ethyl (E)-3-(4-cinnamoyl-1-methyl-1H-pyrrol-2-yl)acrylate | 501125-38-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: ethyl (E)-3-(4-cinnamoyl-1-methyl-1H-pyrrol-2-yl)acrylate
• 英文别名: ethyl (E)-3-[1-methyl-4-[(E)-3-phenylprop-2-enoyl]pyrrol-2-yl]prop-2-enoate
• CAS: 501125-38-8
• 化学式: C₁₉H₁₉NO₃
• 分子量: 309.365
• InChiKey: NYWSXCDJSSVMGJ-WGDLNXRISA-N

物化性质

• 熔点：
  75-76 °C
• 沸点：
  496.9±45.0 °C(predicted)
• 密度：
  1.06±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  48.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl (E)-3-(4-cinnamoyl-1-methyl-1H-pyrrol-2-yl)acrylate 在 氢氧化钾 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以77%的产率得到3-[1-methyl-4-(2-phenylethenyl)-1H-2-pyrrolyl]propenoic acid
  参考文献：
  名称：

  3-(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-alkylamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 1. Design, Synthesis, Biological Evaluation, and Binding Mode Studies Performed through Three Different Docking Procedures

  摘要：

  Recently we reported a novel series of hydroxamates, called 3-(4-aroyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides (APHAs), acting as HDAC inhibitors (Massa, S.; et al. J. Med. Chem. 2001, 44, 2069-2072). Among them, 3-(4-benzoyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide 1 was chosen as lead compound, and its binding mode into the modeled HDAC1 catalytic core together with its histone hyperacetylation, antiproliferative, and cytodifferentiating properties in cell-based assays were investigated (Mai, A.; et al. J. Med. Chem. 2002, 45, 1778-1784). Here we report the results of some chemical manipulations performed on (i) the aroyl portion at the C-4-pyrrole position, (ii) the N-1-pyrrole substituent, and (iii) the hydroxamate moiety of 1 to determine structure-activity relationships and to improve enzyme inhibitory activity of APHAs. In the 1 structure, pyrrole N-1-substitution with groups larger than methyl gave a reduction in HDAC inhibiting activity, and replacement of hydroxamate function with various non-hydroxamate, metal ion-complexing groups yielded poorly active or totally inactive compounds. On the contrary, proper substitution at the C-4-position favorably affected enzyme inhibiting potency, leading to 8 (IC50 = 0.1 muM) and 9 (IC50 = 1.0 muM) which were 38- and 3.8-fold more potent than 1 in in vitro anti-HD2 assay. Against mouse HDAC1, 8 showed an IC50 = 0.5 muM (IC50 of 1 = 4.9 muM), and also in cell-based assay, 8 was endowed with higher histone hyperacetylating activity than 1, although it was less potent than TSA and SAHA. Such enhancement of inhibitory activity can be explained by the higher flexibility of the pyrrole C-4-substituent of 8 which accounts for a considerably better fitting into the HDAC1 pocket and a more favorable enthalpy ligand receptor energy compared to 1. The enhanced fit allows a closer positioning of 8 hydroxamate moiety to the zinc ion. These findings were supported by extensive docking studies (SAD, DOCK, and Autodock) performed on both APHAs and reference drugs (TSA and SAHA).

  DOI：

  10.1021/jm021070e
• 作为产物：
  描述：

  N-甲基吡咯 在 三氯化铝 、 草酰氯 、 potassium carbonate 作用下， 以 乙醇 、 1,2-二氯乙烷 为溶剂， 反应 5.25h， 生成 ethyl (E)-3-(4-cinnamoyl-1-methyl-1H-pyrrol-2-yl)acrylate
  参考文献：
  名称：

  3-(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-alkylamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 1. Design, Synthesis, Biological Evaluation, and Binding Mode Studies Performed through Three Different Docking Procedures

