In this work, three series of ω-3 polyunsaturated fatty acid-alkanolamine derivatives (PUFA-AAs) were synthesized, characterized and their anti-inflammatory activity in vivo was evaluated. Compounds 4a, 4f, and 4k exhibited marked anti-inflammatory activity in LPS-stimulated RAW 264.7 cells. The most promising compound 4k dose-dependently suppressed the cytokines with IC₅₀ values in the low micromolar range. Further, 4k exhibited potential in vitro Nur77-binding affinity (K_d = 6.99 × 10⁻⁶ M) which is consistent with the result of docking studies. Next, the anti-inflammatory mechanism of 4k was found to be through NF-κB signal pathway in a Nur77-dependent manner. Moreover, we also observed 4k significantly inhibited LPS-induced expression of cytokines (IL-6, TNF-α, and IL-1β) through suppressing NF-κB activation and attenuated LPS-induced inflammation in mouse acute lung injury (ALI) model. In conclusion, the study strongly suggests that the PUFA-AA derivatives can be particularly as new Nur77 mediators for further treatment in inflammatory diseases.

在这项工作中，合成了三个系列的ω-3多不饱和脂肪酸-链烷醇胺衍生物（PUFA-AAs），表征并评估了它们的体内抗炎活性。化合物4a，4f和4k在LPS刺激的RAW 264.7细胞中表现出明显的抗炎活性。最有前途的化合物4k剂量依赖性地抑制了细胞因子，其IC ₅₀值在低微摩尔范围内。此外，4k表现出潜在的体外Nur77结合亲和力（K _d  = 6.99×10 ^-6M）与对接研究的结果一致。接下来，发现4k的抗炎机制是通过Nur77依赖性方式通过NF-κB信号途径。此外，我们还观察到在小鼠急性肺损伤（ALI）模型中，4k通过抑制NF-κB激活显着抑制LPS诱导的细胞因子（IL-6，TNF-α和IL-1β）的表达，并减弱LPS诱导的炎症。总之，该研究强烈表明，PUFA-AA衍生物尤其可以作为新的Nur77介质在炎症性疾病中进一步治疗。