| Research Abstract |
Natural antioxidants, o-methoxyphenols such as eugenol (4-allyl-2-methoxyphenol) and isoeugenol (4-propenyl-2-methoxyphenol), which are components of clover oil, are commonly used as a flavoring agent in cosmetics and food products. These compounds show an anti-inflammatory effect but have adverse effects characterized by inflammatory and allergic reactions when they used at higher concentrations, possibly due to their prooxidant activity and consequent formation of reactive quinone methide intermediates. Their beneficial biological activity may be obtained by avoiding these adverse effects by lessening the potent oxidative activity of these compounds. Thus, we recently designed several synthetic dimers of eugenol, isoeugenol or ferulic acid to lessen the prooxidant activity induced by these monomers, and demonstrated that these dimeric compounds showed the reduced cytotoxicity due to the decrease in the radical production. These findings suggest that o-methoxyphenol dimers might act a
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s a potent inhibitor of inflammatory and allergic responses. However, the inhibitory mechanism of these compounds on inflammatory responses has still not been clarified in detail. In the present study, we examined the inhibitory effect of dimer compounds such as bis-eugenol, dehydrodiisoeugenol, and bis-ferulic acid, on the lipopolysaccharide (LPS)- induced inflammatory mediator expression in mouse macrophage cell line RAW264.7. Eugenol, isoeugenol, ferulic acid and isoferulic acid were purchased from Tokyo Kasei Co. ; hesperetin and hesperidin was from Sigma Chemical Co. ; o-vanilin was from Wako Chemical Co. Escherichia coli O111B4 LPS purchased from LBL Inc. LPS-induced inflammatory cytokine such as IL-1β, TNF-α, and mouse neutrophil chemoattractant KC and cyclooxygenase (COX)-2 expressions were strongly inhibited by these dimer compounds, but not by their parent monomers. In addition, other o-methoxyphenol compounds such as hesperetin, hesperidin, o-vanilin and isoferulic acid also inhibited LPS-induced COX-2 expression at higher concentrations. o-Methoxyphenol compounds which exhibited the COX-2 inhibitory effect at low concentrations possessed the moderate bond dissociation energy (BDE) value ; parameter to predict the effect of a phenol function. These observations suggest that dimerization of o-methoxyphenols, leading to a high level of phenolic function, may exhibit a potent anti-inflammatory and anti-carcinogenic action on the various inflammatory or neoplastic diseases, and also may be a useful tool for the discovery of effective NSAID-like compounds. Less
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