Sphingosine kinase (SphK) has emerged as an attractive target for cancer therapeutics due to its role in cell proliferation. SphK phosphorylates sphingosine to form sphingosine-1-phosphate (S1P) which has been implicated as a major player in cancer growth and survival. SphK exists as two different isoforms, namely SphK1 and SphK2, which play different roles inside the cell. The dearth of isoenzyme-selective inhibitors has been a stumbling block for probing the exact roles of these two isoforms in disease progression. This report documents our efforts in developing SphK2-selective inhibitors. We provide the first demonstration of a SphK inhibitor containing a quaternary ammonium salt. We developed highly potent and moderately selective inhibitors that were cell permeable and interfered with S1P signaling inside the cell. In an effort to improve the selectivity of our inhibitors and enhance their in vivo stability, we designed and synthesized second generation inhibitors containing a heteroaromatic linker and a guanidine headgroup. These inhibitors were more potent and selective towards SphK2 and affected S1P signaling in cell cultures and various animal models. / Ph. D.

Yes / The first example of an intramolecular hydroarylation of 1,6-en-α-chloro-enamides was achieved by a palladium-catalysed ligand-free reductive Heck cycloisomerisation with no competing Heck-cyclised by-product.

Im ersten Teil wird eine neue Konstruktion der parabolischen Induktion für pro-p Iwahori-Heckemoduln gegeben. Dabei taucht eine neue Klasse von Algebren auf, die in gewisser Weise als Interpolation zwischen der pro-p Iwahori-Heckealgebra einer p-adischen reduktiven Gruppe $G$ und derjenigen einer Leviuntergruppe $M$ von $G$ gedacht werden kann. Für diese Algebren wird ein Induktionsfunktor definiert und eine Transitivitätseigenschaft bewiesen. Dies liefert einen neuen Beweis für die Transitivität der parabolischen Induktion für Moduln über der pro-p Iwahori-Heckealgebra. Ferner wird eine Funktion auf einer parabolischen Untergruppe untersucht, die als Werte nur p-Potenzen annimmt. Es wird gezeigt, dass sie eine Funktion auf der (pro-p) Iwahori-Weylgruppe von $M$ definiert, und dass die so definierte Funktion monoton steigend bzgl. der Bruhat-Ordnung ist und einen Vergleich der Längenfunktionen zwischen der Iwahori-Weylgruppe von $M$ und derjenigen der Iwahori-Weylgruppe von $G$ erlaubt. Im zweiten Teil wird ein allgemeiner Zerlegungssatz für Polynome über der sphärischen (parahorischen) Heckealgebra einer p-adischen reduktiven Gruppe $G$ bewiesen. Diese Zerlegung findet über einer parabolischen Heckealgebra statt, die die Heckealgebra von $G$ enthält. Für den Beweis des Zerlegungssatzes wird vorausgesetzt, dass die gewählte parabolische Untergruppe in einer nichtstumpfen enthalten ist. Des Weiteren werden die nichtstumpfen parabolischen Untergruppen von $G$ klassifiziert. / The first part deals with a new construction of parabolic induction for modules over the pro-p Iwahori-Hecke algebra. This construction exhibits a new class of algebras that can be thought of as an interpolation between the pro-p Iwahori-Hecke algebra of a p-adic reductive group $G$ and the corresponding algebra of a Levi subgroup $M$ of $G$. For these algebras we define a new induction functor and prove a transitivity property. This gives a new proof of the transitivity of parabolic induction for modules over the pro-p Iwahori-Hecke algebra. Further, a function on a parabolic subgroup with p-power values is studied. We show that it induces a function on the (pro-p) Iwahori-Weyl group of $M$, that it is monotonically increasing with respect to the Bruhat order, and that it allows to compare the length function on the Iwahori-Weyl group of $M$ with the one on the Iwahori-Weyl group of $G$. In the second part a general decomposition theorem for polynomials over the spherical (parahoric) Hecke algebra of a p-adic reductive group $G$ is proved. The proof requires that the chosen parabolic subgroup is contained in a non-obtuse one. Moreover, we give a classification of non-obtuse parabolic subgroups of $G$.

