Thèses sur le sujet « Synthèse (chimie) – Inhibiteurs »
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Balg, Christian. « Synthèse d'inhibiteurs des aminoacyl-ARNt synthétases et des aminoacyl-ARNt amidotransférases ». Thesis, Université Laval, 2011. http://www.theses.ulaval.ca/2011/28241/28241.pdf.
Texte intégralBaumann, Jean Sébastien. « Synthèse de glyconanostructures : inhibiteurs potentiels des interactions sucres-protéines ». Amiens, 2011. http://www.theses.fr/2011AMIE0102.
Texte intégralThe central theme of this thesis is the design and synthesis of diverse family of “multivalent” glyconanostructures as potential inhibitors of glycosyltransferases and glycosylhydrolases. A special emphasis is placed on ppGalNAcTs because of their role in the biosynthesis of O-glycans (mucins). A library of multivalent macromolecules has been targeted based on the supposed mode-of-action of these enzymes. The targeted glycostructures are comprised of various scaffolds (fullerenes, nanodiamonds, boron-doped diamonds, polymers…) and various glycan mimics/iminosugars. New strategies based on dominos reactions have been developed to obtain the iminosugar components. Each of the various fragments have been functionalised with either azido or alkyne groups and then combined employing a 1,3 dipolar cycloaddition reaction. Several members of the targeted glyconanostructure library have been obtained. The successful synthesis of these new glyconano sructures has allowed to probe how weak interactions typically observed between glycans and their biological receptors manifest themselves in the case of little-studied catalytic proteins such as the ppGalNAcTs. The types of glyconanostructures synthesized in this work have great potential as tools in the domain of glycomics which is attracting a good deal of attention at the present time
Xu, Bixue. « Synthèse de Mono- et gem-Difluoro-Carba-glycosides ». Paris 6, 2012. http://www.theses.fr/2012PA066305.
Texte intégralCarbasugars, as hydrolytically stable carbohydrate mimetics in which endocyclic oxygen atom has been replaced by a methylene group, have attracted great interest among chemists and biochemists due to their potential biological properties, particularly as inhibitors of glycosidase or glycosyltransferases. However, the replacement of the endocyclic oxygen by a methylene group has the inherent disadvantage to suppress any possible hydrogen bonding as well as exo-anomeric effect, an important factor in directing the relative positioning between two monosaccharide residues. One way to overcome this problem is to replace the endocyclic oxygen atom by gem-difluoromethylene group (-CF2-) which would hopefully induce conformational bias through stereoelectronic effects to partially restore the exo-anomeric effect as well as provide key polar region for the interaction with potential receptors. In this work, we successfully realized the first syntheses of mono- and gem-difluoro- carba-glycoside analogues of mono- and disaccharides. Our strategy is based on a Lewis acid induced carbocyclization of glycosides of an enolether possessing an electron-donating group with retention of the anomeric group. Two strategies for the synthesis of mono- and gem-difluoro-carbaglycosides were established as illustrated in the retrosynthetic plan Figure 1. They differentiate by the stage of introduction of fluorine atom: before or after the carbocyclization step
Abdo, Marie-Rose. « Synthèses et activités d'agent antibrucelliens : inhibiteurs de l'histidinol déshydrogénase ». Montpellier 2, 2007. http://www.theses.fr/2007MON20107.
Texte intégralLeclercq, Julien. « Conception, synthèse et évaluation pharmacologique de nouveaux inhibiteurs de la kinésine Eg5 ». Thesis, Lille 2, 2014. http://www.theses.fr/2014LIL2S026/document.
Texte intégralCancer is a real problem in our civilization. Indeed, in 2010, it affected more than 10 million people in the world. Today, this disease is the first cause of death in industrialized countries.Unfortunately, the proposed therapies remain frequently insufficient and lead to side effects which remove the benefits of the medical treatment. In order to avoid the toxicity to safe cells, since a few years, researches have been done to develop targeted therapies. Most of the anti-mitotic drugs actually available on the market lead to important side effects such as cardiological, hematological and neurotoxic problems.Thus, we interested to another therapeutic target which still acts at the level of the mitosis but causing fewer side effects and can be overexpressed into the cancer cells: the mitotic kinesin Eg5.The mitotic kinesin Eg5 plays an important role in the early stages of mitosis and is one of the most attractive target enzymes in antimitotic drug development. The modulation of the Eg5 activity has been shown to cause aberrant mitotic spindle formation, cell cycle arrest during mitosis and the inhibition of proliferation of tumor cells in culture. With regard to the potential of Eg5 modulators in the treatment of human cancers, we report the design, synthesis and biological studies of quinazolinone derivatives as mitotic kinesin Eg5 inhibitors. We developed three series of molecules derived from quinazolin-4-one scaffold following a “de novo drug design” strategy
Gessier, Vincent. « Synthèse, ex pool chiral, d'imidazolo-sucres, inhibiteurs de glycosidases et de glycosyltransférases ». Mulhouse, 2001. http://www.theses.fr/2001MULH0657.
Texte intégralChabaud, Laurent. « Carboazidation d'allylsilanes chiraux : application à la synthèse totale d'alcaloïdes polyhydroxyles inhibiteurs de glycosidases ». Bordeaux 1, 2005. http://www.theses.fr/2005BOR13040.
Texte intégralLoidreau, Yvonnick. « Synthèse de composés hétérocycliques [6,5,6] polyhétéroatomiques, inhibiteurs potentiels de kinases ». Rouen, 2013. http://www.theses.fr/2013ROUES001.
Texte intégralIn this manuscript, we describe the design, synthesis and potential applications of a combinatorial library based on polyheteroatomic [6,5,6] planar tricyclic structure. Initially, a study of different synthetic ways to bicyclic [6,5] precursors was carried out. Upon completion of these scaffolds, the third heterocycle was generated by using decomposition of formamide or from the Dimroth rearrangement. More than one hundred molecules were obtained following this work. The products of this library were screened on seven families of kinases (CDK-5, GSK-3, CK-1, DYRK-1A, CK-1, EGF-R and VEGF-R) in order to determine a lead compound 87 (0. 031 nM on CK-1 and 0. 68 microM on CLK-1). A last study consisted in modulating this compound by Suzuki cross-coupling. Finally, more than two hundred molecules were synthetized and this project opens various pharmacological perspectives
Haddoub, Rose. « Synthèse des aloisines immobilisées ». Lyon 1, 2006. http://www.theses.fr/2006LYO10299.
