Inhibition of prostaglandin E-2 production by 2 '-hydroxychalcone derivatives and the mechanism of action

The effects of 14 synthetic 2'-hydroxychalcone derivatives on prostaglandin E-2 (PGE(2)) production in rat peritoneal macrophages stimulated by the pr otein 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 PGE(2) product ion more potently than the other compounds. The IC50 (50% Inhibitory concen tration) value for compounds 3, 8 and 9 was calculated to be 3 muM. The act ivity of cyclooxygenase (COX)-1 was inhibited slightly by compound 9, but t hat of COX-2 was not inhibited. At concentrations that inhibited the produc tion of PGE(2), compound 9 had no effect on the release of radioactivity fr om [H-3]arachidonic acid-labelled macrophages stimulated by TPA. Western-bl ot analysis revealed that the induction of COX-2 protein by TPA was inhibit ed by compound 9 in parallel with the inhibition of PGE(2) production. Comp ounds 3 and 8 had similar effects. These findings suggest that 4'-methoxyl and 6'-methoxyl groups are required for the expression of more potent inhib itory activity against PGE(2) production, and that the inhibition of PGE(2) production by these 2'-hydroxychalcone derivatives is due to the inhibitio n of TPA-induced COX-2 protein expression.