6-(3-bromo-1-propyl)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline | 308246-28-8

• 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: 6-(3-bromo-1-propyl)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
• 英文别名: 6-(3-Bromopropyl)indeno[1,2-c]isoquinoline-5,11-dione
• CAS: 308246-28-8
• 化学式: C₁₉H₁₄BrNO₂
• 分子量: 368.23
• InChiKey: VYOIIOVHKBUVDD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-(3-bromo-1-propyl)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline 在 sodium azide 作用下， 以 二甲基亚砜 为溶剂， 反应 20.0h， 以87%的产率得到6-(3-Azido-propyl)-6H-indeno[1,2-c]isoquinoline-5,11-dione
  参考文献：
  名称：

  Nitrated Indenoisoquinolines as Topoisomerase I Inhibitors:  A Systematic Study and Optimization

  摘要：

  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.

  DOI：

  10.1021/jm070361q
• 作为产物：
  描述：

  3-溴丙胺 、 苯并[d]茚并[1,2-b]吡喃-5,11-二酮 以60%的产率得到6-(3-bromo-1-propyl)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
  参考文献：
  名称：

  新的茚并[1,2-c]异喹啉的合成：细胞毒性非喜树碱拓扑异构酶I抑制剂。

  摘要：

  为了设计和合成通过抑制拓扑异构酶I（top1）发挥作用的潜在抗癌药，制备了一系列新的茚并异喹啉并测试了其在人类癌细胞培养中的细胞毒性以及对top1的活性。该合成依赖于取代的席夫碱与高邻苯二甲酸酐的缩合，以产生顺式-3-芳基-4-羧基异喹啉酮，其在亚硫酰氯存在下环化成茚并异喹啉。在单个化合物6- [3-（2-羟乙基）氨基丙基] -5,6-二氢-2,3-二甲氧基-8，9-亚甲基二氧基-5,11-二氧代-11H中，top1的抑制活性和细胞毒性均最大化。 -茚并[1,2-c]异喹啉盐酸盐（19a）被证明是一种非常有效的top1抑制剂，在55种人类癌细胞培养物中进行细胞毒性测试时，其平均图中点（MGM）为110 nM。还获得了许多与结构相关的茚并异喹啉，它们既具有有效的细胞毒性，又具有top1抑制活性。更有效的化合物的关键特征是在茚并异喹啉氮原子上存在氨基烷基侧链。在存在茚并异喹啉的情况下，top1

  DOI：

  10.1021/jm000029d

文献信息

• Synthesis of indenoisoquinolines
  申请人：Cushman S. Mark

  公开号：US20060025595A1

  公开（公告）日：2006-02-02

  Indenoisoquinolines and dihydroindenoisoquinolines are described. In particular, such compounds possessing one or more electron withdrawing substituents are described. The in vitro anticancer activities of these molecules tested in the National Cancer Institute's screen of 55 cell lines is described. The compounds tested for topoisomerase I (top1) inhibition is described.

  描述了Indenoisoquinolines和dihydroindenoisoquinolines。特别是，描述了具有一个或多个电子提取取代基的这类化合物。描述了这些分子在国家癌症研究所对55种细胞系进行的体外抗癌活性测试。描述了对这些化合物进行的拓扑异构酶I（top1）抑制测试。
• Synthesis and Anticancer Activity of Simplified Indenoisoquinoline Topoisomerase I Inhibitors Lacking Substituents on the Aromatic Rings
  作者：Muthukaman Nagarajan、Andrew Morrell、Brian C. Fort、Marintha Rae Meckley、Smitha Antony、Glenda Kohlhagen、Yves Pommier、Mark Cushman

  DOI：10.1021/jm040025z

  日期：2004.11.1

  where it is involved in a hydrogen bonding interaction with the side chain guanidine group of Arg364. The DNA cleavage patterns observed in the presence of topoisomerase I and various indenoisoquinolines were similar, although significant differences were detected. There were also variations in the DNA cleavage pattern seen with camptothecin vs the indenoisoquinolines, which indicates that these two

