3-amino-6-(3-chloropropyl)-5,6-dihydro-9-methoxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline | 918336-03-5

• 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: 3-amino-6-(3-chloropropyl)-5,6-dihydro-9-methoxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
• 英文别名: 6-(3-chloropropyl)-5,6-dihydro-9-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline；6-(3-chloropropyl)-9-methoxy-5,6-dihydro-3-nitro-5,11-diox-o-11H-indeno[1,2-c]isoquinoline；6-(3-Chloropropyl)-9-methoxy-3-nitroindeno[1,2-c]isoquinoline-5,11-dione
• CAS: 918336-03-5
• 化学式: C₂₀H₁₅ClN₂O₅
• 分子量: 398.803
• InChiKey: BPHWXBCGOWKFEJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  92.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-amino-6-(3-chloropropyl)-5,6-dihydro-9-methoxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline 在 5%-palladium/activated carbon 、 氢气 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以39%的产率得到3-amino-6-(3-chloropropyl)-5,6-dihydro-9-methoxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
  参考文献：
  名称：

  抑制酪氨酰 DNA 磷酸二酯酶 I (Tdp1) 和拓扑异构酶 I (Top1) 的茚并异喹啉的合成和生物学评价

  摘要：

  酪氨酰 DNA 磷酸二酯酶 I (Tdp1) 在修复由拓扑异构酶 I (Top1) 抑制剂喜树碱和多种其他破坏 DNA 的抗癌剂引起的受损 DNA 中发挥关键作用。本报告记录了作为 Tdp1 和 Top1 双重抑制剂的新型茚并异喹啉的设计、合成和评估。来自人类癌细胞培养物的酶抑制数据和细胞毒性数据用于建立结构-活性关系。茚并异喹啉对 Tdp1 的效力范围为 5 μM 到 111 μM，这使得活性更强的化合物成为已知的最有效的该靶标抑制剂。细胞毒性平均图中点范围为 0.02 至 2.34 μM。

  DOI：

  10.1021/jm3014458
• 作为产物：
  描述：

  4-硝基邻苯二价酸酐 在 aluminum (III) chloride 、 氯化亚砜 作用下， 以 氯仿 、 硝基苯 、 甲苯 为溶剂， 反应 1.5h， 生成 3-amino-6-(3-chloropropyl)-5,6-dihydro-9-methoxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
  参考文献：
  名称：

  Synthesis and biological evaluations of novel indenoisoquinolines as topoisomerase I inhibitors

  摘要：

  A series of novel indenoisoquinoline derivatives were synthesized. The anticancer activities of these molecules were tested in human cancer cell lines A549, HepG2, and HCT-116. These compounds were also tested for their activity of topoisomerase I (top1) inhibition. Among them, compound 25 was found to be 10-times more potent in cell-killing activity for both cell lines HepG2 and HCT-116 than reported compound 11, with IC50 of 0.019 and 0.093 mu M, respectively. Compound 25 was also found to have stronger top1 inhibition activity than 11 in our inhibition assay. Further in vivo evaluations of compound 25 are in progress and will be reported in due course. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.10.019

文献信息

• SYNTHESIS AND USE OF DUAL TYROSYL-DNA PHOSPHODIESTERASE I (TDP1)- TOPOISOMERASE I (TOP1) INHIBITORS
  申请人：PURDUE RESEARCH FOUNDATION

  公开号：US20130345252A1

  公开（公告）日：2013-12-26

  The invention described herein pertains to the synthesis and use of certain N-substituted indenoisoquinoline compounds which inhibit the activity Tyrosyl-DNA Phosphodiesterase I (Tdp1) or Topoisomerase I (Top1) or both, or otherwise demonstrate anticancer activity. Also disclosed are novel N-substituted indenoisoquinoline compounds and pharmaceutical compositions comprising the novel N-substituted indenoisoquinoline compounds.

