ethyl 3-[4-(4-N,N-dimethylaminobenzoyl)-1-methyl-1H-2-pyrrolyl]-2-propenoate | 128843-43-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: ethyl 3-[4-(4-N,N-dimethylaminobenzoyl)-1-methyl-1H-2-pyrrolyl]-2-propenoate
• 英文别名: ethyl (E)-3-[4-[4-(dimethylamino)benzoyl]-1-methyl-pyrrol-2-yl]prop-2-enoate；ethyl (E)-3-[4-[4-(dimethylamino)benzoyl]-1-methylpyrrol-2-yl]prop-2-enoate
• CAS: 128843-43-6
• 化学式: C₁₉H₂₂N₂O₃
• 分子量: 326.395
• InChiKey: DQGPPVCGKALUDP-ZHACJKMWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  51.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 3-[4-(4-N,N-dimethylaminobenzoyl)-1-methyl-1H-2-pyrrolyl]-2-propenoate 在 氢氧化钾 作用下， 以 乙醇 为溶剂， 生成 trans-3-<4-<4-(dimethylamino)benzoyl>-1-methyl-1H-pyrrol-2-yl>propenoic acid
  参考文献：
  名称：

  3-（4-芳酰基-1H-吡咯-2-基）-N-羟基-2-丙烯酰胺，一类新型的合成组蛋白脱乙酰基酶抑制剂。

  摘要：

  新型的3-（4-芳酰基-2-吡咯基）-N-羟基-2-丙烯酰胺被公开为新型的组蛋白脱乙酰基酶（HDAC）抑制剂。基于三维结构的药物设计和对组蛋白脱乙酰基酶样蛋白（HDLP）催化核心的构象分析表明化合物7a-h的合成和生物学评估。实验性pK（i）值与新衍生物的VALIDATE预测pK（i）值非常吻合。所有化合物7a-h在微摩尔范围内均显示出HDAC抑制活性，其中7e是最有效的衍生物（IC（50）= 1.9 microM）。芳酰基部分中的4'取代基对抑制活性的影响并不明显，因为所有化合物7a-g的IC（50）值在1.9和3.9 microM之间。除此以外，

  DOI：

  10.1021/jm015515v
• 作为产物：
  描述：

  4-二甲氨基苯甲酰氯 在 草酰氯 、 potassium carbonate 作用下， 以 乙醇 、 1,2-二氯乙烷 为溶剂， 生成 ethyl 3-[4-(4-N,N-dimethylaminobenzoyl)-1-methyl-1H-2-pyrrolyl]-2-propenoate
  参考文献：
  名称：

  3-（4-芳酰基-1H-吡咯-2-基）-N-羟基-2-丙烯酰胺，一类新型的合成组蛋白脱乙酰基酶抑制剂。

  摘要：

  新型的3-（4-芳酰基-2-吡咯基）-N-羟基-2-丙烯酰胺被公开为新型的组蛋白脱乙酰基酶（HDAC）抑制剂。基于三维结构的药物设计和对组蛋白脱乙酰基酶样蛋白（HDLP）催化核心的构象分析表明化合物7a-h的合成和生物学评估。实验性pK（i）值与新衍生物的VALIDATE预测pK（i）值非常吻合。所有化合物7a-h在微摩尔范围内均显示出HDAC抑制活性，其中7e是最有效的衍生物（IC（50）= 1.9 microM）。芳酰基部分中的4'取代基对抑制活性的影响并不明显，因为所有化合物7a-g的IC（50）值在1.9和3.9 microM之间。除此以外，

  DOI：

  10.1021/jm015515v

文献信息

• Synthesis and antimicrobial and cytotoxic activities of pyrrole-containing analogs of trichostatin A
  作者：S. Massa、Marino Artico、F. Corelli、A. Mai、R. Di Santo、S. Cortes、M. E. Marongiu、A. Pani、P. La Colla

