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论文类型：期刊论文

发表时间：2018-01-01

发表刊物：ROYAL SOCIETY OPEN SCIENCE

收录刊物：SCIE、PubMed

卷号：5

期号：1

页面范围：171271

ISSN号：2054-5703

关键字：7, 8-dihydroxycoumarins; human catechol-O-methyltransferase; structure-methylation relationship; metabolic stability

摘要：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 andmethyl donor AdoMet. The results of the kinetic analyses revealed that the Cl-int 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.