Dissertationen zum Thema „Dual inhibitors“
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Meschini, Elisa. „Purine-based dual inhibitors of CDK2 and CDK7“. Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1363.
Der volle Inhalt der QuelleGreen, Ian. „The biology of novel dual histone methyltransferase inhibitors“. Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/25763.
Der volle Inhalt der QuelleApsel, Beth. „Dual-specificity inhibitors of lipid and protein kinases“. Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3311357.
Der volle Inhalt der QuelleRen, Baiping. „Molecular Design and Discovery of Single and Dual Inhibitors of Amyloid Peptides“. University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555257099229697.
Der volle Inhalt der QuelleWong, Jacky Sui Ki. „The Evaluation of Dual PI3K/mTOR Inhibitors as a Superior Alternative to mTOR Inhibitors in Pre-B Acute Lymphoblastic Leukaemia“. Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/13644.
Der volle Inhalt der QuelleFraser, Sasha. „Development of Dual-Pathway Inhibitors of Raf/MEK/ERK and PI3K/Akt Signaling Pathways“. VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2619.
Der volle Inhalt der QuelleSteinemann, Gustav [Verfasser]. „Charakterisierung der Wirkmechanismen des neuartigen, dual wirksamen HDAC-Inhibitors „Animacroxam“ am Beispiel testikulärer Keimzelltumore / Gustav Steinemann“. Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2021. http://d-nb.info/1234984474/34.
Der volle Inhalt der QuelleTamhaev, Rasoul. „Conception, synthèse et caractérisation de dérivés diaryl éthers comme nouveaux inhibiteurs directs de la protéine InhA de Mycobacterium tuberculosis“. Electronic Thesis or Diss., Université de Toulouse (2023-....), 2024. http://thesesups.ups-tlse.fr/6088/.
Der volle Inhalt der QuelleTuberculosis, despite being a very ancient disease, remains one of the major causes of mortality due to a single infectious agent. In 2021, 10 million people contracted the disease and 1.5 million deaths were directly attributable to it. Despite the availability of a variety of antibiotics, few of them prove effective against the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. This ineffectiveness is primarily due to the impermeable nature of the mycobacterial cell envelope, composed mainly of mycolic acids. Isoniazid, the most widely used first-line antitubercular drug, targets the biosynthesis of these mycolic acids through the protein InhA. Isoniazid acts as a pro-drug requiring activation by the protein KatG. However, the emergence of resistance during the activation stage of isoniazid necessitates the development of direct inhibitors of InhA. The work carried out during this thesis aimed to develop new direct inhibitors of InhA. These inhibitors were designed basedon the structure of a diaryl ether motif, known for its ability to inhibit the enzyme. Dynamic combinatorial chemistry combined with X-ray crystallography was used as a fragment screening method to discover new inhibitors. Three adducts, visualized directly within the active site of the protein, were characterized and showed interactions with the major portal of the protein. In another project, a new family of diaryl ethers with three pharmacophores was designed to fully occupy the substrate binding site. One of the synthesized molecules exhibited sub-micromolar inhibitory activity against InhA. The structure of the corresponding complex was resolved by X-ray crystallography, highlighting a wider opening of one of the protein's regions, called the minor portal. Finally, multi-target approaches, targeting both InhA and the dehydratase complex HadABC of the FAS II system, were also developed during this thesis. Several dual molecules were produced, showing inhibition of InhA activity in the nanomolar range. These molecules also demonstrated inhibition of the growth of different mycobacterial strains
Yule, Ian Andrew. „Design, synthesis and biological evaluation of novel, dual targeting inhibitors of bacterial DNA gyrase and topoisomerase IV“. Thesis, University of Leeds, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713881.
Der volle Inhalt der QuelleFoka, Germaine Boulenoue. „Synthesis and evaluation of novel coumarin-donepezil derivatives as dual acting monoamine oxidase B and cholinesterase in Alzheimer's disease“. University of the Western Cape, 2016. http://hdl.handle.net/11394/5549.