Texte intégralRecent results have shown that aloisine A (7-nButyl-6-(4-hydroxyphenyl)[5H]pyrrolo[2,3-b] pyrazine) is a potent inhibitor of CDK. An original methodology aiming at identifying potential secondary inhibition targets relies on the immobilization of the inhibitor on solid matrix, followed by identification of proteins with high affinity for the inhibitor by affinity chromatography of a cellular extract. To this end, both aloisine A and the negative control N-methyl aloisine bearing extended linker chain have been synthesized. We present here the preparation of the new aloisine analogues bearing a triethylene glycol chain at different positions of the molecule, terminated by an amine suitable for the immobilisation on an agarose-based matrix. Furthemore, we show that conjugation of the molecule with the linker via a cycloaddition [3+2] allows efficient coupling to the matrix as well as access to aloisine derivatives conjugated with biologically relevent molecules such as biotine, or a tyrosine residue targeting LAT1 for transport of drugs through the blood-brain barrier
Oulaïdi, Farah. « Conception et synthèse d'iminoglycolipides comme inhibiteurs d'enzymes lysosomales à effet chaperon pharmacologique ». Phd thesis, Université d'Orléans, 2011. http://tel.archives-ouvertes.fr/tel-00623109.
Texte intégralBernier, Stéphane. « Synthèse d'inhibiteurs des glutaminyl, glutamyl et aspartyl-ARNt synthétases ». Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24334/24334.pdf.
Texte intégralChabaud, Pauline [Suzanne Yolande]. « Modélisation, synthèse et évaluation des propriétés antivirales d'inhibiteurs de la protéase NS3/4A du virus de l'hépatite C ». Aix-Marseille 2, 2005. http://www.theses.fr/2005AIX22091.
Texte intégralPichon, Nicolas. « Systèmes diéniques oxygénés en cycloaddition [4+2] : synthèse de nouveaux analogues d'inhibiteurs de la farnésyltransférase. Synthèse et réactivité de diènes 1,2,3,4-trioxygénés ». Rouen, 2004. http://www.theses.fr/2004ROUES061.
Texte intégralLaconde, Guillaume. « Conception, synthèse et évaluation pharmacologique de sulfonamides et benzoindolinothiazépines modulateurs potentiels du cycle cellulaire ». Lille 2, 2002. http://www.theses.fr/2002LIL2P016.
Texte intégralDilmac, Alicia Merve. « Synthèse d'iminosucres d'intérêt thérapeutique ». Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05P609.
Texte intégralIminosugars are a family of powerful glycosidases and glycosyltransferases inhibitors. These properties give them an important therapeutic potential towards various diseases (viral and lysosomal diseases, diabetes, cancers…). A fast and efficient methodology have been recently elaborated for the synthesis of trihydroxylated 2-cyano-6-oxazolopiperidines. This methodology consists in the condensation of a chiral amine onto a polyhydroxylated glutaraldehyde in presence of potassium cyanide. The first objective of this thesis was the study of the reactivity of hexahydro-3-phenyl-6,7,8-trihydroxy-3R-[3R ,5R ,6S ,7R ,8S ,8aR]-5H-oxazolo[3,2-a]pyridine-5-carbonitrile derivatives, obtained by the methodology previously described. Their modifications were performed by alkylation of the α position to their nitrile. This gave access to ten new iminosugars. The objective of this work was the appplication of the mentioned methodology to the synthesis of configurationally related iminosugars. Trihydroxylated 2-cyano-6-oxazolopiperidines mimicking the allose, mannose and galactose configurations were obtained. These compounds were also suitable precursors for piperidine type iminosugars. For example, the hydrogenation of hexahydro-3-phenyl-6,7,8-trihydroxy-3R-[3R ,5R ,6S ,7R ,8S ,8aR]-5H-oxazolo[3,2-a]pyridine-5-carbonitrile afforded an analog of the natural compound D-allo-deoxynojirimycin. An access to pyrrolidine related iminosugars was also proposed. The biological evaluation of the twenty three new iminosugars obtained through this work will be soon performed against various glycosidases (fucosidases, glucosidases, mannosidases, galactosidases)
Toulouse, Jeanne. « Biosynthèse des isoprénoïdes bactériens : Inhibiteurs potentiels de la désoxyxylulose phosphate synthase et caractérisation des étapes de réduction dans la formation des hopanïdes ». Strasbourg, 2011. https://publication-theses.unistra.fr/public/theses_doctorat/2011/TOULOUSE_Jeanne_2011_ED222.pdf.
Texte intégralThe enzymes of the MEP pathway present in many microorganisms but absent in animals, are potential targets for developing new drugs against diseases caused by pathogenic bacteria or parasites. In this objective, the development of potential inhibitors of this pathway has been considered. The deoxyxylulose phosphate synthase (DXS), the first enzyme of the MEP pathway, was chosen as a target and analogues of its substrate, pyruvate, were synthesized and their biochemical characteristics have been established. Signals of 13C. In addition, to improve the understanding of the biosynthesis of isoprenoids, experiments were performed on Zymomonas mobilis to determine the origin of the hydrogen atoms of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) from the MEP . We are particularly interested in studying in vivo the protonation of allylic cationic intermediate in the reaction catalyzed by the last enzyme of the MEP pathway (LytB). The proton donor is the reducing cofactor (FADH2) used both as an electrons donor and protons donor. To highlight the signing of these reduction steps, the metabolism of Zymomonas mobilis is used because it allows the formation of a pool of deuterated NADPH by incubating [1-2H]glucose. Deuterium is incorporated in all reducing cofactors NADP2H and thus FAD2H2 and would be transferred to the isoprene units derived from IPP or DMAPP. The positions of deuterium were determined in hopanoids by 13C NMR by analyzing the shifted signals of 13C
Boeglin, Joel. « Diversification du châssis 1,3,5-triazépane-2,6-dione par synthèse combinatoire : Application à la recherche d’inhibiteurs de phospholipases A2 sécrétées ». Strasbourg, 2010. http://www.theses.fr/2010STRA6094.
