2. Academic Validation
  3. Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis

Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis

  • Bioorg Chem. 2024 Nov:152:107716. doi: 10.1016/j.bioorg.2024.107716.
Hao-Ran Wu 1,  Cai-Neng Zhang 1,  Bo-Qiang Dou 1,  Nan-Ying Chen 1,  De-Feng Gao 1,  Pei-Sen Zou 1,  Cheng-Xue Pan 1,  Ji-Hong Gu 2,  Dong-Liang Mo 3,  Jun-Cheng Su 4
Affiliations

Affiliations

  • 1 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
  • 2 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China. Electronic address: gujh@gzucm.edu.cn.
  • 3 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: moeastlight@mailbox.gxnu.edu.cn.
  • 4 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: su_juncheng@163.com.
PMID: 39178707 DOI: 10.1016/j.bioorg.2024.107716
Abstract

Lycodine Alkaloids are important Natural Products with diverse biological effects. In this manuscript, we set out the first structural optimization of the 2-pyridone moiety of Lycodine alkaloid via selective O-arylation under metal-free conditions and obtained a series of potent bioactive molecules against monosodium urate (MSU)-induced IL-1β production. Further investigations demonstrated that these natural product derivatives could activate the neuro-immunomodulatory cholinergic anti-inflammatory pathway (CAP) to block the initial phase of NLRP3 inflammasome activation. Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, 3k and 3q possessed greater potency against MSU-induced IL-1β production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural Lycodine Alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis.

Keywords

Cholinergic anti-inflammatory pathway; Huperzinine; IL-1β; Natural products.

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