Daphnetin, one of coumarin derivatives, is a protein kinase inhibitor.
Protein kinases play key roles in the control of cell proliferation, differentiation and metabolism. In this work, we studied the effect of coumarin and its derivatives, including daphnetin, esculin, 2-OH-coumarin, 4-OH-coumarin and 7-OH-coumarin, on the activity of protein kinases. It was found that, in these compounds, only daphnetin was a protein kinase inhibitor. This compound inhibited tyrosine-specific protein kinase, EGF receptor (IC(50) = 7.67 microM), and serine/threonine-specific protein kinases, including cAMP-dependent protein kinase (PKA) (IC(50) = 9.33 microM) and protein kinase C (PKC) (IC(50) = 25.01 microM) in vitro. The inhibition of EGF receptor tyrosine kinase by daphnetin was competitive to ATP and non-competitive to the peptide substrate. The inhibition of EGF-induced tyrosine phosphorylation of EGF receptor by daphnetin was not observed in human hepatocellular carcinoma HepG2 cells. The structural comparison of daphnetin with coumarin and other coumarin derivatives suggests that the hydroxylation at C8 may be required for daphnetin acting as a protein kinase inhibitor.
Department of Experimental Surgery, Singapore General Hospital, Outram Road, Singapore, 169608, Republic of Singapore.
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Zhao
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D000255:Adenosine Triphosphate / Q000494:pharmacology; D001667:Binding, Competitive; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D004929:Esculin / Q000737:chemistry / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D007700:Kinetics; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014468:Umbelliferones / Q000737:chemistry / Q000494:pharmacology*
D003374:Coumarins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D014468:Umbelliferones; D004929:Esculin; D004815:Epidermal Growth Factor; D000255:Adenosine Triphosphate; C030123:coumarin; D019833:Genistein; D011494:Protein Kinases; D066246:ErbB Receptors; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C039952:daphnetin