  茚并异喹啉类是一类细胞毒性拓扑异构酶I抑制剂，与喜树碱相比具有某些优势，包括化合物本身的稳定性更高，以及药物-酶-DNA裂解复合物的稳定性更高。为了研究存在于先前合成的茚并异喹啉拓扑异构酶I抑制剂的芳香环上的二（甲氧基）和亚甲基二氧基取代基的可能的生物学作用，合成了一系列缺少这些取代基的化合物，并测试了其在癌细胞培养中的细胞毒性和酶的毒性。抑制活性。结果表明，芳族取代基对生物活性的贡献很小，但可观察到。关于三元复合物中未取代的茚并异喹啉与DNA和拓扑异构酶I结合的分子模型表明，内酰胺氮上的取代基突出于主沟，羰基被引出其参与的次沟。与Arg364的侧链胍基的氢键相互作用。尽管存在显着差异，但在拓扑异构酶I和各种茚并异喹啉存在下观察到的DNA切割模式相似。喜树碱与茚并异喹啉之间的DNA裂解模式也存在差异，这表明这两种拓扑异构酶I抑制剂可能以不同的方式靶向癌细胞基因组，从而产生了不同的抗癌活性谱。
• Synthesis of nitrated indenoisoquinolines as topoisomerase I inhibitors
  作者：Andrew Morrell、Smitha Antony、Glenda Kohlhagen、Yves Pommier、Mark Cushman

  DOI：10.1016/j.bmcl.2004.05.022

  日期：2004.7

  Indenoisoquinolines and dihydroindenoisoquinolines have been synthesized possessing a nitro-substituted isoquinoline ring in an effort to explore the effects of electron-withdrawing substituents on biological activity. The in vitro anticancer activities of these molecules have been tested in the National Cancer Institute's screen of 55 cell lines. The compounds have also been tested for topoisomerase I (topI) inhibition. The results indicate that these substances are a potent class of topI inhibitors with sub-micromolar cytotoxicity mean graph midpoints (MGM) and topI inhibition equal to camptothecin. (C) 2004 Elsevier Ltd. All rights reserved.
• US7495100B2
  申请人：——

  公开号：US7495100B2

  公开（公告）日：2009-02-24
• Synthesis of New Indeno[1,2-<i>c</i>]isoquinolines:  Cytotoxic Non-Camptothecin Topoisomerase I Inhibitors
  作者：Mark Cushman、Muthusamy Jayaraman、Jeffrey A. Vroman、Anna K. Fukunaga、Brian M. Fox、Glenda Kohlhagen、Dirk Strumberg、Yves Pommier

  DOI：10.1021/jm000029d

  日期：2000.10.1

  chloride. Both top1 inhibitory activity and cytotoxicity maximized in a single compound, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline hydrochloride (19a), which proved to be a very potent top1 inhibitor having a 110 nM mean graph midpoint (MGM) when tested for cytotoxicity in 55 human cancer cell cultures. A number of structurally

  为了设计和合成通过抑制拓扑异构酶I（top1）发挥作用的潜在抗癌药，制备了一系列新的茚并异喹啉并测试了其在人类癌细胞培养中的细胞毒性以及对top1的活性。该合成依赖于取代的席夫碱与高邻苯二甲酸酐的缩合，以产生顺式-3-芳基-4-羧基异喹啉酮，其在亚硫酰氯存在下环化成茚并异喹啉。在单个化合物6- [3-（2-羟乙基）氨基丙基] -5,6-二氢-2,3-二甲氧基-8，9-亚甲基二氧基-5,11-二氧代-11H中，top1的抑制活性和细胞毒性均最大化。 -茚并[1,2-c]异喹啉盐酸盐（19a）被证明是一种非常有效的top1抑制剂，在55种人类癌细胞培养物中进行细胞毒性测试时，其平均图中点（MGM）为110 nM。还获得了许多与结构相关的茚并异喹啉，它们既具有有效的细胞毒性，又具有top1抑制活性。更有效的化合物的关键特征是在茚并异喹啉氮原子上存在氨基烷基侧链。在存在茚并异喹啉的情况下，top1