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Ruggieri, Francesca. "Putting nature back into drug discovery : selection, design and synthesis of bioinspired chemical libraries for the discovery of new antibacterials". Electronic Thesis or Diss., Université de Lille (2022-....), 2024. http://www.theses.fr/2024ULILS013.
Pełny tekst źródłaNatural products (NPs) have declined in popularity since the introduction of synthetic small molecules several years ago. Many are the reasons behind this choice, such as difficulties in access and supply, complexities of NP chemistry and the advent of combinatorial chemistry. However, NPs offer many interesting properties compared to conventional synthetic molecules, which confer both advantages and challenges for the drug discovery process. Usually, NPs are characterized by a higher number of sp3 carbons and stereogenic centres, large scaffold diversity and structural complexity. With half of the drugs approved by the FDA since 1994 being NPs or hemisynthetic derivatives and the recent stagnation in new drug research and development, it is becoming more and more evident that NPs should be reintroduced in the drug discovery process as a source of inspiration.Therefore, many strategies are now emerging for the construction of nature-inspired chemical libraries, such as “top-down” and “bottom-up” strategies. In “bottom-up” approaches, complexity is created starting from simple building blocks. On the other hand, “top-down” approaches are assumed to make structural modifications to an already complex NP.Our presented work describes two different approaches to enrich the chemical library of our research unit with NP-derived compounds. A “top-down” semisynthetic strategy was planned to obtain derivatives of lactucin and 11β,13-dihydrolactucin, two sesquiterpene lactones extracted from chicory roots. Thirty-six ester derivatives were synthesized in three steps (classical synthesis), together with two amine derivative libraries (using parallel synthesis). All the compounds were then tested against Mycobacterium tuberculosis and some promising hits were found (MICGFP < 1.2 μM). On the other hand, a “bottom-up” strategy allowed the synthesis of two analogues of the known natural antibiotic hygromycin A. This approach started from simple commercially available building blocks and employed a dearomatization strategy in the synthetic process.Together, we explored a broader chemical space, increased the structural diversity of our chemical library and discovered new potential antibacterial hits. Moreover, this work paves the way for the discovery of new antibacterial targets
Schmitt, Benoît. "5,6,7,8-tétrahydro-1,6-naphtyridines : dérivés et analogues structuraux". Université Louis Pasteur (Strasbourg) (1971-2008), 2004. http://www.theses.fr/2004STR13210.
Pełny tekst źródłaMaiga, Soufiana. "Synthèse et études photobiologique et pyronocoumarines, analogues des psoralènes". Paris 11, 1991. http://www.theses.fr/1991PA114843.
Pełny tekst źródłaSimon, Gaëlle. "Analogues et dérivés des méridianines : Synthèse et Étude structure-activité biologique". Brest, 2004. http://www.theses.fr/2004BRES2011.
Pełny tekst źródłaThe marine environment constitues a very promising source for novel and bioactive molecules, and meridianins have been identified among those recently discovered. These indoles with a 2-aminopyrimidine at C-3 can inhibit cyclin-dependent kinases. In order to conduct additionnal biological tests about these 3-(2-aminopyrimidine)indoles, we first synthesised NH meridianin-analogues through two routes: (i) a Miyaura-Suzuki coupling of indol-3-ylboronic acids to 2-amino-4-chloropyrimidine, and (ii) the formation of a 2-amino-pyrimidine by guanidine condensation with enaminones issued from the reaction of N,N-dimethylformamide dimethylacetal (DMF-DMA) with 3-acetylindoles. Then, in a second stage we prepared N-alkyled derivatives of meridianins by applying the same linear synthesis, using pyrrolidine for the formation of enaminones. At last, various derivatives were prepared by replacing the indole with the 1,2,3,9-tetrahydro-4H-carbazol-4-one cycle or using various pyrimidines. Some of these molecules were finally tested against cyclin-dependent kinases (GSK-3 and CDK1) and cell lines (RAJI, DAUDI and K562) as part of cancer-related researches. Other tests about the fixation of barnacle larvae were also performed to investigate the antifouling properties of these new molecules
Bayrakdar, Hassan. "Synthèse et activité biologique (spectre antibactérien, inhibition de l'ADN gyrase) d'analogues ouverts et monocycliques des quinolones". Nancy 1, 1992. http://docnum.univ-lorraine.fr/public/SCD_T_1992_0428_BAYRAKDAR.pdf.
Pełny tekst źródłaColacino, Evelina. "Synthèse et étude de nouveaux analogues de nucléosides pyrimidiques modifiés sur la base hétérocyclique". Montpellier 2, 2002. http://www.theses.fr/2002MON20074.
Pełny tekst źródłaChioua, Rachid. "Synthèse, structure et réactivité de dérivés de la 1H-pyrazolo[3,4-c]pyridine. Analogues acycliques de nucléosides". Montpellier 1, 1992. http://www.theses.fr/1992MON13526.
