Synthesis of Lathyrol PROTACs and Evaluation of Their Anti- Inflammatory Activities

Lathyrol is a core scaffold structure of many lathyrane diterpenoids with potent anti-inflammatory activity isolated from Euphorbia lathyrism. It was chosen as a framework to design and synthesize a series of proteolysis targeting chimeras. A total of 15 derivatives were obtained. Compound 13 exhibited inhibitory activity on LPS-induced NO production in RAW264.7 cells (IC50 = 5.30 +/- 1.23 mu M) with low cytotoxicity. Furthermore, compound 13 significantly degraded v-maf musculoaponeurotic fibrosarcoma oncogene homologue F (MAFF) protein, a target of lathyrane diterpenoid, concentration-and time-dependently. The mechanism of action of 13 is related to activating the Keap1/Nrf2 pathway. It also inhibited the expression of NF -KB, blocked the nuclear translocation of NF -KB, and activated autophagy in LPS-induced RAW264.7 cells. Based on the results obtained, compound 13 might be a promising anti-inflammatory agent.

Automated summary

Lathyrol, a core scaffold structure of lathyrane diterpenoids, has been found to possess potent anti-inflammatory activity. Researchers designed and synthesized 15 derivatives based on this structure. Compound 13 showed inhibitory activity against LPS-induced NO production in RAW264.7 cells with low cytotoxicity. It also effectively degraded the MAFF protein and activated the Keap1/Nrf2 pathway, leading to inhibition of NF -KB expression, blockade of its nuclear translocation, and activation of autophagy in LPS-induced RAW264.7 cells. Compound 13 could potentially be a promising anti-inflammatory agent.