7-aza-6-(3-bromopropyl)-5,6-dihydro-9-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline | 1558767-23-9

• 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: 7-aza-6-(3-bromopropyl)-5,6-dihydro-9-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
• 英文别名: 9-(3-Bromopropyl)-14-methoxy-5-nitro-9,12-diazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(10),2(7),3,5,11(16),12,14-heptaene-8,17-dione；9-(3-bromopropyl)-14-methoxy-5-nitro-9,12-diazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(10),2(7),3,5,11(16),12,14-heptaene-8,17-dione
• CAS: 1558767-23-9
• 化学式: C₁₉H₁₄BrN₃O₅
• 分子量: 444.241
• InChiKey: RJMPNBLDKMGHPA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  105
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  7-aza-6-(3-bromopropyl)-5,6-dihydro-9-methoxy-3-nitro-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 18.0h， 生成
  参考文献：
  名称：

  Optimization of the Lactam Side Chain of 7-Azaindenoisoquinoline Topoisomerase I Inhibitors and Mechanism of Action Studies in Cancer Cells

  摘要：

  Optimization of the lactam omega-aminoalkyl substituents in a series of 7-azaindenoisoquinolines resulted in new anticancer agents with improved Top1 inhibitory potencies and cancer cell cytotoxicities. The new compounds 14-17 and 19 exhibited mean graph midpoint cytotoxicity (GI(50)) values of 21-71 nM in the NCI panel of 60 human cancer cell cultures. Ternary 7-azaindenoisoquinoline-DNA-Top1 cleavage complexes that persist for up to 6 h were detected in HCT116 colon cancer cells. Ternary complexes containing 7-azaindenoisoquinolines were significantly more stable than those in which camptothecin was incorporated. DNA content distribution histograms showed S-phase block 3 h after drug removal. Drug-induced DNA damage in HCT116 cells was revealed by induction of the histone gamma-H2AX marker. The 7-azaindenoisoquinolines were able to partially overcome resistance in several drug-resistant cell lines, and they were not substrates for the ABCB1 drug efflux transporter. Molecular modeling studies indicate that the 7-azaindenoisoquinolines intercalate at the DNA cleavage site in DNA-Top1 covalent complexes with the lactam side chain projecting into the major groove. Overall, the results indicate that the 7-azaindenoisoquinolines are promising anticancer agents that merit further development.

  DOI：

  10.1021/jm401471v
• 作为产物：
  描述：

  7-aza-5,6-dihydro-9-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline 、 1,3-二溴丙烷 在 sodium hydride 、 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 33.0h， 以72%的产率得到7-aza-6-(3-bromopropyl)-5,6-dihydro-9-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
  参考文献：
  名称：

  人类拓扑异构酶1，酪氨酰-DNA磷酸二酯酶1（Tdp1）和酪氨酰-DNA磷酸二酯酶2（Tdp2）的第一个三重抑制剂的合成和生物学评估。

  摘要：

  Tdp1和Tdp2是两种酪氨酰-DNA磷酸二酯酶，可以修复由拓扑异构酶抑制剂和多种其他破坏DNA的物质造成的受损DNA。假设Tdp1和Tdp2抑制均可以增强拓扑异构酶抑制剂的细胞毒性。这项研究报告了成功的基于结构的设计和合成新的7-氮杂茚异喹啉，它们可作为Top1，Tdp1和Tdp2的三重抑制剂。来自人类癌细胞培养物的酶抑制数据和细胞毒性数据确定，对7-氮杂腺苷异喹啉的内酰胺侧链的修饰可以调节其抑制力和选择性（相对于Top1，Tdp1和Tdp2）。与Top1，Tdp1和Tdp2结合的所选目标化合物的分子模型用于设计抑制剂并促进结构-活性关系分析。

  DOI：

  10.1021/acs.jmedchem.6b01565

文献信息

• [EN] AZAINDENOISOQUINOLINE COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS D'AZAINDÉNOISOQUINOLINE ET LEURS UTILISATIONS
  申请人：PURDUE RESEARCH FOUNDATION

  公开号：WO2018118852A1

  公开（公告）日：2018-06-28

  Tyrosyl-DNA Phosphodiesterases 1 and 2 (Tdp1 and Tdp2) can repair damaged DNA resulting from topoisomerase inhibitors and a variety of other DNA-damaging agents. Both Tdp1 and Tdp2 inhibition could hypothetically potentiate the cytotoxicities of topoisomerase inhibitors. Series of 7-azaindenoisoquinolines that act as triple inhibitors of Top1, Tdp1 and Tdp2 are disclosed. Also described are methods for treating patients of a cancer using the disclosed azaindenoisoquinoline compounds or a pharmaceutical formulation thereof.