Der volle Inhalt der QuelleAlzheimer's disease is a progressive neurodegenerative disease characterised by low acetylcholine (ACh) levels in the hippocampus and cortex of the brain, causing symptoms like progressive memory loss, decline in language skills and other cognitive impairments to occur. The hallmarks of AD include the presence of extracellular insoluble amyloid beta plaques, intracellular neurofibrillary tangles, and the decrease in ACh concentration. The pathophysiology of AD is not well understood, however, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidases (MAO) are conspicuous role players in AD pathogenesis. Based on the cholinergic hypothesis, the AChE inhibitor donepezil was developed and has been used effectively clinically in the management of AD, with minimal side effects. Studies regarding the binding interactions of donepezil with AChE has shown that the benzyl-piperidine moiety of this compound shows substantial binding interactions at the CAS site of AChE where it blocks AChE activity. Coumarin is a compound of natural source that has shown some MAO inhibitory activity. Further studies done to clarify the potential of coumarin as a drug against AD has shown that coumarin has the capacity to bind at the PAS site of AChE, thus giving it the potential to prevent AChE induced amyloid plaque formation. Due to the multifactorial nature of AD, the drugs in the market show limited therapeutic benefits and are mainly for symptomatic relief. In order to address this limitation in AD treatment, researchers are exploring the possibility of designing a multi-target-directed-ligand (MTDL). The aim of this study was to synthesise a series of compounds out of pharmacophoric groups of donepezil and coumarin that will be able to inhibit both cholinesterases and MAO B. Four series of 5 compounds per series were synthesised. The first series of compounds consisted of the coumarin moiety to which a 1,4-dibromo benzene moiety was attached. The second series represented the coumarin moiety to which a piperidine (donepezil moiety shown to confer cholinesterase inhibitory property) was attached. The third series represented the coumarin moiety to which bromobenzyl-piperazine was attached and in the last series were compounds similar in structure to series 1 with an unsubstituted benzyl moiety as opposed to the dibromobenzyl moiety. Prior to the synthesis, molecular modelling was conducted in order to have an idea of the binding capacity of the compounds to MAO A and B and cholinesterases. In vitro biological evaluation of the compounds was done and used to determine the IC₅₀ values of the compounds. Nineteen compounds were synthesised and purified successfully as shown by their NMR, MS and IR spectra. The compounds to which dual inhibitory activity was conferred were those in series 2 and 3, of which series 2 showed the best overall inhibitory activity with IC₅₀ values within the low μM range. The compound with the best overall activity was Cp 9. Molecular modelling of Cp 9 showed that the coumarin core was located in the PAS region of AChE while the benzyl-piperidine moiety was situated in the CAS region of the enzyme. This compound orientation demonstrates the potential of Cp 9 to inhibit AChE induced amyloid beta plaque formation. Cp 9 showed no inhibitory activity towards MAO A, but showed good inhibitory activity towards MAO B with an IC₅₀ value of 0.30 μM. Its inhibitory activity towards cholinesterases also fell within the low μM range (AChE IC50 = 9.1 μM and BuChE IC₅₀ = 5.9 μM). From the results, it can be concluded that Cp 9 was able to inhibit both cholinesterase and MAO B catalytic activities at low μM concentrations. This thus means that our novel compound will not only increase ACh levels in the brain thus improving cognitive activity, but it will also have neuroprotective effect from its MAO B inhibitory property and also potentially slow down amyloid plaque formation due to AChE activity.
National Research Foundation (NRF)
Potter, Nicola Jane. „Design, synthesis, and biological evaluation of novel dual-target inhibitors of aminoacyl-tRNA synthetases as potential antibacterial agents“. Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.536093.
Der volle Inhalt der QuelleHeider, Fabian Andreas [Verfasser]. „Design and synthesis of novel dual GSK3β/p38α MAPK inhibitors and their optimization towards GSK3β selectivity / Fabian Andreas Heider“. Tübingen : Universitätsbibliothek Tübingen, 2021. http://d-nb.info/1238594778/34.
Der volle Inhalt der QuelleLouizos, Connie Celest. „Sexual Inhibition and Sexual Excitation in Erectile Dysfunction“. Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/15843.
Der volle Inhalt der QuelleHamed, Mostafa Mohamed Mostafa [Verfasser], und Rolf W. [Akademischer Betreuer] Hartmann. „Design and synthesis of novel quinazoline-based EGFR kinase inhibitors and dual EGFR/NF-κB inhibitors as potential anti-cancer drugs with enhanced efficacy / Mostafa Mohamed Mostafa Hamed. Betreuer: Rolf W. Hartmann“. Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2013. http://d-nb.info/1078017077/34.
Der volle Inhalt der QuelleWang, Danni. „Synthesis and evaluation of antibacterial activity of the dual-action agents : beta-lactamase inhibitors with cytotoxic agents or beta-lactam antibiotics“. Thesis, Aston University, 2001. http://publications.aston.ac.uk/12362/.
Der volle Inhalt der QuelleSchmitt, Christian [Verfasser], und Rolf W. [Akademischer Betreuer] Hartmann. „Development of new lead-like dual inhibitors of the cdc2-like kinase 1 (Clk1) and dual specificity Y-phosphorylation regulated kinases 1A and 1B (Dyrk1A and Dyrk1B) / Christian Schmitt. Betreuer: Rolf W. Hartmann“. Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2014. http://d-nb.info/1056906855/34.
Der volle Inhalt der QuelleHarmse, Rozanne. „Syntheses of 8-(phenoxymethyl)caffeine analogues and their evaluation as inhibitors of monoamine oxidase and as antagonists of the adenosine A2A receptor / Rozanne Harmse“. Thesis, North-West University, 2013. http://hdl.handle.net/10394/9663.
Der volle Inhalt der QuelleThesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013.
Seegers, Julia [Verfasser], und Oliver [Akademischer Betreuer] Werz. „Identification and Characterization of natural products as dual inhibitors of microsomal Prostaglandin E2 Synthase-1 and 5- Lipoxygenase / Julia Seegers ; Betreuer: Oliver Werz“. Tübingen : Universitätsbibliothek Tübingen, 2014. http://d-nb.info/1196877912/34.
Der volle Inhalt der QuelleFormosa, Márquez Xavier. „Síntesi i avaluació farmacològica d'inhibidors de l'acetilcolinesterasa de lloc d'unió dual com a potencials fàrmacs anti-Alzheimer i estudis relacionats“. Doctoral thesis, Universitat de Barcelona, 2006. http://hdl.handle.net/10803/671014.
Der volle Inhalt der QuelleNörz, Dominik Sebastian [Verfasser], und Manfred [Akademischer Betreuer] Jücker. „Dual Inhibition of PI3K-AKT-mTOR- and RAF-MEK-ERK signaling is synergistic in cholangiocarcinoma and reverses acquired resistance to MEK-Inhibitors / Dominik Sebastian Nörz. Betreuer: Manfred Jücker“. Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1093411325/34.
