Studies of Coumarin Derivatives for Constitutive Androstane Receptor (CAR) Activation

Shin Hun Juang, Min Tsang Hsieh, Pei Ling Hsu, Ju Ling Chen, Hui Kang Liu, Fong Pin Liang, Sheng Chu Kuo, Chen Yuan Chiu, Shing Hwa Liu, Chen Hsi Chou, Tian Shung Wu, Hsin Yi Hung

研究成果: Article同行評審

摘要

Constitutive androstane receptor (CAR) activation has found to ameliorate diabetes in animal models. However, no CAR agonists are available clinically. Therefore, a safe and effective CAR activator would be an alternative option. In this study, sixty courmarin derivatives either synthesized or purified from Artemisia capillaris were screened for CAR activation activity. Chemical modifications were on position 5,6,7,8 with mono-, di-, tri-, or tetra-substitutions. Among all the compounds subjected for in vitro CAR activation screening, 6,7-diprenoxycoumarin was the most effective and was selected for further preclinical studies. Chemical modification on the 6 position and unsaturated chains were generally beneficial. Electron-withdrawn groups as well as long unsaturated chains were hazardous to the activity. Mechanism of action studies showed that CAR activation of 6,7-diprenoxycoumarin might be through the inhibition of EGFR signaling and upregulating PP2Ac methylation. To sum up, modification mimicking natural occurring coumarins shed light on CAR studies and the established screening system provides a rapid method for the discovery and development of CAR activators. In addition, one CAR activator, scoparone, did showed anti-diabetes effect in db/db mice without elevation of insulin levels.

原文English
期刊Molecules (Basel, Switzerland)
26
發行號1
DOIs
出版狀態Published - 2020 十二月 31

All Science Journal Classification (ASJC) codes

  • 分析化學
  • 化學(雜項)
  • 分子醫學
  • 藥學科學
  • 藥物發現
  • 物理與理論化學
  • 有機化學

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