A new family of synthetic diterpenes that regulates cytokine synthesis by inhibiting IκBα phosphorylation

Ta Hsiang Chao, Thanh Lam, Binh G. Vong, Paqui G. Través, Sonsoles Hortelano, Chinmay Chowdhury, F. Rena Bahjat, G. Kenneth Lloyd, Lyle L. Moldawer, Lisardo Boscá, Michael A. Palladino, Emmanuel A. Theodorakis

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10 Scopus citations

Abstract

The synthesis and the biological evaluation of a new family diterpenes are presented. The synthetic studies were inspired by the structural framework of acanthoic acid (1) and yielded a family of compounds that were evaluated as anti-inflammatory agents. Among them, compounds 2, 10, 12, and 16 exhibited a very low nonspecific cytotoxicity and inhibited the synthesis of TNF-α with greater than 65 % efficacy at low micromolar concentrations. Cytokine-specificity studies revealed that these compounds also inhibited the synthesis of the proinflammatory cytokines IL-1β and IL-6, while inhibition of IL-1ra and IL-8 synthesis was marginal and only occurred at high concentrations. Further studies, through EMSA and Western blot analyses, indicated that these compounds decreased the extent of phosphorylation of IκBα; this suggests that they exert their anti-inflammatory profile by inhibiting NF-κB-mediated cytokine synthesis. These findings imply that these diterpenes represent promising leads for the development of novel anti-inflammatory agents.

Original languageEnglish (US)
Pages (from-to)133-144
Number of pages12
JournalChemBioChem
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2005

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Keywords

  • Cytokines
  • Inflammation
  • Inhibitors
  • Natural products
  • Phosphorylation
  • Terpenoids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Cite this

Chao, T. H., Lam, T., Vong, B. G., Través, P. G., Hortelano, S., Chowdhury, C., Bahjat, F. R., Lloyd, G. K., Moldawer, L. L., Boscá, L., Palladino, M. A., & Theodorakis, E. A. (2005). A new family of synthetic diterpenes that regulates cytokine synthesis by inhibiting IκBα phosphorylation. ChemBioChem, 6(1), 133-144. https://doi.org/10.1002/cbic.200400089