Der volle Inhalt der QuelleMohamad, Taib Mohamad Nurul Azmi. „Isolation and identification of cyclic polyketides from endiandra kingiana gamble (lauraceae), as bcl-xl/bak and mcl-1/bid dual inhibitors, and approaches toward the synthesis of kingianins“. Palaiseau, Ecole polytechnique, 2015. https://tel.archives-ouvertes.fr/tel-01260359/document.
Der volle Inhalt der QuelleThe preliminary screening showed that the bark of Endiandra kingiana Gamble exhibited potency as a modulating agent between Bcl-xL and Bak, which prompted its chemical investigation. Two groups of compounds were isolated and characterized; the endiandric acid series and the kingianin series. Eight new endiandric acid analogues (kingianic acids A-H [120-127]) and three new kingianin analogues (kingianin O-Q [128-130]) were isolated and structurally elucidated. The isolated compounds were evaluated for two bioassays; Bcl-xL/Bak and Mcl-1/Bid of binding affinities and cytotoxic effects against various human tumour cells. The second part describes the progression towards the total synthesis of kingianin analogues. The pentacyclic kingianin skeleton was formed by Diels-Alder reaction between two monomers having a bicyclo[4. 2. 0]octadiene backbone formed by a stereospecific electrocyclization of polyenes. The research was focusing on construction of bicyclo[4. 2. 0]octadiene monomer using [2+2] ketene cycloaddition approach at the early stage of the synthesis. One of the main advantages of such a strategy is the rapid assembly of the carbon skeleton of kingianins, thus maximizing the chances for good overall yields of the final products. So far, an efficient synthesis of the bicyclo[4. 2. 0]octene backbone was successfully achieved. Five approaches to synthesize this backbone starting from [2+2] cycloaddition of the cyclohexadienes to functionalized ketenes followed by functionalization of substituent at C-7 and C-8 positions with the correct relative configuration were described. From these approaches, compounds 280 and 311 were identified as the key intermediates. This key step of the synthesis provided an access to the kingianins skeleton
Abdelrahim, Mohamed Salah Rezk [Verfasser]. „Development of the first dual inhibitors for steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) : a novel treatment approach for endometriosis / Mohamed Salah Rezk Abdelrahim“. Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2019. http://d-nb.info/1236897048/34.
Der volle Inhalt der QuelleVALLONE, ALESSANDRA. „INVESTIGATION OF NOVEL THERAPEUTIC TOOLS AGAINST INFECTIOUS DISEASES Part 1. Medicinal Chemistry Investigation of MMV019918 Derivatives as Dual Schizonticide And Gametocytocidal Agents Against Plasmodium falciparum Part 2. Investigation of 5-Aryl-Heterocycles As Potential Inhibitors of Metallo beta-Lactamase Enzymes“. Doctoral thesis, Università di Siena, 2017. http://hdl.handle.net/11365/1004943.
Der volle Inhalt der QuelleChristofakis, Steven. „SCRIBBLE: A POTENTIAL DUAL KINASE INHIBITOR“. VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/72.
Der volle Inhalt der QuelleVenkateswaran, Rashmi. „The dual nature of carbon: Catalyst and inhibitor“. Thesis, University of Ottawa (Canada), 1994. http://hdl.handle.net/10393/9910.
Der volle Inhalt der QuelleCopin, Chloé. „Exploration moléculaire en série imidazo[2, 1-b][1, 3, 4]thiadiazole : applications à la synthèse d'inhibiteurs de kinases impliqués dans les maladies neurodégénératives“. Thesis, Orléans, 2013. http://www.theses.fr/2013ORLE2074.
Der volle Inhalt der QuelleFor more than a century, heterocyclic chemistry is one of the largest area in organic chemistry research. In particular, because of their rarity and their biological potential, [5-5] fused ring heterocycles containing both sulfur and nitrogen atoms are a large area of interest for both academic and industrial research and development teams. Among these numerous [5-5] bicycles, our study is focused on imidazo[2,1-b][1,3,4]thiadiazole scaffold, which is quite few described in the literature and whose pathways are limited to almost one method involving a cyclisation step and drastic conditions. This lock leads inevitably to low functional diversity around this heterocycle, thus restricting its applications, including biological. In order to overcome this problematic, we then initiated the reactivity study of each three positions of the bicycle imidazo[2,1-b][1,3,4]thiadiazole, developing thereby several palladium couplings (Suzuki-Miyaura, direct arylation, Buchwald-Hartwig), as well as aromatic nucleophilic substitution and Pictet-Spengler reaction. The study of the biological properties of the different compounds synthesized in this work and highly valuable led to the discovery of two series of molecules, inhibiting selectively DYRK-1A and CLK-1, two kinases of interest in the treatment of dysfunction of central nervous system (neuropathies, Alzheimer…)
Hall, Drew Anthony. „Investigating the structure and binding mechanism of QseM, a novel dual-target protein-inhibitor“. Thesis, Curtin University, 2021. http://hdl.handle.net/20.500.11937/87895.
Der volle Inhalt der QuelleStröbele, Stephanie [Verfasser]. „Glioblastoma : the effects of the dual kinase inhibitor PI-103 on glioblastoma cells / Stephanie Ströbele“. Ulm : Universität Ulm, 2020. http://d-nb.info/121518851X/34.
Der volle Inhalt der QuelleCAMPANER, ELENA. „A new covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action“. Doctoral thesis, Università degli Studi di Trieste, 2017. http://hdl.handle.net/11368/2908180.
Der volle Inhalt der QuelleLeary, Alexandra. „Laboratory and clinical studies of the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib in breast cancer“. Thesis, Institute of Cancer Research (University Of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538329.
