N-[4-[(2-氨基-6-甲基-4-嘧啶基)氨基]苯基]-4-(4-喹啉基氨基)苯甲酰胺 | 1020149-73-8

• 物质功能分类: 生物化工 - 抑制剂 - 表观遗传学(Epigenetics)
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: N-[4-[(2-氨基-6-甲基-4-嘧啶基)氨基]苯基]-4-(4-喹啉基氨基)苯甲酰胺
• 中文别名: SGI-1027抑制剂；SGI1027游离；DNA甲基转移酶抑制剂(DNMT抑制剂)；化合物SGI-1027；SGI-1027
• 英文名称: N-[4-[(2-amino-6-methyl-4-pyrimidinyl)amino]phenyl]-4-(4-quinolinylamino)benzamide
• 英文别名: N-(4-(2-amino-6-methylpyrimidin-4-ylamino)phenyl)-4-(quinolin-4-ylamino)benzamide；[4-[(2-amino-6-methylpyrimidin-4-yl)amino]phenyl]-4-(quinolin-4-ylamino)benzamide；SGI-1027；SGI1027；S7276；N-(4-((2-amino-6-methylpyrimidin-4-yl)amino)phenyl)-4-(quinolin-4-ylamino)benzamide；N-[4-[(2-amino-6-methylpyrimidin-4-yl)amino]phenyl]-4-(quinolin-4-ylamino)benzamide
• CAS: 1020149-73-8
• 化学式: C₂₇H₂₃N₇O
• 分子量: 461.526
• InChiKey: QSYLKMKIVWJAAK-UHFFFAOYSA-N

物化性质

• 熔点：
  >280℃
• 密度：
  1.387±0.06 g/cm3(Predicted)
• 溶解度：
  溶于DMSO（高达35mg/ml）

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  118
• 氢给体数：
  4
• 氢受体数：
  7

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

生物活性

SGI-1027 是一种 DNMT 抑制剂，针对 DNMT1、DNMT3A 和 DNMT3B 的 IC50 分别为 6 μM、8 μM 和 7.5 μM。这种化合物通过直接抑制 DNMTs 而抑制 DNA 甲基化，并导致 DNMT1 在各种人癌细胞系中选择性降解。

体外研究

在大鼠肝癌 H4IIE 细胞中，SGI-1027 表现出很小或没有毒性作用。在 U937 人白血病细胞系中，剂量为 0 至 100 μM 的 SGI-1027 展现了适度的促凋亡作用，但并未观察到对细胞周期的影响。

特征

SGI-1027 具有潜在用于治疗后生癌症的价值，并能诱导凋亡。

靶点

Target	Value (Cell-free assay)
DNMT1	6 μM
DNMT3B	7.5 μM
DNMT3A	8 μM

反应信息

• 作为产物：
  描述：

  4-氯喹啉 在 盐酸 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 、 potassium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 N-[4-[(2-氨基-6-甲基-4-嘧啶基)氨基]苯基]-4-(4-喹啉基氨基)苯甲酰胺
  参考文献：
  名称：

  Selective Non-nucleoside Inhibitors of Human DNA Methyltransferases Active in Cancer Including in Cancer Stem Cells

  摘要：

  DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other Ado Met-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.

  DOI：

  10.1021/jm4012627

文献信息

• QUINOLINE DERIVATIVES FOR MODULATING DNA METHYLATION
  申请人：Phiasivongsa Pasit

  公开号：US20090285772A1

  公开（公告）日：2009-11-19

  Quinoline derivatives, particularly 4-anilinoquinoline derivatives, are provided. Such quinoline derivatives can be used for modulation of DNA methylation, such as effective inhibition of methylation of cytosine at the C-5 position, for example via selective inhibition of DNA methyltransferase DNMT1. Methods for synthesizing numerous 4-anilinoquinoline derivatives and for modulating DNA methylation are provided. Also provided are methods for formulating and administering these compounds or compositions to treat conditions such as cancer and hematological disorders.

  提供了喹啉衍生物，特别是4-苯胺基喹啉衍生物。这样的喹啉衍生物可用于调节DNA甲基化，例如通过选择性抑制DNA甲基转移酶DNMT1，有效抑制C-5位置的胞嘧啶甲基化。提供了合成多种4-苯胺基喹啉衍生物和调节DNA甲基化的方法。还提供了制剂和给药这些化合物或组合物以治疗癌症和血液疾病的方法。
• Quinoline derivatives for modulating DNA methylation
  申请人：SuperGen, Inc.

