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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

Authors
 Seung-Hwa Kwak  ;  Seungheon Shin  ;  Ji-Hyun Lee  ;  Jin-Kyoung Shim  ;  Minjeong Kim  ;  So-Deok Lee  ;  Aram Lee  ;  Jinsu Bae  ;  Jin-Hee Park  ;  Aliaa Abdelrahman  ;  Christa E Muller  ;  Steve K Cho  ;  Seok-Gu Kang  ;  Myung Ae Bae  ;  Jung Yoon Yang  ;  Hyojin Ko  ;  William A 3rd Goddard  ;  Yong-Chul Kim 
Citation
 European Journal of Medicinal Chemistry, Vol.151 : 462-481, 2018 
Journal Title
 European Journal of Medicinal Chemistry 
ISSN
 0223-5234 
Issue Date
2018
MeSH
Anti-Inflammatory Agents/chemical synthesis/chemistry/pharmacology ; Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Cell Line ; Tumor Cell Line ; Glioblastoma/*drug therapy/metabolism ; Humans ; Purinergic P2X Receptor Antagonists/chemical synthesis/chemistry/*pharmacology ; Quinolines/chemical synthesis/chemistry/*pharmacology ; Quinolones/chemical synthesis/chemistry/*pharmacology ; Purinergic P2X7/metabolism Receptors ; Structure-Activity Relationship
Keywords
Antagonist ; Anti-glioma ; EtBr ; IL-1beta ; Inflammation ; P2X7 receptor ; Quinoline ; Quinolinone
Abstract
Screening 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.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/162262
Full Text
https://www.sciencedirect.com/science/article/pii/S0223523418302666
DOI
10.1016/j.ejmech.2018.03.023
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실)
Yonsei Authors
강석구(Kang, Seok Gu) ORCID logo https://orcid.org/0000-0001-5676-2037
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