Der volle Inhalt der QuelleMorooka, Satoshi. „Identification of a Dual Inhibitor of SRPK1 and CK2 that Attenuates Pathological Angiogenesis of Macular Degeneration in Mice“. Kyoto University, 2015. http://hdl.handle.net/2433/202798.
Der volle Inhalt der QuelleMiguel, Mariana Cardoso. „Produção recombinante e caracterização de duas cistatinas de cana-de-açúcar“. Universidade Federal de São Carlos, 2014. https://repositorio.ufscar.br/handle/ufscar/5553.
Der volle Inhalt der QuelleFinanciadora de Estudos e Projetos
Cystatins are reversible inhibitors of cysteine peptidases. The cystatins found in plants are called phytocystatins, and represent an independent subfamily of the cystatins superfamily. Some studies have reported significant pleiotropic effects for recombinant cystatins expressed in transgenic plants, notably including tolerance phenotypes against attack of herbivorous arthropods and pathogens, and against abiotic and biotic stresses. Besides, the recombinant sugarcane cystatin, CaneCPI-4, showed potential to inhibit development of melanoma cells. Thus, the study and knowledge about phytocystatins, become interesting from agricultural and medicinal point of view. The sugarcane genome project (SUCEST) allowed the identification of about 25 putative cystatins in this plant, which were gathered in 4 groups, by phylogenetic analysis. In this study, we propose a new classification for the putative cystatins found in the SUCEST database. Furthermore, we describe the heterologous expression, purification and characterization of two novel sugarcane cystatins, CaneCPI-5 and CaneCPI-6, which showed different inhibitory activities against human cathepsin B. While protein CaneCPI-6 was not able to inhibit this enzyme efficiently (Ki = 1,83 μM), the protein CaneCPI-5 showed a good inhibitory capacity against the same enzyme (Ki = 6,87 nM). The CaneCPI-5 cystatin was also analyzed against recombinant cathepsin L from the beetle Sphenophorus levis (rSl-CathL), and showed a good inhibitory capacity against this enzyme (Ki = 0,059 nM). Finally, both of proteins, CaneCPI-5 and CaneCPI-6, proved to be thermostable when kept at 100°C for 30 minutes.
Cistatinas são inibidores reversíveis de cisteíno-peptidases. As cistatinas encontradas em plantas são denominadas fitocistatinas, e constituem uma subfamília independente da superfamília das cistatinas. Alguns estudos têm relatado importantes efeitos pleiotrópicos para cistatinas recombinantes expressas em plantas transgênicas, incluindo principalmente, fenótipos com tolerância ao ataque de artrópodes herbívoros e patógenos, e contra estresses bióticos e abióticos. Ademais, a cistatina recombinante de cana-de-açúcar, CaneCPI-4, apresentou potencial para inibir o desenvolvimento de células de melanoma. Dessa maneira, o estudo e conhecimento sobre as fitocistatinas, tornam-se interessantes do ponto de vista agrícola e na saúde. O projeto genoma da cana-de-açúcar (SUCEST) possibilitou a identificação de 25 possíveis cistatinas nesta planta, que foram reunidas em 4 grupos, por meio de análises filogenéticas. Nesse trabalho propomos uma reanálise das prováveis cistatinas encontradas no banco de dados do SUCEST. Além disso, descrevemos a expressão heteróloga, purificação e caracterização de duas novas cistatinas de cana-de-açúcar, CaneCPI-5 e CaneCPI-6, as quais apresentaram diferenças na ação inibitória contra a catepsina B humana. Enquanto a proteína CaneCPI-6 não foi capaz de inibir esta enzima de forma eficiente (Ki = 1,83 μM), a proteína CaneCPI-5 apresentou um bom poder inibitório contra a mesma enzima (Ki = 6,87 nM). A cistatina CaneCPI-5 foi analisada também contra a catepsina L recombinante do inseto Sphenophorus levis (rSl-CathL), e apresentou alto poder inibitório contra essa enzima (Ki = 0,059 nM). Por fim, ambas as proteínas, CaneCPI-5 e CaneCPI-6, mostraram-se termoestáveis quando mantidas à 100°C durante 30 minutos.
ZUCCOLO, MARCO. „NEW APPROACHES IN THE DISCOVERY OF NATURAL PRODUCT-BASED AGROCHEMICALS“. Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/606602.
Der volle Inhalt der QuelleStarok, Marcelina Anna. „EGFR inhibition by curcumin in cancer cells : a dual mode of action“. Thesis, Compiègne, 2014. http://www.theses.fr/2014COMP2093.
Der volle Inhalt der QuelleEpidermal Growth Factor Receptor (EGFR) is a common target of anticancer therapy. Nowadays the search for new molecules inhibiting this receptor is turning towards natural substances. One of the most promising natural compounds that have shown an anti-EGFR activity is curcumin, the polyphenol found in the rhizomes of Curcuma longa. There are numerous reports describing its effect on the receptor kinase activity, the autophosphorylation yield, the expression level and the processes related to EGFR function like cell proliferation. Nevertheless, the entire mechanism of how curcumin interact with the EGFR is not fully elucidated. We demonstrated that the mode of action of curcumin is dual. Curcumin is able to inhibit directly but partially the enzymatic activity of the EGFR intracellular domain. But the presented work brings attention to the role of the EGFR membrane environment at the curcumin action level. We showed that the curcumin insertion in plasma membrane leads to its rigidification and as a consequence to limitation of the receptor diffusion. Single particle tracking analyses confirmed that the diffusion coefficient of EGFR in the cancer cell membrane significantly decreased in the presence of the curcumin, which might influence the receptor dimerization and in turns its activation
Guéret, Pierre. „Développement clinique de l'EP217609 et de son antidote l'avidine“. Thesis, Brest, 2017. http://www.theses.fr/2017BRES0130.