Texte intégralThe new high throughput screening methods operated by the pharmaceutical industry has increased the demand for new substances to be tested, resulting in a rise of synthetic methods aimed at generating diversity-oriented combinatorial libraries. In this context, dipeptide-derived heterocycles are of particular interest because they take advantage of both the chemical diversity of aminoacids and the conformational rigidity of heterocyclic scaffolds to distribute pharmacophores in the 3D space. The 1,3,5-triazepane-2,6-diones developed in the laboratory are heterocycles obtained in 4 steps by cyclization of an activated dipeptide derivative carbamate precursor. These 7-membered cycles with an amide and a urea function that can be readily modified post-cyclization by alkylation or acylation of urea moiety nitrogen or by thionation of carbonyl groups around the ring. These methods have allowed the introduction of additional side chains bearing reactive functions that have been transformed to prepare biologically active compounds. To increase the diversity of the chemical library of triazepanediones, we developed 2 methods of scaffold synthesis on solid phase applicable in parallel synthesis. In vitro tests on HGV- and HGX-sPLA2s have allowed the identification of new inhibitors in the µM range. Results of co-crystallization with one inhibitor and hGX-sPLA2 suggest for the first time that it may be possible to use a structure-based design approach to further optimize these first hits
Le, Hir de Fallois Loic. « Synthèse et étude de nucléosides et nucléotides inhibiteurs de la ribonucléotide réductase ». Université Joseph Fourier (Grenoble), 1995. http://www.theses.fr/1995GRE10158.
Texte intégralDiab, Sonia Amel. « Synthèse de difluorométhylphosphonates par voies ionique et radicalaire en vue de la préparation d'inhibiteurs de Thymidine phosphorylase ». Caen, 2009. http://www.theses.fr/2009CAEN2054.
Texte intégralThis thesis is devoted to the preparation of fluorinated compounds. In particular are reported new synthetic pathways analogues of phosphates and phosphonates with a difluorométhylphosphonate function. The first introductory chapter points out the general importance of phosphates in the living world. The use of the difluoromethylphosphonates as stable mimic of phosphate in physiological medium is highlighted. The various methods of difluorophosphonates synthesis are then displayed and grouped by categories. It highlighted the difficulties encountered in the different approaches, often limiting the application of these strategies. The third chapter discusses new ways of syntheses difluorophosphonates avoiding hydrohalofluorocarbures (HCFCs). Are reported the preparations of omega-hydroxy-difluoromethylphopshonates by ring opening reactions with the phosphonodifluoromethylanion. The reaction is performed with oxacycles, lactones, and cyclic sulfates. Some work is also devoted to radical addition reactions involving the radical phosphonodifluoromethyle. The last chapter is devoted to the preparation of enzyme inhibitors and evaluation of their activities. The main objective is to produce inhibitors of thymidine phosphorylase (TPase), an enzyme involved in tumor angiogenesis
Pellegatti, Laurent. « Méthodologie en chimie hétérocyclique et application à la synthèse d'inhibiteurs de kinases ». Thesis, Orléans, 2010. http://www.theses.fr/2010ORLE2046.
Texte intégralCancer, one of the leading causes of death, represents today a major public health problem. Over the last few years, marine alkaloids represent a source of inspiration for chemists in order to obtain new anticancer drugs. For this purpose, as a part of our laboratory researches, analogues of marine alkaloids were synthesized possessing a tris-aromatic structure. We developed originals analogs of these alacaloïds formed by a central heterocycle core (1,2,4-triazine et imidazo[1,2-b][1,2,4,5]tetrazine) on wich is graft two arylic moiety variously substituted. Obtaining these compounds was also an opportunity to develop news synthetic methodologies. So a new Buchwald-Hartwig reaction type based on methylsulfanyl-1,2,4-triazines has been perfect, as palladocatalyzed CH arylation pathway on imidazo[1,2-b][1,2,4,5]tetrazine. A part is devoted to Groebke-Blackburn multicomponant reaction. Various pharmacological analyses were carried out in particular with inhibition of various kinases and cytotoxicity evaluation on various human cancer cell lines
Kuntz, Lionel. « La biosynthèse des isoprénoïdes : Une cible pour la synthèse de nouveaux antibactériens ». Strasbourg 1, 2006. http://www.theses.fr/2006STR13015.
Texte intégralIsoprenoids (menthol, cholesterol, β-carotene) are natural compounds which are present in all living organisms. Isoprenoid biosynthesis proceeds via two biosynthetic pathways, depending on the organisms. The mevalonate pathway is found in animals, fungi, the cytoplasm of phototrophic organisms, some eubacteria and archaea, whereas the 2-C-methylerythritol 4-phosphate (MEP) pathway is present in most eubacteria, in unicellular green algae and in the chloroplasts of phototrophic organisms. As the MEP pathway occurs in a number of pathogens but not in humans, all enzymes of this pathway may represent interesting targets for the development of new drugs. Among the enzymes, we focused on the deoxyxylulose phosphate reducto-isomerase (DXR). Several three dimensional DXR structures were resolved, and especially a complex with fosmidomycine, a potent inhibitor of this enzyme. This revealed the chelation of the Mn2+ cation of the active site by the retro-hydroxamate group and the fixation of the phosphonate moiety in a specific positive-charged cavity. We present here the synthesis of analogues of fosmidomycine. We chose to modify either the retro-hydroxamate group by a hydroxamate with different length of the carbon backbone, a hydrazide and a dithiocarbamate group, or the phosphonate moiety by a carboxylic acid. Biochemical studies were performed on all compounds to determine their biological activities. One of our molecules with a hydroxamate group presents an activity comparable to that of fosmidomycine, and is even active on a fosmidomycin-resistant strain of E. Coli
Sarraf, Daad. « Synthèse et propriétés d'oxindoles substitués en C-3 par une chaîne ω-aminée : application à l’inhibition du protéasome ». Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1S135/document.
