Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells
Creators
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1.
Gwangju Institute of Science and Technology
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2.
Yonsei University
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3.
Severance Hospital
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4.
University of Bonn
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Korea Research Institute of Chemical Technology
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6.
California Institute of Technology
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, R_1, R_2 and R_3, of the quinolinone scaffold. SAR analysis suggested that a carboxylic acid ethyl ester group at the R_1 position, an adamantyl carboxamide group at R_2 and a 4-methoxy substitution at the R_3 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-1β 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 IC_(50) values of 4 and 3 nM, 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-1β, from LPS/IFN-γ/BzATP-stimulated THP-1 cells (IC_(50) of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells.
Additional Information
© 2018 Elsevier Masson SAS. Received 21 September 2017, Revised 28 February 2018, Accepted 8 March 2018, Available online 9 March 2018. This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1D1A4A01015910) and this research was supported by GIST-Caltech Research Collaboration grant funded by the GIST in 2017.Additional details
Identifiers
- Eprint ID
- 85728
- DOI
- 10.1016/j.ejmech.2018.03.023
- Resolver ID
- CaltechAUTHORS:20180410-132941529
Related works
- Describes
- 10.1016/j.ejmech.2018.03.023 (DOI)
Funding
- National Research Foundation of Korea
- NRF-2015R1D1A4A01015910
- GIST-Caltech Research Collaboration
Dates
- Created
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2018-04-11Created from EPrint's datestamp field
- Updated
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2021-11-15Created from EPrint's last_modified field