8-bromo-7-(2-(2,6-dimethylphenyl)-2-oxoethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione | 1415838-47-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 8-bromo-7-(2-(2,6-dimethylphenyl)-2-oxoethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione
• 英文别名: 8-Bromo-7-[2-(2,6-dimethylphenyl)-2-oxoethyl]-3-methylpurine-2,6-dione；8-bromo-7-[2-(2,6-dimethylphenyl)-2-oxoethyl]-3-methylpurine-2,6-dione
• CAS: 1415838-47-9
• 化学式: C₁₆H₁₅BrN₄O₃
• 分子量: 391.224
• InChiKey: KMLVLMJUFLURII-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  84.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-bromo-7-(2-(2,6-dimethylphenyl)-2-oxoethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione 在 三氟化硼乙醚 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 6-Butyl-7-(2,6-dimethylphenyl)-4-methylpurino[7,8-a]imidazole-1,3-dione
  参考文献：
  名称：

  Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography

  摘要：

  Inhibition of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) is an effective strategy for the treatment of solid tumors. We have previously reported a low nanomolar ATP-competitive inhibitor of EphB4 discovered in silico by fragment-based high-throughput docking combined with explicit solvent molecular dynamics simulations. Here we present a second generation of EphB4 inhibitors that show high inhibitory potency in both enzymatic and cell-based assays while preserving the appealing selectivity profile exhibited by the parent compound. In addition, respectable levels of antiproliferative activity for these compounds have been obtained. Finally, the binding mode predicted by docking and molecular dynamics simulations is validated by solving the crystal structures of three members of this chemical class in complex with the EphA3 tyrosine kinase whose ATP-binding site is essentially identical to that of EphB4.

  DOI：

  10.1021/jm301187e
• 作为产物：
  描述：

  2,6-二甲基溴苯 在 正丁基锂 、 N,N-二异丙基乙胺 、 pyridinium chlorochromate 、 copper(I) bromide 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 氯仿 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.58h， 生成 8-bromo-7-(2-(2,6-dimethylphenyl)-2-oxoethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione
  参考文献：
  名称：

  Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography

  摘要：

  Inhibition of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) is an effective strategy for the treatment of solid tumors. We have previously reported a low nanomolar ATP-competitive inhibitor of EphB4 discovered in silico by fragment-based high-throughput docking combined with explicit solvent molecular dynamics simulations. Here we present a second generation of EphB4 inhibitors that show high inhibitory potency in both enzymatic and cell-based assays while preserving the appealing selectivity profile exhibited by the parent compound. In addition, respectable levels of antiproliferative activity for these compounds have been obtained. Finally, the binding mode predicted by docking and molecular dynamics simulations is validated by solving the crystal structures of three members of this chemical class in complex with the EphA3 tyrosine kinase whose ATP-binding site is essentially identical to that of EphB4.

  DOI：

  10.1021/jm301187e

文献信息

• Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography
  作者：Karine Lafleur、Jing Dong、Danzhi Huang、Amedeo Caflisch、Cristina Nevado

  DOI：10.1021/jm301187e

  日期：2013.1.10

  Inhibition of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) is an effective strategy for the treatment of solid tumors. We have previously reported a low nanomolar ATP-competitive inhibitor of EphB4 discovered in silico by fragment-based high-throughput docking combined with explicit solvent molecular dynamics simulations. Here we present a second generation of EphB4 inhibitors that show high inhibitory potency in both enzymatic and cell-based assays while preserving the appealing selectivity profile exhibited by the parent compound. In addition, respectable levels of antiproliferative activity for these compounds have been obtained. Finally, the binding mode predicted by docking and molecular dynamics simulations is validated by solving the crystal structures of three members of this chemical class in complex with the EphA3 tyrosine kinase whose ATP-binding site is essentially identical to that of EphB4.