La formation du continent sud américain résulte d'une histoire complexe étalée sur plus de 3.5 Ga. Les processus qui ont façonné le continent ont impliqué l'intégralité de la lithosphère. La structure du manteau supérieur a été étudiée à l'échelle du continent en réalisant un modèle tomographique en ondes de surface, tandis qu'une étude du déphasage des ondes de cisaillement a permis d'appréhender la structure du manteau supérieur sous le sud-est du Brésil.<br /> La tomographie sismique anisotrope en ondes de surface donne une image de la structure en vitesse du manteau supérieur sous le continent et les océans environnants. Une bonne corrélation existe entre les grandes structures géologiques et les hétérogénéités de vitesse. L'anisotropie des ondes de Rayleigh suggère une absence de déformation à grande échelle au-delà de 200 km de profondeur, ce qui contraint verticalement la source de l'anisotropie mise en évidence au sud-est du Brésil. L'étude du déphasage des ondes de cisaillement y a révélé une orientation dominante du plan de polarisation de l'onde quasi-S rapide, parallèle aux chaînes péricratoniques. Un déphasage entre les ondes S rapide et lente supérieur à 2s a été mesuré à l'aplomb des décrochements majeurs. Une telle amplitude suggère que : 1) les décrochements traversent la lithosphère, 2) la lithosphère est caractérisée par une très forte anisotropie intrinsèque, 3) l'asthénosphère contribue au déphasage, par la présence de deux couches ou d'une fabrique tectonique cohérente entre lithosphère et asthénosphère, impliquant une absence de découplage depuis le Néoprotérozoïque.<br /> Une modélisation numérique tridimensionnelle de la déformation lithosphérique a permis d'étudier le couplage mécanique entre la croûte et le manteau supérieur, ainsi que la localisation de la déformation en termes de développement de zones de cisaillement.

<p>Denna uppsats tar sikte på att utreda om det existerar fri rörlighet inom EU även för aktiebolag, d.v.s. om aktiebolag fritt kan flytta sitt säte mellan olika medlemsstater utan att problem uppstår. Dessutom undersöks vad som gjorts inom EU för att harmonisera reglerna på det bolagsrättsliga området. Slutligen och som huvudsyfte för uppsatsen görs en ansats att försöka ta reda på varför den övernationella bolagsformen europabolag inte blivit någon succé bland svenska företagare sedan den infördes i oktober 2004.</p><p>Beträffande den första frågan konstateras att aktiebolag inte har samma fria rörlighet som fysiska personer, trots att EGF föreskriver detta. Anledningen är att medlemsländerna tillämpar olika lagvalsprinciper som i många fall gör det omöjligt för bolag att byta nationalitet utan att först likvideras och sedan omregistreras. Detta har även konstaterats i ett antal rättsfall från EG-domstolen där domstolen ansett att rättsläget inte varit förenligt med EGF och att åtgärder bör vidtas.</p><p>Harmoniseringsarbetet på det bolagsrättsliga området inom EU har pågått sedan 1950-talet och har bl.a. bestått i att ta fram ett antal bolagsdirektiv för att uppnå en minimistandard i samtliga medlemsstaters lagstiftning. Det fjortonde och senaste i raden av dessa direktiv ämnar lösa den problematik som i dagsläget finns beträffande bolagsflytt. Direktivet har dock inte antagits ännu och ingen vet heller när eller om detta sker.</p><p>Utöver bolagsdirektiv finns tre olika övernationella bolagsformer – europeiska ekonomiska intressegrupperingar, europakooperativ och europabolag – vars syfte är att underlätta företagens samarbete över gränserna. Just europabolaget är något som kommissionen är mycket stolta över trots detta har inte många europabolag registrerats. I Sverige finns i maj 2007 endast fem europabolag registrerade och anledningen till detta tycks vara flera men ett svåröverskådligt regelverk och avsaknaden av en övernationell skattelösning verkar vara de största, åtminstone om man tolkar de svar som ett antal svenska företag lämnade på en konsultation från kommissionen våren 2006.</p><p>Mina egna åsikter om europabolag överensstämmer till stor del med de åsikter som finns hos svenska företag och jag skulle gärna se att regleringen om europabolag var mer enhetlig och inte styrs så mycket av nationell rätt, vilket är fallet i dagsläget. Jag är dessutom tämligen övertygad om att mängden europabolag kommer att öka i takt med att SE-förordningen justeras något och fler företag inser europabolagets fördelar.</p> / <p>This essay sets out to investigate if companies are entitled to free movement within the EU and if they without problem can move their residence from country to country. The essay also contains a report on what is done within the EU to harmonize company law. Finally, a study is made to investigate why the European company hasn’t been that successful among companies in Sweden.</p><p>Concerning the first question the answer is that companies in practice aren’t entitled to free movmenet even though it’s prescribed in the EC legislation. The reason to this is that the member states apply different principles that make it impossible for companies to move to another state without being liquidated in the first state and re-established in the second state. The EC court of justice has in several rulings stated that this problem has to be taken care of since it’s inconsistent with the EC legislation.</p><p>The work with harmonization of the company law within the EU has been going on for about fifty years and has consisted of different directives to reach a minimum standard in all members states. The fourteenth and last of these directives will make it easier for companies to move but no one knows when this directive will be adopted by the EC council.</p><p>Besides the directives there also exist three different types of companies that are common within the whole union. These companies are the European Economic Interest Grouping, the European Cooperative Society and the European company. The European company hasn’t been very successful and one reason for that is that the legislation is difficult to understand since it’s different in every member state, at least according to a couple of Swedish companies that participated in a consultation made by the European commission in spring 2006.</p><p>My own opinions on the European company are mostly the same as the Swedish companies and I would like to see an even more uniform legislation. I also think that we in a couple of years will see a lot more European companies as time goes by and the cracks in the legislation has been fixed.</p>

Denna uppsats tar sikte på att utreda om det existerar fri rörlighet inom EU även för aktiebolag, d.v.s. om aktiebolag fritt kan flytta sitt säte mellan olika medlemsstater utan att problem uppstår. Dessutom undersöks vad som gjorts inom EU för att harmonisera reglerna på det bolagsrättsliga området. Slutligen och som huvudsyfte för uppsatsen görs en ansats att försöka ta reda på varför den övernationella bolagsformen europabolag inte blivit någon succé bland svenska företagare sedan den infördes i oktober 2004. Beträffande den första frågan konstateras att aktiebolag inte har samma fria rörlighet som fysiska personer, trots att EGF föreskriver detta. Anledningen är att medlemsländerna tillämpar olika lagvalsprinciper som i många fall gör det omöjligt för bolag att byta nationalitet utan att först likvideras och sedan omregistreras. Detta har även konstaterats i ett antal rättsfall från EG-domstolen där domstolen ansett att rättsläget inte varit förenligt med EGF och att åtgärder bör vidtas. Harmoniseringsarbetet på det bolagsrättsliga området inom EU har pågått sedan 1950-talet och har bl.a. bestått i att ta fram ett antal bolagsdirektiv för att uppnå en minimistandard i samtliga medlemsstaters lagstiftning. Det fjortonde och senaste i raden