  摘要：

  Recently we reported a novel series of hydroxamates, called 3-(4-aroyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides (APHAs), acting as HDAC inhibitors (Massa, S.; et al. J. Med. Chem. 2001, 44, 2069-2072). Among them, 3-(4-benzoyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide 1 was chosen as lead compound, and its binding mode into the modeled HDAC1 catalytic core together with its histone hyperacetylation, antiproliferative, and cytodifferentiating properties in cell-based assays were investigated (Mai, A.; et al. J. Med. Chem. 2002, 45, 1778-1784). Here we report the results of some chemical manipulations performed on (i) the aroyl portion at the C-4-pyrrole position, (ii) the N-1-pyrrole substituent, and (iii) the hydroxamate moiety of 1 to determine structure-activity relationships and to improve enzyme inhibitory activity of APHAs. In the 1 structure, pyrrole N-1-substitution with groups larger than methyl gave a reduction in HDAC inhibiting activity, and replacement of hydroxamate function with various non-hydroxamate, metal ion-complexing groups yielded poorly active or totally inactive compounds. On the contrary, proper substitution at the C-4-position favorably affected enzyme inhibiting potency, leading to 8 (IC50 = 0.1 muM) and 9 (IC50 = 1.0 muM) which were 38- and 3.8-fold more potent than 1 in in vitro anti-HD2 assay. Against mouse HDAC1, 8 showed an IC50 = 0.5 muM (IC50 of 1 = 4.9 muM), and also in cell-based assay, 8 was endowed with higher histone hyperacetylating activity than 1, although it was less potent than TSA and SAHA. Such enhancement of inhibitory activity can be explained by the higher flexibility of the pyrrole C-4-substituent of 8 which accounts for a considerably better fitting into the HDAC1 pocket and a more favorable enthalpy ligand receptor energy compared to 1. The enhanced fit allows a closer positioning of 8 hydroxamate moiety to the zinc ion. These findings were supported by extensive docking studies (SAD, DOCK, and Autodock) performed on both APHAs and reference drugs (TSA and SAHA).

  DOI：

  10.1021/jm021070e

文献信息

• Sterically Controlled C−H Olefination of Heteroarenes
  作者：Hao Chen、Mirxan Farizyan、Francesca Ghiringhelli、Manuel Gemmeren

  DOI：10.1002/anie.202004521

  日期：2020.7.13

  substituted heteroarenes in nature and bioactive compounds. Some substitution patterns remain challenging: While highly efficient methods for the C2‐selective olefination of 3‐substituted five‐membered heteroarenes have been reported, analogous methods to access the 5‐olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting

  由于自然界和生物活性化合物中多取代杂芳烃的普遍存在，杂芳烃的区域选择性官能化是一个非常有吸引力的合成靶点。一些取代模式仍然具有挑战性：虽然已经报道了 3 取代五元杂芳烃的 C2 选择性烯化的高效方法，但获得 5 烯化产物的类似方法仍然受到较差的区域选择性和/或使用要求的限制。过量的有价值的杂芳烃起始材料。在此，我们报道了使用杂芳烃作为限制试剂的空间控制的CH烯化反应。该方法能够实现多种杂芳烃的高度 C5 选择性烯化，并被证明可用于后期官能化。
• 3-(4-Aroyl-1-methyl-1<i>H</i>-2-pyrrolyl)-<i>N</i>-hydroxy-2-alkylamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 1. Design, Synthesis, Biological Evaluation, and Binding Mode Studies Performed through Three Different Docking Procedures
  作者：Antonello Mai、Silvio Massa、Rino Ragno、Ilaria Cerbara、Florian Jesacher、Peter Loidl、Gerald Brosch

  DOI：10.1021/jm021070e

  日期：2003.2.1

  Recently we reported a novel series of hydroxamates, called 3-(4-aroyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides (APHAs), acting as HDAC inhibitors (Massa, S.; et al. J. Med. Chem. 2001, 44, 2069-2072). Among them, 3-(4-benzoyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide 1 was chosen as lead compound, and its binding mode into the modeled HDAC1 catalytic core together with its histone hyperacetylation, antiproliferative, and cytodifferentiating properties in cell-based assays were investigated (Mai, A.; et al. J. Med. Chem. 2002, 45, 1778-1784). Here we report the results of some chemical manipulations performed on (i) the aroyl portion at the C-4-pyrrole position, (ii) the N-1-pyrrole substituent, and (iii) the hydroxamate moiety of 1 to determine structure-activity relationships and to improve enzyme inhibitory activity of APHAs. In the 1 structure, pyrrole N-1-substitution with groups larger than methyl gave a reduction in HDAC inhibiting activity, and replacement of hydroxamate function with various non-hydroxamate, metal ion-complexing groups yielded poorly active or totally inactive compounds. On the contrary, proper substitution at the C-4-position favorably affected enzyme inhibiting potency, leading to 8 (IC50 = 0.1 muM) and 9 (IC50 = 1.0 muM) which were 38- and 3.8-fold more potent than 1 in in vitro anti-HD2 assay. Against mouse HDAC1, 8 showed an IC50 = 0.5 muM (IC50 of 1 = 4.9 muM), and also in cell-based assay, 8 was endowed with higher histone hyperacetylating activity than 1, although it was less potent than TSA and SAHA. Such enhancement of inhibitory activity can be explained by the higher flexibility of the pyrrole C-4-substituent of 8 which accounts for a considerably better fitting into the HDAC1 pocket and a more favorable enthalpy ligand receptor energy compared to 1. The enhanced fit allows a closer positioning of 8 hydroxamate moiety to the zinc ion. These findings were supported by extensive docking studies (SAD, DOCK, and Autodock) performed on both APHAs and reference drugs (TSA and SAHA).