Semisynthesis and biological evaluation of 17-hydroxybrevianamide N derivatives as anti-inflammatory agents by mediating NF-κB and MAPK signaling pathways.

Chronic inflammation is a trigger for many diseases that affect approximately 10-20 % of the population around the world. Herein, (±)-17-hydroxybrevianamide N (1) was isolated from the fungus Aspergillus sp. (CHNSCLM-0151) and exhibited strong inhibitory activity against nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 cell. A series of new derivatives (±)-3-(±)-29 was semisynthesized by structural modification of the imide, phenolic hydroxyl, and carbonyl groups from the natural product (±)-1. The results of anti-inflammatory activity demonstrated that (±)-4, (±)-6, (±)-9, (±)-22, (±)-23, and (±)-24 exhibited obviously NO inhibitory (P < 0.0001) in LPS-stimulated RAW264.7 cells. To further investigate the relationship between chirality and activity, the enantiomers of the above six compounds were obtained by chiral resolution. As expected, the bioactivity results indicated stereoselectivity in the anti-inflammatory effect among the different isomers. In particular, compound (+)-4S-23 inhibited NO concentration with an IC value of 0.5 μM, demonstrating 3-fold greater potency compared to its (R)-enantiomer, and achieving 40-fold superior potency over the positive control NG-monomethyl-l-arginine (L-NMMA). This compound demonstrated suppression of TNF-α (25.7 ± 1.5 %), IL-6 (54.5 ± 3.9 %) and IL-1β (92.9 ± 4.1 %) production at 2 μM. More importantly, mechanistic investigations revealed that (+)-4S-23 (0.2 μM) modulates the MAPK signaling pathway, specifically downregulating phosphorylation of p38, ERK, and JNK. Furthermore, (+)-4S-23 also exhibited potent inhibitory activity against the NF-κB pathway by suppressing the phosphorylation of IκB-α and blocking nuclear translocation of phosphorylated p65. Notably, these findings position (+)-4S-23 as a promising candidate for development as a novel anti-inflammatory therapeutic targeting both MAPK and NF-κB signaling nodes.