- Discovery of new thieno[3,2-d]pyrimidine derivatives targeting EGFRL858R/T790M NSCLCs by the conformation constrained strategy
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Studies on the third-generation of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFRL858R/T790M mutant remain hotspots, specifically for non-small cell lung cancer (NSCLC). In the current study, a new series of EGFR-TKIs with thieno[3,2-d]pyrimidine derivatives(6a-6r) bearing quinolin-2(1H)-ones were designed and synthesized, through conformational constrained strategy from the third generation of EGFR-TKI olmutinib. In vitro structure-activity relationship (SAR) studies indicated that compounds 6a, 6l, 6m, 6n and 6o exhibited good selective inhibition to EGFRL858R/T790M (IC50 ≤ 250 nM) over wild type EGFR (IC50 > 10000 nM). The observed selectivity of compounds 6l and 6o was also proved by the computational molecular docking and the cellular thermal shift assay. These compounds had good growth inhibitory effect on the four tested cancer cell lines. Specifically, 6o could significantly inhibit the colony formation, wound healing and the expression of p-EGFR and its downstream p-ERK in EGFRL858R/T790M H1975 lung cancer cells. Our findings suggest that the thieno[3,2-d]pyrimidine compounds, especially 6l and 6o, can selectively target the mutant EGFRL858R/T790M in vitro and at cellular level and may serve as the lead compounds for generating new series of the third-generation EGFR-TKIs.
- Chen, Yang,Cheng, Zhongyu,Huang, Xin,Jiang, Yaoxuan,Qiao, Hui,Xie, Jiahao,Yang, Linlin,Yu, Bin,Zhao, Wen,Zhou, Wenjuan
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- Structure-Based Design and Optimization of Multitarget-Directed 2 H -Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases
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The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.
- Farina, Roberta,Pisani, Leonardo,Catto, Marco,Nicolotti, Orazio,Gadaleta, Domenico,Denora, Nunzio,Soto-Otero, Ramon,Mendez-Alvarez, Estefania,Passos, Carolina S.,Muncipinto, Giovanni,Altomare, Cosimo D.,Nurisso, Alessandra,Carrupt, Pierre-Alain,Carotti, Angelo
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- A 7 - hydroxy -2 - quinolinone of preparation method
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The invention discloses a formula I compound represented by the preparation method, the method comprises the following steps: in a solvent, in the arrowhead class under the action of the catalyst, on the compound II are shown in the following of the dehydrogenation reaction to obtain the compound I can be. Preparation method of this invention has the following advantages: the raw materials used are cheap, product yield and high purity, the purity of 98% or more, the color white and non-heterogeneous, after treatment is simple, catalyst and solvent can be recycled, wastes very little, for environmental protection, it is suitable for industrial production.
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Paragraph 0044; 0045
(2019/06/07)
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- Containing quinolinone pyrimidine and five-membered heterocyclic compound, preparation method and application thereof (by machine translation)
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The invention discloses containing quinolinone pyrimidine and five-membered heterocyclic compound, preparation method and its application, which belongs to the field of pharmaceutical chemistry. The compounds of the invention of the formula I as shown. The compounds of a plurality of tumor cells such as H1975, A549, PC9, PC3, HGC has significant inhibition and anti-personnel effects, and in the in vitro kinase level to the human epidermal growth factor receptor EGFR - L858R/T790M mutant has good inhibition activity. Can be used as a further development of the candidate or lead compound, is applied to the anti-tumor pharmaceutical preparation. (by machine translation)
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Paragraph 0030; 0031; 0032
(2018/06/26)
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- A process for preparing 7 - hydroxy - 2 - quinolinone of the method (by machine translation)
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The invention discloses a process for preparing 7 - hydroxy - 2 - quinolinone of the method, specific steps are as follows: in the organic solvent, 3, 4 - dihydro - 7 - hydroxy - 2 - quinolone in the catalysis of DDQ heating dehydrogenation, to get the 7 - hydroxy - 2 - quinolinone. The operation is simple, mild reaction conditions, raw materials are easy, simple and efficient, pervasive is good. (by machine translation)
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Paragraph 0036; 0037
(2017/10/06)
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- 3,4-DIHYDRO-2 (1H) - QUINOLINONE AND 2 (1H)-QUINOLINONE DERIVATIVES
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The present invention relates to novel 3,4-dihydro-2(lH)-quinolinone and 2(lH)-quinolinone derivatives, their acceptable acid addition salts, solvates, hydrates and polymorphs thereof. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by atypical antipsychotic agents. The invention further provides methods for using a compound of this invention to determine concentrations of a corresponding 3,4-dihydro-2(lH)- quinolinone or 2(lH)-quinolinone compound, particularly in biological fluids, and to determine metabolism patterns of that 3,4-dihydro-2(lH)-quinolinone or 2(1H)-quinolinone compound.
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Page/Page column 32
(2008/06/13)
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- A concise regiospecific synthesis of 8,8-dimethyl-2H, 8H-pyrano [6, 5- h]quinolin-2-one and related compounds
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An efficient method for the regiospecific synthesis of 8,8-dimethyl- 2H,8H-pyrano[6,5-h]quinolin-2-one and related compounds via a Claisen rearrangement is described.
- Yang, Zheng-Yu,Xia, Yi,Xia, Peng,Brossi, Arnold,Lee, Kuo-Hsiung
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p. 4505 - 4506
(2007/10/03)
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- Lewis acid catalyzed reaction of cinnamanilides: Competition of intramolecular and intermolecular Friedel-Crafts reaction
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The first intermolecular Friedel-Crafts reaction of benzene leading to the formation of 3,3-diphenylpropionanilide 7 is described. 4-Methoxyaniline was reacted with cinnamoyl chloride to give 4-methoxycinnamanilide (5a), the treatment of which with aluminum (III) chloride in chlorobenzene at 120 °C or in benzene at 80 °C afforded exclusively 6-hydroxyquinolin-2(1H)-one (3a) or 4'-hydroxy-3,3-diphenylpropionanilide (7a), respectively. The formation of 7a rather than 3a in benzene indicated that an intermolecular Friedel-Crafts reaction occurred prior to the relatively more facile intramolecular ring cyclization. This intermolecular Friedel-Crafts reaction was observed during the attempted ring cyclization of cinnamanilide and its methoxy derivatives in aluminum (III) chloride/benzene. Preparation of 3a can also be achieved in 17% overall yield via the N-oxidation of 6-hydroxyquinoline followed by acetylation and hydrolysis.
- Wang, Tai-Chi,Chen, Yeh-Long,Lee, Kuan-Han,Tzeng, Cherng-Chyi
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- Synthesis and Biological Evaluation of 2-Styrylquinazolin-4(3H)-ones, a New Class of Antimitotic Anticancer Agents Which Inhibit Tubulin Polymerization
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A novel series of 2-styrylquinazolin-4(3H)-ones which inhibited tubulin polymerization and the growth of L1210 murine leukemia cells was discovered.Extensive structure-activity relationship studies suggest that the entire quinazolinone structure was requi
- Jiang, J. B.,Hesson, D. P.,Dusak, B. A.,Dexter, D. L.,Kang, G. J.,Hamel, E.
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p. 1721 - 1728
(2007/10/02)
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