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

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) (IC 50  = 80 ± 10 nM) and anti-CD3/CD28-stimulated Jurkat T cells (83% inhibition at 10 μM) 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.