Synthesis and anti-viral activity of a series of sesquiterpene lactones and analogues in the subgenomic HCV replicon system

Der Ren Hwang, Yu Shan Wu, Chun Wei Chang, Tzu Wen Lien, Wei Cheng Chen, Uan Kang Tan, John T.A. Hsu, Hsing Pang Hsieh

Research output: Contribution to journalArticlepeer-review

Abstract

Hepatitis C virus (HCV) infection is a severe liver disease that often leads to liver cirrhosis and hepatocellular carcinoma (HCC). Current therapy is inadequate to conquer this viral disease. In this study, we identified parthenolide (1), an active component in feverfew, a popular remedy for fever and migraine, as a lead compound with an EC50 value of 2.21 μM against HCV replication in a subgenomic RNA replicon assay system. Parthenolide is able to potentiate the interferon α-exerted anti-HCV effect. Several commercially available sesquiterpene lactones (2-5) structurally analogous to parthenolide and a series of synthesized Michael-type adducts of parthenolide (12-18) also exhibit micromolar concentrations for anti-HCV activities. Structure-activity relationship was elucidated to reveal that the spatial arrangement of the terpenoid skeleton fused with an α-methylene-γ- lactone moiety produces maximal anti-HCV activity. In addition, a strong anti-HCV potency indicates a possibility of secondary amino adducts (12-18) converting back to parthenolide or being replaced by the nucleophilic residues of proteins inside cells. This work shows that screening of natural products is a viable and fast way for identifying novel molecular diversity as potential drug leads.

Original languageEnglish
Pages (from-to)83-91
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number1
DOIs
Publication statusPublished - 2006 Jan 1

All Science Journal Classification (ASJC) codes

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

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