4,6-dichloro-2-(4-nitrophenoxy)pyrimidine

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4,6-dichloro-2-(4-nitrophenoxy)pyrimidine
• 化学式: C₁₀H₅Cl₂N₃O₃
• 分子量: 286.074
• InChiKey: RZBVMDZJQAKRSV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  18
• 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：
  80.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4,6-dichloro-2-(4-nitrophenoxy)pyrimidine 在 N,N-二异丙基乙胺 、 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-(4-nitrophenoxy)pyrimidin-4-amine
  参考文献：
  名称：

  Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

  摘要：

  Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.

  DOI：

  10.1021/acs.jmedchem.5b01082
• 作为产物：
  描述：

  对硝基苯酚 、 4,6-二氯-2-甲砜基嘧啶 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 生成 4,6-dichloro-2-(4-nitrophenoxy)pyrimidine
  参考文献：
  名称：

  靶向脂质激酶VPS34的新型自噬抑制剂化学型的表型鉴定。

  摘要：

  自噬是细胞稳态和代谢的关键调节剂。干扰这一过程被认为是治疗疾病，特别是癌症和神经系统疾病的一种新方法。因此，对新型小分子自噬调节剂的需求量很大。我们描述了autophinib的发现，autophinib是一种具有新型化学型的强效自噬抑制剂。Autophinib是通过监测自噬诱导的点状细胞形成的表型测定法鉴定的，表明脂化的胞质蛋白LC3堆积在自噬体膜上。靶标的鉴定和验证显示，autophinib通过靶向脂质激酶VPS34抑制饥饿或雷帕霉素诱导的自噬。

  DOI：

  10.1002/anie.201703738

文献信息

• 2,4,6-trichloropyrimidine. Reaction with 4-substituted phenolate ions
  作者：Thomas J. Delia、A. Nagarajan

  DOI：10.1002/jhet.5570350201

  日期：1998.3

  A systematic investigation of the reactivity of 2,4,6-trichloropyrimidine with phenoxide nucleophiles has been conducted. Conditions have been described which lead to mono-, di-, and trisubstituted-pyrimidines. Unexpected product distributions for mono- and disubstituted products were observed and explanations for these results are offered.

  对2,4,6-三氯嘧啶与酚盐亲核试剂的反应性进行了系统的研究。已经描述了导致单，双和三取代的嘧啶的条件。观察到单取代和双取代产品的意外产品分布，并提供了有关这些结果的解释。
• Phenotypic Identification of a Novel Autophagy Inhibitor Chemotype Targeting Lipid Kinase VPS34
  作者：Lucas Robke、Luca Laraia、Marjorie A. Carnero Corrales、Georgios Konstantinidis、Makoto Muroi、André Richters、Michael Winzker、Tobias Engbring、Stefano Tomassi、Nobumoto Watanabe、Hiroyuki Osada、Daniel Rauh、Herbert Waldmann、Yao-Wen Wu、Julian Engel

  DOI：10.1002/anie.201703738

  日期：2017.7.3

  cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small‐molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring

  自噬是细胞稳态和代谢的关键调节剂。干扰这一过程被认为是治疗疾病，特别是癌症和神经系统疾病的一种新方法。因此，对新型小分子自噬调节剂的需求量很大。我们描述了autophinib的发现，autophinib是一种具有新型化学型的强效自噬抑制剂。Autophinib是通过监测自噬诱导的点状细胞形成的表型测定法鉴定的，表明脂化的胞质蛋白LC3堆积在自噬体膜上。靶标的鉴定和验证显示，autophinib通过靶向脂质激酶VPS34抑制饥饿或雷帕霉素诱导的自噬。
• Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach
  作者：Julian Engel、André Richters、Matthäus Getlik、Stefano Tomassi、Marina Keul、Martin Termathe、Jonas Lategahn、Christian Becker、Svenja Mayer-Wrangowski、Christian Grütter、Niklas Uhlenbrock、Jasmin Krüll、Niklas Schaumann、Simone Eppmann、Patrick Kibies、Franziska Hoffgaard、Jochen Heil、Sascha Menninger、Sandra Ortiz-Cuaran、Johannes M. Heuckmann、Verena Tinnefeld、René P. Zahedi、Martin L. Sos、Carsten Schultz-Fademrecht、Roman K. Thomas、Stefan M. Kast、Daniel Rauh

  DOI：10.1021/acs.jmedchem.5b01082

  日期：2015.9.10

  Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.