6-(4-hydroxybutyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione | 220627-59-8

• 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-(4-hydroxybutyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
• 英文别名: 5,6-dihydro-6-(4-hydroxy-1-butyl)-5,11-diketo-11H-indeno[1,2-c]isoquinoline；6-(4-hydroxybutyl)indeno[1,2-c]isoquinoline-5,11-dione
• CAS: 220627-59-8
• 化学式: C₂₀H₁₇NO₃
• 分子量: 319.36
• InChiKey: IXPRAKDVTURUCF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  24
• 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：
  57.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-(4-hydroxybutyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione 在 盐酸 、 三乙胺 、 对甲苯磺酰氯 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 生成 6-[4-(2-Aminoethylamino)butyl]indeno[1,2-c]isoquinoline-5,11-dione
  参考文献：
  名称：

  A Novel Copper(II) Indenoisoquinoline Complex Inhibits Topoisomerase I, Induces G2 Phase Arrest, and Autophagy in Three Adenocarcinomas

  摘要：

  拓扑异构酶是化疗中使用的抑制剂的靶点，它们诱导DNA断裂积累，导致癌细胞死亡。新合成的铜（II）吲哚异喹啉配合物WN197对MDA-MB-231、HeLa和HT-29细胞表现出低于0.5µM的细胞毒性作用。在低剂量下，WN197抑制拓扑异构酶I。在较高剂量下，它抑制拓扑异构酶IIα和IIβ，并显示DNA插入性质。通过γH2AX的存在检测到DNA损伤。DNA损伤响应（DDR）的激活是通过ATM / ATR、Chk1/2激酶的磷酸化和p21（p53靶标）的增加来实现的。WN197诱导G2期阻滞，其特征为未磷酸化的组蛋白H3、磷酸化的Cdk1的积累以及Cdc25C与14.3.3的结合。癌细胞通过自噬死亡，Beclin-1积累，LC3-II形成，p62降解以及mTOR复合物中RAPTOR的磷酸化。最后，WN197在低浓度下高效抑制拓扑异构酶I，是未来DNA损伤化疗药物开发的有前途的药物。

  DOI：

  10.3389/fonc.2022.837373
• 作为产物：
  描述：

  2-(2-Carboxyphenyl)-1,3-indandion 在 水 、 对甲苯磺酸 作用下， 以 氯仿 、 苯 为溶剂， 反应 7.0h， 生成 6-(4-hydroxybutyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
  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

文献信息

• Indenoisoquinolines as antineoplastic agents
  申请人：The United States of America as represented by the Department of Health and Human Services

  公开号：US06509344B1

  公开（公告）日：2003-01-21

  A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity versus topoisomerase I. The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-(11H)indeno[1,2-c]isoquinoline. Two of the most potent topoisomerase I inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2,3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27). Two additional potent topoisomerase I inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydoxybut-1-yl)-2,3-dimethoxy-8,9-methylenedioxy-5,11 dioxo-(11H)-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect topoisomerase II.

  已完成。已准备和评估了多种吲哚异喹啉类化合物在人类癌细胞培养物中的细胞毒性和对拓扑异构酶I的活性。其中两种最具细胞毒性的吲哚异喹啉被证明是顺式-6-乙基-5,6,12,13-四氢-2,3-二甲氧基-8,9-(亚甲二氧基)-5,11-二氧基-11H-吲哚[1,2-c]异喹啉和顺式-6-烯丙基-5,6,12,13-四氢-2,3-二甲氧基-8,9-(亚甲二氧基)-5,11-二氧基-(11H)吲哚[1,2-c]异喹啉。其中两种最有效的拓扑异构酶I抑制剂分别是6-(3-羧基-1-丙基)-5,6-二氢-5,11-二氧基-11H-吲哚[1,2-c]异喹啉 (26) 和6-乙基-2,3-二甲氧基-8,9-(亚甲二氧基)-11H-吲哚[1,2-c]异喹啉盐酸盐 (27)。另外两种强效的拓扑异构酶I抑制剂，6-烯丙基-5,6-二氢-2,3-二甲氧基-8,9-(亚甲二氧基)-5,11-二氧基-11H-吲哚[1,2-c]异喹啉 (13c) 和 5,6-二氢-6-(4-羟基丁-1-基)-2,3-二甲氧基-8,9-亚甲二氧基-5,11-二氧基-(11H)-吲哚[1,2-c]异喹啉 (19a)，未对DNA进行解旋，也不影响拓扑异构酶II。
• Combination of a Cox-2 inhibitor and a DNA topoisomerase I inhibitor for treatment of neoplasia
  申请人：Masferrer L. Jaime