Texte intégralNous nous sommes intéressés au TMC-95A, un tripeptide cyclique naturel inhibant le protéasome humain d'une façon non-covalente à des concentrations de l'ordre du nanomolaire. Nous avons montré que des mimes linéaires du TMC-95A contenant un motif 3-hydroxyoxindolyl alanine conservent l'activité inhibitrice de ce dernier. Mon travail a porté sur la synthèse d'une bibliothèque de mimes linéaires du TMC-95A en partant des amino-acides protéogéniques et des dérivés de la 3-hydroxyoxindolyl alanine. Nous avons préparé des bras espaceurs hydrosolubles contenant des motifs éthylène glycol que nous avons couplés avec les têtes inhibitrices pour l'élaboration de nouveaux inhibiteurs bivalents capables de cibler simultanément deux des six sites catalytiques du protéasome constitutif et de l'immunoprotéasome. Au cours de la synthèse de la 3-hydroxyoxindolyl alanine, il a été observé qu'en milieu basique, ce résidu C-protégé se transpose lentement et d'une façon peu décrite dans la littérature en γ-lactame. Nous avons généralisé cette réaction à la synthèse de lactames de 5 à 12 chaînons par isomérisation d'oxindoles substitués en N-1 par un groupement électroattracteur et en C-3 par une chaine ω-aminée de longueur variable. Ces oxindoles ayant une chaîne aminée ont été obtenus à partir de deux familles différentes : des composés nitrés et des dérivés N-Boc protégés. L'aptitude des différentes molécules synthétisées à inhiber le protéasome et l'immunoprotéasome a été étudiée
Liautard, Virginie. « Conception et synthèse d'imino-C-galactofuranosides comme inhibiteurs de la biosynthèse des galactanes mycobactériens ». Phd thesis, Université d'Orléans, 2008. http://tel.archives-ouvertes.fr/tel-00418214.
Texte intégralNous avons mis au point une méthodologie performante basée sur l'addition de nucléophiles silylés, assistée par acide de Lewis, sur une N-glucosylamine protégée qui a permis la synthèse d'une petite librairie de dérivés alpha-1,4-didésoxy-1,4-imino-D-galactitols substitués en position C-1. L'utilisation de séquences synthétiques convergentes, notamment une métathèse croisée, nous a ensuite conduits à des analogues de l'UDP-Galf possédant un squelette iminosucre diversement lié à l'UridineMonoPhosphate.
D'autre part, la cycloaddition 1,3-dipolaire entre un phosphonate fonctionnalisé et une nitrone cyclique de configuration D-galacto a conduit régio- et stéréosélectivement à l'isoxazolidine, analogue de l'UDP-Galf et précurseur d'UMP-beta-1,4-iminogalactitol. Cette approche concise et efficace permet également l'obtention d'analogues disaccharidiques du Galf. En effet, nous avons constaté qu'une nitrone polyhydroxylée non protégée réagit facilement, dans l'eau, avec des oléfines de sucre pour conduire au cycloadduit correspondant, précurseur d'imino-disaccharide.
L'évaluation biologique de ces composés comme inhibiteurs de l'UGM et de GlfT2 a montré qu'un analogue de l'UDP-Galf présente une activité intéressante de GlfT2.
Biteau, Nicolas Gwenaël. « Synthèse d’acyclonucléotides et hétérocycles visant l’inhibition de la Thymidylate Synthase Flavine-Dépendante ». Thesis, Orléans, 2019. http://www.theses.fr/2019ORLE3027.
Texte intégralOver the past decade, WHO has declared the emergence of multi-drug resistant bacteria as a global public health problem. In this situation, search for new bacterial enzymatic targets and development of selectively active molecules has become a key issue. In recent years, discovery of a new enzymatic target belonging to the Thymidilate synthase family by Myllykalio's team and its comprehensive study make it a promising target in the design of new active molecules. Absent in humans, present in many pathogens with many resistances, with a different structure and mechanism involving an oxydo-reducing NADPH/FAD couple, this enzyme would allow selective inhibition of pathogenic bacteria. In this manuscript, it is described at first the synthesis ANPS as mixed analogs of dUMP/FAD whose modulations relate the heterocycle and on the length of the chain by a regioselective alkylation, a cross metathesis coupling and palladium cross coupling. In a second phase the development was focus on intercalating polyazote heterocycles by SAR involving stages of regioselective alkylation, CH activation and palladium cross coupling. These various processes resulted in a library of molecules that showed low activity on Mycobacterium tuberculosis ThyX
Beauchard, Anne. « Synthèse de composés hétérocycliques à visée anti-cancéreuse ». La Rochelle, 2006. http://www.theses.fr/2006LAROS175.
Texte intégralIn an effort to develope new inhibitors of kinases as anticancer agents, we synthetized original indirubins and azaindirubins substituted in position 5, 5’, 6 and 7. Because of the poor water solubility and low bioavailability, monoxime analogs were also prepared. The effect on cyclin dependant kinase, glycogene synthase kinase-3 and on the survival of human neuroblastoma SH-SY5Y cells were estimated. On the other hand, we synthetized thiazoloindolo[3,2-c]quinolin which are closed to natural alcaloid. We reinvestigated the Graebe-Ullmann condensation under micro-wave. A new scaffold 7H-4,5-diaza-benzo[de]anthracen which is structurally closed to dercitin, a marine alkaloid, was identified. The effect on breast cancers cells, potential DNA intercalating and topoisomerase inhibition were also discussed
Parrot, Isabelle. « Synthèse et étude pharmacologique d'agents cholinergiques promnésiques : Approche par la synthèse parallèle en phase solide, et développement de ligands fluorescents ». Université Louis Pasteur (Strasbourg) (1971-2008), 2001. http://www.theses.fr/2001STR13201.
