5,6-dihydro-6-(3-morpholinopropyl)-2,3-dimethoxy-5,11-dioxo-7-aza-11H-indeno[1,2-c]isoquinoline hydrochloride | 1324006-77-0

• 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: 5,6-dihydro-6-(3-morpholinopropyl)-2,3-dimethoxy-5,11-dioxo-7-aza-11H-indeno[1,2-c]isoquinoline hydrochloride
• 英文别名: 7-aza-5,6-dihydro-6-(3-morpholinopropyl)-2,3-dimethoxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline hydrochloride；4,5-Dimethoxy-9-(3-morpholin-4-ylpropyl)-9,12-diazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(10),2,4,6,11(16),12,14-heptaene-8,17-dione;hydrochloride
• CAS: 1324006-77-0
• 化学式: C₂₄H₂₅N₃O₅*ClH
• 分子量: 471.941
• InChiKey: SDHNEUDUJOBMAL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.77
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  81.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-(3-羟丙基)吗啉 、 5,6-dihydro-2,3-dimethoxy-5,11-dioxo-7-aza-11H-indeno[1,2-c]isoquinoline 在 偶氮二甲酸二异丙酯 、 三苯基膦 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 74.0h， 以68%的产率得到5,6-dihydro-6-(3-morpholinopropyl)-2,3-dimethoxy-5,11-dioxo-7-aza-11H-indeno[1,2-c]isoquinoline hydrochloride
  参考文献：
  名称：

  7-Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents

  摘要：

  A series of 7-azaindenoisoquinoline topoisomerase I (Top 1) inhibitors have been prepared to investigate the effect of increased electron affinity of the aromatic system on the ability to stabilize the Top1-DNA cleavage complex. Ab initio calculations suggest that introduction of nitrogen into the aromatic system of the indenoisoquinolines would facilitate charge transfer complex formation with DNA, thus improving the pi-pi stacking interactions. The present study shows that 7-azaindenoisoquinolines demonstrate improved water solubility without any decrease in Top1 inhibitory activity or cytotoxicity. Analysis of the biological results reveals that smaller lactam ring substituents enable intercalation into both free DNA and Top1-DNA cleavage complex, whereas larger substituents only allow binding to the cleavage complex but not free DNA. Free DNA binding suppresses Top1-catalyzed DNA cleavage at high drug concentrations, whereas DNA cleavage and inhibition of religation occurs at low drug concentration.

  DOI：

  10.1021/jm200719v

文献信息

• 7-Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents
  作者：Evgeny Kiselev、Sean DeGuire、Andrew Morrell、Keli Agama、Thomas S. Dexheimer、Yves Pommier、Mark Cushman

  DOI：10.1021/jm200719v

  日期：2011.9.8

  A series of 7-azaindenoisoquinoline topoisomerase I (Top 1) inhibitors have been prepared to investigate the effect of increased electron affinity of the aromatic system on the ability to stabilize the Top1-DNA cleavage complex. Ab initio calculations suggest that introduction of nitrogen into the aromatic system of the indenoisoquinolines would facilitate charge transfer complex formation with DNA, thus improving the pi-pi stacking interactions. The present study shows that 7-azaindenoisoquinolines demonstrate improved water solubility without any decrease in Top1 inhibitory activity or cytotoxicity. Analysis of the biological results reveals that smaller lactam ring substituents enable intercalation into both free DNA and Top1-DNA cleavage complex, whereas larger substituents only allow binding to the cleavage complex but not free DNA. Free DNA binding suppresses Top1-catalyzed DNA cleavage at high drug concentrations, whereas DNA cleavage and inhibition of religation occurs at low drug concentration.