6,7-dimethoxy-N²,N²-dimethyl-N⁴-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine | 1197196-65-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6,7-dimethoxy-N²,N²-dimethyl-N⁴-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine
• 英文别名: 6,7-dimethoxy-N2,N2-dimethyl-N4-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine；6,7-dimethoxy-2-N,2-N-dimethyl-4-N-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine
• CAS: 1197196-65-8
• 化学式: C₁₈H₂₇N₅O₂
• 分子量: 345.445
• InChiKey: XLDKAPYGJVCXCU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  62.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,4-二氯-6,7-二甲氧基喹唑啉 在 盐酸 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 生成 6,7-dimethoxy-N²,N²-dimethyl-N⁴-(1-methylpiperidin-4-yl)quinazoline-2,4-diamine
  参考文献：
  名称：

  G9a样蛋白（GLP）抑制剂的构效关系研究

  摘要：

  考虑到蛋白质赖氨酸甲基转移酶G9a样蛋白（GLP）和G9a之间的高度同源性，开发针对这两种酶的有效和选择性抑制剂一直是一项挑战。最近，我们报道了两种喹唑啉化合物MS0124和MS012作为GLP选择性抑制剂。为了进一步研究喹唑啉支架的结构-活性关系（SAR），我们设计和合成了一系列带有不同2-氨基取代基的类似物，并评估了它们对GLP和G9a的抑制能力。这些研究导致鉴定出两种新的GLP选择性抑制剂13（MS3748）和17（MS3745），与G9a相比，GLP的效力分别高59倍和65倍，这已通过等温滴定量热（ITC）得以证实。GLP和G9a与13和17形成复合物的晶体结构提供了对抑制剂与这两种蛋白质相互作用的了解。此外，我们生成了带有喹啉核心而不是喹唑啉核心的GLP选择性抑制剂。

  DOI：

  10.1016/j.bmc.2017.06.021

文献信息

• Histone lysine methyltransferase structure activity relationships that allow for segregation of G9a inhibition and anti-Plasmodium activity
  作者：Sandeep Sundriyal、Patty B. Chen、Alexandra S. Lubin、Gregor A. Lueg、Fengling Li、Andrew J. P. White、Nicholas A. Malmquist、Masoud Vedadi、Artur Scherf、Matthew J. Fuchter

  DOI：10.1039/c7md00052a

  日期：——

  We identify key SAR features which demonstrate that high parasite vs. G9a selectivity can be achieved for the quinazoline inhibitor chemotype.

  我们确定了关键的 SAR 特征，表明对于喹唑啉抑制剂化学类型，可以实现高寄生虫与 G9a 的选择性。
• Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines.
  作者：Feng Liu、Xin Chen、Abdellah Allali-Hassani、Amy M. Quinn、Tim J. Wigle、Gregory A. Wasney、Aiping Dong、Guillermo Senisterra、Irene Chau、Alena Siarheyeva、Jacqueline L. Norris、Dmitri B. Kireev、Ajit Jadhav、J. Martin Herold、William P. Janzen、Cheryl H. Arrowsmith、Stephen V. Frye、Peter J. Brown、Anton Simeonov、Masoud Vedadi、Jian Jin

  DOI：10.1021/jm100478y

  日期：2010.8.12

  Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison K(i) = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.
• Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a
  作者：Feng Liu、Xin Chen、Abdellah Allali-Hassani、Amy M. Quinn、Gregory A. Wasney、Aiping Dong、Dalia Barsyte、Ivona Kozieradzki、Guillermo Senisterra、Irene Chau、Alena Siarheyeva、Dmitri B. Kireev、Ajit Jadhav、J. Martin Herold、Stephen V. Frye、Cheryl H. Arrowsmith、Peter J. Brown、Anton Simeonov、Masoud Vedadi、Jian Jin

  DOI：10.1021/jm901543m

  日期：2009.12.24

  SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as it potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.
• Structure-activity relationship studies of G9a-like protein (GLP) inhibitors
  作者：Yan Xiong、Fengling Li、Nicolas Babault、Hong Wu、Aiping Dong、Hong Zeng、Xin Chen、Cheryl H. Arrowsmith、Peter J. Brown、Jing Liu、Masoud Vedadi、Jian Jin

  DOI：10.1016/j.bmc.2017.06.021

  日期：2017.8

  selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure–activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to

  考虑到蛋白质赖氨酸甲基转移酶G9a样蛋白（GLP）和G9a之间的高度同源性，开发针对这两种酶的有效和选择性抑制剂一直是一项挑战。最近，我们报道了两种喹唑啉化合物MS0124和MS012作为GLP选择性抑制剂。为了进一步研究喹唑啉支架的结构-活性关系（SAR），我们设计和合成了一系列带有不同2-氨基取代基的类似物，并评估了它们对GLP和G9a的抑制能力。这些研究导致鉴定出两种新的GLP选择性抑制剂13（MS3748）和17（MS3745），与G9a相比，GLP的效力分别高59倍和65倍，这已通过等温滴定量热（ITC）得以证实。GLP和G9a与13和17形成复合物的晶体结构提供了对抑制剂与这两种蛋白质相互作用的了解。此外，我们生成了带有喹啉核心而不是喹唑啉核心的GLP选择性抑制剂。