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

Seung-Hwa Kwak; Jung-Ah Kang; Minjeong Kim; So-Deok Lee; Jin-Hee Park; Sung-Gyoo Park; Hyojin Ko; Yong-Chul Kim

doi:10.1016/j.bmc.2016.08.051

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. Epub 2016 Aug 29.

Authors

Seung-Hwa Kwak¹, Jung-Ah Kang¹, Minjeong Kim¹, So-Deok Lee¹, Jin-Hee Park¹, Sung-Gyoo Park¹, Hyojin Ko², Yong-Chul Kim³

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Humans
Interleukin-2 / antagonists & inhibitors*
Interleukin-2 / metabolism
Jurkat Cells
Molecular Structure
Quinolones / chemical synthesis
Quinolones / chemistry
Quinolones / pharmacology*
Structure-Activity Relationship

Substances

Interleukin-2
Quinolones