N⁴-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N²-(4-nitrophenyl)pyrimidine-2,4-diamine | 1432515-73-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N⁴-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N²-(4-nitrophenyl)pyrimidine-2,4-diamine
• 英文别名: aurora-A kinase inhibitor 603；AKI603；6-(4-methylpiperazin-1-yl)-4-N-(5-methyl-1H-pyrazol-3-yl)-2-N-(4-nitrophenyl)pyrimidine-2,4-diamine
• CAS: 1432515-73-5
• 化学式: C₁₉H₂₃N₉O₂
• 分子量: 409.451
• InChiKey: UNKOUVAYOLLXER-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  131
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine 在 对甲苯磺酸 作用下， 以 1,4-二氧六环 、 正丁醇 为溶剂， 反应 12.5h， 生成 N⁴-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-N²-(4-nitrophenyl)pyrimidine-2,4-diamine
  参考文献：
  名称：

  Design, synthesis and bioevaluation of N-trisubstituted pyrimidine derivatives as potent aurora A kinase inhibitors

  摘要：

  The design and synthesis of a new series of N-trisubstituted (at C2, C4 and C6 respectively) pyrimidine derivatives were reported, their in vitro structure-activity relationships vs. aurora A kinase were also discussed. Our results demonstrated that the introduction of characteristic N-substituted side chain at C2 of pyrimidines possessed a potent aurora A inhibitory activity, the position and the nature of the substituents on the phenyl ring of aniline side chain played key roles in cellular kinase inhibitory potency. Most tested compounds exhibited good inhibitory activities against aurora A kinase and various human tumor cell lines. Compounds 7j, 7m-n and 7p showed strong growth-inhibitory activities in the solid CNE-2 tumor cell and selectively blocked cell-cycle progression at the G(2)/M phase. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.03.027

文献信息

• A Novel Small-Molecule Aurora Kinase Inhibitor Attenuates Breast Tumor–Initiating Cells and Overcomes Drug Resistance
  作者：Fei-Meng Zheng、Zi-Jie Long、Zhi-Jie Hou、Yu Luo、Ling-Zhi Xu、Jiang-Long Xia、Xiao-Ju Lai、Ji-Wei Liu、Xi Wang、Muhammad Kamran、Min Yan、Shu-Juan Shao、Eric W.-F. Lam、Shao-Wu Wang、Gui Lu、Quentin Liu

  DOI：10.1158/1535-7163.mct-13-1029

  日期：2014.8.1

  Chemoresistance is a major cause of cancer treatment failure. Tumor-initiating cells (TIC) have attracted a considerable amount of attention due to their role in chemoresistance and tumor recurrence. Here, we evaluated the small-molecule Aurora kinase inhibitor AKI603 as a novel agent against TICs in breast cancer. AKI603 significantly inhibited Aurora-A (AurA) kinase and induced cell-cycle arrest. In addition, the intragastric administration of AKI603 reduced xenograft tumor growth. Interestingly, we found that breast cancer cells that were resistant to epirubicin expressed a high level of activated AurA and also have a high CD24Low/CD44High TIC population. The inhibition of AurA kinase by AKI603 abolished the epirubicin-induced enrichment of TICs. Moreover, AKI603 suppressed the capacity of cells to form mammosphere and also suppressed the expression of self-renewal genes (β-catenin, c-Myc, Sox2, and Oct4). Thus, our work suggests the potential clinical use of the small-molecule Aurora kinase inhibitor AKI603 to overcome drug resistance induced by conventional chemotherapeutics in breast cancer. Mol Cancer Ther; 13(8); 1991–2003. ©2014 AACR.

  摘要 化疗耐药性是癌症治疗失败的主要原因。由于肿瘤启动细胞（TIC）在化疗耐药和肿瘤复发中的作用，它们引起了人们的广泛关注。在这里，我们评估了小分子极光激酶抑制剂 AKI603 作为一种新型药物对乳腺癌 TIC 的作用。AKI603能明显抑制极光-A（AurA）激酶并诱导细胞周期停滞。此外，胃内给药 AKI603 还能减少异种移植肿瘤的生长。有趣的是，我们发现对表柔比星耐药的乳腺癌细胞表达了高水平的活化 AurA，同时还具有高 CD24Low/CD44High TIC 群体。AKI603 对 AurA 激酶的抑制作用消除了表柔比星诱导的 TIC 富集。此外，AKI603还抑制了细胞形成乳球的能力，并抑制了自我更新基因（β-catenin、c-Myc、Sox2和Oct4）的表达。因此，我们的研究表明，小分子极光激酶抑制剂AKI603有可能用于临床，以克服传统化疗药物对乳腺癌的耐药性。Mol Cancer Ther; 13(8); 1991-2003。©2014 AACR.
• Design, synthesis and bioevaluation of N-trisubstituted pyrimidine derivatives as potent aurora A kinase inhibitors
  作者：Yu Luo、Yan-Qiu Deng、Jing Wang、Zi-Jie Long、Zheng-Chao Tu、Wei Peng、Ji-Quan Zhang、Quentin Liu、Gui Lu

  DOI：10.1016/j.ejmech.2014.03.027

  日期：2014.5

  The design and synthesis of a new series of N-trisubstituted (at C2, C4 and C6 respectively) pyrimidine derivatives were reported, their in vitro structure-activity relationships vs. aurora A kinase were also discussed. Our results demonstrated that the introduction of characteristic N-substituted side chain at C2 of pyrimidines possessed a potent aurora A inhibitory activity, the position and the nature of the substituents on the phenyl ring of aniline side chain played key roles in cellular kinase inhibitory potency. Most tested compounds exhibited good inhibitory activities against aurora A kinase and various human tumor cell lines. Compounds 7j, 7m-n and 7p showed strong growth-inhibitory activities in the solid CNE-2 tumor cell and selectively blocked cell-cycle progression at the G(2)/M phase. (C) 2014 Elsevier Masson SAS. All rights reserved.