Synthesis of C-4-Substituted Steviol Derivatives and Their Inhibitory Effects against Hepatitis B Virus

Shwu-Jiuan Lin, Ta Chi Su, Chin Nan Chu, Yi Chih Chang, Li Ming Yang, Yu Cheng Kuo, Tsurng Juhn Huang

Research output: Contribution to journalArticle

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Abstract

ent-13-Hydroxykaur-16-ene-19-N-butylureide (6) was one of 33 synthesized C-4-substituted steviol derivatives that were evaluated for their effects on hepatitis B virus (HBV) surface antigen (HBsAg) secretion. The IC50 (16.9 μM) and SI (57.7) values for inhibiting HBV DNA replication of compound 6 were greater than those of the reference compound, lamivudine (3-TC; IC50: 107.5 μM; SI: 22.0). Thus, the anti-HBV mechanism of 6 was investigated, and it specifically inhibited viral gene expression and reduced viral DNA levels, as well as potently attenuated all of the viral promoter activity of HBV-expressing Huh7 cells. Examination of cellular signaling pathways found that 6 inhibited the activities of the nuclear factor (NF)-κB- and activator protein (AP)-1 element-containing promoters, but had no effects on AP-2 or interferon-stimulated response element (ISRE)-containing promoters in HBV-expressing cells. Meanwhile, it significantly eliminated NF-κB and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling-related protein levels and inhibited their phosphorylation in HBV-transfected Huh7 cells. The inhibitory potency of 6 against HBV DNA replication was reversed by cotransfecting the NF-κB p65 expression plasmid. Using the MAPK-specific activator anisomycin also reversed the inhibitory effect of 6 on viral DNA replication. The present findings suggest that the anti-HBV mechanism of 6 is partly mediated through the NF-κB and MAPK signaling pathways.

Original languageEnglish
Pages (from-to)3057-3064
Number of pages8
JournalJournal of Natural Products
Volume79
Issue number12
DOIs
Publication statusPublished - Dec 23 2016

Fingerprint

Viruses
Hepatitis B virus
Derivatives
Mitogen-Activated Protein Kinases
DNA Replication
Viral DNA
Virus Replication
Inhibitory Concentration 50
Anisomycin
Cell signaling
Phosphorylation
Lamivudine
Viral Genes
steviol
DNA
Extracellular Signal-Regulated MAP Kinases
Transcription Factor AP-1
Response Elements
Surface Antigens
Hepatitis B Surface Antigens

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

Cite this

Synthesis of C-4-Substituted Steviol Derivatives and Their Inhibitory Effects against Hepatitis B Virus. / Lin, Shwu-Jiuan; Su, Ta Chi; Chu, Chin Nan; Chang, Yi Chih; Yang, Li Ming; Kuo, Yu Cheng; Huang, Tsurng Juhn.

In: Journal of Natural Products, Vol. 79, No. 12, 23.12.2016, p. 3057-3064.

Research output: Contribution to journalArticle

Lin, Shwu-Jiuan ; Su, Ta Chi ; Chu, Chin Nan ; Chang, Yi Chih ; Yang, Li Ming ; Kuo, Yu Cheng ; Huang, Tsurng Juhn. / Synthesis of C-4-Substituted Steviol Derivatives and Their Inhibitory Effects against Hepatitis B Virus. In: Journal of Natural Products. 2016 ; Vol. 79, No. 12. pp. 3057-3064.
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