Pełny tekst źródłaCharbonnier, Florence. "Synthèses, études structurales et propriétés de complexation d'Ureido-oligosaccharides supramoléculaires". Nancy 1, 1999. http://www.theses.fr/1999NAN12008.
Pełny tekst źródłaJanin, Yves. "Analogues et dérivés inédits des benzo[c]phénanthridines antitumorales. Synthèse et étude biologique". Phd thesis, Université Pierre et Marie Curie - Paris VI, 1993. http://tel.archives-ouvertes.fr/tel-00175198.
Pełny tekst źródła- La découverte d'une nouvelle méthode de synthèse des alcoxy-1-aminonaphthalènes à partir des 1-tétralones correspondantes. A partir de ces amines, la généralisation d'une voie d'accès aux 7,8,9,10-tétrahydro benzo[c]phénanthridin-6(5H)-ones nous a permis de synthétiser 16 dérivés des benzo[c]phénanthridines mono ou bifonctionnalisées.
- Une étude de la voie d'accès aux benzo[c]phénanthridines selon Robinson a été réalisée pour préparer les analogues tétraoxygénés. A ce sujet, nous avons trouvé des conditions de préparation de 2-aryl-1-aminonaphthalènes, jamais décrites auparavant, à partir de 2-aryl-1-tétralone oximes utilisant la réaction de Semmler-Wolff. Au départ de ces amines nous avons pu préparer les uréthanes correspondants, dont la cyclisation thermique engendre les benzo[c]phénanthridin-6(5H)-ones, facilement transformées en dérivés 6-chlorés. Tandis que la substitution de ces derniers par les amines conduit aux analogues tétraoxygénés, cette synthèse correspond aussi, formellement, à une nouvelle voie d'accès aux alcaloïdes de cette famille.
- Par ailleurs, la condensation entre la 6-méthoxy-1-tétralone, le propiolate de méthyle et l'ammoniac qui conduit à la 8-méthoxy-5,6-dihydrobenzo[h]quinoléin-2(1H)-one a permis de préparer quatre dérivés du noyau benzo[h]quinoléine substitués en position 2 par les mêmes chaînes aminées que ci-dessus.
Les résultats des tests de cytotoxicité effectués pour l'ensemble des dérivés aminés, de même que l'activité antitumorale de certains d'entre eux, sont décrits.
Benjahad, Abdellah. "Synthèse, analyse structurale et évaluation antivirale de nouveaux analogues de nucléosides de types pyrazinique et pipérazinique". Limoges, 1996. http://www.theses.fr/1996LIMO0011.
Pełny tekst źródłaGulberti, Sandrine. "Caractérisation structurale et fonctionnelle de la galactose-bêta1,3-glucuronosyltransférase-I recombinante humaine (GlcAT-I)". Nancy 1, 2003. http://www.theses.fr/2003NAN12503.
Pełny tekst źródłaMathieu, Romain. "Dérivés d'adénines et pyrazolotriazines isostères : synthèses et relations structure-activité". Strasbourg 1, 2004. http://www.theses.fr/2004STR13219.
Pełny tekst źródłaThe adenine derivatives are widely distributed in nature and regulate a broad range of cell functions. We have first focused our interest on the adenine derivatives substituted at the 2-position in order to develop new P2Y1 receptor antagonists. Various 2-substituted derivatives of MRS-2179 (N6-methyl-2'-deoxyadenosine-3',5'-bisphosphate) have been synthesized with the goal to better understand structure-activity relationships around this position. Thus, we have adopted a chemical pathway using a selective 2-stannylation of 6-chloropurine on the 2'-deoxyadenosine scaffold, for an efficient synthesis of the 2-iodo intermediate (5 steps, 18% overall yield). Then, the palladium-catalyzed cross-coupling reactions allowed us to introduce various substituents at 2-position in high yields. Finally, the hydroxyls 3' and 5' were phosphorylated to afford the desired nucleotides. This topological exploration of the P2Y1 receptor highlighted a medium hydrophobic pocket which tolerated alkyl substituents until propyl. The 2-ethynyl derivative (LPI-448) was 10-fold more potent than the reference MRS-2179 and strongly inhibited in vitro platelet aggregation. Then, we continued this exploration by means of an isosteric pyrazolo[1,5-a]-1,3,5-triazines series in order to discover new interactions. Various substituents (functional groups linked to the heterocycle by an alkyl chain of variable length) were introduced at 8-position in good yields through Sonogashira and Heck cross-coupling reactions. Among this series, ten derivatives strongly inhibited PDE-4 and the lead compound (LPI-444) exhibited remarkable properties (IC50 = 31 nM and excellent PDE-1, 2, 3, 5 selectivities)
Auguste, Marie-Laure. "Synthèses de dérivés nucléosidiques en série triazole et à conformation restreinte à visée antitumorale". Montpellier 2, 2007. http://www.theses.fr/2007MON20176.
