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Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells

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dc.contributor.author강석구-
dc.date.accessioned2018-08-28T17:06:30Z-
dc.date.available2018-08-28T17:06:30Z-
dc.date.issued2018-
dc.identifier.issn0223-5234-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/162262-
dc.description.abstractScreening a compound library of quinolinone derivatives identified compound 11a as a new P2X7 receptor antagonist. To optimize its activity, we assessed structure-activity relationships (SAR) at three different positions, R1, R2 and R3, of the quinolinone scaffold. SAR analysis suggested that a carboxylic acid ethyl ester group at the R1 position, an adamantyl carboxamide group at R2 and a 4-methoxy substitution at the R3 position are the best substituents for the antagonism of P2X7R activity. However, because most of the quinolinone derivatives showed low inhibitory effects in an IL-1beta ELISA assay, the core structure was further modified to a quinoline skeleton with chloride or substituted phenyl groups. The optimized antagonists with the quinoline scaffold included 2-chloro-5-adamantyl-quinoline derivative (16c) and 2-(4-hydroxymethylphenyl)-5-adamantyl-quinoline derivative (17k), with IC50 values of 4 and 3nM, respectively. In contrast to the quinolinone derivatives, the antagonistic effects of the quinoline compounds (16c and 17k) were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1beta, from LPS/IFN-gamma/BzATP-stimulated THP-1cells (IC50 of 7 and 12nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherEditions Scientifiques Elsevier-
dc.relation.isPartOfEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAnti-Inflammatory Agents/chemical synthesis/chemistry/pharmacology-
dc.subject.MESHAntineoplastic Agents/chemical synthesis/chemistry/*pharmacology-
dc.subject.MESHCell Line-
dc.subject.MESHTumor Cell Line-
dc.subject.MESHGlioblastoma/*drug therapy/metabolism-
dc.subject.MESHHumans-
dc.subject.MESHPurinergic P2X Receptor Antagonists/chemical synthesis/chemistry/*pharmacology-
dc.subject.MESHQuinolines/chemical synthesis/chemistry/*pharmacology-
dc.subject.MESHQuinolones/chemical synthesis/chemistry/*pharmacology-
dc.subject.MESHPurinergic P2X7/metabolism Receptors-
dc.subject.MESHStructure-Activity Relationship-
dc.titleSynthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Neurosurgery-
dc.contributor.googleauthorSeung-Hwa Kwak-
dc.contributor.googleauthorSeungheon Shin-
dc.contributor.googleauthorJi-Hyun Lee-
dc.contributor.googleauthorJin-Kyoung Shim-
dc.contributor.googleauthorMinjeong Kim-
dc.contributor.googleauthorSo-Deok Lee-
dc.contributor.googleauthorAram Lee-
dc.contributor.googleauthorJinsu Bae-
dc.contributor.googleauthorJin-Hee Park-
dc.contributor.googleauthorAliaa Abdelrahman-
dc.contributor.googleauthorChrista E Muller-
dc.contributor.googleauthorSteve K Cho-
dc.contributor.googleauthorSeok-Gu Kang-
dc.contributor.googleauthorMyung Ae Bae-
dc.contributor.googleauthorJung Yoon Yang-
dc.contributor.googleauthorHyojin Ko-
dc.contributor.googleauthorWilliam A 3rd Goddard-
dc.contributor.googleauthorYong-Chul Kim-
dc.identifier.doi10.1016/j.ejmech.2018.03.023-
dc.contributor.localIdA00036-
dc.relation.journalcodeJ00829-
dc.identifier.eissn1768-3254-
dc.identifier.pmid29649742-
dc.identifier.urlhttps://www.sciencedirect.com/science/article/pii/S0223523418302666-
dc.subject.keywordAntagonist-
dc.subject.keywordAnti-glioma-
dc.subject.keywordEtBr-
dc.subject.keywordIL-1beta-
dc.subject.keywordInflammation-
dc.subject.keywordP2X7 receptor-
dc.subject.keywordQuinoline-
dc.subject.keywordQuinolinone-
dc.contributor.alternativeNameKang, Seok Gu-
dc.contributor.affiliatedAuthorKang, Seok Gu-
dc.citation.volume151-
dc.citation.startPage462-
dc.citation.endPage481-
dc.identifier.bibliographicCitationEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, Vol.151 : 462-481, 2018-
dc.identifier.rimsid59848-
dc.type.rimsART-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers

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