5-iodo-4-(1H-indol-3-yl)pyrimidin-2-amine | 1311395-51-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 5-iodo-4-(1H-indol-3-yl)pyrimidin-2-amine
• 英文别名: 4-(1H-indol-3-yl)-5-iodopyrimidin-2-amine
• CAS: 1311395-51-3
• 化学式: C₁₂H₉IN₄
• 分子量: 336.135
• InChiKey: HVRWKGMEVRIHCH-UHFFFAOYSA-N

物化性质

• 熔点：
  167-168 °C
• 沸点：
  603.4±65.0 °C(Predicted)
• 密度：
  1.888±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  67.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-iodo-4-(1H-indol-3-yl)pyrimidin-2-amine 在 三乙酰氧基硼氢化钠 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成
  参考文献：
  名称：

  Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond

  摘要：

  We target the gatekeeper MET 146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X...s halogen bonds in molecular design using computational, synthetic, structural and biophysical techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their sigma-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or thereonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increase the flexibility of C-epsilon of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methioine is the predominant gatekeeper (39%).

  DOI：

  10.1021/jacs.5b07090
• 作为产物：
  描述：

  1H-吲哚,3-乙酰基-1-[(4-甲基苯基)磺酰]- 在 碘 、 potassium carbonate 作用下， 以 甲乙醚 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 生成 5-iodo-4-(1H-indol-3-yl)pyrimidin-2-amine
  参考文献：
  名称：

  子午肽衍生物的合成，蛋白激酶抑制潜能和体外抗增殖活性

  摘要：

  描述了新子午线衍生物的合成。吲哚环系统在C-4至C-7位置被溴原子或被硝基或氨基取代。另外，在2-氨基嘧啶环的C-5位上引入了碘原子或各种芳基。测试了这些化合物及其某些合成中间体的激酶抑制能力和体外抗增殖活性。我们发现，这一系列化合物在开发新的DYRK1A和CLK1激酶抑制剂方面特别有趣。朝向这两个激酶家族的最有效的化合物是6-和7-溴衍生物30，33，和34与其他测试激酶相比，该蛋白对DYRK1A / CLK1激酶的选择性高出45倍以上。因此，子午肽衍生物可以发展为关键的RNA剪接调节剂和潜在治疗剂的有效和选择性抑制剂。

  DOI：

  10.1021/jm200464w

文献信息

• Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond
  作者：Andreas Lange、Marcel Günther、Felix Michael Büttner、Markus O. Zimmermann、Johannes Heidrich、Susanne Hennig、Stefan Zahn、Christoph Schall、Adrian Sievers-Engler、Francesco Ansideri、Pierre Koch、Michael Laemmerhofer、Thilo Stehle、Stefan A. Laufer、Frank M. Boeckler

  DOI：10.1021/jacs.5b07090

  日期：2015.11.25

  We target the gatekeeper MET 146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X...s halogen bonds in molecular design using computational, synthetic, structural and biophysical techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their sigma-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or thereonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increase the flexibility of C-epsilon of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methioine is the predominant gatekeeper (39%).
• Synthesis, Protein Kinase Inhibitory Potencies, and in Vitro Antiproliferative Activities of Meridianin Derivatives
  作者：Francis Giraud、Georges Alves、Eric Debiton、Lionel Nauton、Vincent Théry、Emilie Durieu、Yoan Ferandin、Olivier Lozach、Laurent Meijer、Fabrice Anizon、Elisabeth Pereira、Pascale Moreau

  DOI：10.1021/jm200464w

  日期：2011.7.14

  for their in vitro antiproliferative activities. We found that this series of compounds is particularly interesting in the development of new inhibitors of DYRK1A and CLK1 kinases. The most effective compounds toward these two kinase families are the 6- and 7-bromo derivatives 30, 33, and 34 that showed more than 45-fold selectivity toward DYRK1A/CLK1 kinases over the other kinases tested. Meridianin

  描述了新子午线衍生物的合成。吲哚环系统在C-4至C-7位置被溴原子或被硝基或氨基取代。另外，在2-氨基嘧啶环的C-5位上引入了碘原子或各种芳基。测试了这些化合物及其某些合成中间体的激酶抑制能力和体外抗增殖活性。我们发现，这一系列化合物在开发新的DYRK1A和CLK1激酶抑制剂方面特别有趣。朝向这两个激酶家族的最有效的化合物是6-和7-溴衍生物30，33，和34与其他测试激酶相比，该蛋白对DYRK1A / CLK1激酶的选择性高出45倍以上。因此，子午肽衍生物可以发展为关键的RNA剪接调节剂和潜在治疗剂的有效和选择性抑制剂。