Ferulic acid dimer inhibits lipopolysaccharide-stimulated cyclooxygenase-2 expression in macrophages

Phenylpropanoids may act as nonsteroidal antiinflammatory 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 PAW 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 mu M and by compound 3 at 100 mu M but was not inhibited by compound 1 at 100 mu M. This observation suggests that compound 2 may possess potent antiinflammatory 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 inhibitoty activity, which may be a result of enhancement of its conjugate properties by abstraction of an H atom front 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.