  公开号：EP2174938A1

  公开（公告）日：2010-04-14

  Quinoline derivatives, particularly 4-anilinoquinoline derivatives, are provided. Such quinoline derivatives can be used for modulation of DNA methylation, such as effective inhibition of methylation of cytosine at the C-5 position, for example via selective inhibition of DNA methyltransferase DNMT1. Methods for synthesizing numerous 4-anilinoquinoline derivatives and for modulating DNA methylation are provided. Also provided are methods for formulating and administering these compounds or compositions to treat conditions such as cancer and hematological disorders.

  本研究提供了喹啉衍生物，特别是 4-苯胺基喹啉衍生物。这种喹啉衍生物可用于调节 DNA 甲基化，例如通过选择性抑制 DNA 甲基转移酶 DNMT1，有效抑制胞嘧啶在 C-5 位的甲基化。本文提供了合成多种 4-苯胺基喹啉衍生物和调节 DNA 甲基化的方法。还提供了配制和施用这些化合物或组合物以治疗癌症和血液病等疾病的方法。
• DNA METHYLTRANSFERASE INHIBITORS FOR RETT SYNDROME THERAPY
  申请人：Universität Stuttgart

  公开号：EP3207932A1

  公开（公告）日：2017-08-23

  The invention discloses a DNA methyltransferase inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating Rett syndrome. Further disclosed is a pharmaceutical composition comprising a DNA methyltransferase inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for use in treating Rett syndrome. Further disclosed is an in vitro method for diagnosing Rett syndrome in a subject comprising the step of analysing DNA methylation in a sample of the subject. Further disclosed is a kit for diagnosing Rett syndrome in a subject in vitro comprising reagents for quantifying a level of DNA methylation in a sample of the subject, wherein an increased level of DNA methylation in the sample compared to a reference value obtained from a reference sample of a healthy individual indicates that the subject has Rett syndrome.

  本发明公开了一种用于治疗雷特综合征的 DNA 甲基转移酶抑制剂或其药学上可接受的盐。进一步公开了一种药物组合物，该组合物包含用于治疗 Rett 综合征的 DNA 甲基转移酶抑制剂或其药学上可接受的盐和药学上可接受的载体。进一步公开了一种诊断受试者 Rett 综合征的体外方法，包括分析受试者样本中 DNA 甲基化的步骤。进一步公开了一种用于体外诊断受试者 Rett 综合征的试剂盒，该试剂盒包括用于量化受试者样本中 DNA 甲基化水平的试剂，其中样本中 DNA 甲基化水平与从健康个体的参考样本中获得的参考值相比增加，表明受试者患有 Rett 综合征。
• Using DNA methyltransferase inhibitors to treat calcific aorta valve disease
  申请人：Mayo Foundation for Medical Education and Research

  公开号：US10028973B2

  公开（公告）日：2018-07-24

  Materials and methods for using DNA methyltransferase inhibitors to slow progression of aortic valve calcification and stenosis are provided.

  提供了使用 DNA 甲基转移酶抑制剂减缓主动脉瓣钙化和狭窄进展的材料和方法。
• Methods for production of functional beta cells
  申请人：Janssen Biotech, Inc.

  公开号：US10633635B2

  公开（公告）日：2020-04-28

  The invention provides for methods of differentiating pancreatic endocrine cells into pancreatic beta cells expressing PDX1, NKX6.1, MAFA, UCN3 and SLC2A. These pancreatic beta cells may be obtained by step-wise differentiation of pluripotent stem cells. The pancreatic beta cells exhibit glucose-dependent mitochondrial respiration and glucose-stimulated insulin secretion similar to islet cells.

  本发明提供了将胰腺内分泌细胞分化成表达PDX1、NKX6.1、MAFA、UCN3和SLC2A的胰腺β细胞的方法。这些胰腺β细胞可通过多能干细胞的逐步分化获得。胰岛β细胞表现出与胰岛细胞相似的葡萄糖依赖性线粒体呼吸和葡萄糖刺激的胰岛素分泌。