(Z)-3-bromo-4-chloro-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)benzohydrazide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (Z)-3-bromo-4-chloro-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)benzohydrazide
• 英文别名: (E)-3-bromo-4-chloro-N'-(1-(5-chloro-2-hydroxyphenyl)ethylidene)benzohydrazide；3-bromo-4-chloro-N-[(Z)-1-(5-chloro-2-hydroxyphenyl)ethylideneamino]benzamide
• 化学式: C₁₅H₁₁BrCl₂N₂O₂
• 分子量: 402.075
• InChiKey: ATFNCVWMHFTCOK-UWVJOHFNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  61.7
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3-溴-4-氯苯甲酸甲酯 在 溶剂黄146 、 肼 作用下， 以 甲醇 为溶剂， 反应 0.5h， 生成 (Z)-3-bromo-4-chloro-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)benzohydrazide
  参考文献：
  名称：

  High-Throughput Virtual Screening Identifies Novel N′-(1-Phenylethylidene)-benzohydrazides as Potent, Specific, and Reversible LSD1 Inhibitors

  摘要：

  Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is an attractive therapeutic target in multiple malignancies. Here we report a structure-based virtual screen of a compound library containing similar to 2 million small molecular entities. Computational docking and scoring followed by biochemical screening led to the identification of a novel N'-(1-phenylethylidene)-benzohydrazide series of LSD1 inhibitors with hits showing biochemical IC(50)s in the 200-400 nM range. Hit-to-lead optimization and structure activity relationship studies aided in the discovery of compound 12, with a K-i of 31 nM. Compound 12 is reversible and specific for LSD1 as compared to the monoamine oxidases shows minimal inhibition of CYPs and hERG and inhibits proliferation and survival in several cancer cell lines, including breast and colorectal cancer. Compound 12 may be used to probe LSD1's biological role in these cancers.

  DOI：

  10.1021/jm400870h

文献信息

• High-Throughput Virtual Screening Identifies Novel <i>N</i>′-(1-Phenylethylidene)-benzohydrazides as Potent, Specific, and Reversible LSD1 Inhibitors
  作者：Venkataswamy Sorna、Emily R. Theisen、Bret Stephens、Steven L. Warner、David J. Bearss、Hariprasad Vankayalapati、Sunil Sharma

  DOI：10.1021/jm400870h

  日期：2013.12.12

  Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is an attractive therapeutic target in multiple malignancies. Here we report a structure-based virtual screen of a compound library containing similar to 2 million small molecular entities. Computational docking and scoring followed by biochemical screening led to the identification of a novel N'-(1-phenylethylidene)-benzohydrazide series of LSD1 inhibitors with hits showing biochemical IC(50)s in the 200-400 nM range. Hit-to-lead optimization and structure activity relationship studies aided in the discovery of compound 12, with a K-i of 31 nM. Compound 12 is reversible and specific for LSD1 as compared to the monoamine oxidases shows minimal inhibition of CYPs and hERG and inhibits proliferation and survival in several cancer cell lines, including breast and colorectal cancer. Compound 12 may be used to probe LSD1's biological role in these cancers.