatment product mixture, typically called hydrolysate, contains a variety of degradation products such as aliphatic and aromatic acids, phenols, and aromatic aldehydes. These degradation products formed can be considered potential fermentation inhibitors, and they can be a restricting factor in the achievability of biotechnological conversions of lignocellulosics to ethanol. This project seeks to contribute to the development of biomass conversion technologies by demonstrating a novel process enabling: 1) simultaneous extraction of organic acids and phenols through reactive ion exchange, 2) quantitative recovery of extracted components into aqueous solution, and 3) regeneration of reactive ion exchangers using redox chemistry. The organometallic complex Fe([eta]5-C5H5)([eta]5-10-C2B9H8(n-C12H25)2) is used in combination with tetra-n-heptylammonium hydroxide salt to demonstrate an improved R2ER for the extraction of acids from aqueous solutions. The metal complex itself remains in its neutral state and only acts as a spectator during the extraction step. New synthetic approaches to a single-component reagent have been developed in this study. The new organometallics synthesized have the principal advantage of reducing the process to a one-reagent. In this case the organometallic complex acts as an extractant instead of a spectator. Seven new compounds were synthesized and characterized, and the uses of Fe([eta]5–C5H5)([eta]5-10-(N(CH3)3)-7,8-C2B9H8(n-C12H25)2)] in a R2ER process were studied for the extraction of perchlorate from aqueous solutions.
Ion-exchange and electrochemical properties of tetra-t-alkylferrocenium monolayers on gold electrodes.
(2007-12-04T19:57:53Z) Parisi, Natali.; Chambliss, C. Kevin.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Five penta-substituted ferrocenes, each having one 11-SH-undecanoyl substituent, have been prepared from 1,1′,3,3′-tetra-t-alkylferrocenes and attached as electrochemically-assembled monolayers to gold electrodes (t-alkyl = t-butyl (tetra-talkylferrocene = BUT-SH), 2-methyl-2-butyl (PENT-SH), 2-methyl-2-pentyl (HEX-SH), 2-methyl-2-hexyl (HEP-SH), and 2-methyl-2-nonyl (DEC-SH)). Cyclic voltammetry E1/2 values determined for the Au/S-Fc+/0 redox couples in aqueous 0.1 M H2SO4 decreased significantly in the order shown when the electrolyte also contained 0.001 M of the anions NO3– > BF4– > CF3SO3– > ClO4– > ReO4 – > PF6– > perfluorooctanesulfonate(PFOS–). The largest ΔE1/2(X−) was greater than 0.5 V and was observed for the Au/SDEC+/0 couple in 0.1 M H2SO4/0.001 M PFOS− relative to 0.1 M H2SO4 with no added anion. Additionally, for each of the 0.001 M added anions ΔE1/2(X−) became greater in the order Au/S-BUT+/0 < Au/S-PENT+/0 < Au/S-HEX+/0 < Au/S-HEP+/0 ≤ Au/S-DEC+/0. Equilibrium constants derived from ΔE1/2(HSO4–/X–) values suggest that differences in the electrochemical behavior for the five Au/S-Fc+/0 redox couples are manifestation of changes in the local dielectric constant surrounding Au/S-Fc+X– ion pairs. The novel ionexchange selectivity of Au/S-HEP+/0 monolayers has been exploited to accomplish selective amperometric determination of part per billion levels of the emerging environmental contaminants PFOS– and perfluorooctanoic acid (PFOA) in aqueous mixtures. Finally, idealized electrode array outputs, derived from hydrodynamic voltammograms charted for each of the five Au/S-Fc+/0 monolayers from flow-injection data, demonstrate unique amperometric responses for structurally similar perfluorinated compounds: PFOS−, perfluorooctanoic acid (PFOA) and tetradecafluoroheptanoic acid. Unique current signatures are also demonstrated for structurally similar anions ClO4 − and ReO4−. Collectively, these data demonstrate strong potential for a biologically-inspired sensing approach for interrogation of complex aqueous mixtures.
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.

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