Abstract

To clarify the structure–activity relationships of flavonoids for nitric oxide (NO) production inhibitory activity, we examined the inhibitory effects of 73 flavonoids on NO production in lipopolysaccharide-activated mouse peritoneal macrophages. Among those flavonoids, apigenin (IC 50=7.7 μM), diosmetin (8.9 μM), and tetra- O-methylluteolin (2.4 μM), and hexa- O-methylmyricetin (7.4 μM) were found to show potent inhibitory activity, and the results suggested the following structural requirements of flavonoids: (1) the activities of flavones were stronger than those of corresponding flavonols; (2) the glycoside moiety reduced the activity; (3) the activities of flavones were stronger than those of corresponding flavanones; (4) the flavones and flavonols having the 4′-hydroxyl group showed stronger activities than those lacking the hydroxyl group at the B ring and having the 3′,4′-dihydroxyl group; (5) the flavonols having the 3′,4′-dihydroxyl group (catechol type) showed stronger activities than those having the 3′,4′,5′-trihydroxyl group (pyrogallol type); (6) the 5-hydroxyl group tended to enhance the activity; (7) methylation of the 3-, 5-, or 4′-hydroxyl group enhanced the activity; (8) the activities of isoflavones were weaker than those of corresponding flavones; (9) methylation of the 3-hydroxyl group reduced the cytotoxicity. In addition, potent NO production inhibitors were found to inhibit induction of inducible nitric oxide synthase (iNOS) without iNOS enzymatic inhibitory activity.

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