9-(3-Imidazol-1-ylpropyl)-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;hydrochloride | 1558767-24-0

• 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: 9-(3-Imidazol-1-ylpropyl)-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;hydrochloride
• 英文别名: 9-(3-imidazol-1-ylpropyl)-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;hydrochloride
• CAS: 1558767-24-0
• 化学式: C₂₂H₁₇N₅O₅*ClH
• 分子量: 467.868
• InChiKey: WUULDKCCMSTONL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.23
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  123
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  7-aza-5,6-dihydro-9-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline 在 sodium hydride 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 8.25h， 生成 9-(3-Imidazol-1-ylpropyl)-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;hydrochloride
  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

文献信息

• 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.