av dessa direktiv ämnar lösa den problematik som i dagsläget finns beträffande bolagsflytt. Direktivet har dock inte antagits ännu och ingen vet heller när eller om detta sker. Utöver bolagsdirektiv finns tre olika övernationella bolagsformer – europeiska ekonomiska intressegrupperingar, europakooperativ och europabolag – vars syfte är att underlätta företagens samarbete över gränserna. Just europabolaget är något som kommissionen är mycket stolta över trots detta har inte många europabolag registrerats. I Sverige finns i maj 2007 endast fem europabolag registrerade och anledningen till detta tycks vara flera men ett svåröverskådligt regelverk och avsaknaden av en övernationell skattelösning verkar vara de största, åtminstone om man tolkar de svar som ett antal svenska företag lämnade på en konsultation från kommissionen våren 2006. Mina egna åsikter om europabolag överensstämmer till stor del med de åsikter som finns hos svenska företag och jag skulle gärna se att regleringen om europabolag var mer enhetlig och inte styrs så mycket av nationell rätt, vilket är fallet i dagsläget. Jag är dessutom tämligen övertygad om att mängden europabolag kommer att öka i takt med att SE-förordningen justeras något och fler företag inser europabolagets fördelar. / This essay sets out to investigate if companies are entitled to free movement within the EU and if they without problem can move their residence from country to country. The essay also contains a report on what is done within the EU to harmonize company law. Finally, a study is made to investigate why the European company hasn’t been that successful among companies in Sweden. Concerning the first question the answer is that companies in practice aren’t entitled to free movmenet even though it’s prescribed in the EC legislation. The reason to this is that the member states apply different principles that make it impossible for companies to move to another state without being liquidated in the first state and re-established in the second state. The EC court of justice has in several rulings stated that this problem has to be taken care of since it’s inconsistent with the EC legislation. The work with harmonization of the company law within the EU has been going on for about fifty years and has consisted of different directives to reach a minimum standard in all members states. The fourteenth and last of these directives will make it easier for companies to move but no one knows when this directive will be adopted by the EC council. Besides the directives there also exist three different types of companies that are common within the whole union. These companies are the European Economic Interest Grouping, the European Cooperative Society and the European company. The European company hasn’t been very successful and one reason for that is that the legislation is difficult to understand since it’s different in every member state, at least according to a couple of Swedish companies that participated in a consultation made by the European commission in spring 2006. My own opinions on the European company are mostly the same as the Swedish companies and I would like to see an even more uniform legislation. I also think that we in a couple of years will see a lot more European companies as time goes by and the cracks in the legislation has been fixed.

Ce travail consiste en une étude comparative de deux romans des Amériques, Le premier jardin, d'Anne Hébert, et Los niños se despiden, de Pablo Armando Fernández, sur la problématique de l'appropriation de la mémoire collective chez les protagonistes. L'objectif du travail est d'analyser les différentes stratégies narratives employées par les auteurs pour mettre en scène l'imaginaire collectif et sa fonction dans l'oeuvre québécoise et dans l'oeuvre cubaine. Le premier chapitre aborde la mémoire sous les angles historique, sociologique, et littéraire. D'une part, l'étude porte sur les formes générales, d'appropriation de la mémoire collective chez les nations québécoise et cubaine, ce qui constitue la mémoire d'un peuple. D'autre part, le travail porte sur l'intertextualité et son traitement, ce qui relève de la mémoire du texte. Ces deux formes de mémoire mettent en lumière l'importance du temps-zéro chez Fernández et de l'inscription dans la tradition européenne chez Hébert. Comme la mémoire collective s'articule selon des composantes spatiales et temporelles, le deuxième chapitre est entièrement consacré à l'étude de ces paramètres. Le recours à la notion de chronotope sert à établir les liens pertinents entre temps et espace, entre mémoire personnelle et mémoire collective. Les systèmes chronotopiques diffèrent pour chaque oeuvre, mais indiquent chaque fois une dynamique particulière des forces mnémoniques en présence et contribuent à dégager les manifestations et les fonctions particulières de la mémoire. L'étude de l'ailleurs au troisième chapitre complète le travail amorcé sur les relations entre spatialité et temporalité. L'exil hébertien et l'utopie fernandienne constituent deux modalités de l'ailleurs. Bien que ces hors-temps et hors-lieux se déploient différemment dans les deux romans, ils témoignent chaque fois de l'importance que les protagonistes accordent à la mémoire de leur collectivité. L'étude de l'intertextualité, des formes d'appropriation de l'imaginaire collectif, de la spatio-temporalité et de l'ailleurs confirment une constante qui se dégage de l'étude de ce corpus multiculturel : un même désir des protagonistes de s'approprier l'imaginaire de leur collectivité, mais dans un dessein différent. Chez Hébert, le désir d'inscription dans une longue généalogie justifie le recours à une histoire peuplée de femmes glorieuses; chez Fernández, construire des assises solides à une nouvelle société plus équitable nécessite une appropriation massive d'éléments constitutifs d'une mémoire collective. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Américanité, Anne Hébert, Chronotope, Cuba, Exil, Intertextualité, Mémoire, Mémoire collective, Pablo Armando Fernandez, Québec, Utopie.

Din&ccedil / er-1 (1968) and South Din&ccedil / er-1 (1980) exploration wells are located at Sirnak Province of Southeast (SE) Anatolia. South Fields of SE Anatolia have received a significant attention after the completion of subjected wells and numerous studies have been implemented regarding this area. Many theories about the geological generation of these fields were put forward by people who studied this region.Both wells have penetrated the Arabian Plate autochthonous units. The Cudi Group, of this sequence, mainly consists of dolomites and anhydrites. The samples from the cores of this referred interval and the thin sections of these cores were examined in details by X-Ray Diffraction (XRD) Analyses and petrographic microscope. Thin sections taken from the core samples of the Cudi Group&rsquo / s Bak&uuml / k, &Ccedil / amurlu and Telhasan formations (from older to younger) stand out in the diagenetic manner. The analyses of these thin sections showed that dolomitization is the main diagenetic process along with some textural changes such as the increase in the deformation of algal structures, formation of stylolites and secondary porosity. Clay minerals, mainly illites, shows detritic behaviors rather than characters representing a diagenetic origin. Obtained results from this study showed that the dolomitization as diagenetic process plays an important role in oil and gas formations within Cudi Group. Dolomite stoichiometry studies indicated that Cudi Group formations have modern dolomites since they show poor ordering reflections. They are also younger formations which are subjected to longer periods of diagenetic effects in comparison with Uludere Formation&rsquo / s dolomites.

