5-bromo-N-(3,4-dichlorobenzyl)-N-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide | 1355079-11-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-bromo-N-(3,4-dichlorobenzyl)-N-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide
• 英文别名: 5-bromo-N-[(3,4-dichlorophenyl)methyl]-N-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide
• CAS: 1355079-11-6
• 化学式: C₂₅H₂₂BrCl₂FN₄O
• 分子量: 564.284
• InChiKey: ZATPRXWLTXOXAQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  40.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  对氟苯甲醛 在 sodium methylate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 39.5h， 生成 5-bromo-N-(3,4-dichlorobenzyl)-N-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxamide
  参考文献：
  名称：

  Synthetic studies of centromere-associated protein-E (CENP-E) inhibitors: 1.Exploration of fused bicyclic core scaffolds using electrostatic potential map

  摘要：

  Centromere-associated protein-E (CENP-E), a mitotic kinesin that plays an important role in mitotic progression, is an attractive target for cancer therapeutic drugs. For the purpose of developing novel CENP-E inhibitors as cancer therapeutics, we investigated a fused bicyclic compound identified by high throughput screening, 4-oxo-4,5-dihydrothieno[3,4-clpyridine-6-carboxamide la. Based on this scaffold, we designed inhibitors for efficient binding at the L5 site in CENP-E utilizing homology modeling as well as electrostatic potential map (EPM) analysis to enhance CENP-E inhibitory activity. This resulted in a new lead, 5-bromoimidazo[l,2-a]pyridine 7, which showed potent CENP-E enzyme inhibition (IC50: 50 nM) and cellular activity with accumulation of phosphorylated histone H3 in HeLa cells. Our homology model and EPM analysis proved to be useful tools for the rational design of CENP-E inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.05.067

文献信息

• Synthetic studies of centromere-associated protein-E (CENP-E) inhibitors: 1.Exploration of fused bicyclic core scaffolds using electrostatic potential map
  作者：Takaharu Hirayama、Masanori Okaniwa、Takashi Imada、Akihiro Ohashi、Momoko Ohori、Kenichi Iwai、Kouji Mori、Tomohiro Kawamoto、Akihiro Yokota、Toshimasa Tanaka、Tomoyasu Ishikawa

  DOI：10.1016/j.bmc.2013.05.067

  日期：2013.9

  Centromere-associated protein-E (CENP-E), a mitotic kinesin that plays an important role in mitotic progression, is an attractive target for cancer therapeutic drugs. For the purpose of developing novel CENP-E inhibitors as cancer therapeutics, we investigated a fused bicyclic compound identified by high throughput screening, 4-oxo-4,5-dihydrothieno[3,4-clpyridine-6-carboxamide la. Based on this scaffold, we designed inhibitors for efficient binding at the L5 site in CENP-E utilizing homology modeling as well as electrostatic potential map (EPM) analysis to enhance CENP-E inhibitory activity. This resulted in a new lead, 5-bromoimidazo[l,2-a]pyridine 7, which showed potent CENP-E enzyme inhibition (IC50: 50 nM) and cellular activity with accumulation of phosphorylated histone H3 in HeLa cells. Our homology model and EPM analysis proved to be useful tools for the rational design of CENP-E inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.
• 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.