Discovery, Total Synthesis, and Anti‐inflammatory Evaluation of Naturally Occurring Naphthopyrone‐Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors

• Published in: Angewandte Chemie
• Main Authors: Sun, Chunxiao, Jiang, Yuqi, Li, Changlong, Sun, Simin, Lin, Jiaqi, Wang, Wenxue, Zhou, Luning, Li, Liping, Shah, Mudassir, Che, Qian, Zhang, Guojian, Wang, De, Zhu, Tianjiao, Li, Dehai
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2024
• Subjects: Antarctic; Antarc*
• Online Access: http://dx.doi.org/10.1002/ange.202405860; https://onlinelibrary.wiley.com/doi/pdf/10.1002/ange.202405860

Numerous clinical disorders have been linked to the etiology of dysregulated NLRP3 (NACHT, LRR, and PYD domain‐containing protein 3) inflammasome activation. Despite its potential as a pharmacological target, modulation of NLRP3 activity remains challenging. Only a sparse number of compounds have been reported that can modulate NLRP3 and none of them have been developed into a commercially available drug. In this research, we identified three potent NLRP3 inflammasome inhibitors, gymnoasins A−C (1−3), with unprecedented pentacyclic scaffolds, from an Antarctic fungus Pseudogymnoascus sp. HDN17‐895, which represent the first naturally occurring naphthopyrone‐macrolide hybrids. Additionally, biomimetic synthesis of gymnoasin A (1) was also achieved validating the chemical structure and affording ample amounts of material for exhaustive bioactivity assessments. Biological assays indicated that 1 could significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro‐inflammatory cytokine IL‐1β release, representing a valuable new lead compound for the development of novel therapeutics with the potential to inhibit the NLRP3 inflammasome.