2-chloro-6,7-dimethoxy-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine

• 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: 2-chloro-6,7-dimethoxy-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine
• 英文别名: 2-chloro-6,7-dimethoxy-N-(5-pyrrolidin-1-ylpentyl)quinazolin-4-amine
• 化学式: C₁₉H₂₇ClN₄O₂
• 分子量: 378.902
• InChiKey: XOURROHQQJOAMG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  59.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-chloro-6,7-dimethoxy-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine 在 N,N-二异丙基乙胺 作用下， 以 正丁醇 为溶剂， 生成 6,7-dimethoxy-2-(piperazin-1-yl)-N-(5-(pyrrolidin-1-yl)-pentyl)quinazolin-4-amine trifluoroacetic acid
  参考文献：
  名称：

  Discovery of a Selective, Substrate-Competitive Inhibitor of the Lysine Methyltransferase SETD8

  摘要：

  The lysine methyltransferase SETD8 is the only known methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). Monomethylation of H4K20 has been implicated in regulating diverse biological processes including the DNA damage response. In addition to H4K20, SETD8 monomethylates non-histone substrates including proliferating cell nuclear antigen (PCNA) and promotes carcinogenesis by deregulating PCNA expression. However, selective inhibitors of SETD8 are scarce. The only known selective inhibitor of SETD8 to date is nahuoic acid A, a marine natural product, which is competitive with the cofactor. Here, we report the discovery of the first substrate-competitive inhibitor of SETD8, UNC0379 (1). This small-molecule inhibitor is active in multiple biochemical assays. Its affinity to SETD8 was confirmed by ITC (isothermal titration calorimetry) and SPR (surface plasmon resonance) studies. Importantly, compound 1 is selective for SETD8 over 15 other methyltransferases. We also describe structure-activity relationships (SAR) of this series.

  DOI：

  10.1021/jm500871s
• 作为产物：
  描述：

  5-(吡咯烷-1-基)戊胺 、 2,4-二氯-6,7-二甲氧基喹唑啉 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 生成 2-chloro-6,7-dimethoxy-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine
  参考文献：
  名称：

  Structure–activity relationship studies of SETD8 inhibitors

  摘要：

  对第一个底物竞争性SETD8抑制剂的全面SAR研究揭示了有趣的SAR趋势和新颖的类似物。

  DOI：

  10.1039/c4md00317a

文献信息

• Structure–activity relationship studies of SETD8 inhibitors
  作者：Anqi Ma、Wenyu Yu、Yan Xiong、Kyle V. Butler、Peter J. Brown、Jian Jin

  DOI：10.1039/c4md00317a

  日期：——

  Comprehensive SAR studies of the first substrate-competitive SETD8 inhibitor led to the discovery of interesting SAR trends and novel analogs.

  对第一个底物竞争性SETD8抑制剂的全面SAR研究揭示了有趣的SAR趋势和新颖的类似物。
• Discovery of a Selective, Substrate-Competitive Inhibitor of the Lysine Methyltransferase SETD8
  作者：Anqi Ma、Wenyu Yu、Fengling Li、Rachel M. Bleich、J. Martin Herold、Kyle V. Butler、Jacqueline L. Norris、Victoria Korboukh、Ashutosh Tripathy、William P. Janzen、Cheryl H. Arrowsmith、Stephen V. Frye、Masoud Vedadi、Peter J. Brown、Jian Jin

  DOI：10.1021/jm500871s

  日期：2014.8.14

  The lysine methyltransferase SETD8 is the only known methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). Monomethylation of H4K20 has been implicated in regulating diverse biological processes including the DNA damage response. In addition to H4K20, SETD8 monomethylates non-histone substrates including proliferating cell nuclear antigen (PCNA) and promotes carcinogenesis by deregulating PCNA expression. However, selective inhibitors of SETD8 are scarce. The only known selective inhibitor of SETD8 to date is nahuoic acid A, a marine natural product, which is competitive with the cofactor. Here, we report the discovery of the first substrate-competitive inhibitor of SETD8, UNC0379 (1). This small-molecule inhibitor is active in multiple biochemical assays. Its affinity to SETD8 was confirmed by ITC (isothermal titration calorimetry) and SPR (surface plasmon resonance) studies. Importantly, compound 1 is selective for SETD8 over 15 other methyltransferases. We also describe structure-activity relationships (SAR) of this series.