Dans cette thèse, nous avons décrit de nouvelles méthodes pour la préparation de polymères et de produits chimiques à partir de ressources renouvelables:Premièrement, nous avons défini une nouvelle méthode de préparation de sulfonamides, utilisant des nitro-aromatiques et des sels de sulfinate de sodium, dans une solution aqueuse de bisulfite de sodium, en tant qu’agent réducteur non toxique. Le produit a été séparé par une simple filtration. La réaction montre une chimio-sélectivité complète, seuls les substrats nitro déficitaire en électrons sont réactifs. Cependant, et contrairement à la littérature, les sels de sulfinate de sodium aromatiques et aliphatiques se sont révélés réactifs dans nos conditions. De plus, nous avons utilisé cette méthode pour préparer de manière écologique le catalyseur de zinc décrit par Karamé et al. et utilisé pour la cycloaddition du dioxyde de carbone avec des époxydes, afin d'accéder aux monomères de polycarbonates pour la préparation de polyuréthane non isocyanate.Ensuite, nous avons étudié la préparation de bis-carbonate de mannitol à partir de mannitol, en utilisant le carbonate de diméthyle comme réactif et comme solvant. Le carbonate de glycérol a été utilisé comme co-solvant en raison de ses propriétés de solubilisation intéressantes. La possibilité de synthèse des monomères diamines entièrement renouvelables a également été étudiée en utilisant des derives des sucres comme la furfurylamine et le 5-méthylfurfural. Nous avons également etudier l’aminolyse du bis-carbonate du mannitol avec la furfurylamine à la température ambiante. De plus, nous avons comparé la stabilité de ce carbonate avec les monomères carbonates commerciaux en utilisant une analyse gravimétrique thermique.Enfin, nous avons préparé le diester de 4,4'-oxydipentanoate de diéthyle à partir de lévulinate d'éthyle par éthérification réductrice sans solvant, catalysée par du triflate de cuivre, en utilisant du tétraméthydisiloxane comme agent réducteur. En outre, nous avons prouvé que ce nouveau monomère était utilisable dans la préparation des polyesters et des polyamides, dans des conditions de polycondensation classiques, en utilisant le propane diol et l’hexaméthylène diamine comme monomères modèles / In this thesis, we describe new methods for the preparation of polymers and chemicals from renewable resources: First we have defined new method for the preparation of sulfonamides, using nitro aromatics and sodium sulfinate salts, in aqueous sodium bisulfite solution as a non toxic reducing agent. The product was separated by simple filtration and the reaction show full chemoslectivity, only electron poor nitro substrates are reactive. However, in contrast with the literature, aromatic and aliphatic sodium sulfinate salts were found reactive under our conditions. In addition, we have used this method to prepare, in a green way, the active zinc catalyst reported by Karamé et al. for the cycloaddition of carbon dioxide with epoxydes, in order to access to polycarbonates monomers for non-isocyanate polyurethane preparation.Then, we have investigated the preparation of high purity mannitol bis-carbonate from mannitol using dimethyl carbonate as a reagent and as a solvent. Glycerol carbonate was used as co-solvent due to its interesting solubilization properties. The possibility of the synthesis of fully renewable diamine monomers was also investigated using furfurylamine and 5-methylfurfural derivated from sugars. We have also uncovered its high reactivity toward uncatalyzed aminolysis with furfurylamine at room temperature. Furthermore, we have compared the stability of this carbonate with existing commercial monomers using thermal gravimetric analysis.Finally, we prepared the diethyl 4,4'-oxydipentanoate diester from renewable ethyl levulinate was prepared by solventless reductive etherification, catalyzed by copper triflate, using tetramethydisiloxane as safe and low-cost reducing agent. Besides, we have proved the usability of this new monomer in the preparation of sustainable polyesters and polyamides, under classical polycondensation conditions, using propane diol and hexamethylene diamine as model monomers