Pełny tekst źródłaRycke, Nicolas de. "Nouveaux analogues de la DMAP : synthèse et réactivité". Versailles-St Quentin en Yvelines, 2011. http://www.theses.fr/2011VERS0024.
Pełny tekst źródłaCatalysts which act as Lewis bases show a growing interest because of their capacity to promote a significant number of transformations in organic synthesis. Specifically, since its discover at the end of the 1960’s, 4-(dimethylamino)pyridin (DMAP) has been studied and introduced to accelerate the rate of several reactions such as the acylation of tertiary alcohols. The reactivity of this derivative is sometimes limited with deactivated substrates leading to a very slow conversion in products. First, we were interested on the synthesis of tricyclic triaminopyridins, strong analogs of DMAP and their reactivity was studied with the determinations of kinetic N and Lewis parameters thermodynamic basicity. Secondly, we prepared a new class of chiral DMAP derivatives, the structure of which is included in a paracyclophanic backbone. In parallel to this work, we developed a new nucleophilic probe which was involved in the comparison of the reactivity of aziridinium and azetidinium towards nucleophiles, by measuring their ring opening rates by UV-visible and RMN 1H spectrophotometry. Finally, the last part of this pH. D. Work was about the design and the synthesis of organocatalytic cages. This kind of derivatives would encapsultate substrates within its cavity to promote chemical reactions like enzymes do, while avoiding their difficulties of use such as a limited stability under certain protocols
Zgani, Ibrahim. "Synthèse et évaluation biologique de nouveaux analogues de pyrophosphates de prényles". Montpellier 2, 2001. http://www.theses.fr/2001MON20077.
Pełny tekst źródłaLabssita, Youssef. "Conception et synthèse de nouveaux dérivés benzopyroniques et de leurs analogues comme ligands des récepteurs sigma". Toulouse 3, 1996. http://www.theses.fr/1996TOU30025.
Pełny tekst źródłaSalmi, Chanaz. "Conception et évaluation des activités antimicrobiennes de nouveaux dérivés aminostéroïdiens analogues de la squalamine". Aix-Marseille 3, 2007. http://www.theses.fr/2007AIX30028.
Pełny tekst źródłaExtensive use of antibiotics has raised a serious public health problem due to infections caused by multidrug-resistant bacterial pathogens. Consequently, there is a pressing need to develop new antibiotics to keep pace with bacterial resistance. Recently, a new cationic sterol, squalamine has been isolated from tissues of the dogfish shark Squalus Acanthias exhibiting potent antimicrobial activities. The synthesis of numerous squalamine analogues has been realized involving a diastereoselective titatium reductive amination reaction developed in our laboratory. A structure–activity relationships study has been conduced in order to determine the influence of polyamino, hydroxyl and sulfate moieties on the encountered antimicrobial activities
Fougère, Cécile. "Nouvelle méthode de synthèse de dérivés phosphiniques : Application à la synthèse de nouveaux biomimétiques dérivés de peptide et de PNA". Paris 13, 2009. http://www.theses.fr/2009PA132017.
Pełny tekst źródłaThe use of oligonucleotides and peptides as more selective drug is a new strategy more and more studied to treat several diseases. However the main drawback in the use of these macromolecules as therapeutic agent is their poor stability in biological media. A solution could be to synthesize mimetic with improved properties. In our work we focused on the development of oligonucleotide mimics: peptide nucleic acids PNA and on peptide mimic. For these two mimics we choose to replace amide bond in the peptidic or pseudopeptidic structure by a phosphinic linkage, in order to increase for the peptide the stability towards enzymatic degradation and for the PNA to increase the aqueous solubility. First, we developed a new methodology for the obtaining of asymmetric phosphinic acids (R’P(O)OHR’’). This new synthetic strategy is carry out in mild conditions which allowed the use of functionalized substrates. We then apply this methodology to the synthesis of a simple dipeptide Gly[P(O)(OH)CH2]Gly and secondly of a dipeptide Ala[P(O)(OH)CH2]Ala. We evaluated the incorporation of this later dipeptide in the sequence of an antiangiogenic peptide (A-p-AWLPPR). The last aspect of this work was to study several strategies for the obtaining of a phosphinic dimer synthon of PNA: TpT which could be introduced in diverse position in a PNA sequence (TTTTCTTTT): the sequence of HIV-1 polypurin Tract (PPT) RNA
Mialhe, Samuel. "Synthèse et étude de 2'-C-méthyl-β-D-ribonuléosides à visée anti-hépatite C : dérivés de l'imadazole, dérivés puriques modifiés en position 6, analogues 5'-phosphonates". Montpellier 2, 2005. http://www.theses.fr/2005MON20158.
Pełny tekst źródłaPierra, Claire. "Analogues nucléosidiques et pronucléotides inédits d'anomérie Bêta et d'énantiomérie non naturelle L : synthèse et propriétés antivirales de dérivés de l'adénosine, de la 5-chlorouridine et de la 5-chlorocytidine". Montpellier 2, 1997. http://www.theses.fr/1997MON20135.
Pełny tekst źródłaLevkov, Igor. "Réactivité du 1-aminoisoindole, de ses dérivés et analogues : action des diénophiles en milieu homogène et structuré". Toulouse 3, 2013. http://thesesups.ups-tlse.fr/2054/.
Pełny tekst źródłaWith the Curtin-Hammett principle for the first time isoindoles which are mainly exist in the isoindoline tautomeric form were introduced into the reaction with cyclic dienophiles and the products of these reactions were obtained. We synthesized a series of surfactantson the basis of isoindoles with long alkyl chains and studied their physico-chemical properties of aggregation in water and formamide. The reactivity of 1-aminoisoindole was compared in homogeneous and structured media. It has been shown that structured environment can act as a catalyst in the interaction with maleimides. In the case where the concentration of amphiphilic derivatives of aminoisoindole is lower than the critical aggregation concentration (homogeneous medium), the reaction with maleimide does not happen. We proposed two new methods of the synthesis of fluorescent derivatives of 4-aminobenzo[f]isoindole which have some advantages over described in the literature including the velocity of the reaction, simple way of obtaining products with high purity and better yields
Correia, José. "Synthèse, caractérisation et propriétés de copolymères dérivés du poly(chlorure de vinyle) analogues a l'héparine". Paris 13, 1995. http://www.theses.fr/1995PA132035.
Pełny tekst źródłaLepretre, Jean-Claude. "Synthèse et étude électrochimique de sels de pyridinium 3,5- disubstitués modèles du NAD+ : réactivité et comportement de leurs analogues réduits". Grenoble 1, 1992. http://www.theses.fr/1992GRE10032.
Pełny tekst źródłaBattaglia, Eric. "Contribution d'inhibiteurs compétitifs, de sondes électrophiles et de marqueurs de photoaffinité à l'étude du site actif de l'UDP-glucuronosyltransférase recombinante humaine UGT1*6 (conjugaison des composés phénoliques plans)". Nancy 1, 1993. http://docnum.univ-lorraine.fr/public/SCD_T_1993_0434_BATTAGLIA.pdf.
Pełny tekst źródłaStorme, Thomas. "Conception, synthèse et évaluations d'analogues de l'ifosfamide à moindres neurotoxicité et néphrotoxicité induites". Paris 5, 2007. http://www.theses.fr/2007PA05P625.
Pełny tekst źródłaIfosfamide is a useful prodrug with CYP450 metabolisation associated to both antitumor activity and toxicities. Current evidence suggests that chloroacetaldehyde, a side-chain oxidation metabolite is responsible for neurotoxicity and nephrotoxicity. The aim of our research is to prevent chloroacetaldehyde formation. First, we designed and synthesized new enantioselective synthesized ifosfamide analogues i. E. C7,C9-dimethyl-ifosfamide. Two topics were investigated. First, metabolites determination of the IFO analogues was performed using HPLC-MS² after in vitro biotransformation by drug-induced rat liver microsomes. Secondly, the cytotoxicity of these prodrugs was evaluated. Finally, a mechanistic study using 31P-NMR kinetics allowed to estimate the alkylating activity of the modified mustards. Secondly, electrochemical biomimetic oxidation and preactivation of IFO were studied. This is a first step toward vectorisation of IFO
Zerbet, Mohamed. "Dérivés du benzamidazole à finalité thérapeutique : analogues du Hoechst 33258 et des NICE-NU (NitroImidazole ChloroEthyl NitrosoUrées)". Montpellier 2, 1990. http://www.theses.fr/1990MON20294.
Pełny tekst źródłaJourdan, Fabrice. "Synthèse, études physicochimique et pharmacologique d'inhibiteurs potentiels de la transcriptase inverse comprenant différents analogues de nucléosides cycliques et acycliques thiéno et dihydrothiénopyrimidiniques, différentes pyridin-2-ones et pyrido[3,2-ƒ]pyrollo[1,2-a]diazépines". Caen, 1996. http://www.theses.fr/1996CAEN4018.
Pełny tekst źródłaLe, Roux Antoine. "Synthèse et activité biologique de dérivés et analogues de l’acide pulvinique pour une application en protection contre les rayonnements ionisants". Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/LE_ROUX_Antoine_2010.pdf.
