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

• Published in: Angewandte Chemie International Edition 2024-10, Vol.63 (43), p.e202405860-n/a
• 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
• Language: English
• Subjects: Animals; Antarctic fungi; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological activity; Biomimetic materials; Biomimetics; Chemical synthesis; Drug development; Drug Discovery; Humans; Hybrids; Inflammasomes; Inflammasomes - antagonists & inhibitors; Inflammasomes - metabolism; Inhibitors; Lead compounds; Macrolides - chemical synthesis; Macrolides - chemistry; Macrolides - pharmacology; Mice; Molecular Structure; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; Natural Products; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 Inflammasome Inhibitors; Pyrones - chemical synthesis; Pyrones - chemistry; Pyrones - pharmacology; Total Synthesis
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.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. Three potent NLRP3 inflammasome inhibitors with unprecedented pentacyclic scaffolds, gymnoasins A‐C, were discovered from an Antarctic fungus, and biomimetic asymmetric synthesis of gymnoasin A was achieved. Gymnoasin A significantly inhibited in vitro NLRP3 inflammasome activation and in vivo pro‐inflammatory cytokine IL‐1β release, providing a valuable new drug lead for the development of novel therapeutics targeting the NLRP3 inflammasome.