Les hydrotropes sont de petites molécules amphiphiles utilisées dans de nombreux domaines d'applications (détergence, extraction, solubilisation, etc …). Les hydrotropes sont principalement d'origine pétrosourcée et des molécules alternatives d'origine biosourcée ont été synthétisées selon des voies de synthèse éco-compatibles.Deux tétraols, l'érythritol et le pentaérythritol, ont été utilisés comme tête polaire. La partie apolaire est incorporée via une liaison éther car celle-ci est plus résistante en milieux salins. L'alkylation réductrice directe de dérivés carbonylés conduisant à des résultats non satisfaisants, une synthèse en deux étapes d'acétalisation puis d'hydrogénolyse a donc été développée, conduisant aux éthers de tétraols avec de bons rendements. Les propriétés physico-chimiques de ces éthers sont meilleures que celles d'hydrotropes standards, mais non suffisantes pour l'application visée. Ainsi, des éthers de glycérol fonctionnalisés par une fonction carboxylate ont été synthétisés. Une première étape d'alkylation réductrice permet d'accéder aux mono-éthers de glycérol. Une réaction en cascade d'acétalisation puis d'hydrogénolyse à partir de céto-esters permet de greffer la fonction carboxylate. L'alcool libre peut ensuite être méthylé à l'aide du phosphate de triméthyle. Cette méthode de méthylation a ensuite été étendue à de nombreux polyols (érythritol, glycérol, diglycérol, acide tartrique, etc …). Les produits de perméthylation sont obtenus avec de bons rendements, et le catalyseur acide est une résine recyclable / Hydrotropes are small amphiphilic molecules with applications in numerous fields such as extraction, detergency, solubilization, etc … Generally, hydrotropes are petrosourced, thereby biosourced alternatives molecules have been synthesized using eco-compatible synthesis.Two tetraols, erythritol and pentaerythritol, were used as polar head. Ethers bond was retained to link the two parts of the amphiphilic molecule due to its better resistance in saline media. Using carbonyl derivatives, the reductive alkylation didn’t allow to reach the corresponding ethers. A two-step strategy of acetalisation and hydrogenolysis was developed to reach good yields in ethers. The physico-chemical properties of these compounds are better than standard hydrotropes, but they are not sufficient for the targeted application. Thereby, functionalized glycerol ethers with a carboxylic acid have been synthesized. First, reductive alkylation led to glycerol mono-ethers in good yields. Then, acetalisation/hydrogenolysis cascade using ceto-ester enable the addition of carboxylic acid in good yields. Free hydroxyl group can be methylated using trimethylphosphate. This methylation process has been extended to other polyols (erythritol, pentaerythritol, glycerol, diglycerol, etc …). The permethylated products have been obtained in good yields, and the acid catalyst is a recyclable resin

<p>Let $\mathbf{G}$ be a connected reductive algebraic group defined over an algebraic closure of the finite field of prime order $p>0$, which we assume to be good for $\mathbf{G}$. We denote by $F : \mathbf{G} \to \mathbf{G}$ a Frobenius endomorphism of $\mathbf{G}$ and by $G$ the corresponding $\mathbb{F}_q$-rational structure. If $\operatorname{Irr}(G)$ denotes the set of ordinary irreducible characters of $G$ then by work of Lusztig and Geck we have a well defined map $\Phi_{\mathbf{G}} : \operatorname{Irr}(G) \to \{F\text{-stable unipotent conjugacy classes of }\mathbf{G}\}$ where $\Phi_{\mathbf{G}}(\chi)$ is the unipotent support of $\chi$.