Pełny tekst źródłaThe objective of this thesis was to synthesize and to evaluate the biological activity of hydrophilic derivatives and structural analogues of pulvinic acid, derived from norbadione A, a naturally occurring antioxidant found in mushrooms. This study aimed to develop new protective agents against ionizing radiations. First a scalable synthesis of a bis-lactone as a common intermediate was developed. It is based on the condensation and dehydratation of the anion of a protected tetronic acid on methyl pyruvate and subsequent selective demethylation in presence of magnesium bromide. This intermediate was then employed to prepare several hydrophilic derivatives by regioselective ring-opening of one lactone by functionalized amines. The second study was based on the creation of an in silico activity-predicting model allowed to highlights derivatives of 3-aryl-4-hydroxycoumarines as potential antioxidants. A synthesis pathway was used to prepare several derivatives to perform a structure-activity relationship study. All synthesized compounds were then tested in an in vitro assay, to investigate their radioprotective properties. Radiosensitive cells were exposed to the different compounds and irradiated, after several days their viability was assessed. Finally a third study was conducted to investigate the chelating activity of pulvinic acids towards 137Cs in order to develop new detoxifying agents
Brajeul, Solenn. "Produits naturels terpenoïdes dérivés d'acylphloroglucinols : travaux exploratoires en vue de la synthèse du xanthochymol et de ses analogues". Paris 11, 2005. http://www.theses.fr/2005PA112288.
Pełny tekst źródłaXanthochymol and guttiferones E and F are polyisoprenylated acylphloroglucins which inhibit the desassembly of miciotubules into tubulin. We have a project of total synthesis of these molecules using biogenesis hypothesis. Firstable, some studies about biomimetic synthesis have been done. Preparation of benzoylphloroglucinol has been studied. Then, prenylation under mild conditions using sulfonium salts have been studied. Finally some original electrophilic aromatic substitution have been developped using these salts. In a second part, the construction of the bicyclic moiety has been studied which has given several prenylated intermediairies. The synthesis of a polyprenylated β-ketoester has allowed the study of several methods to synthesize the bicycle. We observed great difficulties to get the bicycle due to the important steric hinderance mostly due to the gem-dimethyle. The synthesis of a diprenylated cyclohexanone should be usefull for the next studies. Finally the activity towards assembly or disassembly of microtubules has been studied for all the intermediary compounds
Vidil, Carole. "Synthèses et évaluations biologiques de phosphonates analogues du mannose 6-phosphate, substrats potentiels du récepteur mannose 6-phosphate". Montpellier 2, 1997. http://www.theses.fr/1997MON20247.
Pełny tekst źródłaMathé, Christophe. "Nouveaux analogues nucléosidiques à visée antivirale : synthèse et étude de dérivés du DRB et de nucléosides de configuration non naturelle L". Montpellier 2, 1994. http://www.theses.fr/1994MON20138.
Pełny tekst źródłaRaboisson, Pierre. "Développement d'inhibiteurs de phosphodiestérase 4 et conception d'antagonistes purinergiques P2Y1 à partir de dérivés de l'adénine et de leurs analogues structuraux". Université Louis Pasteur (Strasbourg) (1971-2008), 2000. http://www.theses.fr/2000STR13243.
Pełny tekst źródłaMontoir, David. "Synthèse de nouveaux analogues de la novobiocine, inhibiteurs potentiels de la Hsp90". Nantes, 2015. http://archive.bu.univ-nantes.fr/pollux/show.action?id=6c48ca52-acbc-4cf1-aaa9-deed157ff1bc.
Pełny tekst źródłaThe 90-kDa Heat shock protein (Hsp90) is an ATP-dependent chaperone known to play a crucial role in protein homeostasis. Hsp90 is directly involved in the conformational stability of « client proteins », many of which are associated with cancer cell survival. Thus, Hsp90 inhibition represents an attractive route for the development of new anticancer drugs. Novobiocin, an aminocoumarin antibiotic, was reported to inhibit Hsp90 targeting C-terminal domain, and showed anti-proliferative properties (IC50 = 700 μM in SKBr3, breast cancer cell line). The work presented here describes the synthesis of new analogs of novobiocin derived from 1,6- naphthyridin-2(1H)-one and 1,6-naphthyridin-4(1H)-one series. Newly synthesized compounds were evaluated against breast cancer cell lines for their antiproliferative activities and selected regarding their capacity to bind the mammalian Hsp90 and its fragments. The best candidates were subsequently tested by Western blot analysis to measure their ability to induce degradation of Hsp90 client proteins. In parallel a synthetic methodology involving palladium-catalyzed coupling reactions was developed to produce original 3,7-disubstituted 1,6-naphthyridin-2(1H)-ones
Kervio, Eric. "Synthons oxo alkyl-1,1-bisphophonates, intermédiaires dans l'obtention d'indoles 2 et/ou 3-alkyl-1',1'bisphophonates selon la réaction de cyclisation de Fischer : ciblage pharmacologique sur quelques analogues et conjugués de l'indométhacine". Brest, 1996. http://www.theses.fr/1996BRES2060.
