A New Family of Synthetic Diterpenes that Regulates Cytokine Synthesis by Inhibiting IκBα Phosphorylation
| Autor: | Paqui G. Través, G. Kenneth Lloyd, Lyle L. Moldawer, Michael A. Palladino, Sonsoles Hortelano, Binh G. Vong, Lisardo Boscá, Emmanuel A. Theodorakis, Chinmay Chowdhury, Ta Hsiang Chao, Thanh Lam, F. Rena Bahjat |
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| Rok vydání: | 2004 |
| Předmět: |
medicine.diagnostic_test
Tumor Necrosis Factor-alpha Organic Chemistry NF-kappa B Inflammation Biology Biochemistry Terpenoid Proinflammatory cytokine IκBα NF-KappaB Inhibitor alpha Western blot medicine Cytokines Humans Molecular Medicine Phosphorylation I-kappa B Proteins Diterpenes medicine.symptom Cytokine synthesis Cytotoxicity Molecular Biology |
| Zdroj: | ChemBioChem. 6:133-144 |
| ISSN: | 1439-4227 |
| DOI: | 10.1002/cbic.200400089 |
| Popis: | 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-alpha 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-1beta 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 IkappaBalpha; this suggests that they exert their anti-inflammatory profile by inhibiting NF-kappaB-mediated cytokine synthesis. These findings imply that these diterpenes represent promising leads for the development of novel anti-inflammatory agents. |
| Databáze: | OpenAIRE |
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