2-Amino-3-cyano-7-dimethylamino-4-(5-methyl-pyridin-3-yl)-4H-chromene

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 2-Amino-3-cyano-7-dimethylamino-4-(5-methyl-pyridin-3-yl)-4H-chromene
• 英文别名: 2-amino-3-cyano-7-dimethylamino-4-(5-methyl-3-pyridyl)-4H-chromene；2-amino-7-(dimethylamino)-4-(5-methylpyridin-3-yl)-4H-chromene-3-carbonitrile
• 化学式: C₁₈H₁₈N₄O
• 分子量: 306.367
• InChiKey: UUKJEMKPYMGHDC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 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：

  5-甲基烟酸甲酯 在 哌啶 、 manganese(IV) oxide 、 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 18.0h， 生成 2-Amino-3-cyano-7-dimethylamino-4-(5-methyl-pyridin-3-yl)-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

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 4-aryl-chromene as activator of caspases and inducer of apoptosis and as antivascular agent and the use thereof
  申请人：Cai Sui Xiong

  公开号：US20080085328A1

  公开（公告）日：2008-04-10

  The present invention is directed to a substituted 4H-chromene represented by the Formula 1R, substantially free from the corresponding (S)-stereoisomer: The present invention also relates to the discovery that compound 1R, substantially free from the corresponding (S)-stereoisomer, is an activator of caspases and inducer of apoptosis, as well as an antivascular agent. Therefore, compound 1R, substantially free from the corresponding (S)-stereoisomer, can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs. Compound 1R, substantially free from the corresponding (S)-stereoisomer, also can be used for the treatment of diseases due to overgrowth of vasculature, such as solid tumors and ocular neovascularization.

  本发明涉及一种由公式1R表示的取代的4H-香豆素，基本上不含相应的（S）立体异构体。本发明还涉及发现化合物1R，基本上不含相应的（S）立体异构体，是caspases的激活剂和诱导凋亡的剂，同时也是抗血管生成剂。因此，基本上不含相应的（S）立体异构体的化合物1R可以用于在各种临床情况下诱导细胞死亡，其中异常细胞的不受控制的生长和扩散发生。基本上不含相应的（S）立体异构体的化合物1R还可用于治疗由于血管增生过度引起的疾病，如实体肿瘤和眼部新生血管形成。
• 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
• SUBSTITUTED 4-ARYL-CHROMENE AS ACTIVATOR OF CASPASES AND INDUCER OF APOPTOSIS AND AS ANTIVASCULAR AGENT AND THE USE THEREOF
  申请人：Cytovia, Inc.

  公开号：EP2049101A2

  公开（公告）日：2009-04-22
• US6906203B1
  申请人：——

  公开号：US6906203B1

  公开（公告）日：2005-06-14