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A New Family of Synthetic Diterpenes that Regulates Cytokine Synthesis by Inhibiting IκBα Phosphorylation
Author(s) -
Chao TaHsiang,
Lam Thanh,
Vong Binh G.,
Través Paqui G.,
Hortelano Sonsoles,
Chowdhury Chinmay,
Bahjat F. Rena,
Lloyd G. Kenneth,
Moldawer Lyle L.,
Boscá Lisardo,
Palladino Michael A.,
Theodorakis Emmanuel A.
Publication year - 2005
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200400089
Subject(s) - proinflammatory cytokine , cytokine , phosphorylation , western blot , chemistry , tumor necrosis factor alpha , cytotoxicity , biochemistry , biology , pharmacology , immunology , inflammation , in vitro , gene
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 I κB α; 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.