Ethynylflavones, Highly Potent, and Selective Inhibitors of Cytochrome P450 1A1

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• 作者：Navneet Goyal ; Jiawang Liu ; La鈥橬ese Lovings ; Patrick Dupart ; Shannon Taylor ; Sydni Bellow ; Lydia Mensah ; Erika McClain ; Brandan Dotson ; Jayalakshmi Sridhar ; Xiaoyi Zhang ; Ming Zhao ; Maryam Foroozesh
• 刊名：Chemical Research in Toxicology
• 出版年：2014
• 出版时间：August 18, 2014
• 年：2014
• 卷：27
• 期：8
• 页码：1431-1439
• 全文大小：574K
• ISSN：1520-5010

文摘

The flavone backbone is a well-known pharmacophore present in a number of substrates and inhibitors of various P450 enzymes. In order to find highly potent and novel P450 family I enzyme inhibitors, an acetylene group was incorporated into six different positions of flavone. The introduction of an acetylene group at certain locations of the flavone backbone lead to time-dependent inhibitors of P450 1A1. 3鈥?Ethynylflavone, 4鈥?ethynylflavone, 6-ethynylflavone, and 7-ethynylflavone (K_I values of 0.035鈥?.056 渭M) show strong time-dependent inhibition of P450 1A1, while 5-ethynylflavone (K_I value of 0.51 渭M) is a moderate time-dependent inhibitor of this enzyme. Meanwhile, 4鈥?ethynylflavone and 6-ethynylflavone are highly selective inhibitors toward this enzyme. Especially, 6-ethynylflavone possesses a K_i value of 0.035 渭M for P450 1A1 177- and 15-fold lower than those for P450s 1A2 and 1B1, respectively. The docking postures observed in the computational simulations show that the orientation of the acetylene group determines its capability to react with P450s 1A1 and 1A2. Meanwhile, conformational analysis indicates that the shape of an inhibitor determines its inhibitory selectivity toward these enzymes.