The synthetic methodology of tri- and pentamethine carbocyanines and their interactions with biomolecules will be discussed in two chapters. The first chapter describes the preparation of halogenated carbocyanine dyes that display multiple charges; furthermore, these particular compounds were examined for their ability to bind G-quadruplex DNA with selectivity over duplex DNA and have potential for developing novel chemotherapeutic agents. The second section discusses the synthetic methods utilized to prepare trimethine cyanine fluorophores. This chapter will show how varying the N-indolenyl substituients’ hydrophobicity from ethyl to phenylpropyl influences the binding to Human Serum Albumin (HSA); additionally, alternating the terminal heterocyclic moieties of the cyanine dye has a direct quantitative effect on the biomolecular interaction. These identical compounds were recognized to be structurally analogous to agents that commonly interact with Protein Arginine Methyl Transferase (PRMT) and these compounds display low IC50 values toward inhibition of PRMT1 with unique NIR imaging properties.

Gas phase kinetics and thermochemistry of several halogenated species relevant to atmospheric, combustion and plasma chemistry were studied using experimental and ab initio theoretical techniques.

No description available.

Thesis (PhD (Chemistry and Polymer Science))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: The use of fluorine in medicinal chemistry has increased dramatically in the last 20 years. The addition of fluorine to a lead compound has various advantages such as the blocking of metabolic active sites, the increase of solubility and lipophilicity of a compound, acting as conformational probes for the active site of an enzyme, and influencing (in most cases increasing) the binding affinity of a compound to a target protein. Their use as mechanism based inhibitors is also well known. In this study we set out to synthesize hydroxyl- and fluorinated-amino acid analogues as potential inhibitors and probes towards the active site of various enzymes. The synthesis of the hydroxylamino acid analogues would precede the fluorinated analogues to serve as precursors with fuorination achieved via a fluoro-dehydroxylation reaction. These aims have successfully been achieved with the synthesis of the two enantiopure isomers of 3-fluoro-aspartic acid. The fluorinated aspartic acid analogues were subsequently used in a conformational analysis, with regards to substrate- and binding activity, which investigated the interaction of these compounds with aspartate decarboxylase (PanD). The synthesis of the 3- hydroxy-analogues of ornithine and diamino pimelic acid was also successfully achieved. These syntheses were done in a stereospecific manner to provide one enantiomer of the L-amino acid analogue. However, our efforts toward the synthesis of the other enantiomer of hydroxy analogues as well as our attempts at the conversion of the hydroxyl group to a fluorine were unsuccessful to date. Nevertheless, these results gave us a new direction towards the synthesis of the desired compounds and have led us to new strategies and ideas. Hopefully, the work done in this study will be part of the ground work towards new methodologies for the synthesis of desired halogenated amino acid analogues as small molecule inhibitors. / AFRIKAANSE OPSOMMING: The use of fluorine in medicinal chemistry has increased dramatically in the last 20 years. The addition of fluorine to a lead compound has various advantages such as the blocking of metabolic active sites, the increase of solubility and lipophilicity of a compound, acting as conformational probes for the active site of an enzyme, and influencing (in most cases increasing) the binding affinity of a compound to a target protein. Their use as mechanism based inhibitors is also well known. In this study we set out to synthesize hydroxyl- and fluorinated-amino acid analogues as potential inhibitors and probes towards the active site of various enzymes. The synthesis of the hydroxylamino acid analogues would precede the fluorinated analogues to serve as precursors with fuorination achieved via a fluoro-dehydroxylation reaction. These aims have successfully been achieved with the synthesis of the two enantiopure isomers of 3-fluoro-aspartic acid. The fluorinated aspartic acid analogues were subsequently used in a conformational analysis, with regards to substrate- and binding activity, which investigated the interaction of these compounds with aspartate decarboxylase (PanD). The synthesis of the 3- hydroxy-analogues of ornithine and diamino pimelic acid was also successfully achieved. These syntheses were done in a stereospecific manner to provide one enantiomer of the L-amino acid analogue. However, our efforts toward the synthesis of the other enantiomer of hydroxy analogues as well as our attempts at the conversion of the hydroxyl group to a fluorine were unsuccessful to date. Nevertheless, these results gave us a new direction towards the synthesis of the desired compounds and have led us to new strategies and ideas. Hopefully, the work done in this study will be part of the ground work towards new methodologies for the synthesis of desired halogenated amino acid analogues as small molecule inhibitors.

