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

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6 Citations (Scopus)

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

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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    Kwak, S. H., Shin, S., Lee, J. H., Shim, J. K., Kim, M., Lee, S. D., Lee, A., Bae, J., Park, J. H., Abdelrahman, A., Müller, C. E., Cho, S. K., Kang, S. G., Bae, M. A., Yang, J. Y., Ko, H., Goddard, W. A., & Kim, Y. C. (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, 462-481. https://doi.org/10.1016/j.ejmech.2018.03.023