Inhibition of prostaglandin E₂ production by 2′-hydroxychalcone derivatives and the mechanism of action

The effects of 14 synthetic 2′-hydroxychalcone derivatives on prostaglandin E₂ (PGE₂) production in rat peritoneal macrophages stimulated by the protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA), were examined to clarify the structure-activity relationship. 2′,4-Dihydroxy-4′-methoxychalcone (compound 3), 2′,4-dihydroxy-6′-methoxychalcone (compound 8) and 2′-hydroxy-4′-methoxychalcone (compound 9) suppressed PGE₂ production more potently than the other compounds. The IC50 (50% Inhibitory concentration) value for compounds 3, 8 and 9 was calculated to be 3 μM. The activity of cyclooxygenase (COX)-1 was inhibited slightly by compound 9, but that of COX-2 was not inhibited. At concentrations that inhibited the production of PGE₂, compound 9 had no effect on the release of radioactivity from [³H]arachidonic acid-labelled macrophages stimulated by TPA. Western-blot analysis revealed that the induction of COX-2 protein by TPA was inhibited by compound 9 in parallel with the inhibition of PGE₂ production. Compounds 3 and 8 had similar effects. These findings suggest that 4′-methoxyl and 6′-methoxyl groups are required for the expression of more potent inhibitory activity against PGE₂ production, and that the inhibition of PGE₂ production by these 2′-hydroxychalcone derivatives is due to the inhibition of TPA-induced COX-2 protein expression.