2-ethyl-3-isonicotinoyl-4H-chromen-4-one | 1029852-84-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 2-ethyl-3-isonicotinoyl-4H-chromen-4-one
• 英文别名: 2-ethyl-3-(pyridine-4-carbonyl)chromen-4-one
• CAS: 1029852-84-3
• 化学式: C₁₇H₁₃NO₃
• 分子量: 279.295
• InChiKey: XXAWBUPRPQJWCR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  56.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1-(2-hydroxyphenyl)-3-(pyridin-4-yl)propane-1,3-dione 、 丙酸酐 在 三乙胺 作用下， 反应 12.0h， 以43.2%的产率得到2-ethyl-3-isonicotinoyl-4H-chromen-4-one
  参考文献：
  名称：

  Modeling and synthesis of novel tight-binding inhibitors of cytochrome P450 2C9

  摘要：

  Cytochrome P450 2C9 (2C9) is one of the three major drug metabolizing cytochrome P450 enzymes in human liver. Although the crystal structure of 2C9 has been solved, the important physicochemical properties of substrate-enzyme interactions remain difficult to be determined. This is due in part to the conformational flexibility of mammalian P450 enzymes. Therefore, probing the active-site with high-affinity substrates is important in further understanding substrate-enzyme interactions. Three-dimensional quantitative structure-activity relationships (3D-QSAR) and docking experiments have been shown to be useful tools in correlating biological activity with structure. In particular we have previously reported that the very tight-binding inhibitor benzbromarone can provide important information about the active-site of 2C9. In this study we report the binding affinities and potential substrate-enzyme interactions of 4H-chromen-4-one analogs, which are structurally similar to benzbromarone. The chromenone structures are synthetically accessible inhibitors and give inhibition constants as low as 4.2 nM, comparable with the very tightest-binding inhibitors of 2C9. Adding these compounds to our previous 2C9 libraries for CoMFA models reinforces the important electrostatic and hydrophobic features of substrate binding. These compounds have also been docked in the 2C9 crystal structure and the results indicate that Arg 108 plays significant roles in the binding of chromenone substrates. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.01.021

文献信息

• Modeling and synthesis of novel tight-binding inhibitors of cytochrome P450 2C9
  作者：Chi-Chi Peng、Tom Rushmore、Gregory J. Crouch、Jeffrey P. Jones

  DOI：10.1016/j.bmc.2008.01.021

  日期：2008.4.1

  Cytochrome P450 2C9 (2C9) is one of the three major drug metabolizing cytochrome P450 enzymes in human liver. Although the crystal structure of 2C9 has been solved, the important physicochemical properties of substrate-enzyme interactions remain difficult to be determined. This is due in part to the conformational flexibility of mammalian P450 enzymes. Therefore, probing the active-site with high-affinity substrates is important in further understanding substrate-enzyme interactions. Three-dimensional quantitative structure-activity relationships (3D-QSAR) and docking experiments have been shown to be useful tools in correlating biological activity with structure. In particular we have previously reported that the very tight-binding inhibitor benzbromarone can provide important information about the active-site of 2C9. In this study we report the binding affinities and potential substrate-enzyme interactions of 4H-chromen-4-one analogs, which are structurally similar to benzbromarone. The chromenone structures are synthetically accessible inhibitors and give inhibition constants as low as 4.2 nM, comparable with the very tightest-binding inhibitors of 2C9. Adding these compounds to our previous 2C9 libraries for CoMFA models reinforces the important electrostatic and hydrophobic features of substrate binding. These compounds have also been docked in the 2C9 crystal structure and the results indicate that Arg 108 plays significant roles in the binding of chromenone substrates. (C) 2008 Elsevier Ltd. All rights reserved.