8-(4-氨基苯基)-2-(4-吗啉基)-4H-1-苯并吡喃-4-酮 | 942289-87-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 中文名称: 8-(4-氨基苯基)-2-(4-吗啉基)-4H-1-苯并吡喃-4-酮
• 英文名称: PI 828
• 英文别名: PI828；8-(4-Aminophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one；8-(4-aminophenyl)-2-morpholin-4-ylchromen-4-one
• CAS: 942289-87-4
• 化学式: C₁₉H₁₈N₂O₃
• 分子量: 322.364
• InChiKey: WUKMIBOGGXMBAC-UHFFFAOYSA-N

物化性质

• 沸点：
  534.2±50.0 °C(Predicted)
• 密度：
  1.316±0.06 g/cm3(Predicted)
• 溶解度：
  DMF：25mg/mL； DMSO：25mg/mL；乙醇：微溶

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  64.8
• 氢给体数：
  1
• 氢受体数：
  5

制备方法与用途

生物活性

PI-828 是一种双重 PI3K 和 casein kinase 2 (CK2) 抑制剂，分别抑制 p110α、CK2 和 CK2α2 的 IC50 值分别为 173 nM、149 nM 和 1.127 μM。

靶点	IC50
p110α	173 nM (IC50)
CK2	149 nM (IC50)
CK2α2	1.127 μM (IC50)

体外研究

PI-828 在浓度为 0.01 至 100 µM 的范围内对 4T1 前列腺癌细胞和 4306 卵巢癌细胞表现出细胞毒性作用。在浓度为 0.78 至 3.12 µM 下，PI-828（48 小时）可降低 caspase 3 激活；更高浓度的 PI-828（6.25 至 12.5 µM）单独作用下导致细胞凋亡。

细胞活力测定

实验参数	值
细胞系	4T1乳腺癌细胞和4306卵巢癌细胞
浓度	0.01, 0.1, 1, 10 和 100 µM
孵育时间	-
结果	展现了细胞毒性作用

细胞凋亡分析

实验参数	值
细胞系	人胚胎癌NCCIT细胞
浓度	0.78, 1.56, 3.12, 6.25, 12.5 µM
孵育时间	48 小时
结果	在 0.78 到 3.12 µM 浓度范围内，caspase 3 活性降低；更高浓度导致细胞凋亡。

反应信息

• 作为产物：
  描述：

  4-乙酰基吗啉 在 四(三苯基膦)钯 、 三氟甲磺酸酐 、 potassium carbonate 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 正己烷 、 二氯甲烷 为溶剂， 反应 96.0h， 生成 8-(4-氨基苯基)-2-(4-吗啉基)-4H-1-苯并吡喃-4-酮
  参考文献：
  名称：

  Discovery of Potent Chromen-4-one Inhibitors of the DNA-Dependent Protein Kinase (DNA-PK) Using a Small-Molecule Library Approach

  摘要：

  Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxysubstituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNAPK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6',7',8',9'-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32{38} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 mu M. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.

  DOI：

  10.1021/jm050444b

文献信息

• COMPOSITIONS FOR TREATING CANCER AND METHODS FOR MAKING THE SAME
  申请人：The Brigham and Women's Hospital, Inc.

  公开号：US20150174263A1

  公开（公告）日：2015-06-25

  Described herein are compositions and methods relating to chemotherapeutic agent conjugates and the treatment of cancer.

  本文描述了与化疗药物结合物和癌症治疗相关的组合物和方法。
• Methods for identifying therapeutic targets and treating monitoring cancers
  申请人：Fred Hutchinson Cancer Research Center

  公开号：US10676746B2

  公开（公告）日：2020-06-09

  The present invention provides methods for treating cancers having a mutation in one or more tumor suppressor genes, comprising providing to a subject in need thereof an inhibitor of a kinase, as well as related methods and compositions.

  本发明提供了治疗一种或多种肿瘤抑制基因发生突变的癌症的方法，包括向有需要的受试者提供激酶抑制剂以及相关的方法和组合物。
• Producing mesodermal cell types and methods of using the same
  申请人：The Board of Trustees of the Leland Stanford Junior University

  公开号：US10787640B2

  公开（公告）日：2020-09-29

  Methods are provided for the generation of mesodermal cell types and derivatives thereof. Also provided are methods for generating purified populations of mesodermal cell types and derivatives thereof. The instant disclosure also provides methods of screening for cellular responses of the generated mesodermal cell types and derivatives thereof. Also provide are methods for screening for organismal phenotypes induced by introduction of the generated mesodermal cell types and derivatives thereof. Treatment methods making use of the generated mesodermal cell types and derivatives thereof are also provided. The instant disclosure also provides systems, compositions, and kits for practicing the methods of the disclosure.

  提供了生成中胚层细胞类型及其衍生物的方法。还提供了生成纯化的中胚层细胞类型及其衍生物的方法。本发明还提供了筛选所产生的中胚层细胞类型及其衍生物的细胞反应的方法。本发明还提供了通过引入所产生的中胚层细胞类型及其衍生物来筛选生物表型的方法。还提供了利用生成的中胚层细胞类型及其衍生物的治疗方法。本发明还提供了用于实施本发明方法的系统、组合物和试剂盒。
• METHODS FOR IDENTIFYING THERAPEUTIC TARGETS AND TREATING MONITORING CANCERS
  申请人：FRED HUTCHINSON CANCER RESEARCH CENTER

  公开号：US20160289686A1

  公开（公告）日：2016-10-06

  The present invention provides methods for treating cancers having a mutation in one or more tumor suppressor genes, comprising providing to a subject in need thereof an inhibitor of a kinase, as well as related methods and compositions.
• CO-TARGETING ANDROGEN RECEPTOR SPLICE VARIANTS AND MTOR SIGNALING PATHWAY FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER
  申请人：British Columbia Cancer Agency Branch

  公开号：US20170056336A1

  公开（公告）日：2017-03-02

  The present invention provides methods, compositions, and combinations for treating cancer via combined use of a compound of formula (I), and/or their subgenra, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 8 , R 9 , R 11a , R 11b , R 11c , and R 11d are as defined herein, and at least one therapeutically active agents selected from inhibitors of PI3K/AKT/mTOR pathway, active agents associated with the treatment of prostate cancer, and anticancer agents.