Discovery of new DHA ethanolamine derivatives as potential anti-inflammatory agents targeting Nur77

Docosahexaenoic acid (DHA) has a strong anti-inflammatory effect and is reported to bind to the ligand-binding domain (LBD) of the anti-inflammatory modulator Nur77. Recently, we have found that DHA ethanolamine (DHA-EA) exerts anti-inflammatory activity as a Nur77 modulator. Herein, using a fragment splicing-based drug design strategy, nineteen new DHA-EA derivatives were synthesized starting from DHA algae oil and then evaluated for their anti-inflammatory activity. The cell-based cytotoxicity assays showed that compounds J2, J9, and J18 had no noticeable effect on the cell morphology and viability of RAW 264.7, LO2, and MCR-5 cells. Meanwhile, J9 was identified as the most potent anti-inflammatory molecule in LPS-stimulated RAW 264.7 cells. Also, the molecular docking study and SPR assay demonstrated that J9 exhibited in vitro Nur77-binding affinity (K_D = 8.58 × 10^-6 M). Moreover, the mechanism studies revealed that the anti-inflammatory activity of J9 was associated with its inhibition of NF-κB activation in a Nur77-dependent manner. Notably, J9 could attenuate LPS-induced inflammation in the mouse acute lung injury (ALI) model. Overall, the DHA-EA derivative J9 targeting Nur77 is a potential candidate for developing anti-inflammatory and ALI-treating agents.