2. Academic Validation
  3. Synthesis of new ent-labdane diterpene derivatives from andrographolide and evaluation of their anti-inflammatory activities

Synthesis of new ent-labdane diterpene derivatives from andrographolide and evaluation of their anti-inflammatory activities

  • Eur J Med Chem. 2019 Jan 15:162:70-79. doi: 10.1016/j.ejmech.2018.11.002.
Wang Wang 1,  Yanli Wu 1,  Xinxin Chen 1,  Peng Zhang 1,  Hua Li 2,  Lixia Chen 3
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: li_hua@hust.edu.cn.
  • 3 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: syzyclx@163.com.
PMID: 30419492 DOI: 10.1016/j.ejmech.2018.11.002
Abstract

Two series of andrographolide derivatives with nitrogen-containing heterocycles, Phenols and aromatic acids as bioisostere moiety of lactone ring were synthesized. 8 from 18 tested compounds showed stronger inhibitory effect on LPS-induced NO production in RAW264.7 macrophage than hydrocortisone. Among them, compound 8m exhibited the most potent inhibition with IC50 of 3.38 ± 1.03 μM. The structure-activity relationships (SARs) suggested that the replacement of lactone ring with small-molecule Phenols could improve the anti-inflammatory efficacy. Furthermore, compound 8m significantly reduced the levels of pro-inflammatory cytokine IL-1β and IL-6 with no influence on cell survival, decreased the expression of iNOS and COX-2, and down-regulated the level and phosphorylation of IκBα, as well as the expression of NF-κB. Also it blocked the nuclear translocation of NF-κB in LPS-induced macrophage. Therefore, the anti-inflammation mechanism of compound 8m was related to the inhibition of COX-2, iNOS and NF-κB signal pathway.

Keywords

Andrographolide; Anti-inflammatory effect; Bioisostere; Structure modification.

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