New lathyrane diterpenoid hybrids have anti-inflammatory activity through the NF-κB signaling pathway and autophagy
Wang Wang, Liangliang Xiong, Yanli Wu, Yirong Zhou, Yutong Li, Mengzhu Zheng, Zhuorui Song, Dejuan Sun, Lixia Chen
Abstract
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.