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

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

Research output: Contribution to journalArticle

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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, 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-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 IC50 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 (IC50 of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells.

Original languageEnglish
Pages (from-to)462-481
Number of pages20
JournalEuropean Journal of Medicinal Chemistry
Volume151
DOIs
Publication statusPublished - 2018 May 10

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Purinergic P2X7 Receptors
Quinolones
Structure-Activity Relationship
Glioblastoma
Derivatives
Interleukin-1
Scaffolds
Inhibitory Concentration 50
Carboxylic Acids
Skeleton
Chlorides
Assays
Screening
Esters
Substitution reactions
Enzyme-Linked Immunosorbent Assay
quinoline
Cytokines

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Kwak, Seung Hwa ; Shin, Seungheon ; Lee, Ji Hyun ; Shim, Jin Kyoung ; Kim, Minjeong ; Lee, So Deok ; Lee, Aram ; Bae, Jinsu ; Park, Jin Hee ; Abdelrahman, Aliaa ; Müller, Christa E. ; Cho, Steve K. ; Kang, Seok-Gu ; Bae, Myung Ae ; Yang, Jung Yoon ; Ko, Hyojin ; Goddard, William A. ; Kim, Yong Chul. / Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 151. pp. 462-481.
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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, 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-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 IC50 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 (IC50 of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells.",
author = "Kwak, {Seung Hwa} and Seungheon Shin and Lee, {Ji Hyun} and Shim, {Jin Kyoung} and Minjeong Kim and Lee, {So Deok} and Aram Lee and Jinsu Bae and Park, {Jin Hee} and Aliaa Abdelrahman and M{\"u}ller, {Christa E.} and Cho, {Steve K.} and Seok-Gu Kang and Bae, {Myung Ae} and Yang, {Jung Yoon} and Hyojin Ko and Goddard, {William A.} and Kim, {Yong Chul}",
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Kwak, SH, Shin, S, Lee, JH, Shim, JK, Kim, M, Lee, SD, Lee, A, Bae, J, Park, JH, Abdelrahman, A, Müller, CE, Cho, SK, Kang, S-G, Bae, MA, Yang, JY, Ko, H, Goddard, WA & Kim, YC 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, vol. 151, pp. 462-481. https://doi.org/10.1016/j.ejmech.2018.03.023

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; Shin, Seungheon; Lee, Ji Hyun; Shim, Jin Kyoung; Kim, Minjeong; Lee, So Deok; Lee, Aram; Bae, Jinsu; Park, Jin Hee; Abdelrahman, Aliaa; Müller, Christa E.; Cho, Steve K.; Kang, Seok-Gu; Bae, Myung Ae; Yang, Jung Yoon; Ko, Hyojin; Goddard, William A.; Kim, Yong Chul.

In: European Journal of Medicinal Chemistry, Vol. 151, 10.05.2018, p. 462-481.

Research output: Contribution to journalArticle

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T1 - Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells

AU - Kwak, Seung Hwa

AU - Shin, Seungheon

AU - Lee, Ji Hyun

AU - Shim, Jin Kyoung

AU - Kim, Minjeong

AU - Lee, So Deok

AU - Lee, Aram

AU - Bae, Jinsu

AU - Park, Jin Hee

AU - Abdelrahman, Aliaa

AU - Müller, Christa E.

AU - Cho, Steve K.

AU - Kang, Seok-Gu

AU - Bae, Myung Ae

AU - Yang, Jung Yoon

AU - Ko, Hyojin

AU - Goddard, William A.

AU - Kim, Yong Chul

PY - 2018/5/10

Y1 - 2018/5/10

N2 - 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-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 IC50 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 (IC50 of 7 and 12 nM, respectively). In addition, potent P2X7R antagonists significantly inhibited the sphere size of TS15-88 glioblastoma cells.

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