4-cynnamoyl-1-methyl-1H-2-pyrrolecarboxaldehyde | 501125-35-5

• 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: 4-cynnamoyl-1-methyl-1H-2-pyrrolecarboxaldehyde
• 英文别名: 4-(3-phenyl-2-propenoyl)-1-methyl-1H-pyrrole-2-carboxaldehyde；1-methyl-4-[(E)-3-phenylprop-2-enoyl]pyrrole-2-carbaldehyde
• CAS: 501125-35-5
• 化学式: C₁₅H₁₃NO₂
• 分子量: 239.274
• InChiKey: UQCBCBZCLPHSLP-BQYQJAHWSA-N

物化性质

• 熔点：
  94-95 °C
• 沸点：
  434.7±45.0 °C(predicted)
• 密度：
  1.07±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  39.1
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-cynnamoyl-1-methyl-1H-2-pyrrolecarboxaldehyde 在 氢氧化钾 、 potassium carbonate 作用下， 以 乙醇 为溶剂， 反应 5.0h， 生成 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 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 3.25h， 生成 4-cynnamoyl-1-methyl-1H-2-pyrrolecarboxaldehyde
  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

• 3-(4-Aroyl-1-methyl-1<i>H</i>-2-pyrrolyl)-<i>N</i>-hydroxy-2-propenamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 2. Effect of Pyrrole-C₂ and/or -C₄ Substitutions on Biological Activity
  作者：Antonello Mai、Silvio Massa、Ilaria Cerbara、Sergio Valente、Rino Ragno、Patrizia Bottoni、Roberto Scatena、Peter Loidl、Gerald Brosch

  DOI：10.1021/jm030990+

  日期：2004.2.1

  pyrrole-C2 ethene chains of 1a-c, which were replaced with methylene, ethylene, substituted ethene, and 1,3-butadiene chains (compounds 2). Biological results clearly indicated the unsubstituted ethene chain as the best structural motif to get the highest HDAC inhibitory activity, the sole exception to this rule being the introduction of the 1,3-butadienyl moiety into the 1a chemical structure (IC50(2f)

  先前的SAR研究（第1部分：Mai，A .；等人，J。Med。Chem。2003，46，512-524）在3-（- 4-苯甲酰基-1-甲基-1H-吡咯-2-基）-N-羟基-2-丙烯酰胺（1a）突出显示了其4-苯基乙酰基（1b）和4-肉桂酰基（1c）类似物是抑制玉米的更有效化合物体外HD2活性。在本文中，我们研究了化学取代对1a-c的吡咯-C2乙烯链进行的化学取代对抗HD2活性的影响，这些链被亚甲基，乙烯，取代的乙烯和1,3-丁二烯链（化合物2）。生物学结果清楚地表明，未取代的乙烯链是获得最高HDAC抑制活性的最佳结构基序，唯一的例外是引入了1，3-丁二烯基部分变成1a化学结构（IC50（2f）= 0.77 microM; IC50（1a）= 3.8 microM）。化合物3的IC50值（制备为1b的同系物）显示，吡咯C-（4）位置的苯和羰基之间的APHA模板很好地接受了2至5个亚甲基的烃间