6-(3'-tert-butoxycarbonyl-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline | 796974-85-1

• 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'-tert-butoxycarbonyl-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
• 英文别名: 6-(3-(Boc-amino)propyl)-6H-indeno[1,2-c]isoquinoline-5,11-dione；5,11-dioxo-5-(propyl-3'-t-butoxycarbamoyl)-11H-i ndeno[1,2-c]isoquinoline；tert-butyl N-[3-(5,11-dioxoindeno[1,2-c]isoquinolin-6-yl)propyl]carbamate
• CAS: 796974-85-1
• 化学式: C₂₄H₂₄N₂O₄
• 分子量: 404.466
• InChiKey: HOQOQCKVHSRAKU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  75.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-(3'-tert-butoxycarbonyl-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline 在 盐酸 、 三乙胺 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 16.0h， 生成 N-(3-(5,11-dioxo-5H-indeno[1,2-c]isoquinolin-6(11H)-yl)propyl)-4-methylbenzenesulfonamide
  参考文献：
  名称：

  首个双酪氨酰-DNA 磷酸二酯酶 I (Tdp1)-拓扑异构酶 I (Top1) 抑制剂的合成和生物学评价

  摘要：

  在一种低分子量化合物中具有双重酪氨酰-DNA 磷酸二酯酶 I-拓扑异构酶 I 抑制活性的物质将构成一类独特的抗癌剂，可能比针对单个酶的药物具有显着的优势。本研究证明了基于茚并异喹啉化学型的第一个双 Top1-Tdp1 抑制剂的成功合成和评估。一种双（茚并异喹啉）对人 Tdp1 具有显着活性（IC 50= 1.52 ± 0.05 μM)，并且作为 Top1 抑制剂与喜树碱等效。通过该系列的结构-活性关系研究，获得了对酶-药物相互作用的重要见解。目前的结果还证明了先前报道的磺酰酯药效团未能在这种茚并异喹啉类抑制剂中赋予 Tdp1 抑制作用，尽管它被证明对类固醇 NSC 88915 有效 ( 7 )。目前的研究将促进未来优化双 Top1-Tdp1 抑制剂的努力。

  DOI：

  10.1021/jm300335n
• 作为产物：
  描述：

  3-羟基异苯并呋喃-1(3H)-酮 在 sodium methylate 作用下， 以 甲醇 、 氯仿 、 乙酸乙酯 为溶剂， 反应 91.0h， 生成 6-(3'-tert-butoxycarbonyl-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
  参考文献：
  名称：

  一种稳定氮氧自由基标记的茚并异喹啉衍生物、制备方法及用途

  摘要：

  本发明公开一种稳定氮氧自由基标记的茚并异喹啉衍生物，及这种化合物的制备方法及其在制备抗肿瘤药物中的用途。本发明所述的化合物对肿瘤细胞株表现出良好的抑制活性，且部分化合物活性与目前临床药物拓扑替康相当，因此，本发明的化合物可用于制备抗肿瘤的药物。

  公开号：

  CN108689992A

文献信息

• 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 and biological activity of ferrocenyl indeno[1,2-c]isoquinolines as topoisomerase II inhibitors
  作者：Nathalie Wambang、Nadège Schifano-Faux、Alexandre Aillerie、Brigitte Baldeyrou、Camille Jacquet、Christine Bal-Mahieu、Till Bousquet、Sylvain Pellegrini、Peter T. Ndifon、Samuel Meignan、Jean-François Goossens、Amélie Lansiaux、Lydie Pélinski

  DOI：10.1016/j.bmc.2015.12.033

  日期：2016.2

  Three series of indeno[1,2-c]isoquinolines bearing a ferrocenyl entity were synthesized and evaluated for DNA interaction, topoisomerase I and II inhibition, and cytotoxicity against breast human cancer cell lines. In the first and second series, the ferrocenyl scaffold was inserted as a linker between the two nitrogen atoms. In the last series, it was introduced at the end of the carbon chain. The