  DOI：10.1021/jm00172a026

  日期：1990.10

  A number of aroylpyrroleacrylic acid derivatives were synthesized by standard procedures and evaluated for cytotoxicity in Vero cells and for capacity to inhibit the multiplication of viruses, bacteria, and fungi. While none of the test compounds showed any activity against bacteria and fungi, most of them inhibited the replication of some DNA viruses at concentrations allowing the exponential growth of uninfected cells. In particular three compounds (8, 9c, and 10h) showed an antiviral activity at doses that were from 4- to greater than 8-fold lower than the maximum nontoxic doses.
• Binding Mode Analysis of 3-(4-Benzoyl-1-methyl-1<i>H</i>-2-pyrrolyl)-<i>N</i>-hydroxy-2-propenamide:  A New Synthetic Histone Deacetylase Inhibitor Inducing Histone Hyperacetylation, Growth Inhibition, and Terminal Cell Differentiation
  作者：Antonello Mai、Silvio Massa、Rino Ragno、Monica Esposito、Gianluca Sbardella、Giuseppina Nocca、Roberto Scatena、Florian Jesacher、Peter Loidl、Gerald Brosch

  DOI：10.1021/jm011088+

  日期：2002.4.1

  The binding mode of 3-(4-aroyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides 1a-c, belonging to a recently reported class of synthetic histone deacetylase (HDAC) inhibitors (Massa, S.; et al. J. Med. Chem. 2001, 44, 2069-2072), into the new modeled HDAC 1 catalytic core is presented, and enzyme/inhibitor interactions are discussed. HDAC1 X-ray coordinates were obtained by virtual "mutation" of those of histone deacetylase-like protein, a bacterial HDAC homologue. In in vitro antimaize HD2 as well as antimouse HDAC1 assay, compounds 1a-c showed inhibitory activities in the low micromolar range. Similarly, 1a-C are endowed with anti-HDAC activity in vivo: on mouse A20 cells, 1a-c induced histone hyperacetylation leading to a highly increased acetylation level of H4 as compared to control histones. Results obtained with acid-urea-triton polyacrylamide gel electrophoresis have been confirmed by Western Blot experiments. Finally, compound 1a, chosen as a representative member of this class of HDAC inhibitors, resulted endowed with antiproliferative (45 and 85% cell growth inhibition at 40 and 80 muM, respectively) and cellular differentiation (18 and 21% of benzidine positive cells at the same concentrations) activities in murine erythroleukemic cells.
• MASSA, S.;ARTICO, M.;CORELLI, F.;MAI, A.;SANTO, R. DI;CORTES, S.;MARONGIU+, J. MED. CHEM., 33,(1990) N0, C. 2845-2849
  作者：MASSA, S.、ARTICO, M.、CORELLI, F.、MAI, A.、SANTO, R. DI、CORTES, S.、MARONGIU+

  DOI：——

  日期：——
• 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).
• 3-(4-Aroyl-1<i>H</i>-pyrrol-2-yl)-<i>N</i>-hydroxy-2-propenamides, a New Class of Synthetic Histone Deacetylase Inhibitors
  作者：Silvio Massa、Antonello Mai、Gianluca Sbardella、Monica Esposito、Rino Ragno、Peter Loidl、Gerald Brosch

  DOI：10.1021/jm015515v

  日期：2001.6.1

  class of histone deacetylase (HDAC) inhibitors. Three-dimensional structure-based drug design and conformational analyses into the histone deacetylase-like protein (HDLP) catalytic core suggested the synthesis and biological evaluation of compounds 7a-h. Experimental pK(i) values are in good agreement with VALIDATE predicted pK(i) values of new derivatives. All compounds 7a-h show HDAC inhibitory activity

  新型的3-（4-芳酰基-2-吡咯基）-N-羟基-2-丙烯酰胺被公开为新型的组蛋白脱乙酰基酶（HDAC）抑制剂。基于三维结构的药物设计和对组蛋白脱乙酰基酶样蛋白（HDLP）催化核心的构象分析表明化合物7a-h的合成和生物学评估。实验性pK（i）值与新衍生物的VALIDATE预测pK（i）值非常吻合。所有化合物7a-h在微摩尔范围内均显示出HDAC抑制活性，其中7e是最有效的衍生物（IC（50）= 1.9 microM）。芳酰基部分中的4'取代基对抑制活性的影响并不明显，因为所有化合物7a-g的IC（50）值在1.9和3.9 microM之间。除此以外，