2-Amino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-4-methylchromene

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 新黄酮类化合物
• 英文名称: 2-Amino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-4-methylchromene
• 英文别名: 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-7-(dimethylamino)-4-methylchromene-3-carbonitrile
• 化学式: C₂₁H₂₂BrN₃O₃
• 分子量: 444.328
• InChiKey: IKACBLQZYBUMBA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  80.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-羟基-N,N-二甲基苯胺 在 哌啶 、 copper bromide dimethyl sulfide 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 、 二氯甲烷 为溶剂， 反应 5.5h， 生成 2-Amino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-4-methylchromene
  参考文献：
  名称：

  Discovery of 4-Aryl-4H-chromenes as a New Series of Apoptosis Inducers Using a Cell- and Caspase-based High-Throughput Screening Assay. 1. Structure−Activity Relationships of the 4-Aryl Group

  摘要：

  By applying a novel cell- and caspase-based HTS assay, 2-amino-3-eyano-7-(dimethylamino)4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) has been identified as a potent apoptosis inducer. Compound la was found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G(2)/M stage and to induce apoptosis as determined by the flow cytometry analysis assay in multiple human cell lines (e.g. Jurkat, T47D). Through structure-activity relationship (SAR) studies of the 4-aryl group, a 4- and 7-fold increase in potency was obtained from the screening hit la to the lead compounds 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-(dimethylamino)-4H-chromene (1c) and 2-amino-3-cyano-7-(dimethylamino)4-(5-methyl-3-pyridyl)-4H-chromene (4e), with an EC50 of 19 and 11 nM in the caspase activation assay in T47D breast cancer cells, respectively. The 2-amino-4-aryl-3-cyano-7-(dimethylamino)4H-chromenes also were found to be highly active in the growth inhibition MTT assay, with GI(50) values in the low nanomolar range for compound 1c. Significantly, compound le was found to have a GI(50) value of 2 nM in the paclitaxel resistant, p-glycoprotein overexpressed, MESSA/DX5 tumor cells. Functionally, compound 1c was found to be a potent inhibitor of tubulin polymerization and to effectively inhibit the binding of colchicine to tubulin. These results confirm that the cell-based caspase activation assay is a powerful tool for the discovery of potent apoptosis inducers and suggest that the 4-aryl-4H-chromenes have the potential to be developed into future anticancer agents.

  DOI：

  10.1021/jm049640t

文献信息

• Substituted 4H-chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof
  申请人：Cytovia, Inc.

  公开号：US20030065018A1

  公开（公告）日：2003-04-03

  The present invention is directed to substituted 4H-chromenes and analogs thereof, represented by the general Formula I: 1 wherein R 1 -R 5 , A, Y and Z are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

  本发明涉及被一般式I表示的取代的4H-香豆素及其类似物： 1 其中R 1 -R 5 ，A，Y和Z在此处被定义。本发明还涉及发现具有式I的化合物是caspase的激活剂和凋亡诱导剂。因此，本发明的caspase激活剂和凋亡诱导剂可用于诱导在各种临床病况中发生细胞死亡，其中异常细胞的不受控制的生长和传播。
• SUBSTITUTED 4H-CHROMENES AND ANALOGS AS ACTIVATORS OF CASPASES AND INDUCERS OF APOPTOSIS AND THE USE THEREOF
  申请人：Cai Xiong Sui

  公开号：US20060035925A1

  公开（公告）日：2006-02-16

  The present invention is directed to substituted 4H-chromenes and analogs thereof, represented by the general Formula I: wherein R 1 -R 5 , A, Y and Z are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

  本发明涉及代替的4H-香豆素及其类似物，由通式I表示：其中R1-R5，A，Y和Z在此定义。本发明还涉及发现具有通式I的化合物是caspase的激活剂和凋亡诱导剂。因此，本发明的caspase激活剂和凋亡诱导剂可用于诱导在各种临床情况下不受控制的异常细胞的生长和扩散引起的细胞死亡。
• EP1392683A4
  申请人：——

  公开号：EP1392683A4

  公开（公告）日：2005-10-26
• SUBSTITUTED 4H-CHROMENES AND ANALOGS AS ACTIVATORS OF CASPASES AND INDUCERS OF APOPTOSIS AND THEIR USE AS ANTICANCER AGENTS
  申请人：Cytovia, Inc.

  公开号：EP1392683B1

  公开（公告）日：2009-12-02
• SUBSTITUTED 4 i H /i -CHROMENES AND ANALOGS AS ACTIVATORS OFGASP ASES AND INDUCERS OF APOPTOSIS AND THE USE THEREOF
  申请人：Cytovia, Inc.

  公开号：EP1392683A1

  公开（公告）日：2004-03-03