Pełny tekst źródłaBouraiou, Abdelmalek. "Synthèse d'hétérocycles quinoléiques à visée thérapeutique et d'analogues structuraux de produits naturels". Rennes 1, 2009. http://www.theses.fr/2009REN1S126.
Pełny tekst źródłaThis manuscript describes the preparation of new quinolines derivatives associated to heterocycles eg. Aziridine, pyrrolidine or pyrrole and some structural analogues of flavanones, flavonols and tetrahydroquinolones. In this context, we have developed two methods. The first one consists on the generation of the N-metalated azométhine ylide from a -iminoesters in presence of LiBr in basic medium. The second one is based on the thermolysis of the N-alkylaziridine, which react with DMAD to offer N-alkylpyrroles and Delta-pyrrolines. In second part, we have reported the synthesis of new heterocyclic compounds with likely flavonoïd structures incorporating a quinoline unit, from the corresponding 2-hydroxy and 2-aminochalcones. These intermediates were utilized for the preparation of some new compounds that have a similar structure of flavanones, flavonols, 3-hydroxy-2,3-dihydroquinolin-(4)-ones. A new synthetic approach concerning the preparation of 1,2,3,4-tetrahydroquinolin-(4)-one derivatives through an intramolecular cyclization using a microwave irradiation have used with success
Dembele, Ousmane. "Design, synthèse et étude biologique de dérivés à structure imidazo[4,5-c]-1,6-naphtyridin-2(1H)-one et analogues structuraux à visée antiproliférative". Thesis, Nantes, 2018. http://www.theses.fr/2018NANT4004.
Pełny tekst źródłaProtein kinase is a promising target for the treatment of many cancer pathologies. Enzymes effecting phosphorylation of proteins by transferring a phosphate group of ATP to a substrate protein. The latter then makes a conformational change that gives it new functions. If their action is performed on a phenolic amino acid, it will be called tyrosine kinase (TK) but if it is performed on a non-aromatic alcoholic amino acid, it will be called serine / threonine kinase (STK). The inhibition of its activity represents an important stake in the discovery of new anticancer molecules, thanks in particular to the knowledge of their structural organization. The original idea was to build on a marine-based structure to develop a drug discovery work. It was chosen from the structure of the grossularines A and B extracted from a marine tunicate (Dendrodoa grossularia) as a model since we had anteriority in the work on this type of structure. This made it possible to envisage the development of analogues and / or derivatives of these grossularins, with, in series pyridazinoindole, the identification of hits on PI3K or DYRK1A. Our work focuses on the synthesis of new original imidazo-naphthyridinone series molecules and structural analogues potentially inhibitory to kinases. The synthesized compounds were evaluated in parallel by the Roscoff Biological Station on a panel of kinases (HASPIN, CLK1, DYRK1A, CDK5, CDK9, and GSK3α/β and CK1)
Brunin, Thierry. "Conception et synthèse de dérivés de la camptothécine inhibiteurs potentiels de la topoisomérase I". Lille 2, 2004. http://www.theses.fr/2004LIL2S028.
Pełny tekst źródłaCancer is one of the most worrying and widespread disease in industrial countries. This disease is due to an anarchic proliferation of cells. Topoisomerase I and II are enzymes involved in cell division. Topoisomerase I is overexpressed in many types of cancer, so its inhibition is a pathway to fighting cancer. Camptothecin is a natural alcaloïd well known for many years for its antitumor properties. Its way of action is the inhibition of topoisomerase I. However, it shows too much toxicity to be used as a medicine. We have synthesised new derivatives of camptothecine modified at position 5
Saniere, Laurent. "Conception de petits peptides et peptidomimétiques dérivés de l'arginine comme modulateurs de la nociception : accès aux 4,5-dihydrotriazinones analogues rigides de dipeptides. Synthèse totale de l'enduracididine". Université Louis Pasteur (Strasbourg) (1971-2008), 2001. http://www.theses.fr/2001STR13154.
Pełny tekst źródłaGrifon, Jean-François. "Analogues nucléosidiques inédits d'anomérie Bêta et d'énantiomérie non naturelle L : synthèse, propriétés antitumorales et antivirales de dérivés de la 5-fluorouracile et de la 5-fluorocytosine". Montpellier 2, 1998. http://www.theses.fr/1998MON20011.
Pełny tekst źródłaTian, Wen. "Etude phytochimique de Zanthoxylum unifoliolatum T. G. Hartley, ined. : synthèse et activité biologique de dérivés aminés et d'aza-analogues de la benzo[b]acronycine". Paris 5, 2004. http://www.theses.fr/2004PA05P617.
