2. Academic Validation
  3. Design and synthesis of novel derivatives of bisepoxylignans as potent anti-inflammatory agents involves the modulation of the M1/M2 microglia phenotype via TLR4/NF-κB signaling pathway

Design and synthesis of novel derivatives of bisepoxylignans as potent anti-inflammatory agents involves the modulation of the M1/M2 microglia phenotype via TLR4/NF-κB signaling pathway

  • Eur J Med Chem. 2025 Jan 15:282:117092. doi: 10.1016/j.ejmech.2024.117092.
Liang Xiong 1,  Huilin Zhu 2,  Jie Liu 2,  Rongtao Wang 1,  Ting Zhong 1,  Xiaowen Jiang 3,  Lei Tang 4,  Yanhua Fan 5
Affiliations

Affiliations

  • 1 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China; Natural Products Research Center of Guizhou Province, Guiyang, 550014, China.
  • 2 School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 3 School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: 13840267257@163.com.
  • 4 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China; Natural Products Research Center of Guizhou Province, Guiyang, 550014, China. Electronic address: tlei1974@163.com.
  • 5 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China; Natural Products Research Center of Guizhou Province, Guiyang, 550014, China. Electronic address: yhfan@gmc.edu.cn.
PMID: 39612567 DOI: 10.1016/j.ejmech.2024.117092
Abstract

Bisepoxylignans have been reported to possess a variety of biological functions, especially in anti-inflammatory aspects. However, the bis-tetrahydrofuran scaffold restricts the type and position of substituents, which further limits the further optimization of their biological activity and druggability. Here, a series of novel derivative s of bisepoxylignans bearing 7H-pyrrolo[2,3-d]pyrimidin-4-amine and 1H-pyrazolo[3,4-d]pyrimidin-4-amine scaffolds were designed and synthesized by a scaffold hopping strategy. Biological evaluation demonstrated that compound 7x exhibited the most potent anti-inflammatory activity, both in vitro and in vivo. Additionally, 7x displayed an excellent oral safety profile at a dose of 500 mg/kg. The anti-inflammatory effect of 7x is potentially mediated by the inhibition of the TLR4/NF-κB pathway and the promotion of M1 to M2 microglial phenotypic conversion. Taken together, 7x could be a promising lead compound for the development of novel therapeutic agents for the treatment of inflammatory diseases.

Keywords

Anti-inflammatory activity; Bisepoxylignans; M1 to M2 microglial phenotypic conversion; TLR4/NF-κB pathway.

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