  本发明涉及合成和使用某些N-取代吲哚异喹啉化合物，这些化合物抑制酪氨酸-DNA磷酸二酯酶I（Tdp1）或拓扑异构酶I（Top1）或两者的活性，或表现出抗癌活性。还公开了新颖的N-取代吲哚异喹啉化合物和包含这些新颖的N-取代吲哚异喹啉化合物的药物组合物。
• SYNTHESIS AND USE OF DUAL TYROSYL-DNA PHOSPHODIESTERASE I (Tdp1) - TOPOISOMERASE I (Top1) INHIBITORS
  申请人：Purdue Research Foundation

  公开号：US20150133445A1

  公开（公告）日：2015-05-14

  The invention described herein pertains to the synthesis and use of certain N-substituted indenoisoquinoline compounds which inhibit the activity Tyrosyl-DNA Phosphodiesterase I (Tdp1) or Topoisomerase I (Top1) or both, or otherwise demonstrate anticancer activity. Also disclosed are novel N-substituted indenoisoquinoline compounds and pharmaceutical compositions comprising the novel N-substituted indenoisoquinoline compounds.

  本发明涉及合成和使用某些N-取代吲哚异喹啉化合物，其抑制酪氨酸-DNA磷酸二酯酶I（Tdp1）或拓扑异构酶I（Top1）或两者的活性，或表现出抗癌活性。还公开了新型N-取代吲哚异喹啉化合物和包含新型N-取代吲哚异喹啉化合物的制药组合物。
• Nitrated Indenoisoquinolines as Topoisomerase I Inhibitors:  A Systematic Study and Optimization
  作者：Andrew Morrell、Michael Placzek、Seth Parmley、Smitha Antony、Thomas S. Dexheimer、Yves Pommier、Mark Cushman

  DOI：10.1021/jm070361q

  日期：2007.9.1

  The biological activity of indenoisoquinoline topoisomerase I (Topl) inhibitors can be greatly enhanced depending on the choice of substituents on the aromatic rings and lactam side chain. Previously, it was discovered that a 3-nitro group and a 9-methoxy group afforded enhanced biological activity. In the present investigation, indenoisoquinoline analogues were systematically prepared using combinations of nitro groups, methoxy groups, and hydrogen atoms in an effort to understand the contribution of each group toward cytotoxicity and Top I inhibition. Analysis of the biological results suggests that the nitro group is important for Top I inhibition and the methoxy group improves cytotoxicity. In addition, previously identified structure-activity relationships were utilized to select favorable lactam side chain functionalities for incorporation on the aromatic skeleton of analogues in this study. As a result, this investigation has provided optimal Topl inhibitors equipotent to camptothecin that demonstrate low nanomolar cytotoxicities toward cancer cells.
• A Systematic Study of Nitrated Indenoisoquinolines Reveals a Potent Topoisomerase I Inhibitor
  作者：Andrew Morrell、Smitha Antony、Glenda Kohlhagen、Yves Pommier、Mark Cushman

  DOI：10.1021/jm060974n

  日期：2006.12.1

  The biological activity of indenoisoquinoline topoisomerase I inhibitors is significantly enhanced by nitration of the isoquinoline ring. In the present study, nitrated analogues were synthesized with the indenone ring substituted with methoxy groups to further explore a previously identified structure-activity relationship between the nitrated isoquinoline ring and a methylenedioxy-substituted indenone ring. The results indicate that a single methoxy group at the 9-position of an indenoisoquinoline affords superior biological activity. Hypothetical binding models have been developed to rationalize these results, and they indicate that pi-stacking between the indenoisoquinolines and the DNA base pairs, as visualized by electrostatic complementarity, is important for the intercalation and biological activity of the indenoisoquinoline analogues. Collectively, the analysis of methoxy groups on the indenone ring also illustrates a strict steric requirement for substituents extending toward the nonscissile DNA backbone and emphasizes a need for planarity to afford potent biological activity.
• US8912213B2
  申请人：——

  公开号：US8912213B2

  公开（公告）日：2014-12-16