methyl 3-chloro-3-(4-fluoro-3-methylphenyl)-2-oxopropanoate

• 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: methyl 3-chloro-3-(4-fluoro-3-methylphenyl)-2-oxopropanoate
• 化学式: C₁₁H₁₀ClFO₃
• 分子量: 244.65
• InChiKey: OKQGSRSEFRPOFX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 3-chloro-3-(4-fluoro-3-methylphenyl)-2-oxopropanoate 在 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 31.92h， 生成 5-cyclopropyl-N-(3,4-dichlorobenzyl)-N-[2-(dimethylamino)ethyl]-3-(4-fluoro-3-methylphenyl)imidazo[1,2-a]pyridine-2-carboxamide dihydrochloride
  参考文献：
  名称：

  Synthetic Studies on Centromere-Associated Protein-E (CENP-E) Inhibitors: 2. Application of Electrostatic Potential Map (EPM) and Structure-Based Modeling to Imidazo[1,2-a]pyridine Derivatives as Anti-Tumor Agents

  摘要：

  To develop centromere-associated protein-E (CENP-E) inhibitors for use as anticancer therapeutics, we designed novel imidazo[1,2-a]pyridines, utilizing previously discovered 5-bromo derivative la. By site-directed mutagenesis analysis, we confirmed the ligand binding site. A docking model revealed the structurally important molecular features for effective interaction with CENP-E and could explain the superiority of the inhibitor (S)-isomer in CENP-E inhibition vs the (R)-isomer based on the ligand conformation in the LS loop region. Additionally, electrostatic potential map (EPM) analysis was employed as a ligand-based approach to optimize functional groups on the imidazo[1,2-a]pyridine scaffold. These a]pyridine derivative (+)-(S)-12, which showed potent CENP-E (p-HH3) elevation (EC50: 180 nM), and growth inhibition demonstrated antitumor activity (T/C: 40%, at 75 mg/kg) in a efforts led to the identification of the 5-methoxy imidazo [1,2-inhibition (IC50: 3.6 nM), cellular phosphorylated histone H3 (GI(50): 130 nM) in HeLa cells. Furthermore, (+)-(S)-12 human colorectal cancer Colo205 xenograft model in mice.

  DOI：

  10.1021/acs.jmedchem.5b00836
• 作为产物：
  描述：

  二氯乙酸甲酯 、 4-氟-3-甲基苯甲醛 在 sodium t-butanolate 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 生成 methyl 3-chloro-3-(4-fluoro-3-methylphenyl)-2-oxopropanoate
  参考文献：
  名称：

  Synthetic Studies on Centromere-Associated Protein-E (CENP-E) Inhibitors: 2. Application of Electrostatic Potential Map (EPM) and Structure-Based Modeling to Imidazo[1,2-a]pyridine Derivatives as Anti-Tumor Agents

  摘要：

  To develop centromere-associated protein-E (CENP-E) inhibitors for use as anticancer therapeutics, we designed novel imidazo[1,2-a]pyridines, utilizing previously discovered 5-bromo derivative la. By site-directed mutagenesis analysis, we confirmed the ligand binding site. A docking model revealed the structurally important molecular features for effective interaction with CENP-E and could explain the superiority of the inhibitor (S)-isomer in CENP-E inhibition vs the (R)-isomer based on the ligand conformation in the LS loop region. Additionally, electrostatic potential map (EPM) analysis was employed as a ligand-based approach to optimize functional groups on the imidazo[1,2-a]pyridine scaffold. These a]pyridine derivative (+)-(S)-12, which showed potent CENP-E (p-HH3) elevation (EC50: 180 nM), and growth inhibition demonstrated antitumor activity (T/C: 40%, at 75 mg/kg) in a efforts led to the identification of the 5-methoxy imidazo [1,2-inhibition (IC50: 3.6 nM), cellular phosphorylated histone H3 (GI(50): 130 nM) in HeLa cells. Furthermore, (+)-(S)-12 human colorectal cancer Colo205 xenograft model in mice.

  DOI：

  10.1021/acs.jmedchem.5b00836

文献信息

• Synthetic Studies on Centromere-Associated Protein-E (CENP-E) Inhibitors: 2. Application of Electrostatic Potential Map (EPM) and Structure-Based Modeling to Imidazo[1,2-<i>a</i>]pyridine Derivatives as Anti-Tumor Agents
  作者：Takaharu Hirayama、Masanori Okaniwa、Hiroshi Banno、Hiroyuki Kakei、Akihiro Ohashi、Kenichi Iwai、Momoko Ohori、Kouji Mori、Mika Gotou、Tomohiro Kawamoto、Akihiro Yokota、Tomoyasu Ishikawa

  DOI：10.1021/acs.jmedchem.5b00836

  日期：2015.10.22

  To develop centromere-associated protein-E (CENP-E) inhibitors for use as anticancer therapeutics, we designed novel imidazo[1,2-a]pyridines, utilizing previously discovered 5-bromo derivative la. By site-directed mutagenesis analysis, we confirmed the ligand binding site. A docking model revealed the structurally important molecular features for effective interaction with CENP-E and could explain the superiority of the inhibitor (S)-isomer in CENP-E inhibition vs the (R)-isomer based on the ligand conformation in the LS loop region. Additionally, electrostatic potential map (EPM) analysis was employed as a ligand-based approach to optimize functional groups on the imidazo[1,2-a]pyridine scaffold. These a]pyridine derivative (+)-(S)-12, which showed potent CENP-E (p-HH3) elevation (EC50: 180 nM), and growth inhibition demonstrated antitumor activity (T/C: 40%, at 75 mg/kg) in a efforts led to the identification of the 5-methoxy imidazo [1,2-inhibition (IC50: 3.6 nM), cellular phosphorylated histone H3 (GI(50): 130 nM) in HeLa cells. Furthermore, (+)-(S)-12 human colorectal cancer Colo205 xenograft model in mice.