Abstract
Daphnetin (7,8-dihydroxycoumarin (7,8-DHC)) and its C-4 derivatives have multiple pharmacological activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Methylation plays important roles in catechol elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of human catechol-O-methyltransferase (COMT) remain unclear. This study was aimed at exploring the structure–methylation relationship of daphnetin and its C-4 derivatives, including 4-methyl, 4-phenyl and 4-acetic acid daphnetin. It was achieved by identifying the methylated products generated and by careful characterization of the reaction kinetics. These catechols are selectively metabolized to the corresponding 8-O-methyl conjugates, and this regioselective methylation could be elucidated by flexible docking, in which all the 8-OH groups of these catechols are much closer than the 7-OH groups to catalytic residue LYS144 and methyl donor AdoMet. The results of the kinetic analyses revealed that the Clint values of the compounds could be strongly affected by the C-4 substitutions, which could be partially explained by the electronic effects of the C-4 substituents and the coordination modes of 7,8- dihydroxycoumarins in the active site of COMT. These findings provide helpful guidance for further structural modification of 7,8-DHCs to improve metabolic stability.
Highlights
IntroductionHigh solubility, good permeability and extensive pharmacological activities, this family has received widespread attention [1]
Coumarins are widely distributed in food and Chinese medical herbs
One product peak was eluted when each 7,8-DHC (10 μM) was incubated with human liver cytosol (HLC) (0.5 mg ml−1) in the presence of S-(5 -adenosyl)-L-methionine (SAM). These peaks were not detected in the control samples without SAM, 7,8DHCs or HLC
Summary
High solubility, good permeability and extensive pharmacological activities, this family has received widespread attention [1]. Daphnetin (7,8-dihydroxycoumarin (7,8-DHC)) is a naturally occurring catechol from the family Thymelaeaceae. Similar to other coumarin derivatives, daphnetin has been reported to have many pharmacological actions including anti-malarial, anti-arthritic, anti-pyretic and anti-cancer properties [2,3,4,5]. This family suffers from low oral bioavailability due to poor metabolic stability [7,8]. Pharmacokinetic study after administration in rats shows that daphnetin is rapidly eliminated with quite a short half-life (15 min), due to extensive first-pass metabolism in the liver [7,8]
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