Texte intégralDessinges, Aimée. « Synthèse d'hydrates de carbone fluorés et applications biologiques (médecine nucléaire, antibiotiques, inhibiteurs d'enzymes) : les isotopes de l'oxygène en chimie des substances naturelles ». Paris 11, 1986. http://www.theses.fr/1986PA112018.
Texte intégralZelli, Renaud. « Synthèse sans catalyseurs métalliques de systèmes multivalents à base d'iminosucres, nouveaux inhibiteurs de glycosidases ». Thesis, Montpellier, Ecole nationale supérieure de chimie, 2015. http://www.theses.fr/2015ENCM0015.
Texte intégralIminosugars are naturally occurring, polyhydroxylated monocyclic (pyrrolidine, piperidine, azepane) and bicyclic (pyrrolizidine, indolizidine, nortropane) nitrogenated compounds endowed with strong inhibition activity against glycosidases, the enzymes that catalyse the cleavage of the glycosidic bonds in glycoconjugates. The development of new iminosugar derivatives is essential to obtain new treatments against diseases such as type II diabetes, cystic fibrosis or lysosomal storage disorders (Gaucher and Fabry diseases). Although the development of glycosidase inhibitors based on iminosugar clusters was not explored for a long period of time, recent studies have demonstrated that multivalent iminosugars are stronger and more selective inhibitors than the corresponding monovalent compounds. However, nearly two thirds of all the di- and multivalent iminosugars known to date, including the calixarene-based iminosugar clusters synthesized at the beginning of the thesis work, were obtained by means of the copper-mediated azide-alkyne cycloaddition (CuAAC). Unfortunately, this highly efficient reaction leads to the contamination of the multivalent compounds by significant amounts of noxious copper ions. Thus, the main aim of the present PhD research was the development of new ligation tools for the synthesis of multivalent iminosugars in the absence of metal catalysts. First, the ligations already exploited for the preparation of multivalent sugars, such as the photoinduced radical addition of thiol to terminal akenes (thiol-ene coupling) and the oxime ligation, were successfully applied to the iminosugars. Both approaches allowed the synthesis of iminosugar clusters based on calixarene and cyclopeptide scaffolds, respectively. Then, an unprecedented approach to multivalent sugars and iminosugars was developed taking advantage of the uncommon stability and reactivity of the sulfonyl fluoride moieties. The coupling of the latter with partners bearing a primary amine group afforded the corresponding sulfonamide-linked sugar and iminosugar clusters in high yield. Finally, the above-mentioned thiol-ene coupling also allowed the straightforward preparation of new iminosugar pseudo-disaccharides, a class of inhibitors endowed with higher glycosidase selectivity than the corresponding monosaccharidic iminosugar. This feature is due to the presence of the sugar unit which improves the analogy with the natural oligosaccharidic substrates of the glycosidases
Cerniauskaite, Deimante. « Glucosinolates - myrosinase : synthèse de substrats naturels et artificiels, inhibiteurs et produits de transformation enzymatique ». Phd thesis, Université d'Orléans, 2010. http://tel.archives-ouvertes.fr/tel-00739777.
Texte intégralWilland, Nicolas. « Conception et synthèse de chimiothèques généralistes et focalisées : applications à plusieurs modèles biologiques et structuraux ». Lille 1, 2003. https://ori-nuxeo.univ-lille1.fr/nuxeo/site/esupversions/93f99bde-0eae-4409-aa6a-870d1848acc5.
Texte intégralGuihéneuf, Solène. « Synthèse et évaluation biologique d'analogues d'un alcaloïde marin, le dispacamide A, contre le cancer et la maladie d'Alzheimer ». Rennes 1, 2012. http://www.theses.fr/2012REN1S070.
Texte intégralSince several years, marine molecules have been widely studied. Some of these natural compounds from marine organisms have been evaluated as kinase inhibitors in cancer or in neurodegenerative diseases (Alzheimer). Our goal is to synthesize and to evaluate marine alkaloid analogs derived from the Dispacamide A, a member of C11N5 pyrrole-imidazole family extracted from a marine sponge (Agelas Dispar) in 1992. Few pharmacologic exploration and biological evaluation are described in literature. In our laboratory, many projects combinating green chemistry (microwaves, multicomponent reactions…) and synthesis of 2-amino-imidazol-4-ones, have led to the development of new kinase inhibitors (mostly Leucettamine B analogs). Based on this experience, we aim at synthesize and evaluate new Dispacamide A analogs, derived from imidazolin-4-ones and thiazolin-4-ones, as potential kinase inhibitors against cancer and Alzheimer disease (DYRK, CDK, GSK3, CLK, PI3K, CK1). Biological screening is realized in partnership with the Station Biologique de Roscoff, the Plateforme kinase d’Orléans and the Inserm de Rennes
Souffrin, Agathe. « Conception, synthèse et évaluation pharmacologique de maléimides, inhibiteurs potentiels de l'intégrase du VIH-1 ». Thesis, Tours, 2012. http://www.theses.fr/2012TOUR3801/document.
Texte intégralOur research team has recently developed the first inhibitors of a DDE enzyme, MOS1 transposase, an enzyme similar to the HIV-1 integrase. These molecules, having a bisfurylmaleimide structure, also showed efficacy against enzymatic activities of HIV integrase. Based on these results, we undertook the synthesis of new bisfurylmaleimides in order to identify new integrase inhibitors and propose new molecules in the fight against the virus that causes AIDS. The originality of our approach is the use of MOS1 transposase as a model for designing our molecules. Methodologies used to access these molecules are essentially involving chemistry catalyzed by transition metals but also reactions of heterocyclic chemistry such as Mitsunobu, Knoevenagel or Horner-Wadsworth-Emmons reactions. All synthesized molecules has been evaluated for their inhibitory activities on the MOS1 transposase and HIV-1 integrase. Their antiviral properties against HIV were also evaluated. Parallel to this work, we investigated the reactivity of the maleimide core in palladium-catalyzed cross-coupling reactions especially in Sonogashira couplings
Letribot, Boris. « Synthèse et évaluation biologique de nouveaux composés hétérocycliques potentiellement inhibiteurs de protéine-kinases ». Thesis, La Rochelle, 2015. http://www.theses.fr/2015LAROS002/document.
