(E)-4-methoxy-N-(3-(4-methoxybenzylidene)-2-oxoindolin-6-ylcarbamoyl)benzamide | 1474049-13-2

• 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: (E)-4-methoxy-N-(3-(4-methoxybenzylidene)-2-oxoindolin-6-ylcarbamoyl)benzamide
• 英文别名: N-[3-(4-methoxybenzylidene)-2-oxoindolin-6-yl-carbamoyl]4-methoxybenzamide；4-methoxy-N-[[(3E)-3-[(4-methoxyphenyl)methylidene]-2-oxo-1H-indol-6-yl]carbamoyl]benzamide
• CAS: 1474049-13-2
• 化学式: C₂₅H₂₁N₃O₅
• 分子量: 443.459
• InChiKey: QLRCMIVXNZZUFX-FYJGNVAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,4-二硝基苯乙酸 在 四氢吡咯 、 盐酸 、 palladium on activated charcoal 、 氢气 作用下， 以 甲醇 、 乙醇 、 水 、 乙腈 为溶剂， 反应 6.25h， 生成 (E)-4-methoxy-N-(3-(4-methoxybenzylidene)-2-oxoindolin-6-ylcarbamoyl)benzamide 、 N-[3-(4-methoxybenzylidene)-2-oxoindolin-6-yl-carbamoyl]4-methoxybenzamide
  参考文献：
  名称：

  Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia

  摘要：

  A series of 6-acylureido derivatives containing a 3-(pyrrol-2-ylmethylidene)indolin-2-one scaffold were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2-one-based multi-kinase inhibitors. (Z)-N-(2-(pyrrolidin-l-yl)ethyl)-5-((6-(3-(2-fluoro-4-methoxybenzoyflureido)-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (54) was identified as a dual Aurora B/FLT3 inhibitor (IC50 = 0.4 nM and 0.5 nM, respectively). Compound 54 also exhibited potent cytotoxicity with single-digit nanomolar IC50 values against the FLT3 mutant-associated human acute myeloid leukemia (AML) cell lines MV4-11 (FLT3-ITD) and MOLM-13 (FLT3-ITD). Compound 54 also specifically induced extrinsic apoptosis by inhibiting the phosphorylation of the Aurora B and FLT3 pathways in MOLM-13 cells. Compound 54 had a moderate pharmacokinetic profile. The mesylate salt of 54 efficiently inhibited tumor growth and reduced the mortality of BALB/c nude mice (subcutaneous xenograft model) that had been implanted with AML MOLM-13 cells. Compound 54 is more potent than sunitinib not only against FLT3-WT AML cells but also active against sunitinib-resistant FLT3-ITD AML cells. This study demonstrates the significance of dual Aurora B/FLT3 inhibitors for the development of potential agents to treat AML. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.07.108

文献信息

• INDOLIN-2-ONE DERIVATIVES AS PROTEIN KINASE INHIBITORS
  申请人：ANNJI PHARMACEUTICAL CO., LTD.

  公开号：US20130281451A1

  公开（公告）日：2013-10-24

  A novel class of indoline-2-one derivatives are disclosed. These compounds are protein kinase inhibitors which are useful for treating hyperproliferative diseases such as cancer.

  揭示了一类新型的吲哚啉-2-酮衍生物。这些化合物是蛋白激酶抑制剂，可用于治疗癌症等过度增殖性疾病。
• US8946282B2
  申请人：——

  公开号：US8946282B2

  公开（公告）日：2015-02-03
• Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia
  作者：Ajit Dhananjay Jagtap、Pei-Teh Chang、Jia-Rong Liu、Hsiao-Chun Wang、Nagendra B. Kondekar、Li-Jiuan Shen、Hsiang-Wen Tseng、Grace Shiahuy Chen、Ji-Wang Chern

  DOI：10.1016/j.ejmech.2014.07.108

  日期：2014.10

  A series of 6-acylureido derivatives containing a 3-(pyrrol-2-ylmethylidene)indolin-2-one scaffold were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2-one-based multi-kinase inhibitors. (Z)-N-(2-(pyrrolidin-l-yl)ethyl)-5-((6-(3-(2-fluoro-4-methoxybenzoyflureido)-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (54) was identified as a dual Aurora B/FLT3 inhibitor (IC50 = 0.4 nM and 0.5 nM, respectively). Compound 54 also exhibited potent cytotoxicity with single-digit nanomolar IC50 values against the FLT3 mutant-associated human acute myeloid leukemia (AML) cell lines MV4-11 (FLT3-ITD) and MOLM-13 (FLT3-ITD). Compound 54 also specifically induced extrinsic apoptosis by inhibiting the phosphorylation of the Aurora B and FLT3 pathways in MOLM-13 cells. Compound 54 had a moderate pharmacokinetic profile. The mesylate salt of 54 efficiently inhibited tumor growth and reduced the mortality of BALB/c nude mice (subcutaneous xenograft model) that had been implanted with AML MOLM-13 cells. Compound 54 is more potent than sunitinib not only against FLT3-WT AML cells but also active against sunitinib-resistant FLT3-ITD AML cells. This study demonstrates the significance of dual Aurora B/FLT3 inhibitors for the development of potential agents to treat AML. (C) 2014 Elsevier Masson SAS. All rights reserved.