The fundamental attribute of neurons is their cellular electrical excitability, which is based on the expression of a plethora of ligand- and voltage-gated membrane channels that give rise to prominent membrane currents and membrane potential variations that represent the biophysical substrate underlying the transfer and integration of information at the cellular level. Dendrites have both an electrical and a biochemical character, which are closely linked. In contrast, glial cells are non-electrically excitable but nevertheless display a form of excitability that is based on variations of the Ca2+ concentration in the cytosol rather than electrical changes in the membrane. Cytoplasmic Ca2+ serves as an intracellular signal that is responsible for controlling a multitude of cellular processes. The key to this pleiotropic role is the complex spatiotemporal organization of the [Ca2+]i rise evoked by extracellular agonists, which allows selected effectors to be recruited and specific actions to be initiated. Ca2+ handling in the cell is maintained by operation of multiple mechanisms of Ca2+ influx, internal release, diffusion, buffering and extrusion. Ca2+ tends to be a rather parochial operator with a small radius of action from its point of entry at the cytoplasm resulting in the concept of microdomains. Dendritic Ca2+ signaling have been shown to be highly compartmentalized and astrocytic processes have been reported to be constituted by hundreds of microdomains that represent the elementary units of the astrocyte Ca2+ signal, from where it can eventually propagate to other regions of the cell. The astrocyte Ca2+ elevation may thus act as intra and intercellular signal that can propagate within and between astrocytes, signaling to different regions of the cell and to different cells. The spatio-temporal features of neuron-to-astrocyte communication, results from diverse neurotransmitters and signaling pathways that converge and cooperate to shape the Ca2+ signal in astrocytes. Alterations in Ca2+ homeostasis have been shown to be associated with major pathological conditions of the brain such as epilepsy, ischemia and neurodegenerative diseases. Although there are evidences of Ca2+ rise in hippocampal neurons in in vitro models of epilepsy (Pal et al., 1999; Limbrick et al., 2001), there is no information on the Ca2+ regulatory mechanisms operating in discrete compartments of the epileptic neuron following Ca2+ influx through voltage gated calcium channels (VGCCs). In the first part of the work, the spatial and temporal profiles of depolarization induced changes in the intracellular Ca2+ concentration in the dendrites of cultured autaptic hippocampal pyramidal neurons rendered epileptic experimentally have been addressed. Our in vitro epilepsy model consisted of hippocampal neurons in autaptic culture that were grown in the presence of kynurenate and high Mg2+, and subsequently washing the preparation free of the blockers. To understand the differences in Ca2+ handling mechanisms in different compartments of a control neuron and the kynurenate treated neuron, a combination of whole-cell patch-clamp recording and fast Ca2+ imaging methods using the Ca2+ indicator Oregon Green 488 BAPTA-1 was applied. All our analysis was focused on localized regions in the dendrite that showed pronounced Ca2+ transients upon activation of high voltage activated (HVA) Ca2+ channels. The spatial extent of Ca2+ signals suggested the presence of distinct dendritic compartments that respond to the depolarizing stimulus. Further, the local Ca2+ transients were observed even in the presence of NMDA and AMPA receptor antagonists, suggesting that the opening of VGCCs primarily triggered the local Ca2+ changes. The prominent changes in intracellular Ca2+ observed in these dendritic regions appear to be sites where Ca2+ evoked dendritic exocytosis (CEDE) takes place. Since cellular Ca2+ buffers determine the amplitude and diffusional spread of neuronal Ca2+ signals, quantitative estimates of the time-dependent spread of intracellular Ca2+ in the dendritic compartments in the control and treated neurons were done using image processing techniques. Physiological changes in Ca2+ channel functioning were also induced by kynurenate treatment and one such noticeable difference was the observation of Ca2+ dependent inactivation in the treated neurons. We provide evidences of localized Ca2+ changes in the dendrites of hippocampal neurons that are rendered epileptic by kynurenate treatment, suggesting that these sites are more vulnerable (Padmashri et al., 2006). This might contribute to the epileptiform activity by local changes in cellular and membrane properties in complex ways that remains to be clearly understood. Status Epilepticus (SE), stroke and traumatic brain injury are all associated with large increases in extracellular glutamate concentrations. The concentration of glutamate in the extracellular fluid is around 3-4 µM and astrocytes are primarily responsible for the uptake of glutamate at the synapses. The extracellular levels of glutamate has been shown to increase dramatically (16 fold) in human SE suggesting an important role of glutamate in the mechanism of seizure activity and seizure related brain damage (Carlson et al., 1992). Several other studies have also shown a persistent increase in extracellular glutamate concentration to potentially neurotoxic concentrations in the epileptogenic hippocampus (During and Spencer, 1993; Sherwin, 1999; Cavus et al., 2005). We addressed the problem related to the effects of prolonged glutamate pretreatment on Ca2+ signaling in an individual astrocyte and its adjoining astrocyte (astrocyte pair), rather than on a syncytium of astrocytes in culture. Individual astrocytes may have functional domains that respond to an agonist through distinct receptor signaling systems. These are difficult to observe in studies that are done on glial syncytium because of spatial limits of image capture. This was examined with simultaneous somatic patch-pipette recording of a single astrocyte to evoke voltage-gated calcium currents, and Ca2+ imaging using the Ca2+ indicator Oregon Green 488 BAPTA-1 to identify the Ca2+ microdomains. Transient Ca2+ changes locked to the depolarization were observed in certain compartments in the astrocyte processes of the depolarized astrocyte and the responses were more pronounced in the adjoining astrocyte of the astrocyte pair. The Ca2+ transient amplitudes were enhanced on pretreatment of cells with glutamate (500 µM for 20 minutes). Estimation of local Ca2+ diffusion coefficients in the astrocytic processes indicated higher values in the adjoining astrocyte of the glutamate pretreated group. In order to understand the underlying mechanisms, we performed the experiments in the presence of different blockers for the metabotropic glutamate receptor, inositol 1,4,5 triphosphate (IP3) receptors and gap junctions. Ca2+ transients recorded on pretreatment of cells with glutamate showed attenuated responses in the presence of the metabotropic glutamate receptor (mGluR) antagonist α-Methyl(4-Carboxy-Phenyl) Glycine (MCPG). Intracellular heparin (an antagonist of IP3 receptor) introduced in the depolarized astrocyte did not affect the Ca2+ transients in the heparin loaded astrocyte, but attenuated the [Ca2+]i responses in the adjoining astrocyte suggesting that IP3 may be the transfer signal. The uncoupling agent 1-Octanol attenuated the [Ca2+]i responses in the adjoining cell of the astrocyte pair in both the control and glutamate pretreated astrocytes indicating the role of gap junctional communication. The findings of [Ca2+]i responses within discrete regions of astrocytic processes suggest that astrocytes may be comprised of microdomains whose properties are altered by glutamate pretreatment. The data also indicates that glutamate induced alterations in Ca2+ signaling in the astrocyte pair may be mediated through phospholipase C (PLC), IP3, internal Ca2+ stores, VGCCs and gap junction channels (Padmashri and Sikdar, 2006). Neuronal (EAAC-1) and glial (GLT-1 and GLAST) glutamate transporters facilitate glutamate reuptake after synaptic release. Transgenic mice with GLT-1 knockout display spontaneous epileptic activity (Tanaka et al., 1997) and loss of glial glutamate transporters using chronic antisense nucleotide administration was reported to result in elevated extracellular glutamate levels and neurodegeneration characteristic of excitotoxity (Rothstein et al., 1996). Dysfunction of glutamate transporters and the resulting increase of glutamate have been speculated to play an important role in infantile epilepsies (Demarque et al., 2004). We examined the effects of pretreatment with glutamate in the presence of the glutamate transport inhibitor threo-β-hydroxy-aspartate (TBHA) and in Na+-free extracellular medium to understand whether this resulted in any alteration in the astrocytic intracellular Ca2+ dynamics following activation of voltage gated calcium channels. The Ca2+ responses were found to be attenuated in both the cases indicating that the elevated levels of extracellular glutamate due to blockade of glutamate transporters may influence the responses mediated by the astrocytic glutamate receptors. Our studies indicate that the heightened extracellular glutamate concentration is not gliotoxic in our experimental system, although it may have a profound effect on altering the activity of surrounding neurons which was not addressed in the present work. Several studies have indicated that neurons control the level of gap junction mediated communication between astrocytes (Giaume and McCarthy, 1996; Rouach et al, 2000). All our earlier studies were done on process bearing astrocytes that were co-cultured with neurons. We have addressed the question as to whether the spatio-temporal changes in [Ca2+]i in astrocyte pairs differ if the astrocytes are cultured in the absence of neurons. The results indicate that there is indeed a significant reduction in the responses that are evoked in response to the depolarization pulse in the adjoining cell of the astrocyte pair. These experiments demonstrate that neurons in the cocultures may selectively enhance the Ca2+ responses possibly by increasing the coupling between the two cells.