Texte intégralDeregulation of protein kinases leads to numerous pathologies such as cancers and neurodegenerative diseases. In order to identify new scaffolds able to inhibit this proteins we synthesized new 3-alkenyl-oxindoles. By the mean of Appel’s salt chemistry, we develop a new synthetic route to this skeleton. Our approach allows variation of the substituent of the exocyclic akene which can be functionalized by heterocycles, amino-nitriles or thio-nitrile which are obtained after selective ring opening of (1,2,3)-dithiazoles. In another part, given powerful indirubin kinase inhibitory potency, we synthesized new analogs indiribunoids and isoindigoids. In both cases (3-akenyl-oxindoles from Appel’s salt chemistry and indigoids), the aromatic ring were substituted by various electron withdrawing group and nitrogen were incorporated to determinate structure activity relationship. All this 80 original 3-alkenyl-oxindoles were evaluated for their ability to inhibit kinase activity and cell proliferation
Juillet, Charlotte. « Conception, synthèse et évaluation pharmacologique d’analogues simplifiés de métabolites marins, inhibiteurs de la kinase Aurora B, à visée anticancéreuse ». Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASF019.
Texte intégralThis manuscript describes the design, synthesis and biological evaluation of oroidin analogs. Oroidin is a monomer of benzosceptrin C, belonging to the pyrrole-2-aminoimidazole family, isolated from marine sponges. The simplification and structural diversification approaches led us to the identification of a non-natural hit displaying selective inhibitory activity against the kinase Aurora B. This kinase plays a key role in cell division and its inhibition leads to severe mitotic abnormalities. Aurora B is found to be up-regulated in many human cancers, indicating that this kinase is a cancer-relevant target. The objective of the study at the interface between chemistry and biology is to optimize the discovered hit into a lead. The hit scaffold is divided in three parts: the 4,5-dibromopyrrole, the imidazo[1,2-a]pyrimidine and the alkyne moieties. After the first introductive chapter, chapters II to IV are dedicated to the pharmacomodulations of each part. We finally managed to synthesize eighty-two analogs for in vitro evaluations toward Aurora B and a panel of kinases involved in diverse human pathologies. Several compounds were found to be very active with IC50 down to 34 nM, displaying a 150-fold higher activity than the initial hit. The last chapter discusses the mode of action of the most active inhibitors from the hit expansion. The enzymatic kinetic assays revealed an uncommon mode of action with allosteric inhibitors (type IV) of Aurora B. Immunostaining experiments highlighted the typical effects of Aurora B inhibition in treated cells as well as its quantification. At last, molecular docking study with the best inhibitor showed the most probable allosteric binding pocket of Aurora B, providing crucial support in hit-to-lead optimization. In conclusion and perspectives, the efforts to be pursued in order to improve physicochemical and pharmacokinetic properties in the lead-to-candidate process are pointed
Decroocq, Camille. « Conception et synthèse de nouvelles classes d'iminosucres d'intérêt thérapeutique : chimie click, multivalence et maladies génétiques rares ». Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAF043/document.
Texte intégralRecently an innovative concept for the treatment of lysosomal diseases as emerged called pharmacological chaperone. Pharmacological chaperones are reversible inhibitors of the deficient glycosidases involved in these diseases. These molecules are able, at sub-inhibitory concentrations, to stabilize the enzymes and rescue them from the destruction by the quality control system of the endoplasmic reticulum. A part of the catalytic activity of the enzyme could be restored. Iminosugars are known to be an important class of pharmaceutical chaperones. During this PhD work, novel classes of mono- and multivalent iminosugars were designed and synthesized in order to identify novel pharmacological chaperones for the glycosidase: β-glucocerebrosidase involved in Gaucher’s disease and novel inhibitors of the α-glucosidases involved in the destruction of the defective protein delF508CFTR in cystic fibrosis. Several strategies were applied to achieve this aim. These strategies consist in the use of a synthetic methodology of palladium catalyzed alkenes diamination, the use of an efficient methodology to synthesize a library of novel iminosugars by click chemistry and the use of multivalency. A full study on the impact of multivalency on glycosidases inhibition was also completed by changing crucial structural parameters including valency, scaffold, linker and ligand. The first strong multivalent effect on glycosidases inhibition up to four orders of magnitude was reported with multivalent iminosugars based on β-cyclodextrin or C60 fullerene cores
Letellier, Marie-Anne. « Synthèse et évaluation pharmacologique de dérivés des noyaux 4,4-dyméthil-3,4-dihydro-1H-quinoléin-2-one et 1H-pyrrolo[2,3-b]pyridin-2(3H)-one en tant qu'inhibiteurs de la Rho-kinase en vue d'un traitement contre l'hypertension ». Tours, 2007. http://www.theses.fr/2007TOUR3803.
Texte intégralOver a billion people are suffering from arterial hypertension, a disease defined by a rise in the blood pressure in the arteries due to the abnormal contraction of the smooth-muscle. The contraction is regulated by the cytosolic calcium concentration to which the Rho/Rho-kinase intracellular pathway is associated. Designing compounds that inhibit the enzyme is of great interest. We have elaborated new potential Rho-kinase inhibitors. Various molecules were synthesized based on the 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one and the 1H-pyrrolo[2,3-b]pyridin-2(3H)-one chemistry. The new compounds were then studied by our collaborators, les laboratories SERVIER, for their activity on Rho-kinase inhibition
Oyallon, Bruno. « Conception, synthèse et évaluation de quinoxalines et d'analogues comme inhibiteurs de la kinase HsPim-1 ». Thesis, Tours, 2019. http://www.theses.fr/2019TOUR3803.
