Effects of natural flavones and flavonols on the kinase activity of Cdk5.
A number of natural and synthetic flavonoids have been assessed previously with regard to their effects on the activity of cyclin-dependent kinases (Cdk1 and -2) related to the inhibition of cell cycle progression. On the other hand, the Cdk5/p35 system is of major importance in neuronal migration phenomena and brain development, and its deregulation is implicated in neurodegenerative diseases, particularly Alzheimer's. Here we show that some natural flavonoids inhibit the activity of the Cdk5/p35 system in the micromolar range, while others are practically inactive. Ring B-unsubstituted and highly methoxylated flavones were inactive or gave irreproducible results, and 6-methoxyapigenin and 6-methoxyluteolin were the most potent Cdk5 complex inhibitors within this series, while the common flavonols kaempferol and quercetin showed intermediate behavior. The reported crystal structure of the Cdk5 complex with its activator p25 was used for docking studies, which also led to the identification of the two 6-methoxyflavones, kaempferol and quercetin, as well as the untested 6-methoxy derivatives of kaempferol and quercetin and the corresponding 6-hydroxy analogues as compounds exhibiting a good fit to the active site of the enzyme.
Zapata-Torres
Gerald
G
Millennium Institute for Advanced Studies in Cell Biology and Biotechnology (CBB) and Department of Chemistry, Faculty of Sciences, University of Chile, P.O. Box 653, Santiago, Chile.
Opazo
Felipe
F
Salgado
Cristián
C
Muñoz
Juan Pablo
JP
Krautwurst
Hans
H
Mascayano
Carolina
C
Sepúlveda-Boza
Silvia
S
Maccioni
Ricardo B
RB
Cassels
Bruce K
BK
D000465:Algorithms; D031179:Centaurea / Q000737:chemistry*; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000187:drug effects* / Q000378:metabolism*; D005419:Flavonoids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D044948:Flavonols / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D044949:Kaempferols / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D011794:Quercetin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D005419:Flavonoids; D044948:Flavonols; D044949:Kaempferols; C006552:kaempferol; D011794:Quercetin; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases