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archives@tulane.edu / There are three major architectural categories of polymeric materials: linear, branched, and dendritic. Each of these architectures have specific advantages that make them suitable for different applications. However, some of these architectures are inaccessible depending on the monomer system employed. In fact, monomers that can be synthesized into all three of these architectures are extremely rare. This is due to several factors including the lack of a monomer branch point or the poor chemoselectivity of the monomer in use. As a result, there are few monomers, such as 3,5-dihydroxybenzoic acid, that can be synthesized into homopolymers of all three categories. Demonstrations of this level of monomer adaptability are few, but with some recent advancements, another monomer, known as 2,2’-bis(hydroxymethyl)propionic acid (bis-MPA), can be added to this short list of versatile monomers. Bis-MPA is a biocompatible monomer that has been used to synthesize linear, branched, and dendritic materials over the last few decades. Its popularity has grown in academic and industrial settings which has led to numerous publications that show the range of applications it can be used for. However, most of these publications use branched and dendritic bis-MPA architectures. These architectures of bis-MPA have existed for some time and have been well studied. Unlike dendritic and branched bis-MPA, linear bis-MPA has only recently been discovered and detailed (last ~20 years) which has led to the publication of several new applications of bis-MPA materials. While linear bis-MPA has been used to synthesize all three architectures, it is important to note that these linear bis-MPA materials all contain a polycarbonate backbone. This is in stark contrast to traditional bis-MPA materials which contain polyester backbones. Though bis-MPA has been used to synthesize polymeric materials of all three architectures, its important to note that the linear bis-MPA materials published thus far are dissimilar to traditional branched and dendritic bis-MPA. To firmly cement bis-MPA as a versatile monomer, much like 3,5-dihydroxybenzoic acid, a linear polyester bis-MPA material would need to be synthesized. Therefore, the goal of this work is to not only develop a synthetic method for producing linear, polyester bis-MPA but use it to better understand the behavior of dendritic bis-MPA materials and explore its potential application. Herein, linear, polyester bis-MPA was synthesized using a brominated bis-MPA monomer derivative followed by a chain-addition polymerization in mildly basic conditions. This polymerization can take place in a range of solvents and unexpectedly occurs through a chain growth mechanism, which will be discussed. Linear, polyester bis-MPA also proved to be a great analog for traditional bis-MPA dendrimers due to their similar atom economy and repeat unit molecular weight. As such, linear and dendritic bis-MPA analogs were compared in a solution size variation investigation along with poly(caprolactone). These analogs were analyzed using size-measuring techniques including gel permeation chromatography (GPC) and diffusion ordered spectroscopy-nuclear magnetic resonance (DOSY-1H NMR). Finally in this work, a potential application for linear, polyester bis-MPA was explored through the use of triazole chemistry via copper catalyzed azide alkyne cycloaddition (CuAAC). The incorporation of triazole moieties into the linear bis-MPA backbone could be of interest due to the antimicrobial properties of the triazole functional groups. Through the discovery of linear, polyester bis-MPA, bis-MPA can not only be cemented as one of a few highly versatile monomers, but this work opens the door for the exploration of a new class of bis-MPA material. / 1 / Oluwapelumi Kareem

Tris(hydroxymethyl)phosphine (THP) was prepared by the addition of a stoichiometric amount of base to tetrakis(hydroxymethyl)phosphonium chloride (THPC). Freshly prepared THP was successfully immobilised onto wool through a Mannich-type condensation reaction between a hydroxymethyl group and an amine on the wool surface, forming stable gt;P-CH2-Nlt; coupling links. The immobilisation of THP to wool stabilised the THP, which resulted in the decreased oxidation of THP to tris(hydroxymethyl)phosphine oxide (THPO). The presence of immobilised phosphine groups was determined colorimetrically by reaction with Ni2+ ions, which produced a bright orange nickel-phosphine complex, as well as quantitatively, by measuring nickel uptake using ICP-MS. Immobilised THP-wool showed proportional binding for varying concentrations of metal solution. Decreasing or increasing the concentration of the metal solution resulted in a corresponding proportional response of metal binding. Following immobilisation onto wool, oxidation of the system by 6% H2O2 resulted in a reduced binding of 24% for Cu, 25% for Co, 27% for Ni, and 93% for Cd relative to unoxidised THP immobilised onto wool. Additional modification of the THP-wool systems via reaction with amino acids and other related compounds overall did not appear to enhance the metal binding capacity relative to the unmodified THP-wool system. The only modified THP-wool system that showed either retention or an increase in metal binding capacity for all metals analysed was that of 2-aminopyridine, followed by oxidation with H₂O₂.

Introduction. 5-HMF and novel INN-compounds are left-shifting AEH, shown to have anti-sickling action by forming transiently covalent Schiff-base adducts with hemoglobin (Hb), thereby increasing the Hb O2-affinity. They are hypothesized to be substrates for aldehyde dehydrogenase (ALDH) in the liver and red blood cells (RBC). Methods. Biopharmaceutical assessments were made for AEH, using calculated physicochemical properties. Their in-vitro hepatic metabolism (mediated by ALDH) was characterized using hepatic cytosol, and in-vitro-in-vivo extrapolations (IVIVE) were made. Inter-species differences in hepatic cytosolic ALDH activity were investigated using acetaldehyde as a model substrate in different mammalian species. Time- and concentration-dependent in-vitro disposition of 5-HMF in human whole blood was fully characterized and quantitatively modeled. In-vitro time- and concentration-dependent pharmacodynamic (PD) profiling of AEH (0.5 – 5 mM) was carried out in normal whole blood. 5-HMF binding to (normal) HbA and (sickle) HbS was studied in systematic time- and concentration-dependency studies using isolated Hb solutions. Quantitative PK/PD models were developed to fit the experimental data by nonlinear regression (Scientist®). Results. 5-HMF and the two INN-compounds were classified as BCS-I and BCS-II, respectively. All AEH were substrates for hepatic ALDH, with predicted low/intermediate hepatic extraction. Intrinsic ALDH activity varied significantly between mammalian species. In whole blood, 5-HMF plasma concentrations declined rapidly (t1/2 of 0.8 – 4 hrs), with nonlinear kinetics, due to saturable Hb-binding. AEH showed a time-dependent, biphasic PD effect in whole blood, suggesting transiently covalent Hb binding, with slow recovery to the baseline, corresponding to dissociation from Hb and subsequent metabolism by RBC-ALDH. Binding studies with HbA and HbS demonstrated slight differences in binding affinity, but sustained adduct formation - with slow dissociation t1/2. A novel semi-mechanistic target-site drug disposition (TSDD)/PD model was developed, integrating the information, for simultaneous modeling of 5-HMF concentrations in plasma, and its effect in whole blood. Conclusions. This translational research investigated in detail the in-vitro PK/PD of AEH, and systematically compared findings with older generation compounds. A (generic) novel TSDD/PD model was developed for disposition of AEH, identifying k-1 (dissociation constant of AEH from Hb) and kmet (RBC-ALDH metabolism rate constant) as key properties for the time course of PD effect.

Ressonância Paramagnética Eletrônica (RPE) e Absorção Ótica Eletrônica foram utilizadas para estudar-se os complexos de Cobre (II) com tris-hidroximetil aminometano em solução. A análise dos parâmetros de RPE e óticos medidos na solução a diversos pHs foi feita tendo-se à mão as curvas de formação dos complexos. Estas curvas foram construídas em função do pH da solução, usando os dados de equilíbrio químico publicado por K. S. Bai e Martell (J. Inorg. Nucl. Chem. 31 (1969) 1697-1707), numa faixa de concentração de tris na qual este reagente é usando como tampão em estudos biológicos e químicos. Determinou-se cinco conjunto de parâmetros de RPE (go, ao, a11 e A11, correspondentes a diferentes complexos de íon metálico. Cada um desses espectros é encontrado em determinados intervalos de pH, sendo possível associá-los aos complexos previstos nas curvas de formação. A maior estabilidade dos complexos que se formam a pHs mais altos segundo as constantes de equilíbrio é evidenciada pelos valores e go isotrópico (RPE) menores pelos desdobramentos hiperfino isotrópico ao (RPE) e de campo cristalino (ótica) maiores do que os encontrados nas soluções menos alcalinas. A formação do complexo quelato neutro a pH alcalino foi observada, e obteve-se seu tensor g, das medidas do cristal simples. Este tensor encontra-se em bom acordo com o valor de g isotrópico determinado em solução (go=1/3(gxx+gyy+gzz)). Existe evidência de que este complexo seja pentacoordenado). Observou-se similaridade entre os parâmetros para os complexos coordenados por: 2N e 1N+1 0‾ 3N e 2N+1 0&#8254 ; 4N e 2N+2 0&#8254. Isto leva à conclusão de que do ponto de vista energético a coordenação de nitrogênio Cu2+ e a coordenação do oxigênio negativo ao Cu2+ nestes complexos são equivalentes, pelo menos dentro de nossa resolução experimental. / Electron Paramagnetic Ressonance (EPR) and optical visible spectroscopies were used to study the complexes of Cu (II) íon with tris-hydroxymethylamino methane (tris) in solution. Analyses of EPR and optical parameters measured in solution were made using the calculated formation curvesof the complexes. These formation curves were calculated as function of the solution pH, on the basis of the equilibrium constants published by K.S. Bai and Martell (J. Inorg.Nucl. Chem. 31 (1969)-1967-1707), for a concentration of this normally employed in a buffer in biochemical studies. Five sets of EPR parameters ((go, ao, a11 e A11) were determined corresponding to different metal complexes. Each det is found in a characteristic pH range and it was possible to make a correlation of these complexes with the appear in the formation curve plot. The greater stability of the complexes in the high pH range is indicated by the values of go, wich are smaller and the values of the hyperfine splittings ao and the crystal field splittings (from optical measurements) which are greater tahn at the less alcaline solutions. The formation of the neural chelate complexa t alcaline pH was observed, and its g-factors were obtained from measurements with the single crystal. These g-factors agree very well with the solution value (go=1/3(gxx+gyy+gzz)) and the orthorombic symmetriy is obtained. Evidence is present that this complex is penta-coordinated. It was observed a similarity between the EPR parameters for the complexes coordinated by: : 2N e 1N+1 0‾ 3N e 2N+1 0&#8254 ; 4N e 2N+2 0&#8254. This lead us the conclusion that from the energetical point of view the coordination of Cu2+ to nitrogen or to negative oxigen in these cases are equivalent, at or our resolution is not sufficent to differentiate between them.

Currently, the major sources of fuel, energy, and chemicals are nonrenewable fossil resources such as petroleum, natural gas, and coal. Additionally, petroleum is used for the production of most transportation fuels and for the production of about 95% of organic chemicals. However, the production and use of non-renewable fossil fuels are unsustainable. For economic and environmental sustainability, there is a need to search for new and/or renewable resources and technologies for energy, fuels, and chemicals production that have the potential of effectively substituting fossil resources. In this context, lignocellulosic biomass is one of the candidates that meet these requirements due to its abundance and renewability. Lignocellulosic biomass-derived sugars can be chemically converted into 5-(hydroxymethyl)furfural (HMF), a versatile platform chemical that can used to generate intermediates for the production of biofuels and chemicals. In this dissertation novel catalytic processes for converting monosaccharides into HMF are described. In chapter one, a literature review of the significance of HMF and the chemical intermediates derived from HMF is presented. The chapter also describes some of recent developments in the catalytic production of HMF from lignocellulosic sugars using homogeneous and heterogeneous catalysts. Chapter two discusses the catalytic activity of dimethylaluminum complexes bearing (aminomethyl)phenolate ligands that I developed for converting glucose to HMF in ionic liquids. A systematic study on the effects of modification of the aluminum ancillary ligands on the efficiency of glucose conversion is presented. High HMF yield were obtained with substitution of an aryl substituent on the amino groups of the (aminomethyl)phenolate ligands. In an effort to improve HMF yield, the effects of modifying the ligands on the phenolate moiety of the (aminomethyl)phenolate ligands were investigated in chapter three. Using bulky ortho-phenoxide substituents achieved high HMF yields. The selectivity for HMF production with respect to fructose dehydration was also discussed, together with spectroscopic characterization of the polymeric humins produced from the dehydration reactions. In chapter four a study of the structural differences of poor vs. effective dimethylaluminum complexes bearing (aminomethyl)phenolate ligands is described. Insights from this study shows that different precatalyst intermediate could be formed depending on the aluminum complex used, which in turn affects HMF selectivity of dehydration reactions. The isomerization of glucose to fructose using aluminum complexes in N-methyl-2-pyrrolidone (NMP) is discussed in chapter five. Using NMR spectroscopy on isotopically labeled glucose, a mechanism for glucose isomerization to fructose is presented. Finally, chapter six gives a summary and describes potential future directions for the research detailed in this dissertation.

Cyclitols have attracted a great deal of attention in recent years because of diverse biological activities exhibited by them and also synthetic usefulness in the synthesis of other natural compounds or pharmaceuticals. The presence of hydroxymethyl groups in many cyclitols units building natural products is also attracting a remarkable attention. In this study, novel synthetic strategies leading to cyclitol derivatives including hydroxymethyl groups were investigated and the syntheses of bis-homoinositol derivative 127 and hydroxymethyl containing conduritol derivative 137 were achieved successfully. For the synthesis of bishomo-chiro-inositol (127), lactone derivative 132 was synthesized as key compound. The molecule was functionalized with the use of photooxygenation and epoxidation reactions to get target stereochemistry. For the synthesis of hydroxymethyl containing conduritol 137, hydroxymethyl substituted p-benzoquinone derivative 136 was synthesized as a key compound. Bromination of related double bond, reduction of carbonyl groups and the following substitution of bromine atoms form the basis of our strategy. As a result we enabled to synthesize novel cyclitol derivatives stereoselectively by using commercially available starting compounds and well known reactions.

Human exposure to harmful compounds in the environment, from intake via food, occupational exposures or other sources, could have health implications. Exposure to reactive compounds/metabolites can be identified and quantified as hemoglobin (Hb) adducts by mass spectrometry. This thesis aimed at improved synthetic pathways for reference standards, and improved analytical methods for adducts to N-terminal valine in Hb from a range of reactive compounds; isocyanates, aldehydes, methyl vinyl ketone (MVK), and diepoxybutane (DEB). Isocyanates form urea adducts with N-terminal valine by carbamoylation, which are detachable as hydantoins by hydrolysis. A new synthetic pathway for reference standards of adducts from isocyanates and a method for their analysis by liquid chromatography/mass spectrometry (LC/MS) were developed. Aldehydes form reversible imines (Schiff bases) with N-termini in Hb. After stabilisation by reduction and detachment by isothiocyanates using modified Edman methods, these adducts could be analysed by gas chromatography/mass spectrometry (GC/MS) or LC/MS. 5-Hydroxymethylfurfural, its metabolites, and other aldehydes related to exposure via food, were studied with regard to analysis by these methods with synthesised standard references. A considerably improved analytical method for imines was developed. Many of the studied adducts are too short-lived in vivo or in vitro to be used for long-term biomonitoring. However, different approaches for the analysis were evaluated. Through synthesised reference standards, an observed unknown adduct in blood was verified as the adduct from MVK. There exist both natural and anthropogenic sources for MVK. DEB, metabolite of butadiene, forms a cyclic adduct to valine-N. A new approach using hydrazinolysis of protein and enrichment by molecularly imprinted solid-phase extraction was tested on synthesised reference DEB-adduct and gave promising results. Synthesised standards were characterized by NMR, LC/MS and GC/MS. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Submitted. Paper 3: Submitted. Paper 4: Submitted.</p>

Glutamate formiminotransferase deficiency (OMIM 229100) is an autosomal recessive disorder marked by clinical heterogeneity. The severe phenotype, first identified in patients of Japanese descent, includes high levels of formiminoglutamate (FIGLU) in the urine in response to histidine loading, megaloblastic anemia, and mental retardation. The mild phenotype is marked by high levels of FIGLU in the urine in the absence of histidine loading, mild developmental delay and no hematological abnormalities. The gene for human glutamate formiminotransferase-cyclodeaminase consists of 15 exons and is located at 21q22.3. The protein consists of a tetramer of dimers, with dimerization essential for both formiminotransferase and cyclodeaminase activity. / Genomic DNA extracted from cell lines from three patients with suspected glutamate formiminotransferase deficiency was analyzed by PCR and sequencing of individual exons. Cell lines WG 1758 and WG 1759 are from two siblings of Germanic descent. Both siblings are heterozygous for the mutations c457 C &rarr; T and c940 G &rarr; C. The c457 C &rarr; T changes a conserved arginine to a cysteine in a loop involved in the binding of formiminotetrahydrofolate to the enzyme. The c940 G &rarr; C mutation converts an arginine to a proline in an alpha-helix essential for the dimerization of the formiminotransferase domain. Cell line WG 1795 is from a patient of Danish descent. The patient appears to be hemizygous for a c1033 insG mutation. Quantitative PCR suggests the presence of a deletion on the other chromosome, which minimally encompasses exon 9. All of the FTCD gene changes were absent in 100 control individuals (200 alleles).

