2. Academic Validation
  3. Synthesis of Lathyrol PROTACs and Evaluation of Their Anti-Inflammatory Activities

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

  • J Nat Prod. 2023 Apr 28;86(4):767-781. doi: 10.1021/acs.jnatprod.2c00912.
Wang Wang 1 2 3,  Yang Liu 2,  Liangliang Xiong 2,  Dejuan Sun 2,  Hui Wang 2,  Zhuorui Song 2,  Yutong Li 2,  Hua Li 1 2,  Lixia Chen 1 2
Affiliations

Affiliations

  • 1 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
  • 2 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Luoyang Key Laboratory of Organic Functional Molecules, College of Food and Drug, Luoyang Normal University, Luoyang 471934, China.
PMID: 37002536 DOI: 10.1021/acs.jnatprod.2c00912
Abstract

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 μM) 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-κB, blocked the nuclear translocation of NF-κB, and activated Autophagy in LPS-induced RAW264.7 cells. Based on the results obtained, compound 13 might be a promising anti-inflammatory agent.

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