Pełny tekst źródłaThe first part of this work describes the chemical investigation of a new neocaledonian endemic species of Zanthoxylum, Zanthoxylum unifoliolatum. From the bark of Zanthoxylum unifoliolatum T. G. Hartley, ined, were isolated one coumarin and twelve alkaloids, two furoquinolines and ten benzo[c]phenanthridines. Two compounds of the benzo[c]phenanthridine series are new and were determined on the basic of the spectral data as the 6-methoxynoravicine and the 6-methoxynornitidine. The alkaloid acronycine ( 6-methoxy-3,3,12-trimethyl-3,12-dihydro-7H-pyrano-[2,3-c]acridin-7-one ), first isolated from Acronychia baueri Schott (Rutaceae), was subsequently shown to exhibit a broad spectrum of activity against numerous experimental tumors models. Neverthless, clinical trials gave only poor results, probably due to the moderate potency of this alkaloid. Further on, structural analogues with an additional aromatic ring linearly fused on the natural alkaloid skeleton were developed, and several cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one diesters proved even more potent. Among them, the cis-1,2-diacetate, currently under preclinical development under the code S 23906-1, and two series of amino derivatives have been prepared. Their in vitro cytotoxic activities have been evaluated against the murine L1210 leukemia cell line and the human colon tumor HT29, and are shown to exhibit cytotoxic activities comparable to those of their benzo[b]acronycine counterparts. One of the compounds is currently evaluating in vivo against the tumors colon 38 in mice
Gasnereau, Anne. "Conception, synthèse et évaluation pharmacologique d'analogues tétrahydroisoquinoléiniques et isoquinoléiniques de la mélatonine". Lille 1, 2005. https://pepite-depot.univ-lille.fr/LIBRE/Th_Num/2005/50376-2005-Gasnereau.pdf.
Pełny tekst źródłaDesfougères-Fontaine, Aline. "Synthèse d'isoflavones prénylées dérivées de la génistéine". Université Joseph Fourier (Grenoble), 1997. http://www.theses.fr/1997GRE18002.
Pełny tekst źródłaMinard, Corinne. "Doubles couplages de Suzuki-Miyaura sélectifs sur des dérivés dihalogénés symétriques - Application à la synthèse de la ningaline B et de ses analogues". Phd thesis, Université Paris Sud - Paris XI, 2013. http://tel.archives-ouvertes.fr/tel-00919884.
Pełny tekst źródłaVille, Alexia. "Métabolites secondaires et analogues hémisynthétiques en série vitaminique E : Obtention et évaluation du potentiel anti-inflammatoire". Thesis, Angers, 2018. http://www.theses.fr/2018ANGE0062.
Pełny tekst źródłaMany studies highlighted the biological potential of tocotrienols (T3), a vitamin E subfamily, especially in the field of cardiovascular diseases and chronic inflammation. A phytochemical study, previously conducted at SONAS, led to the isolation and characterization of δ-amplexichromanol (δ-AC) as the main and original secondary metabolite from Garcinia amplexicaulis barks (dichloromethane extract) along with other oxidized T3 analogs such as δ-garcinoic acid (δ-GA). A pharmacophore based virtual screening of these derivatives against various anti-inflammatory targets showed that this class of T3 analogs could be considered as potential 5-LOX inhibitors. It was confirmed by in vitro assays when δ-AC and δ-GA were evaluated as inhibitors of purified 5-LOX, or in polymorphonuclear leukocytes. We then decided to carry on our study to further understand the original mode of action of these metabolites while optimizing the anti-inflammatory properties of the first hits. Such approach requires large amounts of tocotrienolic derivatives. However, usual natural sources of T3 provide complex mixtures involving particularly challenging purification processes. Thus, this work aim at designing efficient semisynthesis towards pharmacologically relevant T3 derivatives were developed from -GA, the main T3 derivative isolated from Garcinia kola nuts, a renewable and easily available vegetal source. Moreover, pharmacomodulation of the tocotrienolic backbone relied on preliminary docking studies and then required the development of various synthetic strategies to access original vitamin E analogs as potential 5-LOX inhibitors
Brossard, Dominique. "Synthèse de stéroïde-hétérocycles azotés analogues d'alcaloïdes stéroïdiques à activité anti-tumorale sur des lignées cancéreuses du colon et inhibiteurs d'enzymes impliquées dans les cancers hormono-dépendants". Caen, 2011. http://www.theses.fr/2011CAEN4073.