</p> <p>Lusztig has given a classification of the irreducible characters of $G$ and obtained their degrees. In particular he has shown that for each $\chi \in \operatorname{Irr}(G)$ there exists an integer $n_{\chi}$ such that $n_{\chi}\cdot\chi(1)$ is a monic polynomial in $q$. Given a unipotent class $\mathcal{O}$ of $\mathbf{G}$ with representative $u \in \mathbf{G}$ we may define $A_{\mathbf{G}}(u)$ to be the finite quotient group $C_{\mathbf{G}}(u)/C_{\mathbf{G}}(u)^{\circ}$. If the centre $Z(\mathbf{G})$ is connected and $\mathbf{G}/Z(\mathbf{G})$ is simple then Lusztig and H\'zard have independently shown that for each $F$-stable unipotent class $\mathcal$ of $\mathbf$ there exists $\chi \in \operatorname(G)$ such that $\Phi_(\chi)=\mathcal$ and $n_ = |A_(u)|$, (in particular the map $\Phi_$ is surjective).</p> <p>The main result of this thesis extends this result to the case where $\mathbf$ is any simple algebraic group, (hence removing the assumption that $Z(\mathbf)$ is connected). In particular if $\mathbf$ is simple we show that for each $F$-stable unipotent class $\mathcal$ of $\mathbf$ there exists $\chi \in \operatorname(G)$ such that $\Phi_(\chi) = \mathcal$ and $n_ = |A_(u)^F|$ where $u \in \mathcal^F$ is a well-chosen representative. We then apply this result to prove, (for most simple groups), a conjecture of Kawanaka's on generalised Gelfand--Graev representations (GGGRs). Namely that the GGGRs of $G$ form a $\mathbf{Z}$-basis for the $\mathbf{Z}$-module of all unipotently supported class functions of $G$. Finally we obtain an expression for a certain fourth root of unity associated to GGGRs in the case where $\mathbf{G}$ is a symplectic or special orthogonal group.</p>

Strong bond activation mediated by pincer ligated transiton-metal complexes has been the subject of intense study in recent years, due to its potential involvement in catalytic transformations. This dissertation has focused on the net heterolytic cleavage of B-H and B-B bonds across the N-Pd bond in a cationic (PNP)Pd fragment, the C-H oxidative addition to a (PNP)Ir center and the recent results on the C-H and C-O oxidative addition in reactions of aryl carboxylates with the (PNP)Rh fragment. Transition metal carbene and carbyne complexes are of great interest because of their role in a wide variety of catalytic reactions. Our work has resulted in the isolation of a rhodium(I) difluorocarbene. Reaction of the rhodium difluorocarbene complex with a silylium salt led to the C-F bond cleavage and the formation of a terminal fluorocarbyne complex. Reductive elimination is a critical step of cross coupling reactions. In order to examine the effect of the pincer ligand on the reductive elimination reactions from Rh(III), the first pi-accepting PNP ligand bearing pyrrolyl substituents was prepared and installed onto the rhodium center. Arylhalide (halide = Br, I) oxidative addition was achieved in the presence of donor ligands such as acetonitrile to form stable six-coordinate Rh(III) compounds. The C-O reductive elimination reactions in this system were also explored.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Actuellement, la mise au point de systèmes de vectorisation d'agents chimio-thérapeutiques performants fait l'objet d'une intense recherche. Les nanoparticules en particulier sont étudiées, car elles permettent de solubiliser des molécules hydrophobes en milieux aqueux tout en diminuant leur toxicité et leur dégradation. Toutefois, le devenir à long terme des nanoparticules est un paramètre important qu'il faut considérer dans la conception de ces nanovecteurs. Pour cette raison, le développement de nanoparticules auto-assemblées constituées de copolymères à bloc entièrement biocompatibles, biodégradables et aux propriétés de libération contrôlée est recommandé. Dans cette perspective, nous avons étudié les propriétés d'auto-organisation de copolymères greffés amphiphiles de type chitooligosaccharide-grafted-polycaprolactone. Le premier chapitre révèle l'utilisation de l'aniline et de son dérivé alcyne comme un outil efficace pour l'amination réductrice de chitooligosaccharides. Dans le second chapitre, différentes familles de polycaprolactone avec des fonctions azide latérales sont décrites. Le troisième chapitre traite du couplage par chimie « click » de chaque bloc ainsi que de la caractérisation physico-chimique des nanoparticules en solution aqueuse. La réticulation de ses particules a permis