Availability of amorphous semiconductors in the form of high quality multilayers provide potential applications in the field of micro- and optoelectronics. Although the misfit problems in amorphous multilayers (AML) are considerably reduced compared to crystalline superlattices, there are still some physical processes (e.g. quantum confinement, diffusion) that are not well understood. Recently chalcogenide glass multilayers were prepared with high quality nanomodulation, which demonstrated their potential for tailoring the optical properties. Moreover studies on amorphous nanolayered chalcogenide structures (ANC) are still at the infant stage. These ANCs are similar to the crystalline superlattices, yet distinct from ideal crystalline superlattices produced by molecular beam epitaxy. The ANCs can be considered as well-correlated layers with good periodicity and smooth interface. They are attractive because of the prominent photoinduced effects, similar to those exhibited by uniform thin films. For example, photoinduced diffusion in short period multilayer systems is important because of its potential applications in holographic recording and fabrication of phase gratings. In spite of its practical usefulness, the mechanism of photoinduced interdiffusion is not properly understood. Since most structural changes are related to atomic diffusion, understanding of the structural transformation must be based on the diffusion process. Moreover, in AML, the process of interdiffusion is not well understood. The main aim of this thesis is to study the photoinduced interdiffusion in Se/As2S3 and Bi/As2S3 nanolayered films. In literature, there are reports about the photoinduced interdiffusion in Se/As2S3 and Bi/As2S3 nanolayered films, but the mechanisms of photoinduced interdiffusion of these elements are not properly understood. Raman scattering and infrared spectroscopy techniques were used to study the photoinduced interdiffusion in Se/As2S3 and Bi/As2S3 nanolayered films by Kikineshi et al, but the results were not satisfactory. The characteristic spectra of components in the multilayer and those of the mixed layer were rather similar. In the present thesis, photoinduced interdiffusion in Se/As2S3 and Bi/As2S3 nanolayered samples are studied by optical absorption spectroscopy, X-ray photoelectron spectroscopy (XPS) and Photoluminescence (PL). The detailed information about the distribution of electronic states in the absorption edge, localized states and the new bonds formed between the components due to photoinduced interdiffusion elucidated from the above studies will give more insight into the mechanism and kinetics of photoinduced interdiffusion. The thesis consists of six chapters. References are given at the end of each chapter. Various general and unique physical properties of amorphous chalcogenides are discussed in Chapter 1. This chapter summarizes the fundamental aspects of amorphous state, such as the structure and its models, electronic band structure, defects as well as the physical properties like d.c conductivity, a.c conductivity, optical absorption, photoconductivity and PL. A more detailed account of the various photoinduced effects are also discussed. Apart from this, similar photoinduced effects observed in other systems like a-Si:H, oxide glasses, Polymers etc are described in brief. Finally, the scope of present investigations is furnished. Chapter 2 has been devoted to photoinduced interdiffusion and related changes in optical properties of nanolayered Se/As2S3 films. It begins with a brief introduction followed by a survey of the earlier work done on these multilayered films. The theory of optical absorption and experimental procedures are discussed. Photoinduced interdiffusion was observed with above band gap light in nanolayered Se/As2S3 films. It is discussed in terms of the optical parameters such as bandgap, Urbach edge (Ee) and Tauc’s parameter (B1/2). From the analysis of the optical absorption spectra, it was concluded that the optical bandgap, Ee and B1/2 change with photoinduced interdiffusion. These changes in properties are ascribed to the solid solution formation due to the intermixing of adjacent layers. The photoinduced intermixing of the adjacent layers are obviously related to the photoinduced viscous flow and it depends on the number of excited chalcogen bridge atoms, which determine the local deformations due to the bond switching and displacements. Experimental data of B1/2 and Ee for as prepared samples do not show a clear correlation implied by the Mott-Davis model. It is also observed that the optical parameters can be changed with a change in the Se sublayer thickness. Variations of these optical parameters as a function of modulation period and photoinduced interdiffusion were discussed in terms of the quantum confinement effect and changes in the valence and conduction bands. Chapter 3 deals with the PL studies on as prepared and irradiated samples of Se/As2S3 nanolayered films. The theory of PL, experimental procedures and data analysis are discussed in detail. PL studies were carried out on as prepared and irradiated nanolayered samples of Se/As2S3 films. None of the samples showed PL at 77 K, which clearly indicate that there exists a competitive non-radiative mechanism. We observed a broad PL in the range of 0.8–1.2 eV for as prepared and irradiated samples at 4.2 K. The observed stoke shift in PL is discussed in terms of the strong electron-phonon coupling at the recombination centers. We found that the PL intensity can be increased by several orders of magnitude by irradiating the samples with appropriate wavelengths in the range of the absorption edge. The broadening of luminescence bands takes place either with a decrease in Se layer thickness or with irradiation. The former is due to the change in interface roughness while the latter is due to photoinduced interdiffusion. Deconvolution showed that the PL spectrum consists of five transitions. The deconvoluted peak PL intensity, PL quantum efficiency and full width at half maximum are varying according to the function of sublayer thickness and interdiffusion. All these results indicate the high impact of interdiffusion on the luminescence intensity in the given AML is due to changes of defect states, which in turn are not directly connected to the band structure, i.e., confinement effects are not essential for this type of luminescence. The whole picture is complex due to more complicated carrier relaxation and recombination process, possibly with several interconnected effects, which are not properly understood, but the possibility for tuning the optical parameters of the Se/As2S3 nanolayered films, including the low temperature luminescence, is established. Chapter 4 is on kinetics and chemical analysis of photoinduced interdiffusion in nanolayered Se/As2S3 films. The basic formalism of X-ray photoelectron spectroscopy and in situ optical absorption spectroscopy together with a brief description of the theory and data analysis adopted in the present studies are given. We have studied the kinetics of photoinduced interdiffusion in nanolayered Se/As2S3 film by in situ optical absorption measurements. All previous measurements were performed ex situ, i.e., a film exposed under light irradiation during the measurement was never studied. In situ changes in the transmission spectra were measured, but at a fixed wavelength. Since the measurements were done on a single wavelength, the kinetics of the variation of optical bandgap and Tauc parameter were missing. In short, information has been missing about the metastable changes in the multilayer structure during photoinduced interdiffusion. In situ changes in transmission spectra were