New lathyrane diterpenoid hybrids have anti-inflammatory activity through the NF-κB signaling pathway and autophagy

• Published in: Acta Materia Medica Vol. 1; no. 2; pp. 224 - 243
• Main Authors: Wang, Wang, Xiong, Liangliang, Wu, Yanli, Zhou, Yirong, Li, Yutong, Zheng, Mengzhu, Song, Zhuorui, Sun, Dejuan, Chen, Lixia
• Format: Journal Article
• Language: English
• Published: Compuscript Ltd 01-05-2022
• Subjects: 1,2,3-triazole; 3-hydroxyflavone; anti-inflammation; hybrid; lathyrane; structural modification
• ISSN: 2737-7946; 2737-7946
• DOI: 10.15212/AMM-2022-0008

In our ongoing work on the identification of potent anti-inflammatory agents, we designed and synthesized three series of lathyrane diterpenoid hybrids in which the lathyrane diterpenoid skeleton was hybridized with other anti-inflammatory pharmacophores. Unexpectedly, lathyrane diterpenoid/3-hydroxyflavone hybrids showed more potent anti-inflammatory activity in RAW264.7 cells than did the corresponding parent compounds. Compound
8d1
exhibited potent anti-inflammatory activity with low cytotoxicity (IC
50
= 1.55 ± 0.68 μM), and downregulated LPS-induced expression of iNOS and COX-2, as well as IκBα phosphorylation. This compound also inhibited the expression and nuclear translocation of NF-κB, and stimulated autophagy induction. Thus,
8d1
’s anti-inflammatory mechanism is associated with inhibition of the NF-κB signaling pathway and increasing autophagy. This compound may serve as a promising anti-inflammatory agent.