Der volle Inhalt der QuellePentasaccharides are indirect inhibitors of factor Xa with highly predictable pharmacokinetic profiles. Because of the high affinity binding of pentasaccharides to antithrombin, this pharmacokinetics can be predicted but also transferred to other molecules covalently bound to them. EP42675 combines in a single molecule, a reversible direct antithrombin (α-NAPAP peptidomimetic analog), and a pentasaccharide similar to fondaparinux with an indirect anti-factor Xa activity. EP217609 is the biotinylated derivative of EP42675 whose anticoagulant activity can be neutralized by avidin which binds with high affinity and specificity to the biotin moiety of EP217609.The first target indication of EP217609 and its antidote avidin is cardiac surgery requiring extracorporeal circulation. The second target indication is the treatment of acute coronary syndromes requiring or not a percutaneous coronary intervention.The preclinical and clinical Phase I and IIa studies summarized here demonstrate the value of such a coupling concept to the pentasaccharide: absence of dissociation between the two entities, low intra- and interindividual variability of the pharmacokinetic and pharmacodynamic parameters, and an almost complete neutralization of the EP217609 anticoagulant activity with no rebound effect
Bendjeddou, Lyamin. „Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires“. Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P615.
Der volle Inhalt der QuellePhosphorylation by protein kinases is one of the most important post-translational modification in cellular processes such as division, differentiation, proliferation and apoptosis. Kinase deregulation is associated with numerous diseases such as cancer or neurodegenerative diseases. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine were prepared to inhibit protein kinases involved in diseases targeted in the laboratory. The imidazo[1,2-b]pyridazines were synthesized to identify inhibitors of CLK1 and DYRK1A, potential targets in Alzheimer's disease. Among the imidazo[1,2-b]pyridazines synthesized, several molecules were found selective of DYRKs and CLKs, with IC50 < 100 nM. A structure-activity relationship based on the synthesis of 70 molecules, led to the identification of the structural bases of the selectivity. Products were also evaluated against parasite kinases. It was possible to identify some highly potent inhibitors on PfCLK1. The aim of second part of this thesis was to optimize the synthetic process to obtain imidazo[4,5-b]pyridines, which are close analogues of roscovitine. Derivatives had proved capable of inhibiting the formation of cysts in a cellular model of polycystic kidney disease. A seven-step synthesis has led to several grams of 3,5,7-trisubstituted imidazo[4,5-b]pyridine which is now available for evaluation in vivo
Schweppenhäuser, Johannes. „Selektive und duale COX-1-COX-2-Inhibitoren aus der Reihe der Methanone Synthese, Testung, Struktur-Wirkungs-Beziehungen /“. [S.l.] : [s.n.], 1999. http://deposit.ddb.de/cgi-bin/dokserv?idn=960235728.
Der volle Inhalt der QuelleEyermann, Barbara [Verfasser], Stephan A. [Akademischer Betreuer] Sieber, Wolfgang [Gutachter] Eisenreich und Stephan A. [Gutachter] Sieber. „A Dual Inhibitor Attenuates Biofilm Formation and Virulence in Staphylococcus aureus and Manipulation of ClpP Activity / Barbara Eyermann ; Gutachter: Wolfgang Eisenreich, Stephan A. Sieber ; Betreuer: Stephan A. Sieber“. München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1201482755/34.
Der volle Inhalt der QuelleRennó, André Lisboa 1984. „Efeitos de duas estatinas sobre células-tronco neoplásicas em modelo murino de carcinogênese mamária por indução química“. [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312485.
Der volle Inhalt der QuelleTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: O câncer mamário é a neoplasia maligna mais incidente e a principal causa de óbito por malignidade no sexo feminino no Brasil e no mundo. Estipula-se que há mais de 1.2 milhões de novos casos anuais de câncer de mama, e que a heterogeneidade e a complexidade molecular do câncer de mama dificultam estratégias terapêuticas de prevenção e tratamento desta doença. Atualmente, acredita-se que, em diversas neoplasias, incluindo o câncer de mama, a célula alvo de mutações cumulativas responsáveis pelo desenvolvimento do fenótipo canceroso é uma célula-tronco adulta. Independentemente da origem da neoplasia (se em célula madura/diferenciada ou em CT), é possível constatar in vitro e in vivo, na grande maioria dos tumores malignos, uma subpopulação de células indiferenciadas, com características fenotípicas de célula-tronco. Tais células são designadas como "células tronco cancerosas ou neoplásicas (CTNs)". Com frequência, especula-se se as CTNs seriam responsáveis pela heterogeneidade morfológica e molecular de algumas neoplasias mamárias. Em conjunto, essas peculiaridades das CTNs as tornam importantes alvos no desenvolvimento de novas abordagens farmacoterapêuticas antineoplásicas. Recentemente, Gauthaman et al (2009) demonstraram de forma inédita em estudos in vitro que estatinas apresentam efeito inibitório específico sobre células tronco embrionárias com alterações cariotípicas e células de linhagens neoplásicas mamárias com fenótipo CTN, não afetando o crescimento de células tronco normais. As estatinas são inibidores competitivos da 3-hidroxi-3-metilglutaril coenzima A (HMG-CoA) e são amplamente utilizada para o tratamento de doenças cardiovascular primário e secundário. Além de amplamente utilizadas na prevenção e tratamento de doenças cardiovasculares secundárias