  公开号：US20050187172A1

  公开（公告）日：2005-08-25

  The present invention provides combinations of a Cox-2 inhibitor and a DNA topoisomerase inhibitor and methods of use thereof for preventing and/or treating neoplasia or or a neoplasia-related disorder in a subject.

  本发明提供了一种COX-2抑制剂和DNA拓扑异构酶抑制剂的组合物，以及它们的使用方法，用于预防和/或治疗受试者中的肿瘤或与肿瘤相关的疾病。
• indenoisoquinolines as topoisomerase inhibitors I useful as antineoplastic agents
  申请人：Purdue Research Foundation

  公开号：EP2050452A1

  公开（公告）日：2009-04-22

  A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs. topoisomerase I. The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-(11H)indeno[1,2-c]isoquinoline. Two of the most potent topoisomerase I inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2,3-dimethoxy-8,9-(methylenedioxy)11H-indeno[1,2-c]isoquinolinium chloride (27). Two additional potent topoisomerase I inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-(11H)indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect topoisomerase II.

  研究人员制备了多种茚并异喹啉，并对其在人类癌细胞培养物中的细胞毒性以及对拓扑异构酶 I 的活性进行了评估。结果表明，两种细胞毒性最强的茚异喹啉分别是顺式-6-乙基-5,6,12,13-四氢-2,3-二甲氧基-8,9-（亚甲基二氧基）-5,11-二氧代-11H-茚并[1、2-c]异喹啉和顺式-6-烯丙基-5,6,12,13-四氢-2,3-二甲氧基-8,9-（亚甲基二氧基）-5,11-二氧代-11H-茚并[1,2-c]异喹啉。两种最有效的拓扑异构酶 I 抑制剂是 6-(3-羧基-1-丙基)-5,6-二氢-5,11-二氧代-11H-茚并[1,2-c]异喹啉（26）和 6-乙基-2,3-二甲氧基-8,9-(亚甲二氧基)11H-茚并[1,2-c]异喹啉氯化铵（27）。另外两种强效拓扑异构酶 I 抑制剂是 6-烯丙基-5,6-二氢-2,3-二甲氧基-8,9-（亚甲基二氧基）-5,11-二氧代-11H-茚并[1,2-c]异喹啉（13c）和 5、6-(4-羟基丁-1-基)-2,3-二甲氧基-8,9-亚甲基二氧基-5,11-二氧代-11H-茚并[1,2-c]异喹啉（19a）不会解开 DNA，也不会影响拓扑异构酶 II。
• Synthesis of Cytotoxic Indenoisoquinoline Topoisomerase I Poisons
  作者：Dirk Strumberg、Yves Pommier、Kenneth Paull、Muthusamy Jayaraman、Pamela Nagafuji、Mark Cushman

  DOI：10.1021/jm9803323

  日期：1999.2.1

  A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-6,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2,3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators. However, two additional potent top1 inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect top2, Some of the DNA cleavage sites detected in the presence of the indenoisoquinolines were different from those seen with the camptothecins. The cleavage sites induced by the indenoisoquinolines were reversed by salt treatment, which is consistent with the reversible trapping of top1 cleavable complexes by the indenoisoquinolines. In general, the potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxic agents, as some of the most cytotoxic agents had little if any effect on top1. On the other hand, the most potent of the indenoisoquinolines vs top1 were not the most-cytotoxic. In several cases, moderate activity was observed for both cytotoxicity and activity vs top1.
• NOVEL INDENOISOQUINOLINES AS ANTINEOPLASTIC AGENTS
  申请人：Purdue Research Foundation

  公开号：EP1123099B1

  公开（公告）日：2009-03-04