A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2

作者：Liu Jiawang; Pham Peter T; Skripnikova Elena V; Zheng Shilong; Lovings La'nese J; Wang Yuji; Goyal Navneet; Bellow Sydni M; Mensah Lydia M; Chatters Amari J; Bratton Melyssa R; Wiese Thomas E; Zhao Ming; Wang Guangdi; Foroozesh Maryam^*

来源：Journal of Medicinal Chemistry, 2015, 58(16): 6481-6493.

DOI：10.1021/acs.jmedchem.5b00494

In humans, cytochrome P450 1A2 is the major enzyme metabolizing environmental arylamines or heterocyclic amines into carcinogens. Since evidence shows that planar triangle-shaped molecules are capable of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin derivatives were designed and synthesized for these studies. Among these compounds, 7,8-furanoflavone time-dependently inhibits P450 1A2 with a K-I value of 0.44 mu M. With a 5 min preincubation in the presence of NADPH, 0.01 mu M 7,8-furanoflavone completely inactivates P450 1A2 but does not influence the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin, is found to be a competitive inhibitor, showing high selectivity for the inhibition of P450 1A2 with a K-i of 0.39 mu M, 155- and 52-fold lower than its K-i values against P450s 1A1 and 1B1, respectively. In yeast AhR activation assays, 7,8-pyrano-4-trifluoromethylcoumarin does not activate aryl hydrocarbon receptor when the concentration is lower than 1 mu M, suggesting that this compound would not up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition assays show that 7,8-pyrano-4-trifluoromethylcoumarin decreases the MROD activity in HepG2 cells at concentrations higher than 1 mu M. Thus, using 7,8-pyrano-4-trifluoromethylcoumarin, a selective and specific P450 1A2 action suppression could be achieved, indicating the potential for the development of P450 1A2-targeting cancer preventive agents.

• 出版日期2015-8-27
• 单位首都医科大学