ethyl 4-(3-fluorophenyl)-2-hydroxy-4-oxobut-2-enoate | 191014-91-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ethyl 4-(3-fluorophenyl)-2-hydroxy-4-oxobut-2-enoate
• 英文别名: Ethyl 2-hydroxy-4-(3'-fluorophenyl)-4-oxo-2-butenoate
• CAS: 191014-91-2
• 化学式: C₁₂H₁₁FO₄
• 分子量: 238.215
• InChiKey: AYVOAGRUMSVREB-UHFFFAOYSA-N

物化性质

• 沸点：
  359.8±42.0 °C(Predicted)
• 密度：
  1.283±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.01
• 重原子数：
  17.0
• 可旋转键数：
  4.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  63.6
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  ethyl 4-(3-fluorophenyl)-2-hydroxy-4-oxobut-2-enoate 在 sodium hydroxide 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 0.75h， 以77%的产率得到4-(3'-fluorophenyl)-4-oxo-2-hydroxy-2-butenoic acid
  参考文献：
  名称：

  Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

  摘要：

  Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of alpha,gamma-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50 = 21.8 mu M] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 mu M] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50 = 7.5 mu M] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50 = 5.2 mu M] and 24a [IC50 = 2.4 mu M]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.08.028
• 作为产物：
  描述：

  草酸二乙酯 、 3'-氟苯乙酮 在 sodium ethanolate 、 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 0.5h， 以73%的产率得到ethyl 4-(3-fluorophenyl)-2-hydroxy-4-oxobut-2-enoate
  参考文献：
  名称：

  Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

  摘要：

  Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of alpha,gamma-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50 = 21.8 mu M] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 mu M] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50 = 7.5 mu M] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50 = 5.2 mu M] and 24a [IC50 = 2.4 mu M]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.08.028

文献信息

• 3-Aroylmethylene-2,3,6,7-tetrahydro-1<i>H</i>-pyrazino[2,1-<i>a</i>]isoquinolin-4(11b<i>H</i>)-ones as Potent Nrf2/ARE Inducers in Human Cancer Cells and AOM-DSS Treated Mice
  作者：Mei-yang Xi、Jian-min Jia、Hao-peng Sun、Zhong-ying Sun、Jie-wei Jiang、Ya-jing Wang、Min-ye Zhang、Jun-feng Zhu、Li-li Xu、Zheng-yu Jiang、Xin Xue、Ming Ye、Xi Yang、Yuan Gao、Lei Tao、Xiao-ke Guo、Xiao-li Xu、Qing-long Guo、Xiao-jin Zhang、Rong Hu、Qi-dong You

  DOI：10.1021/jm400944k

  日期：2013.10.24

  Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation, and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1, and nuclear translocation of Nrf2 in HCT116 cells. In vivo potency of 1 was studied using AOM-DSS models, showing that the development of colorectal adenomas was significantly inhibited. Administration with 1 lowered the expression of IL-6, IL-1 beta, and promoted Nrf2 nuclear translocation. These results indicated that 1 is a potent Nrf2/ARE activator, both in vitro and in vivo. Forty-one derivatives were synthesized for SAR study, and a more potent compound 17 was identified. To our knowledge, this is a potent ARE activator. Besides, its novel structure makes it promising for further optimization.