Pełny tekst źródłaThis work concerns the synthesis of heterocycle-steroid hybrids for promising therapeutic strategy. After a general literature review of heterocycle-steroid and nitrogen-containing heterocycle-steroid derivatives of cholic acids and androstene, syntheses of bile acid derivatives, androstene derivatives and cholesterol derivatives were carried out. The synthesized derivatives have been the subject of biological assays. On the one hand the activity studies of cholic acid derivatives on glioblastoma multiform, multiple myeloma and colonic carcinoma cell line, on the other hand the activity studies of cholic acid derivatives, abiraterone analogues and cholesterol derivatives as inhibitors of cytochrome P450 CYP 17 and CYP 19 (aromatase), therapeutic targets on hormone-dependent cancers. Promising results have been obtained, especially concerning cholic acid derivatives on colonic carcinoma cell lines, these derivatives acting by a pro-apoptotic mechanism. Abiraterone analogues showed good inhibition of cytochrome P450 CYP 17 and CYP 19 by interaction with the heme moiety of the enzyme. The experimental part of this document describes the procedures and physicochemical data of new synthesized compounds. Nearly 120 bibliographical references place this study in its chemical and biological context
Brugier, Delphine. "Synthèse et réactivité de β-aminothiophènes diversement substitués". Rouen, 1999. http://www.theses.fr/1999ROUES036.
Pełny tekst źródłaBillard, Luc. "Nouvelles méthodes de synthèse d'analogues de nucléosides". Limoges, 2001. http://www.theses.fr/2001LIMO0045.
Pełny tekst źródłaThe aim of this work is to report new methods of synthesis of nucleoside analogs. .
Marty-Tommasi, Laurence. "Modélisation du centre actif de métalloprotéines à fer non hème. Complexes du fer avec des analogues de PQQ et des ligands à donneurs soufre et N-imidazole". Toulouse 3, 1995. http://www.theses.fr/1995TOU30022.
Pełny tekst źródłaChaulet, Charlotte. "Synthèse et étude du mécanisme d'action de nouveaux analogues de la thalidomide, dérivés du noyau 1H-pyrrolo (2, 3-b) pyridine, sur la modulation des cellules NK et la production des cytokines TNF-a et IL-6". Thesis, Tours, 2010. http://www.theses.fr/2010TOUR3802/document.
Pełny tekst źródłaThalidomide is a sedative hypnotic on the market for the first time in Germany in October 1957 and subsequently sold widely in the 46 countries under 51 different trade names. It was also used as antiemetic in pregnant women and from the Christmas Day of 1956, a first child with phocomelia born, six months before placing on the market. Thalidomide was withdrawn from the market in late 1961, because of its devastating effects on fetal development. Many mechanisms of action of thalidomide embryopathy have been reported, including an antiangiogenic effect with inhibition of neurovascularisation during limb development during fetal life. Subsequently, thalidomide has emerged as a treatment of many diseases. It was also demonstrated its ability to induce an increase or inhibition of expression of chemokines or growth factor. The development of new molecules like more effective remains the focus of many research studies. Based on studies on the regulation of cytokines production and modulation of NK cells by thalidomide and its analogs, we worked on the 1H-pyrrolo [2,3-b] pyridine. This study led us to functionalize 7-azaindole on various positions and by different organic synthesis: desulfonylation, Michael addition, peptide coupling… These synthetized compounds have been tested in pharmacologic studies
Petrocchi, Consuelo. "Synthèse de nouvelles nitrones ß-phosphorylées (PPNs) dérivées de la PBN et leurs analogues vectorisés pour le ciblage mitochondrial : évaluation par RPE et mesure de l'activité antioxydante et vasorelaxante dans un modèle d'endothélium aortique". Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM4739/document.
Pełny tekst źródłaNitrones are diamagnetic compounds commonly used as probes to monitor biological free radical formation by the spin trapping (ST)/electron paramagnetic resonance coupling (EPR). In addition the growing interest in the therapeutic potential of α-phenyl-N-tert-butylnitrone (PBN) derivatives led researchers to develop analogs having improved protective properties and bioavailability. Among these, PPNs are β-phosphorylated analogues of PBN which form more persistent spin adducts than PBN toward oxygen-centered radicals. In this context we have synthesized twenty new hybrid PPNs having their aromatic ring substituted either by groups which can bring electronic and steric effects to the nitrone function or mimic natural antioxidant moieties. We evaluated the antioxidant properties of the new PPNs with a series of specific assays and we used ESR to study PPNs properties in ST toward a wide array of biologically-relevant free radicals, and their intrinsic nitric oxide releasing properties. The most promising compounds were than tested as vasorelaxant and antioxidant free radicals detectors in rat aortic rings. Protection by PPNs was assessed by measuring vascular response preservation and biochemical indices in aortic tissue. The second purpose dealt with the synthesis of new mitochondrial targeted PPNs with the aim to reach the primary biological source of endogenous production of free radicals. Using EPR we have assessed their ability to scavenge alkyl and alkoxy free radicals in vitro which allowed us to envisage a potential use of this probe against lipid peroxidation at mitochondrial level