2-Amino-3-cyano-7-dimethylamino-4-(3-quinolyl)-4H-chromene

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 2-Amino-3-cyano-7-dimethylamino-4-(3-quinolyl)-4H-chromene
• 英文别名: 2-amino-7-(dimethylamino)-4-quinolin-3-yl-4H-chromene-3-carbonitrile
• 化学式: C₂₁H₁₈N₄O
• 分子量: 342.4
• InChiKey: RBOAFXIUZYLSHU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  75.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-喹啉甲醛 、 丙二腈 、 3-羟基-N,N-二甲基苯胺 在 哌啶 作用下， 以 乙醇 为溶剂， 反应 12.0h， 生成 2-Amino-3-cyano-7-dimethylamino-4-(3-quinolyl)-4H-chromene
  参考文献：
  名称：

  4-Aryl-4H-Chromene-3-Carbonitrile Derivatives: Evaluation of Src Kinase Inhibitory and Anticancer Activities

  摘要：

  Src 激酶突变和/或过度表达与结肠癌、乳腺癌和肺癌等多种人类癌症的发病有关。因此，设计强效且具有选择性的 Src 激酶抑制剂作为抗癌药物是一个备受关注的课题。在哌啶的存在下，利用适当取代的芳香醛、丙二腈和 3-（二甲基氨基）苯酚的一锅反应，合成了一系列 2-amino-7-dimethylamino-4H-chromene- 3-carbonitrile 的 4-芳基取代衍生物。对所有 23 种化合物在人结肠腺癌（HT-29）和白血病（CCRF-CEM）细胞系中对 Src 激酶和细胞增殖的抑制作用进行了评估。在测试的化合物中，2-氯苯基（4c）、3-硝基苯基（4h）、4-三氟甲基苯基（4i）和 2,3-二氯苯基（4k）取代的色烯类化合物具有抑制 Src 激酶的作用，IC50 值为 11.1-18.3 μM。与选定的激酶、表皮生长因子受体（EGFR，IC50 300 μM）、C-末端 Src 激酶（Csk，IC50 = 101.7 μM）和淋巴细胞特异性蛋白酪氨酸激酶（Lck，IC50 = 46.8 μM）相比，化合物 4c 对 Src 具有相对的选择性（IC50 = 11.1 μM）。3-氯苯基取代的噻唑（4v）和 2-氯苯基取代的噻唑（4u）色烯衍生物在 50 μM 浓度下分别抑制 HT-29 和 CCRF-CEM 细胞增殖 80% 和 50%。这些数据表明，4H-色烯-3-甲腈支架具有进一步优化的潜力，可用于设计更有效的 Src 激酶抑制剂和/或抗癌先导化合物。

  DOI：

  10.2174/157340611796799258

文献信息

• Substituted 4H-chromene and analogs as activators of caspases and inducers of apoptosis and the use thereof
  申请人：Drewe A. John

  公开号：US20050154015A1

  公开（公告）日：2005-07-14

  The present invention is directed to substituted 4H-chromene and analogs thereof, represented by the general Formula I: wherein A, B, X, Y, Z and R 5 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.

  本发明涉及取代的4H-香豆素及其类似物，通式如下：其中A、B、X、Y、Z和R5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以用于诱导各种临床情况下不受控制的异常细胞的生长和扩散导致的细胞死亡。
• SUBSTITUTED 4H-CHROMENE AND ANALOGS AS ACTIVATORS OF CASPASES AND INDUCERS OF APOPTOSIS AND THE USE THEREOF
  申请人：Cytovia, Inc.

  公开号：EP1230232B1

  公开（公告）日：2004-02-25
• 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. 1. Structure−Activity Relationships of the 4-Aryl Group
  作者：William Kemnitzer、John Drewe、Songchun Jiang、Hong Zhang、Yan Wang、Jianghong Zhao、Shaojuan Jia、John Herich、Denis Labreque、Richard Storer、Karen Meerovitch、David Bouffard、Rabindra Rej、Real Denis、Charles Blais、Serge Lamothe、Giorgio Attardo、Henriette Gourdeau、Ben Tseng、Shailaja Kasibhatla、Sui Xiong Cai

  DOI：10.1021/jm049640t

  日期：2004.12.1

  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.
• US6906203B1
  申请人：——

  公开号：US6906203B1

  公开（公告）日：2005-06-14
• US7507762B2
  申请人：——

  公开号：US7507762B2

  公开（公告）日：2009-03-24