Biological Evaluation and Structural Determinants of p38α Mitogen-Activated-Protein Kinase and c-Jun-N-Terminal Kinase 3 Inhibition by Flavonoids

A series of 42 naturally occurring flavonoids and one flavonoid glucuronide were tested for their ability to inhibit p38 alpha mitogen-activated protein kinase (p38 alpha) and c-Jun-N-terminal kinase 3 (JNK3). Potent inhibitors with IC50 values in the low micromolar range were identified. Structure-activity relationships were evaluated and the most promising compounds were docked into the ATP binding site of these kinases. Among the different classes of flavonoids, the flavonol group showed better inhibition of p38a. Of this class, kaempferol-7,4'-dimethylether was a potent p38 alpha inhibitor, displaying 13-fold selectivity for p38 alpha over JNK3. The flavone compounds without a 6-methoxy group preferentially inhibited JNK3. The flavone glycoside, luteolin-7-O-glycoside, was identified as a potent inhibitor with the greatest selectivity toward JNK3. In contrast, the flavanol compounds displayed similar inhibitory activities toward both kinases.