RRC ID 42484
Author Murakami Y, Ito S, Atsumi T, Fujisawa S.
Title Theoretical prediction of the relationship between phenol function and COX-2/AP-1 inhibition for ferulic acid-related compounds.
Journal In Vivo
Abstract Ferulic acid-related compounds possess antioxidant activity. Dehydrodiisoeugenol and ferulic acid dimer (bis-FA), but not the parent monomers isoeugenol and ferulic acid, inhibit lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2) gene expression in RAW 264.7 cells. To clarify the mechanism of their inhibitory effects on COX-2 expression, the phenolic O-H bond dissociation enthalpy (BDE) and ionization potential (IP) of 8 ferulic acid-related compounds were calculated by both semi-empirical molecular orbital (AM1, PM3) and ab initio (3-21G* 6-31G*) and density function theory (DFT) (B3LYP) methods. COX-2 inhibition appeared in compounds with phenolic O-H BDE higher than 85.76 kcal/mol, as calculated by the density function theory (DFT) approach. The phenolic O-H BDEs of the most potent compounds, dehydrodiisoeugenol and bis-FA, were 85.99 and 85.76 kcal/mol, respectively. No causal relationship between COX-2 inhibition and IP was found. Neither dehydrodiisoeugenol nor bis-FA possessed significant scavenging activity against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. The NSAID-like activity of dehydrodiisoeugenol and bis-FA appears to be related to their phenol function. Binding of activator protein-1 (AP-1) to the 12-tetradecanoylphorbol-13-acetate-responsive element (TRE) sequence in LPS-stimulated cells was inhibited by bis-FA at 1 microM and dehydrodiisoeugenol at 0.1 microM, but not by the parent monomers isoeugenol and ferulic acid.
Volume 19(6)
Pages 1039-43
Published 2005-11-1
PMID 16277019
MeSH Animals Anti-Inflammatory Agents, Non-Steroidal / pharmacology Antioxidants / pharmacology* Biphenyl Compounds / pharmacology Bridged Bicyclo Compounds, Heterocyclic / chemistry Bridged Bicyclo Compounds, Heterocyclic / pharmacology Cell Line Coumaric Acids / chemistry Coumaric Acids / pharmacology* Cyclooxygenase 2 Inhibitors / metabolism* Dimerization Electrophoretic Mobility Shift Assay Eugenol / analogs & derivatives* Eugenol / chemistry* Eugenol / pharmacology* Free Radical Scavengers / pharmacology Gene Expression Regulation / drug effects Guaiacol / analogs & derivatives Guaiacol / chemistry Guaiacol / pharmacology Hydrazines / pharmacology Lipopolysaccharides / pharmacology Macrophages / drug effects Macrophages / enzymology* Mice Models, Chemical Models, Theoretical Phenol / chemistry* Picrates Structure-Activity Relationship Tetradecanoylphorbol Acetate / chemistry Tetradecanoylphorbol Acetate / metabolism Thermodynamics Transcription Factor AP-1 / antagonists & inhibitors* Transcription Factor AP-1 / metabolism
IF 1.609
Times Cited 20
Human and Animal Cells