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.
- 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: [email protected].
- 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: [email protected].
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.