d'obtenir les nanogels finaux. Pour conclure, des tests d'encapsulation et de libération contrôlée de la Doxorubicine (avec ou sans ajout de glutathion) ont été effectués / Currently, the development of efficient drug delivery systems has a great attention. Nanoparticles are particularly studied for their capacity to solubilise hydrophobic drugs in aqueous media and to decrease their toxicity and degradability. However, long term compatibility has to be considered in the conception of this nanocarrier. For this reasons, the development of self-assembled particles constituted of biocompatible, biodegradable block copolymers is highly recommended. In this perspective, we have studied the self-assembled properties of chitooligosaccharide-grafted-polycaprolactone copolymers. The first chapter reveals aniline catalysis and its alkyne derivative as an efficient way for reductive amination of chitooligosaccharides. The second chapter describes the synthesis of different polycaprolactones with pendant azide groups. The third chapter is dedicated to the grafting of each bloc performed by “click” chemistry as well as the formation and characterisation of nanoparticle conducted in aqueous media. These nanoparticles were cross-linked to form reduction-sensitive final nanogels. At last, entrapment and controlled Doxorubicine release (with or without glutathione) were explored.

abstract: This dissertation explores the use of bench-scale batch microcosms in remedial design of contaminated aquifers, presents an alternative methodology for conducting such treatability studies, and - from technical, economical, and social perspectives - examines real-world application of this new technology. In situ bioremediation (ISB) is an effective remedial approach for many contaminated groundwater sites. However, site-specific variability necessitates the performance of small-scale treatability studies prior to full-scale implementation. The most common methodology is the batch microcosm, whose potential limitations and suitable technical alternatives are explored in this thesis. In a critical literature review, I discuss how continuous-flow conditions stimulate microbial attachment and biofilm formation, and identify unique microbiological phenomena largely absent in batch bottles, yet potentially relevant to contaminant fate. Following up on this theoretical evaluation, I experimentally produce pyrosequencing data and perform beta diversity analysis to demonstrate that batch and continuous-flow (column) microcosms foster distinctly different microbial communities. Next, I introduce the In Situ Microcosm Array (ISMA), which took approximately two years to design, develop, build and iteratively improve. The ISMA can be deployed down-hole in groundwater monitoring wells of contaminated aquifers for the purpose of autonomously conducting multiple parallel continuous-flow treatability experiments. The ISMA stores all sample generated in the course of each experiment, thereby preventing the release of chemicals into the environment. Detailed results are presented from an ISMA demonstration evaluating ISB for the treatment of hexavalent chromium and trichloroethene. In a technical and economical comparison to batch microcosms, I demonstrate the ISMA is both effective in informing remedial design decisions and cost-competitive. Finally, I report on a participatory technology assessment (pTA) workshop attended by diverse stakeholders of the Phoenix 52nd Street Superfund Site evaluating the ISMA's ability for addressing a real-world problem. In addition to receiving valuable feedback on perceived ISMA limitations, I conclude from the workshop that pTA can facilitate mutual learning even among entrenched stakeholders. In summary, my doctoral research (i) pinpointed limitations of current remedial design approaches, (ii) produced a novel alternative approach, and (iii) demonstrated the technical, economical and social value of this novel remedial design tool, i.e., the In Situ Microcosm Array technology. / Dissertation/Thesis / Ph.D. Biological Design 2013