a dislipidemias, evidências cumulativas apontam para um possível papel destas drogas na prevenção ou regressão de processos neoplásicos. Entre os efeitos antineoplásicos comprovados das estatinas, destacam-se: a inibição da proliferação celular, a promoção de apoptose, a inibição da angiogênese e a prevenção de metástases. Assim, buscou-se neste trabalho elucidar o efeito da sinvastatina e pravastatina sobre células progenitoras e CTNs e em algumas vias de sinalização intracelular em modelo de carcinogênese mamária (baseado na indução com 7,12 dimetilbenz(a)antraceno[DMBA]) em ratas Sprague-Dawley. Após um tratamento de 14 dias com as estatinas, as mamas das ratas foram analisadas para verificar a imunoexpressão de células progenitoras e CTNs (CD133, CD24, CD44 e EpCAM), variáveis biológicas (volume tumoral, mitose, índice proliferativo) além da análise proteica de Akt e Src. A maior dose da sinvastatina testada (40 mg/Kg) diminui o número de tumores desenvolvidos, volume e incremento tumoral e os índices de proliferação celular. Não houve alteração da percentagem de necrose com o tratamento com as estatinas. Ainda, sinvastatina diminuiu os níveis da fosforilação da Akt e aumento da PTEN, não havendo diferenças significantes nos níveis da Src. Sinvastatina também foi capaz de reduzir o número de células positivas CD133, CD24 e CD44. Pelas doses testadas, não houve diferença dos parâmetros biológicos analisados com o tratamento com a pravastatina. Em conclusão, neste modelo, o tratamento crônico com a sinvastatina apresentou efeitos citostáticos, ações reguladoras na via da Akt além do controle de células progenitoras e CTNs em modelo in vivo de carcinoma mamário
Abstract: Breast cancer is the malignant neoplasm with the highest incidence and the main cause of death by cancer within females in Brazil and in the world. It is estimated that there are over 1.2 million new annual cases of breast cancer. The heterogeneity and the molecular complexity of this type of cancer complicate the therapeutic strategies for its prevention and treatment. Nowadays, it is believed that in many different neoplasms, including breast cancer, the cell which is the target of cumulative mutations responsible for the development of the cancerous phenotype is an adult stem cell. Regardless the origin of the neoplasm (whether in mature/differentiated cell or in SC), a subpopulation of undifferentiated cells with phenotypic characteristics of stem cells can be seen in vitro and in vivo in most malignant tumours. These cells are designated as "neoplastics or cancer stem cells (CSCs)". It is often especulated whether CSCs would be responsible for the molecular and morphological heterogeneity in some breast neoplasms. The peculiarities of the CSCs make them a relevant/an important/a serious object for the development of new antineoplastic pharmacotherapeutic approaches. Recently, Gauthaman et al (2009) demonstrated in unprecedented in vitro studies that statins exhibit specific inhibitory effect on embryonic stem cells with karyotypic alterations and neoplastic mammary cell lines with phenotype CSC, not affecting the growth of normal stem cells. Statins are competitive inhibitors of coenzyme 3-hydroxy-3-methylglutaryl A (HMG-CoA) reductase and are widely used for the primary and secondary treatment of cardiovascular diseases. Moreover, cumulative evidence points to a possible role of these drugs in the prevention or regression of neoplastic processes. Amongst the proven anticancer effects of statins, some of them stand out such as: inhibition of cell proliferation, promotion of apoptosis, inhibition of angiogenesis and metastasis prevention. Thus, this study sough to elucidate simvastatin and pravastatin effects on progenitor cells and NSCs, and on some signaling pathways in breast carcinogenesis model (based on induction 7,12 dimethylbenz (a) anthracene [DMBA]) in female Sprague-Dawley rats. After a 14 days treatment with the statins, the rats' breasts were examined to verify immunostaining of progenitor cells and CSCs (CD133, CD24, CD44 and EpCAM), biological variables (tumor volume, mitosis, proliferation index) in addition to protein analysis of Akt and Src. The highest dose of the tested simvastatin (40mg/kg) decreased the number of tumors developed, volume and tumor growth as well as the cell proliferation index. There was no change in the percentage of necrosis to treatment with statins. Furthermore, simvastatin decreased the levels of Akt phosphorylation and increased PTEN levels, without significant differences in Src levels. Simvastatin was also able to reduce the number of CD133, CD24 and CD44 positive cells. For the doses tested, there was no difference on the analyzed parameters in the treatment with pravastatin. As a conclusion, in this model, chronic treatment with simvastatin showed cytostatic effects, regulatory actions towards Akt, as well as the control of CSCs and progenitor cells in the in vivo model of mammary carcinoma
Doutorado
Farmacologia
Doutor em Farmacologia
Yokota, Asumi. „INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph[+] leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity“. Kyoto University, 2009. http://hdl.handle.net/2433/126449.
Der volle Inhalt der Quelle0048
新制・課程博士
博士(医学)
甲第14902号
医博第3387号
新制||医||977(附属図書館)
27340
UT51-2009-M816
京都大学大学院医学研究科医学専攻
(主査)教授 武藤 誠, 教授 武田 俊一, 教授 松岡 雅雄, 教授 戸井 雅和
学位規則第4条第1項該当
Moraes, Bibiana Silveira. „Alterações fisiológicas e morfológicas de duas cultivares de arroz irrigado após aplicação do herbicida imazamox na fase reprodutiva“. Universidade Federal de Santa Maria, 2013. http://repositorio.ufsm.br/handle/1/3216.
