Structure-Activity Relationship (SAR) of Flavones on Their Anti-Inflammatory Activity in Murine Macrophages in Culture through the NF-κB Pathway and c-Src Kinase Receptor

Flavones benefit human health through their anti-inflammatory activity; however, their structure-activity relationship is unclear. Herein, we selected 15 flavones with the same backbone but different substituents and systematically assessed their anti-inflammatory activities in RAW 264.7 regarding cellular-Src kinase (c-Src) affinity, suppression of I kappa B alpha phosphorylation, inhibition of nitric oxide (NO) and inducible nitric oxidase (iNOS) production, and downregulation of genes of proinflammatory cytokines interleukin 6 (IL-6), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF-alpha). Overall, our results showed that the double bond between C2-C3 and C3'-and C4'-OH promoted anti-inflammatory activity, while C8- and C5'-OH and the methoxy group on C4' attenuated the overall anti-inflammatory and antioxidant activities. The hydroxyl groups at other positions exhibited more complicated functions. The two most effective flavones are 3',4'-dihydroxyflavone and luteolin with inhibitory concentration (IC50) values for inhibiting the LPS-induced nitric oxide level are 9.61 +/- 1.36 and 16.90 +/- 0.74 mu M, respectively. Furthermore, they suppressed the production of iNOS by approximately 90% and inhibited IL-1 beta and IL-6 by more than 95%. Taken together, our results established a relationship between the flavone structure and anti-inflammatory activity in vitro.