3-(2-amino-5-bromopyrimidin-4-yl)-1H-indole | 954421-23-9

• 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: 3-(2-amino-5-bromopyrimidin-4-yl)-1H-indole
• 英文别名: 5-bromo-4-(1H-indol-3-yl)pyrimidin-2-amine
• CAS: 954421-23-9
• 化学式: C₁₂H₉BrN₄
• 分子量: 289.134
• InChiKey: FEEDRMWWCFKAFL-UHFFFAOYSA-N

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：

  3-(2-amino-5-bromopyrimidin-4-yl)-1H-indole 在 三乙酰氧基硼氢化钠 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 4-((5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-N-ethylpiperidine-1-carboxamide
  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：

  1-[1-(苯磺酰基)-1H-吲哚-3-基]乙酮 在 N-溴代丁二酰亚胺(NBS) 、 碳酸胍 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 生成 3-(2-amino-5-bromopyrimidin-4-yl)-1H-indole
  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

文献信息

• Synthesis and biological activities of aminopyrimidyl-indoles structurally related to meridianins
  作者：Rufine Akue-Gedu、Eric Debiton、Yoan Ferandin、Laurent Meijer、Michelle Prudhomme、Fabrice Anizon、Pascale Moreau

  DOI：10.1016/j.bmc.2009.05.017

  日期：2009.7

  The synthesis of new meridianin derivatives substituted at the C-5 position of the 2-aminopyrimidine ring by various aryl groups and substituted or not by a methyl group on the indole nitrogen is described. These compounds were tested for their kinase inhibitory potencies toward five kinases (CDK5/p25, CK1δ/ε, GSK-3α/β, Dyrk1A and Erk2) as well as their in vitro antiproliferative activities toward

  描述了在2-氨基嘧啶环的C-5位被各种芳基取代并在吲哚氮上被甲基取代或未被甲基取代的新子午线衍生物的合成。测试了这些化合物对五种激酶（CDK5 / p25，CK1δ/ε，GSK-3α/β，Dyrk1A和Erk2）的激酶抑制能力，以及对人成纤维细胞原代培养物和两种人实体癌的体外抗增殖活性细胞系（MCF-7和PA 1）。
• Synthesis of aminopyrimidylindoles structurally related to meridianins
  作者：Emilie Rossignol、Ali Youssef、Pascale Moreau、Michelle Prudhomme、Fabrice Anizon

  DOI：10.1016/j.tet.2007.07.095

  日期：2007.10

  The synthesis of new meridianin derivatives substituted at the C-5′ position of the 2-aminopyrimidine ring by various aryl groups and substituted or not by a methyl group on the indole nitrogen is described. The 2-aminopyrimidine ring was obtained via a Bredereck synthesis. Aryl groups were introduced by Suzuki cross-coupling after bromination of the 2-aminopyrimidine ring at the C-5′ position.

  描述了在2-氨基嘧啶环的C-5'位置被各种芳基取代并被吲哚氮上的甲基取代或未被甲基取代的新子午线衍生物的合成。通过布雷德雷克合成获得2-氨基嘧啶环。在C-5'位置将2-氨基嘧啶环溴化后，通过Suzuki交叉偶联引入芳基。
• 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%).