  合成了三个带有二茂铁基实体的茚并[1,2- c ]异喹啉，并对其DNA相互作用，拓扑异构酶I和II抑制以及对乳腺癌细胞的细胞毒性进行了评估。在第一和第二系列中，二茂铁基支架被插入作为两个氮原子之间的连接基。在上一个系列中，它是在碳链的末端引入的。本研究表明二茂铁基实体增强了拓扑异构酶II的抑制作用。大多数化合物对MDA-MB-231细胞系均具有有效的生长抑制作用，IC 50在μM范围内。
• Indeno[1,2-c]isoquinolin-5,11-diones conjugated to amino acids: Synthesis, cytotoxicity, DNA interaction, and topoisomerase II inhibition properties
  作者：Gang Ahn、Amélie Lansiaux、Jean-François Goossens、Christian Bailly、Brigitte Baldeyrou、Nadège Schifano-Faux、Pierre Grandclaudon、Axel Couture、Adina Ryckebusch

  DOI：10.1016/j.bmc.2010.08.025

  日期：2010.11.15

  Three series of indeno[1,2-c]isoquinolin-5,11-dione-amino acid conjugates were designed and synthesized. Amino acids were connected to the tetracycle through linkers with lengths of n = 2 and 3 atoms using ester (series I), amide (series II), and secondary amine (series III) functions. DNA binding was evaluated by thermal denaturation and fluorescence measurements. Lysine and arginine substituted derivatives with n = 3 provided the highest DNA binding. Arginine derivative 32 (n = 2, series II) and glycine derivative 34 (n = 2, series III) displayed high topoisomerase II inhibition. Incrementing the length of the N-6 side chain from two to three methylene units provided a significant increase in DNA affinity but a substantial loss in topoisomerase II inhibition. The most cytotoxic compounds toward HL60 leukemia cells were 19, 33, and 34 displaying micromolar IC50 values. When tested with the topoisomerase II-mutated HL60/MX2 cell line, little variation of IC50 values was found, suggesting that topoisomerase II might not be the main target of these compounds and that additional targets could be involved. (C) 2010 Elsevier Ltd. All rights reserved.
• Investigation of the Lactam Side Chain Length Necessary for Optimal Indenoisoquinoline Topoisomerase I Inhibition and Cytotoxicity in Human Cancer Cell Cultures
  作者：Andrew Morrell、Michael S. Placzek、Jamin D. Steffen、Smitha Antony、Keli Agama、Yves Pommier、Mark Cushman

  DOI：10.1021/jm0613119

  日期：2007.5.1

  Indenoisoquinolines with lactam substituents such as ethylamino, propylamino, and butylamino have previously demonstrated potent biological activity, but an optimal length has never been established. In the present study, a series of simplified indenoisoquinoline analogues possessing a linker spacing of 0-12 carbon atoms between the lactam nitrogen and the terminal amino group have been prepared, determining that 2-4-atom lengths are optimal for topoisomerase I inhibition and cytotoxicity. Using these lengths, analogues were prepared with the amino group and portions of the linker replaced by a pyridine ring. A three-carbon spacer within the pyridine series still demonstrated potent topoisomerase I inhibition.
• Synthesis and Biological Evaluation of the First Dual Tyrosyl-DNA Phosphodiesterase I (Tdp1)–Topoisomerase I (Top1) Inhibitors
  作者：Trung Xuan Nguyen、Andrew Morrell、Martin Conda-Sheridan、Christophe Marchand、Keli Agama、Alun Bermingam、Andrew G. Stephen、Adel Chergui、Alena Naumova、Robert Fisher、Barry R. O’Keefe、Yves Pommier、Mark Cushman

  DOI：10.1021/jm300335n

  日期：2012.5.10

  Substances with dual tyrosyl-DNA phosphodiesterase I–topoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1–Tdp1 inhibitors, which are based

  在一种低分子量化合物中具有双重酪氨酰-DNA 磷酸二酯酶 I-拓扑异构酶 I 抑制活性的物质将构成一类独特的抗癌剂，可能比针对单个酶的药物具有显着的优势。本研究证明了基于茚并异喹啉化学型的第一个双 Top1-Tdp1 抑制剂的成功合成和评估。一种双（茚并异喹啉）对人 Tdp1 具有显着活性（IC 50= 1.52 ± 0.05 μM)，并且作为 Top1 抑制剂与喜树碱等效。通过该系列的结构-活性关系研究，获得了对酶-药物相互作用的重要见解。目前的结果还证明了先前报道的磺酰酯药效团未能在这种茚并异喹啉类抑制剂中赋予 Tdp1 抑制作用，尽管它被证明对类固醇 NSC 88915 有效 ( 7 )。目前的研究将促进未来优化双 Top1-Tdp1 抑制剂的努力。