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The catalytic necessity of tyrosine residues in uridine diphospho- glucose pyrophosphorylase [E.C. 2.7.7.9] was investigated. Chemical modification of the pyrophosphorylase by N-acetylimidazole indicated that tyrosine residues were essential for activity. Approximately 23 of 112 tyrosines per molecule of 475,000 Daltons could be 0-acetylated. Solvent perturbation difference spectroscopy supported this number of exposed tyrosine side chains and in conjunction with chemical modification indicated that at least 11 to 12 tyrosyl residues per protein molecule are fully exposed. it her subst rate, uridine t riphosphate or uridine diphosphoglucose, afforded significant protection against inactivation by N-acetylimidazole. The significance of these tyrosine residues is discussed in terms of a quaternary subunit model for uridine diphosphoglucose pyrophosphorylase.

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Foodborne illnesses caused by Listeria monocytogenes have long been associated with ready-to-eat (RTE) meats contaminated after the primary thermal process has been applied. It is believed that brine solutions used to chill cooked RTE products may serve as a reservoir for L. monocytogenes becoming a potential point of post-processing contamination for RTE meats. Re-circulating ultraviolet light (UV) systems are being used to inactivate L. monocytogenes in chill brines; however very little has been reported on the dose response of healthy and stressed L. monocytogenes to UV in brine solutions. The objectives of this research were to determine 1) minimum dose of UV required to inactivate L. monocytogenes in distilled water, fresh brine, undiluted spent brine, and diluted spent brine, 2) if adaptation to food processing stresses affects the dose response, and 3) if the acquisition of antibiotic resistance mechanisms provides resistance to ultraviolet light 4) effect of stress adaptation on survival in brine solutions. After UV exposure, populations were reduced as follows from greatest to least: water > fresh brine > 5% spent brine > 35% spent brine > 55% spent brine > 100% spent brine (P ≤ 0.05). There were no population differences between acid stressed and antibiotic resistant or healthy and heat shocked (P > 0.05). However, acid-stressed and sulfanilamide-resistant were more resistant to UV light than healthy and heat shocked L. monocytogenes (P ≤ 0.05). Survival in brine solutions (no UV) followed the trend, from greatest to least (P ≤ 0.05): sulfanilamide-resistant > acid-stressed > healthy > heat-shocked. Population estimates decreased from initial inoculation to final sampling for each cell type suspended in spent brine (P ≤ 0.05), but only healthy and heat- shocked cells suspended in fresh brine were significantly reduced (P ≤ 0.05). Knowledge of UV dosing required to control L. monocytogenes in brines used during RTE meat processing, and a greater understanding of the interactions that may influence dose will aid manufacturers in establishing appropriate food safety interventions for these products. / Ph. D.

(thesis): Palmar-plantar erythrodysesthesia (PPE) frequently accompanies the therapy with a continuous 5-FU infusion or peroral capecitabine (5-FU prodrug). In the most severe cases this adverse effect leads to discontinuation of a needful therapy. Local 10 % uridine ointment is used to prevent and treat the said adverse event. Nevertheless, this method is not generally accepted as an effective one because it has never been proved in a randomized controlled clinical trial. Most probably, a direct effect of a cytostatic compound on the skin of hands and foots causes PPE. The toxicity of 5-FU is mediated primarily by its incorporation into RNA and by thymidylate synthase (TS) inhibition and subsequent DNA synthesis disruption. The importance of particular 5-FU toxicity mechanisms varies in different cell types. For choosing the best PPE local antidote it is necessary to find out which molecular mechanism applies in keratinocytes. We have chosen pyrimidine nucleosides as the most suitable compounds for the local PPE therapy because the uridine ointment is already being used in several oncology centers in the Central Europe. In order to find out the 5-FU toxicity mechanism, we further tested the effect of calciumfolinate (CF) which strengthens the TS inhibition by 5-FU. We studied also uracil and...

