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 (IC(50)=10.5 μM), while catechin and epicatechin showed weak activity (IC(50)=415.3 μM). 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.