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: 111. This compound exhibits potent inhibitory activity toward IL-2 release in both 12-o-tetradecanoylphorbol-13-acetate (PMA)/A23187 (ionomycin) (IC50 = 80 +/- 10 nM) and anti-CD3/CD28-stimulated Jurkat T cells (83% inhibition at 10 mu M) without cytotoxic effects. Further investigation into the underlying mechanism of 111 indicated the suppression of NF-kappa B and nuclear factor of activated T cells (NFAT) promoter activities in Jurkat T cells. (C) 2016 Published by Elsevier Ltd.