- Palladium-Catalyzed Cyclization Reaction of o-Iodoanilines, CO2, and CO: Access to Isatoic Anhydrides
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Isatoic anhydrides, a class of valuable synthetic intermediates and RNA structure probing reagents, are usually prepared with highly toxic phosgene or stoichiometric oxidants. Herein we report a highly selective palladium-catalyzed cyclization reaction for the efficient synthesis of isatoic anhydrides from readily available o-iodoanilines, CO2, and CO. The reaction proceeds under mild conditions and is redox-neutral. Both CO2 and CO are indispensable C1 building blocks for this catalytic reaction.
- Zhang, Wen-Zhen,Zhang, Ning,Sun, Yu-Qian,Ding, Yu-Wei,Lu, Xiao-Bing
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p. 8072 - 8076
(2017/12/08)
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- Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases
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Glycogen synthase kinase 3 β (GSK-3β) is a central target in several unmet diseases. To increase the specificity of GSK-3β inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3β activity. Design synthesis, structure-Activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3β are presented here. Furthermore, we show how allosteric binders may overcome the β-catenin side effects associated with strong GSK-3β inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3β may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3β inhibition exhibits therapeutic effects.
- Palomo, Valle,Perez, Daniel I.,Roca, Carlos,Anderson, Cara,Rodríguez-Muela, Natalia,Perez, Concepción,Morales-Garcia, Jose A.,Reyes, Julio A.,Campillo, Nuria E.,Perez-Castillo, Ana M.,Rubin, Lee L.,Timchenko, Lubov,Gil, Carmen,Martinez, Ana
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p. 4983 - 5001
(2017/06/28)
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- IMPROVED SOLUBILITY FOR TARGET COMPOUNDS
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The present disclosure relates to compounds having an improved solubility thereby increasing their bioavailability, lower dosages, etc. The target compounds, may include but are not limited to, macrophage migration inhibitory factor (MIF) inhibitors, epid
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- Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives
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Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation is considered a potential powerful tool in regenerative medicine to treat severe tissue injuries. Starting from GSA-10, a recently reported Hh activator acting on Smo, we have designed and synthesized a new class of quinolone-based compounds. Modification and decoration of three different portions of the original scaffold led to compounds able to induce differentiation of multipotent mesenchymal cells into osteoblasts. The submicromolar activity of several of these new quinolones (0.4–0.9?μM) is comparable to or better than that of SAG and purmorphamine, two reference Smo agonists. Structure-activity relationships allow identification of several molecular determinants important for the activity of these compounds.
- Manetti, Fabrizio,Petricci, Elena,Gabrielli, Annalisa,Mann, Andrè,Faure, Hélène,Gorojankina, Tatiana,Brasseur, Laurent,Hoch, Lucile,Ruat, Martial,Taddei, Maurizio
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p. 747 - 757
(2016/07/21)
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- Synthesis, regioselectivity, and DFT analysis of new antioxidant pyrazolo[4,3-c]quinoline-3,4-diones
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The condensation of hydrazine, N-methylhydrazine, and N-phenylhydrazine with ethyl 4-chloro-2-oxo- 1,2-dihydroquinoline-3-carboxylate derivatives has been investigated. As a result, 12 new antioxidant pyrazolo[4,3- c]quinolin-3,4-diones were obtained with good to high yields. When two cross-products could be possible, only one isomer bearing the methyl or the phenyl group at the N1 position is isolated and unequivocally characterized using 1D and 2D NMR techniques, FT-IR, and combustion analyses. DFT analysis of the reaction mechanism was carried out in the Pearson’s hard soft acid base framework, confirming the assigned structure to the observed pyrazolo[4,3-c]quinolin-3,4-diones. These calculations indicate a favored kinetic control for the synthesized pyrazolo[4,3- c]quinolin-3,4-diones compared to its possible regioisomer.
- Tomassoli, Isabelle,Herlem, Guillaume,Picaud, Fabien,Benchekroun, Mohamed,Bautista-Aguilera, Oscar M.,Luzet, Vincent,Jimeno, María-Luisa,Gharbi, Tijani,Refouvelet, Bernard,Ismaili, Lhassane
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p. 1069 - 1079
(2017/01/11)
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- Quinolone-benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer Disease
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Design, synthesis and evaluation of new acetylcholinesterase inhibitors by combining quinolinecarboxamide to a benzylpiperidine moiety are described. Then, a series of hybrids have been developed by introducing radical scavengers. Molecular modeling was performed and structure activity relationships are discussed. Among the series, most potent compounds show effective AchE inhibitions, high selectivities over butyrylcholinesterase and high radical scavenging activities. On the basis of this work, the ability of quinolone derivatives to serve in the design of N-benzylpiperidine linked multipotent molecules for the treatment of Alzheimer Disease has been established.
- Pudlo, Marc,Luzet, Vincent,Ismaili, Lhassane,Tomassoli, Isabelle,Iutzeler, Anne,Refouvelet, Bernard
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p. 2496 - 2507
(2014/05/06)
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- PROLYL HYDROXYLASE ANTAGONISTS
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This invention relates to certain 2-[(quinolin-3-yl)carbonyl]aminoacetic acid derivatives of formula (I), where the various groups are defined herein, and which are useful in treating anemia.
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Page/Page column 19-20
(2010/11/26)
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- 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase
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Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
- Tedesco, Rosanna,Shaw, Antony N.,Bambal, Ramesh,Chai, Deping,Concha, Nestor O.,Darcy, Michael G.,Dhanak, Dashyant,Fitch, Duke M.,Gates, Adam,Gerhardt, Warren G.,Halegoua, Dina L.,Han, Chao,Hofmann, Glenn A.,Johnston, Victor K.,Kaura, Arun C.,Liu, Nannan,Keenan, Richard M.,Lin-Goerke, Juili,Sarisky, Robert T.,Wiggall, Kenneth J.,Zimmerman, Michael N.,Duffy, Kevin J.
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p. 971 - 983
(2007/10/03)
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- 1,2-Dihydro-2-oxoquinoline derivatives
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A 1,2-dihydro-2-oxoquinoline derivative represented by the formula: wherein Ar is a pyridyl group or a group represented by the formula: (wherein X3and X4are the same or different, and are each a hydrogen atom, a halogen atom, a Csu
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- 4-HYDROXY-2-QUINOLONES. 22. SYNTHESIS AND BIOLOGICAL PROPERTIES OF 1-ALKYL(ARYL)-2-OXO-3-CERBETHOXY-4-HYDROXYQUINOLINES AND THEIR DERIVATIVES
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The presently known method for obtaining ethyl esters of 1-alkyl(or aryl)-2-oxo-4-hydroxyquinoline-3-carboxylic acids and their derivatives has been improved.Results are presented from an investigation of the anticoagulant, analgesic, and antiinflammatory activities of the synthesized compounds.
- Ukrainets, I.V.,Gorokhova, O.V.,Taran, S.G.,Bezuglyi, P.A.,Turov, A.V.,et al.
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p. 829 - 836
(2007/10/02)
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