2-(3-bromo-4-hydroxy-5-methoxybenzylidene)malononitrile | 99972-15-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 2-(3-bromo-4-hydroxy-5-methoxybenzylidene)malononitrile
• 英文别名: (3-bromo-4-hydroxy-5-methoxy-benzylidene)-malononitrile；(3-Brom-4-hydroxy-5-methoxy-benzyliden)-malononitril；3-bromo-4-hydroxy-5-methoxybenzylidene-malononitrile；Malononitrile, 5-bromovanillylidene-；2-[(3-bromo-4-hydroxy-5-methoxyphenyl)methylidene]propanedinitrile
• CAS: 99972-15-3
• 化学式: C₁₁H₇BrN₂O₂
• mdl: MFCD00610941
• 分子量: 279.093
• InChiKey: RMTVRMJDCJSEMW-UHFFFAOYSA-N

物化性质

• 熔点：
  160-162 °C
• 沸点：
  390.7±42.0 °C(Predicted)
• 密度：
  1.621±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  77
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 海关编码：
  2926909090

反应信息

• 作为反应物：
  描述：

  2-(3-bromo-4-hydroxy-5-methoxybenzylidene)malononitrile 、 3-羟基-N,N-二甲基苯胺 在 哌啶 作用下， 以 乙醇 为溶剂， 以8.4%的产率得到2-Amino-4-(3-bromo-4-hydroxy-5-methoxyphenyl)-3-cyano-7-dimethylamino-4H-chromene
  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
• 作为产物：
  描述：

  5-溴香兰素 、 丙二腈 在 哌啶 作用下， 以 乙醇 为溶剂， 以77%的产率得到2-(3-bromo-4-hydroxy-5-methoxybenzylidene)malononitrile
  参考文献：
  名称：

  Substituted 4-aryl-4h-pyrrolo[2,3-h]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof

  摘要：

  本发明涉及被代替的4H-香豆素及其类似物，由式（I）表示：其中R1，R3-R5，A，D，Y和Z在此处定义。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发生细胞不受控制生长和异常细胞扩散的各种临床状况中的细胞死亡。

  公开号：

  US20060104998A1

文献信息

• Substituted 4-aryl-4h-pyrrolo[2,3-h]chromenes and analogs as activators of caspases and inducers of apoptosis and the use thereof
  申请人：Cai Xiong Sui

  公开号：US20060104998A1

  公开（公告）日：2006-05-18

  The present invention is directed to substituted 4H-chromenes and analogs thereof, represented by the Formula (I): wherein R 1 , R 3 -R 5 , A, D, 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.

  本发明涉及被代替的4H-香豆素及其类似物，由式（I）表示：其中R1，R3-R5，A，D，Y和Z在此处定义。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发生细胞不受控制生长和异常细胞扩散的各种临床状况中的细胞死亡。
• Discovery of 4-Aryl-4<i>H</i>-chromenes as a New Series of Apoptosis Inducers Using a Cell- and Caspase-Based High-Throughput Screening Assay. 3. Structure−Activity Relationships of Fused Rings at the 7,8-Positions
  作者：William Kemnitzer、John Drewe、Songchun Jiang、Hong Zhang、Jianghong Zhao、Candace Crogan-Grundy、Lifen Xu、Serge Lamothe、Henriette Gourdeau、Réal Denis、Ben Tseng、Shailaja Kasibhatla、Sui Xiong Cai

  DOI：10.1021/jm070216c

  日期：2007.6.1

  As a continuation of our efforts to discover and develop the apoptosis-inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of fused rings at the 7,8-positions. It was found that a five-member aromatic ring, such as pyrrolo with nitrogen at either the 7- or 9-position, is preferred. A six-member aromatic ring, such as benzo or pyrido, also led to potent compounds. The SAR of the 4-aryl group was found to be similar for chromenes with a fused ring at the 7,8-positions. These compounds were found to inhibit tubulin polymerization, indicating that cyclization of the 7,8-positions into a ring does not change the mechanism of action. Compound 2h was identified to be a highly potent apoptosis inducer with an EC50 of 5 nM and a highly potent inhibitor of cell proliferation with a GI(50) of 8 nM in T47D cells.
• Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors
  作者：Aviv Gazit、Pnina Yaish、Chaim Gilon、Alexander Levitzki

  DOI：10.1021/jm00130a020

  日期：1989.10

  A novel class of low molecular weight protein tyrosine kinase inhibitors is described. These compounds constitute a systematic series of molecules with a progressive increase in affinity toward the substrate site of the EGF receptor kinase domain. These competitive inhibitors also effectively block the EGF-dependent autophosphorylation of the receptor. The potent EGF receptor kinase blockers examined were found to competitively inhibit the homologous insulin receptor kinase at 10(2)-10(3) higher inhibitor concentrations in spite of the significant homology between these protein tyrosine kinases. These results demonstrate the ability to synthesize selective tyrosine kinase inhibitors. The most potent EGF receptor kinase inhibitors also inhibit the EGF-dependent proliferation of A431/clone 15 cells with little or no effect on EGF independent cell growth. These results demonstrate the potential use of protein tyrosine kinase inhibitors as selective antiproliferative agents for proliferative diseases caused by the hyperactivity of protein tyrosine kinases. We have suggested the name "tyrphostins" for this class of antiproliferative compounds which act as protein tyrosine kinase blockers.
• GAZIT, AVIV;YAISH, PNINA;GILON, CHAIM;LEVITZKI, ALEXANDER, J. MED. CHEM., 32,(1989) N0, C. 2344-2352
  作者：GAZIT, AVIV、YAISH, PNINA、GILON, CHAIM、LEVITZKI, ALEXANDER

  DOI：——

  日期：——
• EP1509515A4
  申请人：——

  公开号：EP1509515A4

  公开（公告）日：2006-07-05