In chronic inflammatory diseases like asthma or rheumatoid arthritis, erroneous and exaggerated accumulation of leukocytes in a tissue inadvertently causes the body harm. Several efficient anti-inflammatory drugs exist, for example corticosteroids and cyclo-oxygenase inhibitors. However, these drugs have potent and diverse effects and often act by inhibiting events subsequent to initiation of the inflammatory response, leading to more or less severe side-effects, especially when used in high doses for long periods of time. For this reason, strategies aimed at early inhibition of recruitment and activation of leukocytes have been suggested as safer and more specific approaches to reduce inflammation. Leukocyte adhesion to activated endothelium is a prerequisite to the following activation and extravasation, and takes place in the initial phase of inflammation. By using a model that allows leukocytes to adhere to tumour necrosis factor (TNF)-activated endothelial cells, thus mimicking aspects of an inflammatory reaction, we found that uridine, 4-thiouridine and isomaltitol could all reduce adhesion. This suggested that they may have anti-inflammatory potential. We therefore tried the three substances in a Sephadex-induced lung inflammation model and found that uridine and 4-thiouridine have several anti-inflammatory effects, such as being able to reduce leukocyte accumulation, decrease TNF protein levels and partly inhibit the oedema induced by Sephadex. Isomaltitol turned out to have immunomodulating, rather than anti-inflammatory, effects, which could be of interest in diseases where inadequate inflammatory responses are a problem.

The thesis is divided in to five chapters. Chapter I: Synthesis of New thiolevomannosan derivatives In this chapter, a general and efficient method for the synthesis of conformationally locked thiosugars has been discussed. An unprecedented synthesis of a novel thioorthoester and its synthetic utility in glycosylation has been demonstrated. Chapter II: Studies on -Mannosidase Inhibitors The synthesis and evaluation of novel, conformationally locked glycomimic, thiolevomannosan and its analogs sulfoxide and sulfone starting from readily available D-mannose is discussed in this chapter. This is the first report of thiosugar derivatives with enhanced potency compared to kifunensine. Docking and biochemical studies have been discussed. Chapter III: Studies on Novel Cyclic Tetraselenides of Mannose In this chapter, the syntheses and structural properties of novel cyclic tetraselenides starting from mannose have been discussed. These tetraselenides are the first of their kind where all four selenium atoms are arranged in a cyclic manner as the backbone of mannose. X-ray structures have been reported for the tetraselenides. Chapter IV: Novel Chalcogenides of Uridine and Thymidine: Synthesis and Applications An efficient and simple method to synthesise disulfides and diselenides of thymidine and uridine derivatives has been demonstrated in this chapter. The utility of these disulfides in various ring opening reactions as well in Michael addition reactions has been demonstrated. Chapter V: Studies on New, Potent Urease Inhibitors In this chapter, a facile one-pot synthesis of thio and selenourea derivatives under mild conditions by the reaction of amines and commercially available Viehe’s iminium salt in the presence of benzyltriethylammonium tetrathiomolybdate as sulfur transfer reagent and tetraethylammonium tetraselenotungstate as selenium transfer reagent has been discussed. A few of the urea derivatives have shown potent inhibitor activity in the nanomolar range for jackbean urease.

Le virus de l'hépatite C est un problème de santé publique majeur, puisque 180 millions de personnes sont chroniquement infectées dans le monde, et sont susceptibles de présenter une cirrhose ou un cancer du foie. Un seul traitement a été approuvé, à base de Ribavirine et d'interféron alpha, mais il permet de traiter moins de 50 % des personnes infectées, et présente de nombreux effets secondaires. Devant ce constat, il parait urgent d'aboutir à une polythérapie plus adaptée. En dépit du succès des nucléosides en chimie antivirale, visant plusieurs enzymes clefs intervenant dans la réplication virale, peu d'entre eux ont été conçus pour viser l'ARN polymérase ARN dépendante nécessaire au VHC. Dans cette optique, de nouveaux dérivés carbocycliques de la Ribavirine, et des dérivés nucléosidiques du type 5-haloéthynyl- ou 5-(1,2-dihalo)vinyluracile, ont été synthétisés en utilisant deux méthodes : la réaction de Sonogashira et la cyclisation 1,3-dipolaire. Ce sont des outils puissants de la chimie organique qui permettent l'accès à de nouvelles structures nucléosidiques et la réalisation de modifications chimiques ultérieures. Les nouveaux composés ainsi préparés ont été testés pour leur activité antivirale.

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