8-bromo-3,7-dihydro-3-methyl-7-[2-(2-methylphenyl)-2-oxoethyl]-1H-purine-2,6-dione | 1192215-77-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 8-bromo-3,7-dihydro-3-methyl-7-[2-(2-methylphenyl)-2-oxoethyl]-1H-purine-2,6-dione
• 英文别名: 8-bromo-3-methyl-7-(2-oxo-2-(o-tolyl)ethyl)-1H-purine-2,6(3H,7H)-dione；8-Bromo-3-methyl-7-[2-(2-methylphenyl)-2-oxoethyl]purine-2,6-dione
• CAS: 1192215-77-2
• 化学式: C₁₅H₁₃BrN₄O₃
• 分子量: 377.197
• InChiKey: OOVVXEPCXYAVBS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 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-3,7-dihydro-3-methyl-7-[2-(2-methylphenyl)-2-oxoethyl]-1H-purine-2,6-dione 在 aluminum (III) chloride 作用下， 以 乙醇 为溶剂， 反应 0.5h， 生成 4-Methyl-7-(2-methylphenyl)-6-pentylpurino[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：

  1-甲基苯基乙酮 在 N,N-二异丙基乙胺 、 copper(I) bromide 作用下， 以 氯仿 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.08h， 生成 8-bromo-3,7-dihydro-3-methyl-7-[2-(2-methylphenyl)-2-oxoethyl]-1H-purine-2,6-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

• Structure-Based Optimization of Potent and Selective Inhibitors of the Tyrosine Kinase Erythropoietin Producing Human Hepatocellular Carcinoma Receptor B4 (EphB4)
  作者：Karine Lafleur、Danzhi Huang、Ting Zhou、Amedeo Caflisch、Cristina Nevado

  DOI：10.1021/jm9009444

  日期：2009.10.22

  hydroxyl groups, to compound 4 has yielded the single-digit nanomolar inhibitor 66, with a remarkable improvement of the ligand efficiency from 0.26 to 0.37 kcal/(mol per non-hydrogen atom). Compound 66 shows very high affinity for a few other tyrosine kinases with threonine as gatekeeper residue (Abl, Lck, and Src). On the other hand, it is selective against kinases with a larger gatekeeper. A 45 ns molecular

  酪氨酸激酶EphB4由于在癌症相关血管生成中的公认作用而成为药物设计的诱人靶标。最近，通过基于高通量片段的对接进入激酶域的ATP结合位点，一系列可商购的黄嘌呤衍生物被鉴定为EphB4的微摩尔抑制剂。在这里，我们利用通过自动对接获得的结合模式来通过化学合成优化这些EphB4抑制剂。仅将两个重原子，甲基和羟基加到化合物4中，产生了一位数的纳摩尔抑制剂66，配体效率从0.26kcal /（mol /非氢原子摩尔）显着提高。化合物66对苏氨酸作为看门者残基（Abl，Lck和Src）的其他酪氨酸激酶具有很高的亲和力。另一方面，它对具有较大网守的激酶具有选择性。EphB4和化合物66的复合物的45 ns分子动力学（MD）模拟提供了通过基于片段的对接获得的结合模式的进一步验证。
• [EN] NEW ANTI-ANGIOGENIC COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS ANTIANGIOGÉNIQUES
  申请人：UNIV ZUERICH

  公开号：WO2011009695A1

  公开（公告）日：2011-01-27

  The invention relates to compounds of formula (I), tautomers and salts thereof wherein R1 is methyl or ethyl, R2 is n-butyl or o-methoxyphenyl, R3 is hydrogen or hydroxy; and R4 is hydrogen or methyl. These compounds are receptor tyrosine kinase EphB4 inhibitors useful for the treatment of angiogenesis dependent cancers and intraocular neovascular syndromes.

  本发明涉及公式（I）的化合物，互变异构体和其盐，其中R1为甲基或乙基，R2为正丁基或邻甲氧基苯基，R3为氢或羟基；R4为氢或甲基。这些化合物是受体酪氨酸激酶EphB4的抑制剂，可用于治疗依赖于血管生成的癌症和眼内新生血管综合症。
• 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.