Texte intégralPim (proviral integration site for Moloney murine leukemia virus) kinases play a crucial role in cell survival, proliferation and cell differentiation as well as in apoptosis and chemoresistance. They act as oncogenic survival factors. Due to their structural features and their role in oncogenesis, Pim kinases are relevant targets for new anti-cancer therapies.Preliminary studies permitted to identify quinoxaline-2-carboxylic acid 1 as a new lead compound. This compound was able to inhibit Pim-1 in vitro activity (IC50 = 74 nM). In silico studies have shown that this compound could act as a non-mimetic ATP inhibitor. Our objective was to design and synthesize analogues of compound 1 with an optimised activity on Pim-1. These compounds were tested on a panel of mammalian kinases and on 3 leukemic cell lines
Compain, Sandy. « Conception, synthèse et évaluation biologique d'une nouvelle série d'inhibiteurs, de type N-hydroxy Pyridine-2-one, visant la méthionine aminopeptidase d'E. coli : amélioration des activités antibactériennes via les métallodrogues ». Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB094.
Texte intégralMethionine aminopeptidase (MetAP) is an ubiquitous metalloprotein present in allprokaryotes and essential to the maturation of proteins in bacteria. Despite to be also present in eukaryotes, it is an attractive target to design new antibacterial agents. Numerous inhibitors targeting MetAP have been developed these last years, but none of then have been further studied because of too low antibacterial activities. We chose to work on MetAP1 from E. coli strain (EcMetAP), as an example of Gram negative bacteria, for which several X-ray structures of the enzyme in complex with inhibitors are available in the literature. A new series of inhibitors functionalized by a 1-hydroxypyrdin-2-one (HOPO) as chelating group has been designed and synthesized. The backbone of these HOPOs has been designed by molecular modeling, starting from the X-ray structure of EcMetAP loaded with Mn(II) incomplex with simple hydroxamic acids and previously solved in the lab. Three types of ligands have been selected and further synthesized. However HOPO substituted in position 5 by a methyl indole could not be obtained, instead a polyfunctionalized molecule with a HOPO substituted by a ring-opening derivative of the indole was isolated and completely characterized. The biological activities of all the molecules were determined. Five of them displayed inhibitory effect against EcMetAP-Mn with IC50 lower than 5 μM. The antibacterial activities are modest againt a wild type E. coli strain and an E. coli strain deleted from the AcrAB efflux pump system, but the sensitivity is increased by adding polymyxin nonapeptide. So, the results can be improved using the metal- chaperone strategy previously developed in the team, which allows, by grafing a permeabilizing agent on an ancillary ligand complexed to a metal cation with the HOPO inhibitor, to favor the uptake of the drug by the bacteria
Gealageas, Ronan. « Synthèse d’analogues de la coelentérazine pour l’imagerie in vivo dynamique des signaux calciques - Synthèse d’analogues du (-)-EGCG comme inhibiteurs de Dyrk1a dans la thérapie symptomatique de la trisomie 21 ». Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112264.
Texte intégralDuring this thesis, two distinct projects were studied: on the one hand, the synthesis of coelenterazine analogs, substrate of several luciferases, in the purpose of using them for in vivo imaging, and on the other, the synthesis of (-)-EGCG analogs, inhibitor of the Dyrk1a kinase, which interests us for the role it plays in the mental retardation existing in the Down Syndrome disease.The problematic of the first project consisted in obtaining coelenterazine analogs that would not only maintain their activity on two luciferases, the Renilla luciferase and aequorine, but they should also induce a red-shift of the bioluminescence produced by these enzymes. Because of its sensitivity to calcium, aequorine was the main biologic target of this project.Seven analogs, of which six had an original structure, were synthesized through usual synthetic methodologies and their activities on both aequorine and Renilla luciferase were tested in vitro, with interesting results: even if the intensities of light emission were weaker than those obtained with native coelenterazine, several molecules produced a red-shift of the emission wavelength of bioluminescence, up to 27nm for aequorine and more than 120nm for the Renilla luciferase. The second project, of classical medicinal chemistry, mainly consisted in the synthesis of epigallocatechin gallate analogs (EGCG) with a simplified backbone and in which the pyranic ring typical of catechins was replaced by a carbocycle. Several molecules were synthesized, two of them possessing the hexaphenol motif. Their inhibiting activity of Dyrk1a was tested in vitro and one already showed a better activity than natural EGCG
Baumann, Delphine. « Synthèse d'inhibiteurs potentiels de glycosidases et d'urées cycliques de conformation restreinte ». Phd thesis, Université Blaise Pascal - Clermont-Ferrand II, 2007. http://tel.archives-ouvertes.fr/tel-00718540.
Texte intégralZipfel, Pauline. « Conception, synthèse et évaluation biologique d'inhibiteurs de MT5-MMP : nouvelle cible d'intéret thérapeutique potentiel dans le traitement de la maladie d'Alzheimer ». Thesis, Normandie, 2020. http://www.theses.fr/2020NORMC412.
Texte intégralAlzheimer's disease (AD), the most common form of dementia, is a neurodegenerative and incurable brain disorder, for which only 4 symptomatic treatments are available at this time. Because of the heavy economic and societal impacts, there is an urgent need to find new treatments that target the molecular causes of the neurodegenerative process, but these remain elusive in 2020. In this context, some matrix metalloproteinases (MMPs), in particular MT5-MMP, have been recently highlighted in the literature as potential new relevant biological targets in AD. However, the design of selective inhibitors of MMPs remains quite challenging, considering the high structural homology MMPs share. We therefore explored different drug design strategies during this thesis to find first-in-class small molecule inhibitors of MT5-MMP. This manuscript describes the experimental results of medicinal chemistry work, as well as molecular modeling studies and biological assesments. Different promising compounds were identified with good in vitro activity on MT5-MMP, opening new perspectives in the field of AD
Quellier, Pauline. « Synthèse d’inhibiteurs d’endosulfatases humaines : vers de nouveaux outils thérapeutiques contre le cancer et les maladies inflammatoires ». Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASF008.
