Back to Search
Start Over
Discovery, Total Synthesis, and Anti-Inflammatory Evaluation of Naturally Occurring Naphthopyrone-Macrolide Hybrids as Potent NLRP3 Inflammasome Inhibitors.
- Source :
-
Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Oct 21; Vol. 63 (43), pp. e202405860. Date of Electronic Publication: 2024 Jul 17. - Publication Year :
- 2024
-
Abstract
- 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.<br /> (© 2024 Wiley-VCH GmbH.)
- Subjects :
- Humans
Mice
Anti-Inflammatory Agents pharmacology
Anti-Inflammatory Agents chemical synthesis
Anti-Inflammatory Agents chemistry
Animals
Molecular Structure
Pyrones pharmacology
Pyrones chemistry
Pyrones chemical synthesis
Drug Discovery
Naphthalenes pharmacology
Naphthalenes chemistry
Naphthalenes chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Anti-Inflammatory Agents, Non-Steroidal chemistry
Anti-Inflammatory Agents, Non-Steroidal chemical synthesis
NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Inflammasomes metabolism
Inflammasomes antagonists & inhibitors
Macrolides pharmacology
Macrolides chemistry
Macrolides chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1521-3773
- Volume :
- 63
- Issue :
- 43
- Database :
- MEDLINE
- Journal :
- Angewandte Chemie (International ed. in English)
- Publication Type :
- Academic Journal
- Accession number :
- 38837604
- Full Text :
- https://doi.org/10.1002/anie.202405860