Made available in DSpace on 2014-06-11T19:29:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-07-14Bitstream added on 2014-06-13T18:38:53Z : No. of bitstreams: 1 contente_tc_me_ararfcf.pdf: 1404141 bytes, checksum: c1aea04ca84c3e65fb12bd24e6720f34 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / A doença de Chagas é uma infecção generalizada, de natureza endêmica e evolução essencialmente crônica causada por um protozoário, o Trypanosoma cruzi. Esta continua a representar sérios problemas médico-sanitários na América Latina, sendo considerada como uma das maiores doenças parasitárias pela Organização Mundial de Saúde. Estima-se que entre 16 a 18 milhões de pessoas estejam infectadas, e aproximadamente 120 milhões expostas ao risco de infecção. Do ponto de vista terapêutico, apenas dois fármacos estão disponíveis, o benznidazol e o nifurtimox, sendo apenas o primeiro utilizado no Brasil. A quimioterapia para doença de Chagas é muito deficiente, estes agentes produzem sérios efeitos adversos e apresentam-se ativos apenas na fase aguda da doença. Dentre as alternativas de obtenção de novos fármacos, os processos de modificação molecular são promissores, destacando-se a latenciação, transformação do fármaco em transporte inativo, que in vivo, mediante reação química e/ou enzimática, libera a porção ativa no local de ação ou próximo dele. Uma das formas latentes obtidas mediante este processo denomina-se pró-fármaco. Para o desenvolvimento de fármacos mais seletivos e com menor toxicidade, a descoberta de alvos específicos é fator preponderante. Assim ao se promover a ligação do hidroximetilnitrofural a um transportador bifosfonato (ácido alendrônico) empregando-se o método da latenciação pode-se obter pró-fármaco recíproco com ação sinérgica e seletiva às células do T.cruzi, promovendo ataque a dois sistemas enzimáticos distintos do parasito, inibindo a tripanotiona redutase e comprometendo o sistema de defesa redox do parasito e favorecendo o acúmulo do bifosfonato nos acidocalcissomas e inibindo seu metabolismo do pirofosfato. / Chaga's disease is a widespread infection, of endemic nature and chronicle evolution caused essentially by a protozoan, Trypanosoma cruzi. This continues to represent serious sanitarium problems in Latin America, being considered as one of the largest parasitic disease by the World Health Organization. About 16 to 18 million people are infected, and approximately 120 million exposed to the risk of infection. From therapeutic point of view, only two drugs are available, benznidazole and nifurtimox, but only the first is being used in Brazil. The chemotherapy available for Chaga's disease is very deficient, as these agents produce serious adverse effects and that drugs are not efficient in the chronic phase of the disease. Among the alternatives for developing new drugs, the molecular modification processes are promising, standing out the latentiation process, which comprehends the transformation of a drug in an inactive form that in vivo, through chemical or enzymatic reactions, release the drug either at or near the site of action. Prodrugs can be obtained by this process of latentiation. For the development of more selective drugs and with lower toxicity, the discovery of specific targets is a preponderant factor. This work proposes a mutual prodrug design, with synergic and selective action against T. cruzi using a nitrofurazone hydroxymethyl derivative and a bisphosphonate carrier (alendronic acid). This prodrug would be able to attack two distinct enzymatic systems of the parasite, inhibiting tripanotione reductase and committing its redox system of defense and promoting a specific accumulation of the bisphosphonate in acidocalcisomes, inhibiting the parasite pyrophosphate metabolism.