Inhibition of prostalglandin E2 production by 2'-hydoxychalcone 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 microM. 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.
Kim
Y P
YP
Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
Ban
H S
HS
Lim
S S
SS
Kimura
N
N
Jung
S H
SH
Ji
J
J
Lee
S
S
Ryu
N
N
Keum
S R
SR
Shin
K H
KH
Ohuchi
K
K
D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D047188:Chalcones; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D007527:Isoenzymes / Q000096:biosynthesis; D017737:Macrophages, Peritoneal; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002273:Carcinogens; D047188:Chalcones; D007527:Isoenzymes; D002599:Chalcone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; C013031:2'-hydroxychalcone