Current FDA approved anti-cytomegalovirus antivirals are ganciclovir, foscarnet, and cidofovir. These drugs target the viral polymerase to inhibit DNA synthesis. Halogenated benzimidazoles target a step later in viral replication during packaging and cleavage of the viral genome. The compounds 2-Bromo-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole (BDCRB) and 2,5,6-trichloro-1-(β-D-ribofuranosyl)benzimidazole (TCRB) are novel inhibitors of human cytomegalovirus (HCMV) and resistance to these compounds are found within the human cytomegalovirus viral terminase. Terminase is unique to the virus and in theory provides a good target for antiviral development. Beginning with a BDCRB resistant guinea pig cytomegalovirus observations found a single mutation located in the viral terminase gene UL89 and unique formation found in genomic ends. In guinea pigs, the virus continued to produce large amounts of monomer. This is in contrast to human cytomegalovirus treated with either BDCRB or TCRB. Both compounds produced very little monomer DNA but created a supergenomic species, called monomer-plus that migrates to the apparent size of 270-kb on a pulse field gel. A model was developed to explain formation of monomer plus and my project aims originated from the model. In the presence of BDCRB and TCRB, packaging is relaxed resulting in the normal cleavage site being skipped and cleavage occurring at the next available cleavage site creating a short-long-short genome. In guinea pigs, cleavage has been relaxed by premature cleavage of the terminal ends. Current antivirals do not block viral entry therefore, patients are infected with HCMV. Blocking entry of HCMV into cells would prevent HCMV infection. It has been shown that antibodies to epitopes within the gH/gL/UL128-131 complex can block viral entry into endothelial, epithelial, and other cell types while antibodies to gB block entry into fibroblasts. The majority of the current work on entry into epithelial cells has been performed in retinal pigment epithelium and epithelial cells derived from tumors. Viral entry into cell lines derived from mucosa cells was dependent on the complex gH/gL/UL128-131. Rabbit antibodies raised against UL130 and UL131 peptides neutralized epithelial entry with effects as potent as human seropositive sera. This suggests that the entry complex can be blocked by single epitopes.

O pinguim-de-Magalhães é a espécie de pinguim mais presente em águas jurisdicionais brasileiras e frequente na clínica de animais marinhos, vítimas de desorientação, da poluição, da pesca e outras ações antrópicas. Com o estudo objetivou-se estabelecer as concentrações anestésicas mínimas (CAM) do isofluorano e sevofluorano em pinguins-de-Magalhães e posteriormente avaliá-las sob a influência de diferentes frações inspiradas de O2 (FiO2). Foram utilizados 20 animais adultos, saudáveis e sem distinção quanto ao sexo. Durante a primeira etapa, focou-se no estabelecimento da CAM para ambos os anestésicos. Os animais foram inicialmente submetidos à contenção física e sequencialmente induzidos a anestesia com auxílio de máscara facial, seguindo-se a intubação traqueal, após adequada indução e posterior manutenção sob ventilação controlada, para ambos os halogenados. A determinação da CAM foi realizada de acordo com o delineamento \"up-and-down\". Desta forma, cada animal foi exposto uma única vez a uma concentração anestésica pré-determinada, por um período de 15 minutos, seguido da aplicação de um estímulo elétrico. De acordo com a resposta obtida, o próximo animal foi submetido a uma fração aumentada em 0,1 (resposta positiva) ou reduzida em 0,1 (resposta negativa). Para realização da segunda etapa, 12 animais foram distribuídos entre os grupos isofluorano e sevofluorano, com seis indivíduos em cada um. Todos os animais foram anestesiados e mantidos com 1 CAM de cada halogenado, obtido na primeira etapa, sendo ambos os agentes anestésicos diluídos em frações de 1,0, 0,6, 0,4 e 0,2 de O2. As aves foram mantidas sob anestesia por 80 minutos, sendo que a cada 20 minutos era alterada a fração de O2, por sorteio, seguindo-se um modelo de quadrado latino. Foram monitorados durante a anestesia FC, FR, PAS, PAM, PAD, temperatura, pH, HCO3-, PaO2 e PaCO2 e eletrólitos (Na+ e K+). Os valores de CAM para isofluorano e sevofluorano foram de 1,91 V% e 3,53 V% respectivamente. Diante dos resultados obtidos conclui-se que as FiO2 de 1,0, 0,6 e 0,4 mostram-se seguras para pinguins-de-Magalhães anestesiados com 1 CAM de isofluorano ou sevofluorano mantidos sob ventilação controlada. / The Magellanic penguin is the most present penguin species in Brazilian coast. It is frequent in the marine animal clinic, victims of disorientation, pollution, fishing and other anthropic actions. The objective of this study was to establish the minimum anesthetic concentrations (MAC) of isofluorane and sevoflurane in Magellanic penguins and later evaluate them under the influence of different inspired fractions of O2 (FiO2). Twenty adult animals, healthy and without distinction as to sex, were used. During the first stage, we focused on the establishment of MAC for both anesthetics. The animals were initially submitted to physical restraint and sequentially induced anesthesia with the aid of facial mask, followed by tracheal intubation, after adequate induction and subsequent maintenance under controlled ventilation, for both halogenates. MAC determination was performed according to the up-and-down design. In this way, each animal was exposed once to a predetermined anesthetic concentration, for a period of 15 minutes, followed by the application of an electric stimulus. According to the answer obtained, the next animal was submitted increased by 0.1 fraction (positive response) or reduced by 0.1 (negative response). To perform the second step, 12 animals were divided between the isofluorane and sevofluoran groups, with 6 individuals in each. All animals were anesthetized and maintained with 1 MAC of each halogenated, obtained in the first step, both anesthetic agents being diluted in fractions of 1.0, 0.6, 0.4 and 0.2 of O2. The penguins were kept under anesthesia for 80 minutes, and every 20 minutes the O2 fraction was changed, by lot, followed by a Latin square model. They were monitored during anesthesia FC, FR, PAS, MAP, PAD, temperature, pH, HCO3-, PaO2 and PaCO2 and electrolytes (Na+ and K+). The MAC values for isofluorane and sevoflurane were 1.91 V% and 3.53 V% respectively. In view of these results, FiO2 of 1.0, 0.6 and 0.4 were shown to be safe for Magellanic penguins anesthetized with 1 MAC of isofluorane or sevofluorane maintained under controlled ventilation.

