N⁴-(2-bromophenyl)-2-chloropyrimidine-4-amine | 260046-14-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N⁴-(2-bromophenyl)-2-chloropyrimidine-4-amine
• 英文别名: N-(2-bromophenyl)-2-chloropyrimidine-4-amine；N-(2-bromophenyl)-2-chloropyrimidin-4-amine
• CAS: 260046-14-8
• 化学式: C₁₀H₇BrClN₃
• 分子量: 284.543
• InChiKey: SQURNEFVYXUGME-UHFFFAOYSA-N

物化性质

• 沸点：
  423.7±25.0 °C(Predicted)
• 密度：
  1.673±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  37.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N⁴-(2-bromophenyl)-2-chloropyrimidine-4-amine 在 potassium carbonate 作用下， 以 二甲基亚砜 、 正丁醇 为溶剂， 生成
  参考文献：
  名称：

  细胞周期蛋白依赖性激酶4抑制剂可治疗癌症。第2部分：取代的2,4-双苯胺嘧啶的鉴定和优化。

  摘要：

  通过化学修饰和X射线晶体学，我们确定了2,4-双苯胺嘧啶是CDK4的有效抑制剂。在此，我们描述了该系列的优化。

  DOI：

  10.1016/s0960-894x(03)00203-8
• 作为产物：
  描述：

  2,4-二氯嘧啶 、 2-溴苯胺 在 N,N-二异丙基乙胺 作用下， 以 正丁醇 为溶剂， 生成 N⁴-(2-bromophenyl)-2-chloropyrimidine-4-amine
  参考文献：
  名称：

  细胞周期蛋白依赖性激酶4抑制剂可治疗癌症。第2部分：取代的2,4-双苯胺嘧啶的鉴定和优化。

  摘要：

  通过化学修饰和X射线晶体学，我们确定了2,4-双苯胺嘧啶是CDK4的有效抑制剂。在此，我们描述了该系列的优化。

  DOI：

  10.1016/s0960-894x(03)00203-8

文献信息

• PHA-680626 Is an Effective Inhibitor of the Interaction between Aurora-A and N-Myc
  作者：Dalila Boi、Fani Souvalidou、Davide Capelli、Federica Polverino、Grazia Marini、Roberta Montanari、Giorgio Pochetti、Angela Tramonti、Roberto Contestabile、Daniela Trisciuoglio、Patrizia Carpinelli、Camilla Ascanelli、Catherine Lindon、Alessandro De Leo、Michele Saviano、Roberto Di Santo、Roberta Costi、Giulia Guarguaglini、Alessandro Paiardini

  DOI：10.3390/ijms222313122

  日期：——

  Neuroblastoma is a severe childhood disease, accounting for ~10% of all infant cancers. The amplification of the MYCN gene, coding for the N-Myc transcription factor, is an essential marker correlated with tumor progression and poor prognosis. In neuroblastoma cells, the mitotic kinase Aurora-A (AURKA), also frequently overexpressed in cancer, prevents N-Myc degradation by directly binding to a highly conserved N-Myc region. As a result, elevated levels of N-Myc are observed. During recent years, it has been demonstrated that some ATP competitive inhibitors of AURKA also cause essential conformational changes in the structure of the activation loop of the kinase that prevents N-Myc binding, thus impairing the formation of the AURKA/N-Myc complex. In this study, starting from a screening of crystal structures of AURKA in complexes with known inhibitors, we identified additional compounds affecting the conformation of the kinase activation loop. We assessed the ability of such compounds to disrupt the interaction between AURKA and N-Myc in vitro, using Surface Plasmon Resonance competition assays, and in tumor cell lines overexpressing MYCN, by performing Proximity Ligation Assays. Finally, their effects on N-Myc cellular levels and cell viability were investigated. Our results identify PHA-680626 as an amphosteric inhibitor both in vitro and in MYCN overexpressing cell lines, thus expanding the repertoire of known conformational disrupting inhibitors of the AURKA/N-Myc complex and confirming that altering the conformation of the activation loop of AURKA with a small molecule is an effective strategy to destabilize the AURKA/N-Myc interaction in neuroblastoma cancer cells.

  神经母细胞瘤是一种严重的儿童疾病，占所有婴儿癌症的约10％。MYCN基因的扩增，编码N-Myc转录因子，是与肿瘤进展和不良预后相关的重要标志。在神经母细胞瘤细胞中，有时也会过度表达的有丝分裂激酶Aurora-A（AURKA），它直接结合到高度保守的N-Myc区域，防止N-Myc降解。因此，观察到N-Myc水平升高。近年来，已经证明，一些AURKA的ATP竞争性抑制剂也会导致激酶激活环的结构发生重要构象变化，从而防止N-Myc结合，从而损害AURKA / N-Myc复合物的形成。在本研究中，从AURKA与已知抑制剂复合物的晶体结构筛选开始，我们确定了其他影响激酶激活环构象的化合物。我们使用表面等离子体共振竞争测定在体外评估了这些化合物破坏AURKA和N-Myc之间相互作用的能力，并在过度表达MYCN的肿瘤细胞系中进行了近距离连接测定。最后，我们研究了它们对N-Myc细胞水平和细胞存活率的影响。我们的结果确定PHA-680626是一种在体外和MYCN过度表达的细胞系中均具有两亲性抑制剂的药物，从而扩展了已知的破坏AURKA / N-Myc复合物的构象抑制剂的库存，并确认使用小分子改变AURKA激酶激活环的构象是破坏神经母细胞瘤癌细胞中AURKA / N-Myc相互作用的有效策略。
• AURORA KINASE INHIBITORS AND METHODS OF MAKING AND USING THEREOF
  申请人：Sebti Said M.

  公开号：US20140057913A1

  公开（公告）日：2014-02-27

  Described herein are inhibitors of Aurora kinase and their use in the treatment of cancer. Methods of screening for selective inhibitors of Aurora kinases are also disclosed.

  本文描述了Aurora激酶的抑制剂及其在癌症治疗中的应用。还公开了筛选选择性抑制Aurora激酶的方法。
• [EN] AURORA KINASE INHIBITORS AND METHODS OF MAKING AND USING THEREOF<br/>[FR] INHIBITEURS DE KINASE AURORA ET PROCÉDÉS POUR LES FABRIQUER ET LES UTILISER
  申请人：H LEE MOFFITT CANCER CT AND RES INST

  公开号：WO2012135641A3

  公开（公告）日：2012-12-27
• Development of <i>o</i>-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors
  作者：Harshani R. Lawrence、Mathew P. Martin、Yunting Luo、Roberta Pireddu、Hua Yang、Harsukh Gevariya、Sevil Ozcan、Jin-Yi Zhu、Robert Kendig、Mercedes Rodriguez、Roy Elias、Jin Q. Cheng、Saïd M. Sebti、Ernst Schonbrunn、Nicholas J. Lawrence

  DOI：10.1021/jm300334d

  日期：2012.9.13

  The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC50 = 6.1 +/- 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.
• US9249124B2
  申请人：——

  公开号：US9249124B2

  公开（公告）日：2016-02-02