  酪氨酸-DNA磷酸二酯酶1和2（Tdp1和Tdp2）可以修复由拓扑异构酶抑制剂和各种其他损伤DNA的药物引起的受损DNA。Tdp1和Tdp2的抑制理论上可能增强拓扑异构酶抑制剂的细胞毒性。公开了一系列作为Top1、Tdp1和Tdp2的三重抑制剂的7-氮杂吲哚异喹啉类化合物。还描述了使用公开的氮杂吲哚异喹啉类化合物或其药物制剂来治疗癌症患者的方法。
• Azaindenoisoquinoline compounds and uses thereof
  申请人：Purdue Research Foundation

  公开号：US10875860B2

  公开（公告）日：2020-12-29

  Tyrosyl-DNA Phosphodiesterases 1 and 2 (Tdp1 and Tdp2) can repair damaged DNA resulting from topoisomerase inhibitors (e.g. Top1) and a variety of other DNA-damaging agents. 7-Azaindenoisoquinolines that are inhibitors of each of Top1, Tdp1 and Tdp2 are disclosed. Also described are methods for preparing azaindenoisoquinoline and methods for treating patients of a cancer using the disclosed azaindenoisoquinoline compounds or a pharmaceutical formulation thereof.

  酪氨酰-DNA 磷酸二酯酶 1 和 2（Tdp1 和 Tdp2）可以修复拓扑异构酶抑制剂（如 Top1）和其他多种 DNA 损伤剂造成的受损 DNA。7-Azaindenoisoquinolines 是 Top1、Tdp1 和 Tdp2 的抑制剂。还描述了制备偶氮亚氨基异喹啉的方法和使用所公开的偶氮亚氨基异喹啉化合物或其药物制剂治疗癌症患者的方法。
• AZAINDENOISOQUINOLINE COMPOUNDS AND USES THEREOF
  申请人：Purdue Research Foundation

  公开号：US20200095243A1

  公开（公告）日：2020-03-26

  Tyrosyl-DNA Phosphodiesterases 1 and 2 (Tdp1 and Tdp2) can repair damaged DNA resulting from topoisomerase inhibitors (e.g. Top1) and a variety of other DNA-damaging agents. 7-Azaindenoisoquinolines that are inhibitors of each of Top1, Tdp1 and Tdp2 are disclosed. Also described are methods for preparing azaindenoisoquinoline and methods for treating patients of a cancer using the disclosed azaindenoisoquinoline compounds or a pharmaceutical formulation thereof.
• Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl–DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl–DNA Phosphodiesterase 2 (Tdp2)
  作者：Ping Wang、Mohamed S. A. Elsayed、Caroline B. Plescia、Azhar Ravji、Christophe E. Redon、Evgeny Kiselev、Christophe Marchand、Olga Zeleznik、Keli Agama、Yves Pommier、Mark Cushman

  DOI：10.1021/acs.jmedchem.6b01565

  日期：2017.4.27

  two tyrosyl–DNA phosphodiesterases that can repair damaged DNA resulting from topoisomerase inhibitors and a variety of other DNA-damaging agents. Both Tdp1 and Tdp2 inhibition could hypothetically potentiate the cytotoxicities of topoisomerase inhibitors. This study reports the successful structure-based design and synthesis of new 7-azaindenoisoquinolines that act as triple inhibitors of Top1, Tdp1

  Tdp1和Tdp2是两种酪氨酰-DNA磷酸二酯酶，可以修复由拓扑异构酶抑制剂和多种其他破坏DNA的物质造成的受损DNA。假设Tdp1和Tdp2抑制均可以增强拓扑异构酶抑制剂的细胞毒性。这项研究报告了成功的基于结构的设计和合成新的7-氮杂茚异喹啉，它们可作为Top1，Tdp1和Tdp2的三重抑制剂。来自人类癌细胞培养物的酶抑制数据和细胞毒性数据确定，对7-氮杂腺苷异喹啉的内酰胺侧链的修饰可以调节其抑制力和选择性（相对于Top1，Tdp1和Tdp2）。与Top1，Tdp1和Tdp2结合的所选目标化合物的分子模型用于设计抑制剂并促进结构-活性关系分析。
• Optimization of the Lactam Side Chain of 7-Azaindenoisoquinoline Topoisomerase I Inhibitors and Mechanism of Action Studies in Cancer Cells
  作者：Evgeny Kiselev、Dhriti Sooryakumar、Keli Agama、Mark Cushman、Yves Pommier

  DOI：10.1021/jm401471v

  日期：2014.2.27

  Optimization of the lactam omega-aminoalkyl substituents in a series of 7-azaindenoisoquinolines resulted in new anticancer agents with improved Top1 inhibitory potencies and cancer cell cytotoxicities. The new compounds 14-17 and 19 exhibited mean graph midpoint cytotoxicity (GI(50)) values of 21-71 nM in the NCI panel of 60 human cancer cell cultures. Ternary 7-azaindenoisoquinoline-DNA-Top1 cleavage complexes that persist for up to 6 h were detected in HCT116 colon cancer cells. Ternary complexes containing 7-azaindenoisoquinolines were significantly more stable than those in which camptothecin was incorporated. DNA content distribution histograms showed S-phase block 3 h after drug removal. Drug-induced DNA damage in HCT116 cells was revealed by induction of the histone gamma-H2AX marker. The 7-azaindenoisoquinolines were able to partially overcome resistance in several drug-resistant cell lines, and they were not substrates for the ABCB1 drug efflux transporter. Molecular modeling studies indicate that the 7-azaindenoisoquinolines intercalate at the DNA cleavage site in DNA-Top1 covalent complexes with the lactam side chain projecting into the major groove. Overall, the results indicate that the 7-azaindenoisoquinolines are promising anticancer agents that merit further development.