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 p38α mitogen-activated protein kinase (p38α) and c-Jun-N-terminal kinase 3 (JNK3). Potent inhibitors with IC(50) 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 p38α. Of this class, kaempferol-7,4'-dimethylether was a potent p38α inhibitor, displaying 13-fold selectivity for p38α 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.
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University of Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
Márcia
M
Goettert
Verena
V
Schattel
Pierre
P
Koch
Irmgard
I
Merfort
Stefan
S
Laufer
D000818:Animals; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D048057:Mitogen-Activated Protein Kinase 10; D048308:Mitogen-Activated Protein Kinase 14