Der volle Inhalt der QuelleWeed control is one of the main agricultural practices indispensable to ensure profitability and crop success. In paddy rice field, red rice is the most important weed due to its difficult control. A widespread control method is the use of rice cultivars resistant to herbicides which are inhibitors of ALS, since it is possible to have a selective chemical control. Studies showed that the late control with imazamox promotes efficient control of red rice escapes. Thus, the objective of this research was to check the effects of imazamox application in the reproductive phase of two rice cultivars that differ in the level of resistance to imidazolinones. Two studies were carried out at the Federal University of Santa Maria in the years of 2009/10 and 2010/11. Imazamox was applied in different stadium of development and doses. At the end of the application the final dose was 80 g a.i ha-1 for all treatments. Results showed that independent of the date of the imazamox application in the reproductive phase of rice, the grain yield reduced and spikelet sterility of IRGA 422 CL increased. In general, the parameters 1000-grain weight, flag leaf length, panicule length, fresh and dry weight of panicles, and panicles per m2 showed a reduction in practically all imazamox treatments in the IRGA 422 CL cultivar. Changes in the biochemical parameters (chlorophyll, carotenoids, thiobarbituric acid reactive substances, superoxide dismutase, catalase and ascorbate peroxidase) were observed in leaves and panicles from main culm in some treatments, demonstrating that the oxidative stress promoted by imazamox may have contributed to grain yield reduction and the high percentage of sterile spikelet from IRGA 422 CL cultivar. Morphologic and anatomical changes showed that imazamox application in the panicle differentiation promoted similar changes to homeotic changes observed in rice mutant. Moreover, in the other treatments different morphologic and anatomical changes were observed. Therefore, morphologic and anatomical changes were likely to be responsible for grain yield reduction and high percentage of spikelet sterile from IRGA 422 CL.
O controle de plantas daninhas é uma das práticas agrícolas indispensáveis para garantir rentabilidade e sucesso no cultivo. No cultivo de arroz irrigado, o arroz vermelho é a planta daninha de maior importância, devido sua dificuldade de controle. Um método de controle bastante difundido é o uso de cultivares resistentes aos herbicidas inibidores da ALS, pois permite um controle químico seletivo. Estudos demonstram que o controle tardio com o herbicida imazamox promove controle eficiente de escapes de arroz vermelho. Por isso, o objetivo deste trabalho foi verificar os efeitos da aplicação do imazamox na fase reprodutiva de duas cultivares de arroz irrigado (IRGA 422 CL e PUITÁ INTA CL) que diferem quanto ao nível de resistência as imidazolinonas. Em vista do exposto, foram conduzidos dois estudos na área experimental da Universidade Federal de Santa Maria (2009/10 e 2010/11). O imazamox foi aplicado em diferentes estádios de desenvolvimento e doses, sendo que a dose final foi de 80 g i.a ha-1. Com os resultados obtidos conclui-se que independente da data de aplicação do imazamox na fase reprodutiva da cultura ocorreu redução da produtividade de grãos e aumentou a esterilidade de espiguetas da cultivar IRGA 422 CL. De maneira geral, os parâmetros: peso de mil grãos, comprimento da folha bandeira, comprimento de panícula, peso fresco e seco de panículas, e número de panículas por metro quadrado mostraram redução em praticamente todos os tratamentos na cultivar IRGA 422 CL. Alterações nos parâmetros bioquímicos (clorofila, carotenoides, substâncias reativas ao ácido tiobarbitúrico, superóxido dismutase, catalase e ascorbato peroxidase) foram observadas em folhas e panículas do colmo principal em alguns tratamentos, demonstrando que o estresse oxidativo provocado pela aplicação do imazamox pode ter contribuído para a redução da produtividade de grãos e o elevado percentual de espiguetas estéreis da cultivar IRGA 422 CL. A cultivar PUITÁ INTA CL não sofreu alterações em todos os parâmetros avaliados neste estudo. As alterações morfológicas e anatômicas demonstraram que a aplicação de 80 g i.a ha-1 imazamox na diferenciação da panícula promoveu alterações semelhantes às alterações homeóticas observadas em arroz mutante. Além disso, nas plantas que receberam a dose de 80 g i.a ha-1 após 14 dias da diferenciação do primórdio floral (DPF) e as plantas que receberam a dose de 80 g i.a ha-1 em aplicação fracionada (metade da dose 7 dias após DPF e metade da dose aos 14 dias após DPF) mostraram alterações morfológicas e anatômicas do grão de pólen. Dado o exposto, os resultados obtidos sugerem que as alterações morfológicas e anatômicas foram responsáveis pela redução da produtividade de grãos e alto percentual de espiguetas estéreis da cultivar IRGA 422 CL.
Wang, Qinzhe. „Developing Approaches to Treat Canavan Disease“. University of Toledo / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1493301078219765.
Der volle Inhalt der QuelleGeny, Charlotte. „Recherche d'inhibiteurs naturels des protéines anti-apoptotiques Bcl-xL et Mcl-1“. Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114833/document.