Texte intégralEndosulfatases 1 and 2 belong to the sulfatase family and are enzymes that catalyse the 6-O-desulfation of Heparan Sulfate (HS), a polysaccharide highly sulfated belonging to the glycosaminoglycan family. HS chains interact with numerous signalling proteins including chimiokines, cytokines, growth factors ... through their sulfation pattern. By desulfating the HS chains, the endosulfatases play a key role in the signalling regulation and in the organism’s biological process. The human endosulfatase 2 (HSulf2) is over expressed in many cancers (breast, ovarian, pancreas, lungs ...) and represents thus an interesting therapeutic target. To obtain specific HSulf2 inhibitors, four oligosaccharides with different lengths, mimicking the HS chains with a sulfamoyl function were synthesised. To do so, a key step was optimised, the N, O-sulfonation. Then, the four molecules were tested to assess their capacity to inhibit HSulf2.To broaden the choice of potential HSulf2 inhibitors, monosaccharides with hydroxylamine and hydrazine function were synthesised
Abou, Hamdan Hussein. « Synthèse de nouveaux agents anticancéreux ». Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAF012.
Texte intégralCancers represent a major public health problem hence the need to use new classes of medicines. Among the opportunities for developing new treatments, two have caught our attention and that of our collaborators: the modulation of splicing by compounds such as NVS-SM2, and the inhibition of the oncogene KRAS by derivatives of natural products, the flavaglines.In this context, we have developed the first robust synthesis of NVS-SM2, which can satisfy the global demand of this agent to examine in detail its therapeutic potential in different types of disorders. In addition, the synthetic strategy reported here could be extended to new analogues of this compound. Furthermore, we have synthesized new flavaglines that have been examined for their effects on KRAS inhibition. During this study, we discovered new reactions, including a dimethylcarbamoyl chloride-induced amine inversion of configuration
Bouclé, Sébastien. « Synthèse d'analogues d'alcaloides marins à potentiel anti-tumoral ». Thesis, Tours, 2010. http://www.theses.fr/2010TOUR3803/document.
Texte intégralAt this beginning of 21th century, the cancer makes several million victims in the world every year. If this disease asserts itself as a problem of public health, the economic concern which it exercises with societies isnot less important.Carbazoles and Pyrroloirninoquinones are families of very diversified molecules belonging to alkaloids,being able to offer numerous therapeutic activities in particular as anticancer drugs.If the list of the known active molecules and their treatments connected to the molecules of natural orsynthetic origin is long, it seems c1 early that the research for new structures remains important even today topropose of new treatment or to understand better this pathology. In our approach and through diverse objectives of chemical interest, this report present the synthesis of variouscompounds, analogues of these natural molecules with potentiel antitumoral properties, with as particularity the 4,4-dimethyl-1 ,2,3,4-tetrahydroquinoleine pattern
Baglin, Isabelle. « Contribution à l'étude de nouveaux ligands sérotoninergiques en série thiénopyrrolizine et pyrroloindole ». Caen, 1999. http://www.theses.fr/1999CAEN4064.
Texte intégralTiabi, Mourad. « Préparation de chromannes, chromènes et de polyisoprenylhydroquinones : application à la synthèse de substances naturelles : précocènes, cordiachromène et dictyochroménol ». Tours, 1989. http://www.theses.fr/1989TOUR4003.
Texte intégralChevot, Franciane. « Conception et synthèse d'inhibiteurs de la tyrosine kinase Tyro3 ». Thesis, Paris 11, 2012. http://www.theses.fr/2012PA112024.
Texte intégralAfter heart diseases, cancer is the most important cause of death. Cancerous cells are normal cells which multiplication and regulation system have been affected. They anarchically grow and give tumors. We have investigated in bladder cancer which is fourth cancer among men and ninth cancer among women in industrial countries. Amongst overexpressed receptors in bladder cancerous cells, Tyro3 seems to be essential for the survival of bladder cancerous cells. First goal of this thesis is to synthesize a potent and selective inhibitor of Tyro3 with a purine scaffold. Two approaches have done. The first approach is the synthesis of a type I inhibitor whereas the second approach is the synthesis of a type II inhibitor. Two compounds have shown an interesting activity against Tyro3 at 1 µM and they seem to be type II inhibitors. The second part of the thesis was the functionalization of position 2 and 8 of purine scaffold. We show first the double deprotonation by lithium species of 6-chloro-9-(tétrahydro-2H-pyran-2-yl)-9H-purine following by substitution with different electrophiles. Obtained 2,8-di-iodine compound is engaged in Sonogashira reaction which gives 2-alkyne or 2,8-di-alkyne compunds. And, we investigate in palladium catalyzed amidation and amination of 8-iodo-6-(phénylsulfanyl)-9-(tétrahydro-2H-pyran-2-yl)-9H-purine
Saugues, Emmanuelle. « Synthèse de nouveaux inhibiteurs de kinases Pim et de modulateurs des protéines de la famille des Bcl-2, anticancéreux potentiels ». Phd thesis, Université Blaise Pascal - Clermont-Ferrand II, 2011. http://tel.archives-ouvertes.fr/tel-00743912.
Texte intégralKeita, Massaba. « Conception, synthèse et évaluation biologique d'inhibiteurs fluorés non covalents du protéasome ». Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-01059792.
Texte intégralChaillou, Bérénice. « Conception, synthèse et évaluation biologique d’inhibiteurs de PfA-M17, potentielle cible antipaludéenne ». Thesis, Mulhouse, 2015. http://www.theses.fr/2015MULH8176/document.
Texte intégralMalaria is an infectious disease due to Plasmodium parasites, still causing numerous deaths in intertropical areas of Africa, America and Asia. Existing treatments face problems of high cost and resistance, hence the need to discover new targets and to develop new compounds. This work focused on a recent antimalarial target, a bimetallic leucyl aminopeptidase, named PfA-M17. Inhibition of this aminopeptidase shows it is essential for parasite survival and growth. PfA-M17 may be involved in the last step of hemoglobin digestion during the intraerythrocytic cycle of the parasite. This study concerned the design, the synthesis and the evaluation of selective PfA-M17 inhibitors. Trisubstituted benzocycloheptane analogs were designed as PfA-M17 inhibitors, based on previous works performed in our team and based on molecular modelling. A diastereoselective pathway was developed from D-isoascorbic acid and gave trisubstituted cycloheptanes and cyclohexanes analogs. This pathway was also studied in order to get the trisubstituted benzocycloheptane scaffolds