title: A new family of synthetic diterpenes that regulates cytokine synthesis by inhibiting IkappaBalpha phosphorylation.
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-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.
authors.affiliation: Nereus Pharmaceuticals, Inc, 10480 Wateridge Circle, San Diego, CA 92121, USA.
authors.forename: Ta-Hsiang
authors.initials: TH
authors.lastname: Chao
authors.forename: Thanh
authors.initials: T
authors.lastname: Lam
authors.forename: Binh G
authors.initials: BG
authors.lastname: Vong
authors.forename: Paqui G
authors.initials: PG
authors.lastname: Través
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Hortelano
authors.forename: Chinmay
authors.initials: C
authors.lastname: Chowdhury
authors.forename: F Rena
authors.initials: FR
authors.lastname: Bahjat
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Lloyd
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.forename: Michael A
authors.initials: MA
authors.lastname: Palladino
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
mesh_terms: D016207:Cytokines / Q000096:biosynthesis*; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D004224:Diterpenes; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha