Ferulic acid dimer inhibits lipopolysaccharide-stimulated cyclooxygenase-2 expression in macrophages.
Phenylpropanoids may act as nonsteroidal anti-inflammatory drug (NSAID)-like compounds. 4-cis, 8-cis-Bis (4-hydroxy-3-methoxyphenyl)-3, 7-dioxabicyclo-[3.3.0]octane-2,6-dione (bis-FA, compound 2), a dimer of ferulic acid, was synthesized from ferulic acid (1), and its effect on lipopolysaccharide (LPS)-stimulated cyclooxygenase-2 (COX-2) expression in RAW 264.7 cells was compared with those of the parent ferulic acid (1) and of iso-ferulic acid (3-hydroxy-4-methoxycinnamic acid) (3). LPS-induced gene expression of COX-2 was markedly inhibited by compound 2 at a concentration of 10 microM and by compound 3 at 100 microM, but was not inhibited by compound 1 at 100 microM. This observation suggests that compound 2 may possess potent anti-inflammatory activity. These ferulic acid-related compounds were able to scavenge the stable 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical. The 50% inhibitory concentration for DPPH radicals declined in the order 3 (40.20 mM) > 2 (3.16 mM) > 1 (0.145 mM). Compound 1 possessed potent anti-radical activity, but no COX-2 inhibitory activity, which may be a result of enhancement of its conjugate properties by abstraction of an H atom from the phenolic OH group, causing loss of phenolic function. In contrast, inhibition of COX-2 expression by compounds 2 and 3 could be caused by their increased phenolic function, which is associated with decreased anti-radical activity. Compounds 2 and 3, particularly 2, may have potential as NSAID-like compounds.
Hirata
Atsusi
A
Department of Diagnostic Therapeutic Sciences, Meikai University School of Dentistry, Saitama 350-0283, Japan.
Murakami
Yukio
Y
Atsumi
Toshiko
T
Shoji
Masao
M
Ogiwara
Takako
T
Shibuya
Kazutoshi
K
Ito
Shigeru
S
Yokoe
Ichro
I
Fujisawa
Seiichiro
S
D000199:Actins / Q000737:chemistry; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry; D001713:Biphenyl Compounds / Q000494:pharmacology; D015152:Blotting, Northern; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology; D003373:Coumaric Acids / Q000737:chemistry* / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008956:Models, Chemical; D009693:Nucleic Acid Hybridization; D019800:Phenol / Q000737:chemistry; D010851:Picrates; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*
C504605:4,8-bis(4-hydroxy-3-methoxyphenyl)-3,7-dioxabicyclo(3.3.0)octane-2,6-dione; D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002934:Cinnamates; D003373:Coumaric Acids; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016166:Free Radical Scavengers; D005609:Free Radicals; D006834:Hydrazines; D008070:Lipopolysaccharides; D010851:Picrates; D019800:Phenol; D006139:Guaiacol; D004247:DNA; C004999:ferulic acid; C004931:1,1-diphenyl-2-picrylhydrazyl; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C008180:isoferulic acid