2. Academic Validation
  3. Discovery and structure-activity relationship studies of quinolinone derivatives as potent IL-2 suppressive agents

Discovery and structure-activity relationship studies of quinolinone derivatives as potent IL-2 suppressive agents

  • Bioorg Med Chem. 2016 Nov 1;24(21):5357-5367. doi: 10.1016/j.bmc.2016.08.051.
Seung-Hwa Kwak 1,  Jung-Ah Kang 1,  Minjeong Kim 1,  So-Deok Lee 1,  Jin-Hee Park 1,  Sung-Gyoo Park 1,  Hyojin Ko 2,  Yong-Chul Kim 3
Affiliations

Affiliations

  • 1 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
  • 2 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea. Electronic address: kohyojin@gist.ac.kr.
  • 3 School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea; Department of BioMedical Science and Engineering (BMSE), Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea. Electronic address: yongchul@gist.ac.kr.
PMID: 27647370 DOI: 10.1016/j.bmc.2016.08.051
Abstract

The quinolinone skeleton has been utilized to develop various mechanism-based immune modulators. However, the effects of quinolinone derivatives on the release of T cell-associated interleukin-2 (IL-2) have not been established. In this study, a series of novel quinolinone derivatives was synthesized, and their immunosuppressive activity was evaluated by measuring suppression of IL-2 release from activated Jurkat T cells. Optimizing the three side chains around the quinolinone skeleton revealed the most active compound: 11l. This compound exhibits potent inhibitory activity toward IL-2 release in both 12-o-tetradecanoylphorbol-13-acetate (PMA)/A23187 (ionomycin) (IC50=80±10nM) and anti-CD3/CD28-stimulated Jurkat T cells (83% inhibition at 10μM) without cytotoxic effects. Further investigation into the underlying mechanism of 11l indicated the suppression of NF-κB and nuclear factor of activated T cells (NFAT) promoter activities in Jurkat T cells.

Keywords

Immuno-suppressor; Interleukin-2; Jurkat T cells; Quinolinone.

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