Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: structure-activity relationship.
Cyclooxygenase-2 (COX-2) plays an important role in carcinogenesis. Investigation of the suppressive action of twelve flavonoids of different chemical classes on the transcriptional activity of the COX-2 gene in human colon cancer DLD-1 cells using a reporter gene assay have revealed quercetin to be the most potent suppressor of COX-2 transcription (IC50 = 10.5 microM), while catechin and epicatechin showed weak activity (IC50 = 415.3 microM). Flavonoids have three heterocyclic rings as a common structure. A structure-activity study indicated that the number of hydroxyl groups on the B ring and an oxo group at the 4-position of the C ring are important in the suppression of COX-2 transcriptional activity. A low electron density of the oxygen atom in the hydroxyl group of the A ring was also important. Further examination of the role of the hydroxyl group in the A ring showed that bromination of resacetophenone to give 3,5-dibromo-2,4-dihydroxyacetophenone resulted in a 6.8-fold increase in potency for suppressing COX-2 promoter activity. These results provide a basis for the design of improved suppressors of COX-2 transcriptional activity.
Cancer Prevention Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
M
M
Mutoh
M
M
Takahashi
K
K
Fukuda
H
H
Komatsu
T
T
Enya
Y
Y
Matsushima-Hibiya
H
H
Mutoh
T
T
Sugimura
K
K
Wakabayashi
D000098:Acetophenones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics; D051546:Cyclooxygenase 2; D004583:Electrons; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics*; D008565:Membrane Proteins; D010100:Oxygen / Q000737:chemistry; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology; D012118:Resorcinols / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000098:Acetophenones; D005419:Flavonoids; D007527:Isoenzymes; D008565:Membrane Proteins; D012118:Resorcinols; D011794:Quercetin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010100:Oxygen; C412963:resacetophenone; C031389:resorcinol