Theoretical prediction of the relationship between phenol function and COX-2/AP-1 inhibition for ferulic acid-related compounds.
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.
Murakami
Yukio
Y
Department of Diagnostic Therapeutic Sciences, Meikai University School of Dentistry, Saitama 350-0283, Japan.
Ito
Shigeru
S
Atsumi
Toshiko
T
Fujisawa
Seiichiro
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000378:metabolism*; D019281:Dimerization; D024202:Electrophoretic Mobility Shift Assay; D005054:Eugenol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006139:Guaiacol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008956:Models, Chemical; D008962:Models, Theoretical; D019800:Phenol / Q000737:chemistry*; D010851:Picrates; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
C504605:4,8-bis(4-hydroxy-3-methoxyphenyl)-3,7-dioxabicyclo(3.3.0)octane-2,6-dione; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003373:Coumaric Acids; D052246:Cyclooxygenase 2 Inhibitors; D016166:Free Radical Scavengers; D006834:Hydrazines; D008070:Lipopolysaccharides; D010851:Picrates; D018808:Transcription Factor AP-1; C496603:dehydrodiisoeugenol; D019800:Phenol; D005054:Eugenol; C036643:isoeugenol; D006139:Guaiacol; C004999:ferulic acid; C004931:1,1-diphenyl-2-picrylhydrazyl; D013755:Tetradecanoylphorbol Acetate