recorded over the wavelength range λ=400-1000 nm, and also at fixed wavelengths to understand the changes in absorption coefficient, optical bandgap and Tauc parameter during photoinduced interdiffusion. The in situ optical absorption measurements reveal that the photo darkening in amorphous nanolayered Se/As2S3 film is followed by photoinduced interdiffusion. An increase in disorder during photodarkening and its subsequent decrease during photoinduced interdiffusion was also observed. The observation of photodarkening of Se at room temperature when confined between As2S3 layers suggests that the glass transition temperature of Se shifts to higher temperature. The analysis shows that the atoms, which take part in photodarkening, play a vital role in photoinduced interdiffusion. We used XPS to analyze the new bonds formed between the components due to photoinduced interdiffusion. The XPS results showed that there is a considerable decrease in the As-S, As-As and S-S bonds after photoinduced interdiffusion; As-O and some of the S-S homopolar bonds are retained. There was a considerable decrease in As-S bond followed by an increase in As-Se and S-Se bonds. XPS analysis also shows that during photodiffusion, heteropolar bonds replace homopolar bonds, i.e., the irradiated samples are chemically ordered than the corresponding as prepared samples. Chapter 5 is concerned with the photoinduced interdiffusion in Bi/As2S3 nanolayered films. A brief description about the photoinduced interdiffusion of metals such as Ag, Zn, etc is given in the introduction. The experimental procedures and data analysis are also given. Two sets of samples with different ratios of sublayer thickness (d), d-Bi/d-As2S3 = 1/12 and 1/6 prepared by cyclic thermal evaporation are employed for the present study. A pump probe optical absorption technique was used to study the photoinduced interdiffusion in Bi/As2S3 nanolayered samples. Photoinduced interdiffusion of Bi into As2S3 was observed in both the films. The XPS analysis shows that the as prepared samples contain a large number of wrong As–As bonds and some of the As-As bonds are converted to As-S bonds during irradiation. The XPS analysis also reveals that the Bi is forming only bond with S during photoinduced interdiffusion. Chapter 6 summarizes the essential features of the present work and also points a few possible directions along which further work can be carried out.

Thyroxine (T4), the main secretory hormone of the thyroid gland, is produced on thyroglobulin by thyroid peroxidase (TPO)/hydrogen peroxide/iodide system. The synthesis of T4 by TPO involves two independent steps: iodination of tyrosine and phenolic coupling of the resulting iodotyrosine residues. The prohormone T4 is then converted to its biologically active form T3 by a selenocysteine-containing iodothyronine deiodinase (ID-I), which is present in highest amounts in liver, kidney, thyroid and pituitary. The 5'-deiodination catalyzed by ID-I is a ping-pong, bisubstrate reaction in which the selenol (or selenolate) group of the enzyme (E-SeH or E-Se-) first reacts with thyroxine (T4) to form a selenenyl iodide (E-SeI) intermediate. Subsequent reaction of the selenenyl iodide with an as yet unidentified intracellular cofactor completes the catalytic cycle and regenerates the selenol. Although the deiodination reactions are essential for the function of thyroid gland, the activation of thyroid stimulating hormone (TSH) receptor by auto-antibodies leads to an overproduction of thyroid hormones. In addition, these antibodies stimulate ID-I and probably other deiodinases to produce relatively more amount of T3. Figure 1. Synthesis of thyroid hormones by heme-containing Thyroid Peroxidase(TPO)(Refer PDF File) As these antibodies are not under pituitary feedback control system, there is no negative influence on the thyroid activity and, therefore, the uncontrolled production of thyroid hormones leads to a condition called “hyperthyroidism”. Under these conditions, the overproduction of T4 and T3 can be controlled by specific inhibitors, which either block the thyroid hormone biosynthesis or reduce the conversion of T4 to T3. A unique class of such inhibitors is the thiourea drugs, methimazole (1, MMI), 6-n-propyl-2-thiouracil (3, PTU), and 6-methyl-2-thiouracil (5, MTU). Although these compounds are the most commonly employed drugs in the treatment of hyperthyroidism, the detailed mechanism of their action is still not clear. According to the initially proposed mechanism, these drugs may divert oxidized iodides away from thyroglobulin by forming stable electron donor-acceptor complexes with diiodine, which can effectively reduce the thyroid hormone biosynthesis. It has also been proposed that these drugs may block the thyroid hormone synthesis by coordinating to the metal center of thyroid peroxidase (TPO). After the discovery that the ID-I is responsible for the activation of thyroxine, it has been reported that PTU, but not MMI, reacts with the selenenyl iodide intermediate (E-SeI) of ID-I to form a selenenyl sulfide as a dead end product, thereby blocking the conversion of T4 to T3 during the monodeiodination reaction. The mechanism of anti-thyroid activity is further complicated by the fact that the gold-containing drugs such as gold thioglucose (GTG) inhibit the deiodinase activity by reacting with the selenol group of the native enzyme. Recently, the selenium analogues 2 (MSeI), 4 (PSeU) and 6 (MSeU) attracted considerable attention because these compounds are expected to be more nucleophilic than their sulfur analogues and the formation of an –Se–Se– bond may occur more readily than the formation of an –Se–S– bond with the ID-I enzyme. However, the data derived from the inhibition of TPO by selenium compounds show that these compounds may inhibit the TPO activity by a different mechanism. Therefore, further studies are required to understand the mechanism by which the selenium compounds exert their inhibitory action. Our initial attempts to isolate 2 were unsuccessful and the final stable compound in the synthesis was characterized to be the diselenide (8). In view of the current interest in anti-thyroid drugs and their mechanism, we extended our approach to the synthesis and biological activities of a number of sulfur and selenium derivatives bearing the methimazole pharmacophore. The thesis consists of five chapters. The first chapter gives a general introduction to thyroid hormone synthesis and anti-thyroid drugs. In this chapter, the biosynthesis of thyroid hormones, structure and function of heme peroxidases, activation of thyroid hormones by iodothyronine deiodinases are discussed. This chapter also gives a brief introduction to some common problems associated with the thyroid gland, with a particular emphasis on hyperthyroidism. The structure and activity of some commonly used anti-thyroid drugs and the role of selenium in thyroid are discussed. The literature references related to this work are provided at the end of the chapter. The second chapter deals with the synthesis and characterization of the selenium analogue (MSeI) of anti-thyroid drug methimazole and a series of organoselenium compounds bearing N-methylimidazole pharmacophore are described. The clinically employed anti-thyroid drug, methimazole (MMI), exists predominantly in its thione form, which is responsible for its anti-thyroidal activity. The selenium analogue MSeI, on the other hand, is not stable in air and spontaneously oxidizes to the corresponding diselenide (MSeIox). Experimental and theoretical studies on MSeI suggest that this compound exists in a zwitterionic form in which the selenium atom carries a large negative charge. The structure of MSeI was studied in solution by NMR spectroscopy and the 77Se NMR chemical shift shows a large upfield shift (-5 ppm) in the signal as compared to the true selones for which the signals normally appear in the downfield range (500-2500 ppm). This confirms that MSeI exists predominantly in its zwitterionic form in solution. Our theoretical studies show that the formation of the diselenide (MSeIox) from selenol tautomer is energetically more favored than the formation of the disulfide (MMIox) from the thiol tautomer of MMI. This study also shows that the replacement of the N−H group in MSeI by an N-methyl or N-benzyl substituent does not affect the nature of C−Se bond. In the third chapter, the inhibition of lactoperoxidase-catalyzed oxidation of ABTS by anti-thyroid drugs and related derivatives is described. The commonly used anti-thyroid agent methemazole (MMI) inhibits the lactoperoxidase (LPO) with an IC50 value of 7.0 µM which is much lower than that of the other two anti-thyroid drugs, PTU and MTU. The selenium analogue of methimazole (MSeI) also inhibits LPO with an IC50 value of 16.4 µM, which is about 4-5 times lower than that of PTU and MTU. In contrast to thiones and selones, the S- and Se-protected compounds do not show any noticeable inhibition under identical experimental conditions. While the inhibition of LPO by MMI cannot be reversed by increasing the hydrogen peroxide concentration, the inhibition by MSeI can be completely reversed by increasing the peroxide concentration. Some of the selenium compounds in the present study show interesting anti-oxidant activity in addition to their inhibition propertities. In the presence of glutathione (GSH), MSeI constitutes a redox cycle involving a catalytic reduction of H2O2 and thereby mimics the glutathione peroxidase (GPx) activity in vitro. These studies reveal that the degradation of the intracellular H2O2 by the selenium analogues of anti-thyroid drugs may be beneficial to the thyroid gland as these compounds may act as antioxidants and protect thyroid cells from oxidative damage. Because the drugs with an action essentially on H2O2 can reversibly inhibit thyroid peroxidase, such drugs with a more controlled action could be of great importance in the treatment of hyperthyroidism. Figure 2. (A) Concentration-inhibition curves for the inhibition of LPO-catalyzed oxidation of ABTS by MMI and MSeI at pH 7.0 and 30 °C. (B) Plot of initial rates (vo) for the LPO-catalyzed oxidation of ABTS vs concentration of H2O2. (a) Control activity, (b) 40 µM of MSeI, (c) 40 µM of MSeIox, (d) 80 µM of PTU, (e) 80 µM of MTU, (f) 40 µM of MMI. The incubation mixture contained 6.5 nM LPO, 1.4 mM ABTS, 0.067 M phosphatebuffer(pH7).(Refer PDF File) The fourth chapter describes the inhibition of lactoperoxidase (LPO)-catalyzed iodination of L-tyrosine by anti-thyroid drug methimazole (MMI) and its selenium analogue (MSeI). These inhibition studies show that MSeI inhibits LPO with an IC50 value of 12.4 µM, which is higher than that of MMI (5.2 µM). The effect of hydrogen peroxide on the inhibition of LPO by MMI and MSeI is also discussed. These studies also reveal that the inhibition of LPO-catalyzed iodination by MSeI can be completely reversed by increasing the peroxide concentration. On the other hand, the inhibition by MMI cannot be reversed by increasing the concentration of the peroxide. To under stand the nature of compounds formed in the reactions between anti-thyroid drugs and iodine, the reactions of MSeI with molecular iodine is described. MSeI reacts with I2 to produce novel ionic diselenides, and the nature of the species formed in this reaction appears to be solvent dependent. The formation of ionic species (mono and dications) in the reaction is confirmed by UV-Vis, FT-IR and FT-Raman spectroscopic investigations and single crystal x-ray studies. The major conclusion drawn from this study is that MSeI reacts with iodine, even in its oxidized form, to form ionic diselenides containing iodide or polyiodide anions, which might be possible intermediates in the inhibition of thyroid hormones. Dication X-ray crystal structure of the monocation X-ray crystal structure of the dication In the fifth chapter, the synthesis and characterization of several thiones and selones having N,N-disubstituted imidazole moiety are described. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as zwitterions in which the selenium atom carries a large negative charge. The structures of selones were studied in solution by NMR spectroscopy and the 77Se NMR chemical shifts for the selones show large upfield shifts in the signals, confirming the zwitterionic structure of the selones in solution. The thermal isomerization of some S- and Se-substituted methyl and benzyl imidazole derivatives to produce the thermodynamically more stable N-substituted derivatives is described. A structure–activity correlation was attempted on the inhibition of LPO-catalyzed oxidation and iodination reactions by several thiouracil compounds, which indicates that the presence of an n-propyl group in PTU is important for an efficient inhibition. In contrast to the S- and Se-substituted derivatives, the selones produced by thermal isomerization exhibited efficient inhibition, indicating the importance of reactive selone (zwitterionic) moiety in the inhibition. The inhibition data on another well-known anti-thyroid agent carbimazole (CBZ) support the assumption that CBZ acts as a prodrug, requiring a conversion to methimazole (MMI) for its inhibitory action on thyroid peroxidase. (Refer pdf file/original thesis)

Contexte : malgr?? les particularit??s de l???environnement de pratique de la m??decine d???urgence, il n???existe pas de recherches sp??cifiquement men??es sur la th??matique du raisonnement clinique dans cette sp??cialit??. Nous avons souhait?? mieux comprendre comment les m??decins urgentologues raisonnent dans le cadre de la prise en charge initiale des patients. M??thode : une posture ??pist??mologique interpr??tative a ??t?? adopt??e ?? travers un devis de recherche qualitatif de type ethnographique. Des entretiens ont ??t?? r??alis??s aupr??s de m??decins urgentologues experts, ?? l???issue de la prise en charge d???un patient r??el. Ces entretiens reposaient notamment sur la visualisation de l???enregistrement vid??o en perspective subjective situ??e, obtenu gr??ce ?? l'usage d'une microcam??ra fix??e sur la tempe ou la branche de lunettes des praticiens. R??sultats : les hypoth??ses diagnostiques sont g??n??r??es tr??s pr??cocement par les m??decins, parfois m??me avant la rencontre avec le patient, sur la base de la prise en compte d???un nombre tr??s limit?? d???informations, pour certaines contextuelles. Cinq hypoth??ses ??taient en moyenne g??n??r??es lors de la rencontre initiale et au moins une ??tait une hypoth??se de gravit??. Aucune n?????tait formellement ??limin??e ou valid??e sans r??sultats d???examens compl??mentaires. Un jugement pr??coce quant ?? la gravit?? de la situation permettait ??galement aux m??decins d???orienter leurs intentions initiales vers des buts diagnostiques ou th??rapeutiques. Les experts raisonnaient le plus souvent de mani??re intuitive. Ils prenaient en compte les sp??cificit??s de leur environnement professionnel en ??tant, par exemple, vigilants au temps, au caract??re potentiellement ??volutif de l?????tat clinique du malade et au devenir d???aval de celui-ci. Conclusion : l???identification du raisonnement clinique des m??decins urgentologues offre des perspectives importantes en mati??re de pratique de la m??decine d???urgence, et de formation des r??sidents dans cette discipline. La m??thode originale de recueil des donn??es pourrait en outre ??tre r??exploit??e dans le cadre de travaux ult??rieurs.

