Total Synthesis of Hispidulin and the Structural Basis for Its Inhibition of Proto-oncogene Kinase Pim-1.
A new method is applied to synthesize hispidulin, a natural flavone with a broad spectrum of biological activities. Hispidulin exhibits inhibitory activity against the oncogenic protein kinase Pim-1. Crystallographic analysis of Pim-1 bound to hispidulin reveals a binding mode distinct from that of quercetin, suggesting that the binding potency of flavonoids is determined by their hydrogen-bonding interactions with the hinge region of the kinase. Overall, this work may facilitate construction of a library of hispidulin-derived compounds for investigating the structure-activity relationship of flavone-based Pim-1 inhibitors.
Shi-Wei
SW
Chao
Institute of Biological Chemistry, Academia Sinica , Taipei 115, Taiwan.|Institute of Biochemical Sciences, College of Life Science, National Taiwan University , Taipei 106, Taiwan.
Ming-Yuan
MY
Su
Lih-Chu
LC
Chiou
Liang-Chieh
LC
Chen
Institute of Biological Chemistry, Academia Sinica , Taipei 115, Taiwan.|Institute of Biochemical Sciences, College of Life Science, National Taiwan University , Taipei 106, Taiwan.
Chung-I
CI
Chang
Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs , Taipei 110, Taiwan.|School of Pharmacy, National Defense Medical Center , Taipei 114, Taiwan.
Wei-Jan
WJ
Huang
D047309:Flavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011794:Quercetin / Q000737:chemistry; D013329:Structure-Activity Relationship
D047309:Flavones; D011794:Quercetin; D051573:Proto-Oncogene Proteins c-pim-1; C055957:hispidulin