Total synthesis/semi-synthesis of natural isopentenyl flavonoids with inhibitory activity on NLRP3 inflammasome

Yingjie Hu, Mengjun Su, Yichao Kong, Caihong Jiang, Yaxia Yuan, Xiabin Chen, Lei Ma

Research output: Contribution to journalArticlepeer-review

Abstract

Inflammation is the body's defense response to stimuli. When the homeostatic balance is disturbed, disease may result. Flavonoids have clear anti-inflammatory effects and the isopentenyl group significantly enhances the pharmacological activity of flavonoids. Therefore, isopentenyl flavonoids have the potential to serve as lead compounds for the development of anti-inflammatory drugs. Throughout this research, eight natural compounds were synthesized, including 5,7-dihydroxy-4′-methoxy-8-prenylflavonoid (1), 4′-O-Methylatalantoflavone (2), Kushenol W (3) and Racemoflavone (5), which were totally synthesized for the first time. Additionally, three flavonols: Licoflavonol (6), 3,5,7,3′,4′-pentahydroxy-6-prenylflavonol (7) and Macarangin (8), can be one-step synthesized by direct C-isopentenylation. In the process, an economical and efficient C-isopentenylation method was also simultaneously explored that could facilitate the efficient synthesis of natural products. These compounds were evaluated for their potential anti-inflammatory activities via the NLRP3 signaling pathway. Notably, Macarangin (8) manifested the most potent inhibitory effect. The SAR (Structure-Activity Relationships) also showed the introduction of the isopentenyl group was determined to enhance these effects, whereas simple flavonoid frameworks or cyclization of isopentenyl groups all diminished anti-inflammatory activity.

Original languageEnglish (US)
Article number129777
JournalBioorganic and Medicinal Chemistry Letters
Volume107
DOIs
StatePublished - Jul 15 2024

Keywords

  • C-isopentenylation
  • Flavonoid
  • Macarangin
  • NLRP3 inflammasome
  • Total synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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