Parkinson’s disease (PD) is a neurodegenerative disorder, which is progressive in nature and usually associated with the elderly. It is the second most common age-related neurodegenerative disorder after Alzheimer’s disease (AD). PD occurs when there is a dramatic loss of dopamine (DA) in the striatum, a substructure of the basal ganglia, of the brain due to the degeneration of the nigrostriatal pathway that contains the dopaminergic neurons. Motor symptoms of PD include bradykinesia, muscular rigidity and resting tremors. Non-motor symptoms include speech and sleep problems, hallucinations and depression. Diverse treatment options are available to treat the symptoms of PD, including levodopa (L-Dopa), DA agonists and monoamine oxidase B (MAO-B) inhibitors. The MAOs are flavoproteins that are bound to the outer membrane of the mitochondria and catalyze the oxidative deamination of neurotransmitters such as serotonin (5-HT), noradrenaline (NA) and DA. Two isoforms occur, namely MAO-A and –B, which share a 70% sequence identity. MAO-A catalyzes the oxidation of 5-HT and MAO-B has a substrate specificity towards benzylamine and 2-phenylethylamine. DA, NA, adrenaline and tryptamine are oxidized by both forms. MAO-A plays an important role in depression while MAO-B plays an important role in PD. The two isoforms are not evenly distributed in the brain. Of particular relevance to PD is the observation that, in the basal ganglia, MAO-B is the predominant form and the oxidation of DA in this region is largely due to MAO-B activity. Also, with an increase in age, there is an up to fourfold increase in MAO-B activity in the brain. In the aged parkinsonian brain, MAO-B is therefore a major DA metabolizing enzyme and MAO-B inhibitors have an important role in the therapy of PD. MAO-B inhibitors may potentially reduce the metabolic destruction of DA and thereby provide relief from the symptoms of PD. MAO-B inhibitors may also exert a neuroprotective effect in PD. In the catalytic cycle of MAO-B, one mole each of an aldehyde, hydrogen peroxide and ammonia are formed for each mole of primary amine substrate oxidized. Ferrous iron, which is abundant in the basal ganglia, may react with the hydrogen peroxide to form hydroxyl radicals in the Fenton reaction. The hydroxyl radical damages virtually all types of biomolecules including proteins, DNA, lipids, carbohydrates and amino acids. The aldehyde, in turn, may react with amino groups of proteins, and thus lead to cell injury. Inhibitors of MAO-B may reduce the MAO-catalyzed formation of hydrogen peroxide and aldehydes in the basal ganglia, and thus act as neuroprotective agents. MAO-B inhibitors that are currently being used in the treatment of PD are selegiline and rasagiline. Both are irreversible inhibitors of MAO-B. While irreversible inhibitors of MAO have been used extensively as drugs, irreversible inhibition has a number of disadvantages. These include the loss of selectivity as a result of repeated drug administration and a slow and variable rate of enzyme recovery following termination of drug treatment. The turnover rate for the biosynthesis of MAO-B in the human brain may require as much as 40 days while with reversible inhibition, enzyme activity is recovered when the inhibitor is eliminated from the tissues. For these reasons the discovery of novel MAO-B inhibitors, which interact reversibly with the enzymes are of value in the therapy of PD. The goal of this study was to design novel and reversible inhibitors of MAO-B, which may find application in the therapy of PD. In the current study, caffeine was used as scaffold for the design of new MAO inhibitors. Caffeine is reported to be a weak inhibitor of MAO-B, with an IC50 value of 5084 μM. Substitution at C-8 of the caffeine moiety, however, yields compounds with potent MAO-B inhibitory properties. Of particular importance to this study is a recent report that a series of 8-sulfanylcaffeine analogues acts as selective inhibitors of human MAO-B. Among the compounds examined, 8-[(phenylethyl)sulfanyl]caffeine was found to be a particularly potent MAO-B inhibitor with an IC50 value of 0.223 μM. In an attempt to further enhance the MAO-B inhibition potency of 8-[(phenylethyl)sulfanyl]caffeine, and possibly to discover highly potent MAO-B inhibitors, a series of five 8-[(phenylethyl)sulfanyl]caffeine analogues was synthesized and evaluated as inhibitors of human MAO-A and –B. For the purpose of this study 8- [(phenylethyl)sulfanyl]caffeine homologues containing C-3 alkyl (CF3, CH3 and OCH3) and halogen (Cl and Br) substituents on the phenyl ring were considered. Furthermore, a series of two 8-sulfinylcaffeine analogues and one 8-sulfonylcaffeine were synthesized and their MAO inhibitory potencies were measured. The purpose with these compounds was to compare the MAO inhibitory properties of the 8-sulfinylcaffeine analogues and 8-sulfonylcaffeine with those of the 8-sulfanylcaffeine analogues. This study also investigates the MAO inhibition properties of three selected 8-[(phenylpropyl)sulfanyl]caffeine and two 8-(benzylsulfanyl)caffeine analogues. Chemistry: The target 8-sulfanylcaffeine analogues were synthesized according to the literature procedure. 8-Chlorocaffeine was reacted with an appropriate mercaptan in the presence of NaOH, to yield the target 8-sulfanylcaffeine analogues in yields of 6.4–50.7%. 8-Chlorocaffeine, in turn, was conveniently synthesized in high yield by reacting chlorine with caffeine in chloroform. In certain instances, the mercaptan starting materials were not commercially available and were thus synthesized according to the literature procedure by reacting an appropriate alkylbromide with thiourea. The resulting thiouronium salt was hydrolyzed in the presence of NaOH to yield the target mercaptan. The 8-sulfinylcaffeine analogues and 8- sulfonylcaffeine were synthesized by reacting the 8-sulfanylcaffeines with H2O2 in the presence of glacial acetic acid and acetic anhydride. The structures and the purities of the inhibitors were verified by NMR, MS and HPLC analyses. MAO inhibition studies: The MAO inhibitory properties of the test compounds were examined using the recombinant human enzymes. The mixed MAO-A/B substrate, kynuramine, was employed as substrate for both enzymes and the inhibition potencies were expressed as the IC50 values. The 8-[(phenylethyl)sulfanyl]caffeine analogues were found to be highly potent inhibitors of MAO-B. The IC50 values recorded for these homologues ranged from 0.017–0.125 μM, making them twofold to 13-fold more potent MAO-B inhibitors than the lead compound, 8- [(phenylethyl)sulfanyl]caffeine (IC50 = 0.223 μM). For comparison, the reversible MAO-B selective inhibitor, lazabemide, exhibits an IC50 value of 0.091 μM under the same conditions (unpublished data from our laboratory). Interestingly, both alkyl (CF3, CH3 and OCH3) and halogen (Cl and Br) substitution lead to highly potent MAO-B inhibition. It may therefore be concluded that substitution on C-3 is a general strategy to enhance the MAO-B inhibition potency of 8-[(phenylethyl)sulfanyl]caffeine. The results of the MAO inhibitory studies with the 8- [(phenylpropyl)sulfanyl]caffeine analogues showed that these compounds are also inhibitors of MAO-B with IC50 values of 0.061–0.500 μM. Those homologues substituted with chlorine on the para and meta positions of the phenyl ring were found to be exceptionally potent inhibitors with IC50 values of 0.061 μM and 0.062 μM, respectively. For the series of 8- (benzylsulfanyl)caffeines, meta substitution with chlorine (IC50 = 0.227 μM) and bromine (IC50 = 0.199 μM) was also found to enhance the MAO-B inhibition potency of 8- (benzylsulfanyl)caffeine (IC50 = 1.86 μM). The results document that the 8-sulfinylcaffeines are also inhibitors of MAO-B with IC50 values of 11.8–131 μM. The 8-sulfonylcaffeine was also found to be a MAO-B inhibitor. Compared to the 8-sulfanylcaffeines, these homologues are, however, weaker inhibitors. It may, therefore, be concluded that 8-sulfinylcaffeines and 8-sulfonylcaffeines are comparatively weak MAO-B inhibitors and less suited for the design of high potency MAO-B inhibitors. The results also document that the 8-[(phenylethyl)sulfanyl]caffeines are relatively weak MAO-A inhibitors with IC50 values of 5.66–141 μM, with one homologue exhibiting no inhibition under the experimental conditions. As evident from the selectivity indices (SI values), the 8- [(phenylethyl)sulfanyl]caffeines were all selective inhibitors of the MAO-B isoform. Two compounds exhibited SI values in excess of 1000. Since these compounds are also highly potent MAO-B inhibitors, they represent suitable leads for the design of potent and selective MAO-B inhibitors. The 8-sulfinylcaffeines and 8-sulfonylcaffeine were found to be weak MAO-A inhibitors with IC50 values of 166–250 μM. The SI values demonstrate that these compounds are MAO-B selective inhibitors, although to a lesser degree than the 8- [(phenylethyl)sulfanyl]caffeines. The 8-[(phenylpropyl)sulfanyl]caffeines are also MAO-A inhibitors with IC50 values of 0.708–6.48 μM. It is noteworthy that these homologues are the most potent MAO-A inhibitors among the compounds evaluated in this study. In fact, one of the 8-[(phenylpropyl)sulfanyl]caffeines, 8-{[3-(4-chlorophenyl)propyl]sulfanyl}caffeine (IC50 = 0.708 μM), is the only compound with an IC50 value for the inhibition of MAO-A in the submicromolar range. The 8-[(phenylpropyl)sulfanyl]caffeines display, in general, lower degrees of selectivity for MAO-B than the corresponding 8-[(phenylethyl)sulfanyl]caffeines. Reversibility studies: The reversibility of the interaction of a representative inhibitor, 8-{[2-(3- (trifluoromethyl)phenyl)ethyl]sulfanyl}caffeine, with MAO-B was investigated by evaluating the recovery of the enzymatic activity after dilution of the enzyme-inhibitor complex. For this purpose, MAO-B was preincubated with the test compound at concentrations of 10 × IC50 and 100 × IC50 for 30 min. The reactions were subsequently diluted 100-fold to 0.1 × IC50 and 1 × IC50, respectively. The results show that, after dilution to 0.1 × IC50 and 1 × IC50, the MAO-B catalytic activities are recovered to 35% and 22%, respectively, of the control value. For reversible enzyme inhibition, the enzyme activities are expected to recover to levels of approximately 90% and 50%, respectively, after 100-fold dilution of the preincubations containing inhibitor concentrations of 10 × IC50 and 100 × IC50. After preincubation of MAO-B with the irreversible inhibitor (R)-deprenyl (at 10 × IC50), and dilution of the resulting complex to 0.1 × IC50, MAO-B activity is not recovered (3.0% of control). These data indicate that the test compound does indeed react reversibly with MAO-B but because enzyme activities are not recovered to the expected 90% and 50% respectively, it may suggest that the test compound possess a quasi-reversible or tight-binding component. Hansch-type structure activity relationship studies: A limited Hansch-type QSAR study was performed for the inhibition of MAO by the 8-[(phenylethyl)sulfanyl]caffeines. For this purpose, five parameters were used to describe the physicochemical properties of the C-3 substituents on the phenyl rings of the inhibitors. The Van der Waals volume (Vw) and Taft steric parameter (Es) served as descriptors of the bulkiness of the substituents, while the lipophilicities were described by the Hansch constant (π). The electronic properties were described by the classical Hammett constant (σm) and the Swain-Lupton constant (F). A one-parameter fit with the Taft steric parameter versus the inhibition potency (logIC50) yielded the best correlation with a correlation coefficient (R2) of 0.912 and a statistical F value of 41.27 (Fmax = 35). The positive sign of the Es (+0.47) parameter coefficient indicated that the inhibition potencies of the 8- [(phenylethyl)sulfanyl]caffeines towards MAO-B may be enhanced by substitution with sterically large groups at C-3 of the phenyl rings of the inhibitors. / Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013