Der volle Inhalt der QuelleIn order to search for natural inhibitors of anti-Apoptotic protein Bcl-XL and Mcl-1, two bioassays were developed on Bcl-XL/Bak-CF and Mcl-1/Bid-CF. Both assays use fluorescent polarisation, and are based on binding of a fluorescein labeled pro-Apoptotic peptide (Bak-CF or-CF Bid) with an anti-Apoptotic protein (Bcl-XL or Mcl-1). Nearly 600 extracts from various parts of the world were screened on both Bcl-XL and Mcl-1 proteins to select the ethyl acetate bark extracts of Knema hookeriana (Myristicaceae) and Fissistigma latifolium (Annonaceae). The chemical analysis of the constituents of K. hookeriana has led to the isolation of 12 phenolic lipids. 6 of them were never isolated from a living organism. Only anacardic acids showed very strong inhibition of the interaction Bcl-XL/Bak-CF and Mcl-1/Bid-CF in fluorescent polarisation assays. Further study of the interactions between the most active anacardic acid and proteins (Bcl-XL, Mcl-1, Bak and Bid) by NMR showed that the modulation of Bcl-XL/Bak and Mcl-1/Bid is not related to the affinity of the compoun to the anti-Apoptotic proteins, Bcl-XL and Mcl-1 but to its affinity for peptides, Bid and Bak. The bioguided fractionation of the AcOEt bark extract of F. latifolium led to the isolation of a novel prenylated chalcone, (±)-Écarlottone having a dual activity on protein, Bcl-XL and Mcl-1. Subsequently, fractionation "NMR-Guided" led to the isolation of 6 new analogs
Huang, Hung-Jin, und 黃泓縉. „Virtual screening and drug design for H1N1 dual-target inhibitors“. Thesis, 2010. http://ndltd.ncl.edu.tw/handle/70524014777917613113.
Der volle Inhalt der Quelle中國醫藥大學
生物科技學系碩士班
98
Influenza viruses contain two major surface glycoproteins, hemagglutinin and neuraminidase, which are therapeutic targets for inhibiting influenza viruses from infecting host cell. Pandemic of H1N1/09 virus has been reported, and drug resistance was regarded as an important issue since 2009. Thus, the purpose of this research is to design novel potent dual inhibitors for the two surface glycoproteins on H1N1 virus. In this study, structure-based and ligand-based drug designs were performed to analyze interactions between target proteins and ligands, and molecular dynamics (MD) simulations were carried out to analyze the interaction of receptor-ligand complexes. Potent derivatives from structure-based design were ranked by sum of DockScore of two target proteins (H1 and N1) and were compared with Tamiflu (Oseltamivir) and Relenza (Zanamivir) to select the top 10 candidates. Among the scaffold of top 10 candidates, five key features were recognized for binding to H1 and N1. In quantitative structure-activity relationship models, these features were able to fit with their steric, electrostatic, hydrogen bond acceptor and donor fields. These fields were close to key residues of H1 and N1 binding site. Finally, 2-aminopyridinium group was noticed to play an important role in binding ability during 20ns MD simulations. From structure-based and ligand-based designs, we hope that we provided useful information for designing anti-viral compounds targeting H1 and N1, and we recommend the top 10 candidates from our experiments for further drug development testing.
Kuo, Chia-Chen, und 郭家珍. „Discovery of dual target inhibitors for Alzheimer's disease by virtual screening“. Thesis, 2017. http://ndltd.ncl.edu.tw/handle/7269ab.
Der volle Inhalt der Quelle國立東華大學
生命科學系
105
The most common type of dementia is Alzheimer's disease (AD), which makes up 60% to 70% of cases. Globally, dementia affects 47 million people. Patients will have cognitive and memory function of brain degeneration symptoms. Acetylcholine (ACh) is the neurotransmitter used at the Central Nervous System (CNS). Pharmacological treatment of AD is based on the use of acetylcholinesterase inhibitors, which have beneficial effects on cognitive, functional, and behavioural symptoms of the disease. Two types of ACh enzyme are found in the CNS, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). BuChE enzyme activity extended to all parts of the brain receiving cholinergic innervation and that it could hydrolyze the ACh surrogate AChE. Screening compounds that inhibit both hydrolases is the primary objective of this study. The experiment by virtual screening, including genetic function approximation (GFA), multiple regression analysis (MLR), support vector machines (SVM), molecular docking and molecular dynamics simulation (MD). The model was subsequently used as a molecular docking to identify potential hits form Traditional Chinese Medicine (TCM) database. The binding stabilities of these hits were further validated using molecular dynamics simulations. Finally, three candidate drugs were identified as Saussureamine B, Scoulerine and Anisodine. It is desirable to provide more inhibitory activity dual target inhibitor for AD.
Capitosti, Scott Michael. „Thalidomide analogues : dual inhibitors of both angiogenesis and human cancer cell proliferation /“. 2004. http://wwwlib.umi.com/dissertations/fullcit/3144655.
Der volle Inhalt der QuelleElsinghorst, Paul Wilhelm [Verfasser]. „Dual-mode cholinesterase inhibitors targeting muscarinic receptors / vorgelegt von Paul Wilhelm Elsinghorst“. 2007. http://d-nb.info/983086427/34.
Der volle Inhalt der QuelleKuo, Po-Hsien, und 郭柏賢. „The Developments of Dual EGFR and c-Met Kinase Inhibitors and DBPR104 Phosphate Prodrugs“. Thesis, 2018. http://ndltd.ncl.edu.tw/handle/eg23ma.
Der volle Inhalt der QuelleSola, I., S. Castellà, E. Viayna, C. Galdeano, M. C. Taylor, Stephen Y. Gbedema, B. Pérez et al. „Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity“. 2015. http://hdl.handle.net/10454/7485.
Der volle Inhalt der QuelleDual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.
Yo-HuaLi und 李祐華. „Targeting Dual-Specificity Phosphatase-2 by Novel Histone Deacetylase Inhibitors as a Cancer Therapeutic Strategy“. Thesis, 2018. http://ndltd.ncl.edu.tw/handle/x9a783.
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