Inhibition of nitric oxide production from lipopolysaccharide-treated RAW 264.7 cells by synthetic flavones: Structure-activity relationship and action mechanism

Recent investigations have shown that certain flavonoids, especially flavone derivatives, inhibit nitric oxide (NO) production by inducible NO synthase (NOS) in macrophages, which contribute their anti-inflammatory action. For the purpose of finding the optimized chemical structures of flavonoids that inhibit NO production, various A- and B-ring substituted flavones were synthesized and evaluated for their inhibitory activity using lipopolysaccharide-treated RAW 264.7 cells. It was found that the optimal chemical structures were A-ring 5,7-dihydroxyflavones having the B-ring 2',3'-dihydroxy or 3',4'-dihydroxy or 3',4'-hydroxy/methoxy (methoxy/hydroxy) groups. These structurally optimized compounds were revealed to be down-regulators of NOS induction, but not direct NOS inhibitors. Of these derivatives that were evaluated, 2',3',5,7-tetrahydroxyflavone and 3',4',5,7-tetrahydroxyflavone (luteolin) showed the strongest inhibition. The IC50 values for these compounds were 19.7 and 17.1 muM, respectively. Therefore, these compounds may have a potential as new anti-inflammatory agents.