(Z)-3-(isoquinolin-5-yl)-2-(1-(2-(4-methylpiperazin-1-yl)acetyl)-1H-indol-3-yl)acrylonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: (Z)-3-(isoquinolin-5-yl)-2-(1-(2-(4-methylpiperazin-1-yl)acetyl)-1H-indol-3-yl)acrylonitrile
• 英文别名: (Z)-3-isoquinolin-5-yl-2-[1-[2-(4-methylpiperazin-1-yl)acetyl]indol-3-yl]prop-2-enenitrile
• 化学式: C₂₇H₂₅N₅O
• 分子量: 435.528
• InChiKey: VRSUHMRVZBPINZ-PXLXIMEGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  65.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (Z)-3-(isoquinolin-5-yl)-2-(1-(2-(4-methylpiperazin-1-yl)acetyl)-1H-indol-3-yl)acrylonitrile 、 三氟乙酸 以 水 、 乙腈 为溶剂， 生成 (Z)-3-isoquinolin-5-yl-2-[1-[2-(4-methylpiperazin-1-yl)acetyl]indol-3-yl]prop-2-enenitrile;2,2,2-trifluoroacetic acid
  参考文献：
  名称：

  Prodrugs of the cancer cell selective anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) are orally efficacious in a mouse model of resistant colon cancer

  摘要：

  A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.

  DOI：

  10.1016/j.bmcl.2018.11.053
• 作为产物：
  描述：

  异喹啉-5-甲醛 、 吲哚-3-乙腈 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 sodium methylate 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.39h， 生成 (Z)-3-(isoquinolin-5-yl)-2-(1-(2-(4-methylpiperazin-1-yl)acetyl)-1H-indol-3-yl)acrylonitrile
  参考文献：
  名称：

  [EN] SELECTIVE ANTI-CANCER COMPOUNDS
  [FR] COMPOSÉS ANTI-CANCÉREUX SÉLECTIFS

  摘要：

  式I的化合物，其中该化合物具有以下结构：其中R1至R5，Y，L，Z和X1至X7的含义如描述中所示，这些化合物在治疗过度增殖性疾病方面具有用途。

  公开号：

  WO2016200339A1

文献信息

• Selective anti-cancer compounds
  申请人：NATIONAL UNIVERSITY OF SINGAPORE

  公开号：US10308631B2

  公开（公告）日：2019-06-04

  A compound of formula I, wherein the compound of formula I has the structure: wherein R1 to R5, Y, L, Z and X1 to X7 have meanings given in the description, said compounds having utility in the treatment of hyperproliferative disease.

  一种式 I 的化合物，其中式 I 的化合物具有如下结构： 其中 R1 至 R5、Y、L、Z 和 X1 至 X7 的含义如描述中所给出，所述化合物在治疗过度增殖性疾病中具有实用性。
• (Z)-2-(1H-INDOL-3-YL)-3-(ISOQUINOLIN-5-YL)ACRYLONITRILE DERIVATIVES AND RELATED COMPOUNDS WITH LYSOSOME INHIBITORY AND ANTI-MITOTIC ACTIVITY FOR TREATING HYPERPROLIFERATIVE DISEASES
  申请人：National University of Singapore

  公开号：EP3307724B1

  公开（公告）日：2020-06-10
• SELECTIVE ANTI-CANCER COMPOUNDS
  申请人：National University of Singapore

  公开号：EP3307724A1

  公开（公告）日：2018-04-18
• ANTI-CANCER COMPOUNDS AND USES THEREOF
  申请人：National University of Singapore

  公开号：EP3551184A1

  公开（公告）日：2019-10-16
• [EN] ANTI-CANCER COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS ANTICANCÉREUX ET LEURS UTILISATIONS
  申请人：NAT UNIV SINGAPORE

  公开号：WO2018106192A1

  公开（公告）日：2018-06-14

  The present invention relates to compounds and their use in modulating the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways to protect normal cells in scenarios such as chemotherapy to kill cancer cells. More particularly, the compounds inhibit phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) and/or increase phosphoinositide 3-kinase-interacting protein 1 (PIK3IP1). Also provided are methods for identifying such compounds, methods of treatment using same and other uses.