A presença de substâncias húmicas em águas destinadas ao abastecimento tem ocasionado diversos problemas, decorrentes da formação de subprodutos orgânicos halogenados, principalmente quando se emprega a pré-oxidação com cloro. Os compostos orgânicos halogenados, reconhecidamente carcinogênicos e que podem ser encontrados nas águas tratadas e distribuída à população, são: trialometanos, ácidos haloacéticos, haloaldeidos, halocetonas, halofenóis e halopicrinas. Nas estações de tratamento de água para abastecimento (ETAs), a utilização da etapa de pré-oxidação da água bruta com cloro contribui para a formação desses subprodutos. A presente pesquisa teve como objetivo avaliar o potencial de formação de vinte e dois subprodutos com a utilização dos seguintes pré-oxidantes: cloro, dióxido de cloro, permanganato de potássio, peróxido de hidrogênio, ozônio e peroxônio. O potencial de formação de subprodutos foi simulado em uma água preparada com adição de substâncias húmicas extraídas de solo turfoso, por meio do uso da pré-oxidação, coagulação, filtração e pós-cloração. Os subprodutos foram quantificados por cromatografia gasosa com detetor de captura de elétrons. Os resultados obtidos mostraram que o uso de pré-oxidantes alternativos, tais como: permanganato de potássio; dióxido de cloro; peróxido de hidrogênio; ozônio e peroxônio, associados à coagulação, filtração e pós-cloração formam quantidades mínimas de subprodutos. / The presence of humic substances in water destined for supply has brought many problems, resulting from the formation of halogenated organic byproducts, especially when preoxidation with chlorine is used. Halogenated organic compounds, which are admittedly carcinogenic and can be found in water treated and distributed for the population, are: trihalometano, haloacetic acid, haloaldehyde, haloacetone, halophenol, and halopicrin. In water treatment plants (WTPs), the use of preoxidation with chlorine of the raw water contributes for forming such byproducts. This research aims at evaluating the potential for the formation of twenty two byproducts using the following preoxidants: chlorine, chlorine dioxide, potassium permanganate, hydrogen peroxide, ozone, and peroxone. The potential of byproducts formation was simulated in water prepared with addition of humic substances extracted from peat soil by preoxidation, coagulation, filtration and post-chlorination. Byproducts were quantified by gas chromatography with electron capture detector. The results obtained showed that the use of alternative preoxidants such as: chlorine, chlorine dioxide, potassium permanganate, hydrogen peroxide, ozone, and peroxone, associated with coagulation, filtration, and post-chlorination form a minimum of byproducts.

Source: Masters Abstracts International, Volume: 47-06, page: 3476. Adviser: Arnold J. Schecter. Includes bibliographical references.

A systematic methodology for quantitative structure-activity relationship (QSAR) development in environmental toxicology is provided. The methodology is summarized in a strategy with six sequential steps. The strategy rests on two cornerstones, namely (1) the use of statistical design to select a series of representative compounds (the so-called training set) on which to base a QSAR, and (2) the multivariate modelling of the relationship between physicochemical and biological properties of the training set compounds. The first step of the strategy is the division of chemicals into classes of structurally similar compounds. Briefly, steps 2 to 6 are: (2) physico-chemical and structural characterization of the compounds in a class, (3) selection of a training set of representative compounds, (4) biological testing of the selected training set, (5) QSAR model development, and (6) experimental validation of the QSAR and predictions for non-tested compounds. The thesis summarizes the results obtained from the application of the strategy to the class of halogenated aliphatic compounds. Biological measurements were made in four biological test systems, reflecting acute toxicity, mutagenicity, relative cytotoxicity and genotoxicity. QSARs were developed relating each biological endpoint to the structural descriptors of the compounds. Multivariate PLS modelling was used in the data analysis. The developed QSARs were used for predicting the biological activity pattern of the non-tested compounds in the class. These predictions may be used as a starting point for a priority ranking for further biological testing of these compounds. The strategy has not been developed solely for establishing QSARs for the halogenated aliphatics class. On the contrary, this work is intended to demonstrate a generally applicable QSAR methodology. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1991</p> / digitalisering@umu

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv. / Härtill 4 uppsatser.