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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

Kwak, Seung-Hwa and Shin, Seungheon and Lee, Ji-Hyun and Shim, Jin-Kyoung and Kim, Minjeong and Lee, So-Deok and Lee, Aram and Bae, Jinsu and Park, Jin-Hee and Abdelrahman, Aliaa and Müller, Christa E. and Cho, Steve K. and Kang, Seok-Gu and Bae, Myung Ae and Yang, Jung Yoon and Ko, Hyojin and Goddard, William A., III and Kim, Yong-Chul (2018) Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells. European Journal of Medicinal Chemistry, 151 . pp. 462-481. ISSN 0223-5234. http://resolver.caltech.edu/CaltechAUTHORS:20180410-132941529

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.ejmech.2018.03.023DOIArticle
https://www.sciencedirect.com/science/article/pii/S0223523418302666PublisherArticle
ORCID:
AuthorORCID
Goddard, William A., III0000-0003-0097-5716
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.
Funders:
Funding AgencyGrant Number
National Research Foundation of KoreaNRF-2015R1D1A4A01015910
GIST-Caltech Research CollaborationUNSPECIFIED
Subject Keywords:P2X7 receptor; Antagonist; IL-1β; EtBr; Inflammation; Quinoline; Quinolinone; Anti-glioma
Record Number:CaltechAUTHORS:20180410-132941529
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180410-132941529
Official Citation: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. Müller, Steve K. Cho, Seok-Gu Kang, Myung Ae Bae, Jung Yoon Yang, Hyojin Ko, William A. Goddard, Yong-Chul Kim, Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells, European Journal of Medicinal Chemistry, Volume 151, 2018, Pages 462-481, ISSN 0223-5234, https://doi.org/10.1016/j.ejmech.2018.03.023. (http://www.sciencedirect.com/science/article/pii/S0223523418302666)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85728
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Apr 2018 14:44
Last Modified:25 Apr 2018 16:01

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