4-乙酰基-3,5-二甲基-1H-吡咯-2-甲酰氯 | 213767-39-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 4-乙酰基-3,5-二甲基-1H-吡咯-2-甲酰氯
• 英文名称: 4-Acetyl-3,5-dimethyl-1H-pyrrole-2-carbonyl chloride
• CAS: 213767-39-6
• 化学式: C₉H₁₀ClNO₂
• 分子量: 199.637
• InChiKey: MSOKTJPGEBJUJW-UHFFFAOYSA-N

物化性质

• 沸点：
  358.4±42.0 °C(Predicted)
• 密度：
  1.261±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  49.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-氨基苯甲酸甲酯 、 4-乙酰基-3,5-二甲基-1H-吡咯-2-甲酰氯 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以38 mg的产率得到methyl 3-(4-acetyl-3,5-dimethyl-1H-pyrrole-2-carboxamido)benzoate
  参考文献：
  名称：

  Discovery of CREBBP Bromodomain Inhibitors by High-Throughput Docking and Hit Optimization Guided by Molecular Dynamics

  摘要：

  We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based high throughput docking. Only 17 molecules from the original library of two-million compounds were tested in vitro. Optimization of the two low-micromolar hits, the 4-acylpyrrole 1 and acylbenzene 9, was driven by molecular dynamics results which suggested improvement of the polar interactions with the Arg1173 side chain at the rim of the binding site. The synthesis of only two derivatives of 1 yielded the 4-acylpyrrole 6 which shows a single-digit micromolar affinity for the CREBBP bromodomain and a ligand efficiency of 0.34 kcal/mol per non-hydrogen atom. Optimization of the acylbenzene hit 9 resulted in a series of derivatives with nanomolar potencies, good ligand efficiency and selectivity (see Unzue, A.; Xu, M.; Dong, J.; Wiedmer, L.; Spiliotopoulos, D.; Caflisch, A.; Nevado, C. Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00172). The in silico predicted binding mode of the acylbenzene derivative 10 was validated by solving the structure of the complex with the CREBBP bromodomain.

  DOI：

  10.1021/acs.jmedchem.5b00171
• 作为产物：
  描述：

  4-乙酰基-3,5-二甲基-1H-吡咯-2-羧酸 在 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 4-乙酰基-3,5-二甲基-1H-吡咯-2-甲酰氯
  参考文献：
  名称：

  Discovery of CREBBP Bromodomain Inhibitors by High-Throughput Docking and Hit Optimization Guided by Molecular Dynamics

  摘要：

  We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based high throughput docking. Only 17 molecules from the original library of two-million compounds were tested in vitro. Optimization of the two low-micromolar hits, the 4-acylpyrrole 1 and acylbenzene 9, was driven by molecular dynamics results which suggested improvement of the polar interactions with the Arg1173 side chain at the rim of the binding site. The synthesis of only two derivatives of 1 yielded the 4-acylpyrrole 6 which shows a single-digit micromolar affinity for the CREBBP bromodomain and a ligand efficiency of 0.34 kcal/mol per non-hydrogen atom. Optimization of the acylbenzene hit 9 resulted in a series of derivatives with nanomolar potencies, good ligand efficiency and selectivity (see Unzue, A.; Xu, M.; Dong, J.; Wiedmer, L.; Spiliotopoulos, D.; Caflisch, A.; Nevado, C. Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00172). The in silico predicted binding mode of the acylbenzene derivative 10 was validated by solving the structure of the complex with the CREBBP bromodomain.

  DOI：

  10.1021/acs.jmedchem.5b00171

文献信息

• Discovery of CREBBP Bromodomain Inhibitors by High-Throughput Docking and Hit Optimization Guided by Molecular Dynamics
  作者：Min Xu、Andrea Unzue、Jing Dong、Dimitrios Spiliotopoulos、Cristina Nevado、Amedeo Caflisch

  DOI：10.1021/acs.jmedchem.5b00171

  日期：2016.2.25

  We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based high throughput docking. Only 17 molecules from the original library of two-million compounds were tested in vitro. Optimization of the two low-micromolar hits, the 4-acylpyrrole 1 and acylbenzene 9, was driven by molecular dynamics results which suggested improvement of the polar interactions with the Arg1173 side chain at the rim of the binding site. The synthesis of only two derivatives of 1 yielded the 4-acylpyrrole 6 which shows a single-digit micromolar affinity for the CREBBP bromodomain and a ligand efficiency of 0.34 kcal/mol per non-hydrogen atom. Optimization of the acylbenzene hit 9 resulted in a series of derivatives with nanomolar potencies, good ligand efficiency and selectivity (see Unzue, A.; Xu, M.; Dong, J.; Wiedmer, L.; Spiliotopoulos, D.; Caflisch, A.; Nevado, C. Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00172). The in silico predicted binding mode of the acylbenzene derivative 10 was validated by solving the structure of the complex with the CREBBP bromodomain.