5-[2-(dimethylamino)ethyl]-10-[3-(dimethylamino)propyl]benzo[de]triazolo[4,5-g]isoquinoline-4,6(5H,10H)-dione | 1353887-22-5

• 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: 5-[2-(dimethylamino)ethyl]-10-[3-(dimethylamino)propyl]benzo[de]triazolo[4,5-g]isoquinoline-4,6(5H,10H)-dione
• 英文别名: 3-[2-(Dimethylamino)ethyl]-11-[3-(dimethylamino)propyl]-3,11,12,13-tetrazatetracyclo[7.6.1.05,16.010,14]hexadeca-1(15),5,7,9(16),10(14),12-hexaene-2,4-dione
• CAS: 1353887-22-5
• 化学式: C₂₁H₂₆N₆O₂
• 分子量: 394.476
• InChiKey: WXUHPAUCHCAIPF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  74.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-[2-(dimethylamino)ethyl]-10-[3-(dimethylamino)propyl]benzo[de]triazolo[4,5-g]isoquinoline-4,6(5H,10H)-dione 在 硝酸 作用下， 以 硫酸 为溶剂， 反应 5.0h， 以68%的产率得到5-(2-dimethylaminoethyl)-10-(3-dimethylaminopropyl)-2-nitrobenzo[de][1,2,3]triazolo[4,5-g]isoquinoline-4,6(5H,10H)-dione
  参考文献：
  名称：

  The Novel Triazolonaphthalimide Derivative LSS-11 Synergizes the Anti-Proliferative Effect of Paclitaxel via STAT3-Dependent MDR1 and MRP1 Downregulation in Chemoresistant Lung Cancer Cells

  摘要：

  多药耐药性（MDR）是导致紫杉醇类化疗无效和反应不佳的主要原因。常规细胞毒性药物的组合是克服紫杉醇耐药性的可行策略。在此，我们研究了新型萘酰亚胺衍生物拓扑异构酶抑制剂LSS-11对紫杉醇耐药A549（A549/T）肺癌细胞的细胞毒性作用和潜在机制。LSS-11通过增加DR5蛋白水平和PARP1裂解诱导细胞凋亡，从而增强A549/T细胞的细胞死亡。重要的是，LSS-11剂量依赖性地降低了STAT3磷酸化并下调了其靶基因MDR1和MRP1，而不会影响P-gp的转运功能。染色质共免疫沉淀（ChIP）分析进一步表明，LSS-11阻碍了STAT3与MDR1和MRP1启动子的结合。此外，萝卜硫素对p-STAT3的药理抑制下调了MDR1和MRP1，通过触发细胞凋亡导致A549/T细胞死亡。总之，我们的数据表明，LSS-11是一种有效的萘酰亚胺类化学增敏剂，可通过DR5/PARP1途径和STAT3/MDR1/MRP1 STAT3抑制增强紫杉醇耐药肺癌细胞的细胞死亡。

  DOI：

  10.3390/molecules22111822
• 作为产物：
  描述：

  3-amino-naphthalene-1,8-dicarboxylic acid-anhydride 在 nitrosonium tetrafluoroborate 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 1.0h， 生成 5-[2-(dimethylamino)ethyl]-10-[3-(dimethylamino)propyl]benzo[de]triazolo[4,5-g]isoquinoline-4,6(5H,10H)-dione
  参考文献：
  名称：

  Unprecedented synthesis, in vitro and in vivo anti-cancer evaluation of novel triazolonaphthalimide derivatives

  摘要：

  An efficient synthesis method for fusing triazole ring onto the naphthalimide core was described. The anti-cancer activities of the generated triazolonaphthalimide derivatives were evaluated with five cancer cell lines. The compounds generally displayed higher potency than amonafide. 4d,4e carrying two amino side chains showed the strongest cytotoxicities. N-oxide 5, a prodrug of 4a, was designed and synthesized. The agent was expected to be activated under the hypoxic condition in tumor tissue. Compared with 4a, 5 manifested much lower cytotoxicity both in cancer cell lines and human normal cells in the in vitro assays. However, N-oxide 5 performed potent anti-cancer activity in vivo using S-180 sarcoma bearing mice. All the results suggested that 5 was a promising anti-cancer agent. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.11.025

文献信息

• Unprecedented synthesis, in vitro and in vivo anti-cancer evaluation of novel triazolonaphthalimide derivatives
  作者：Shasha Li、Wenhe Zhong、Zhongjun Li、Xiangbao Meng

  DOI：10.1016/j.ejmech.2011.11.025

  日期：2012.1

  An efficient synthesis method for fusing triazole ring onto the naphthalimide core was described. The anti-cancer activities of the generated triazolonaphthalimide derivatives were evaluated with five cancer cell lines. The compounds generally displayed higher potency than amonafide. 4d,4e carrying two amino side chains showed the strongest cytotoxicities. N-oxide 5, a prodrug of 4a, was designed and synthesized. The agent was expected to be activated under the hypoxic condition in tumor tissue. Compared with 4a, 5 manifested much lower cytotoxicity both in cancer cell lines and human normal cells in the in vitro assays. However, N-oxide 5 performed potent anti-cancer activity in vivo using S-180 sarcoma bearing mice. All the results suggested that 5 was a promising anti-cancer agent. (C) 2011 Elsevier Masson SAS. All rights reserved.
• The Novel Triazolonaphthalimide Derivative LSS-11 Synergizes the Anti-Proliferative Effect of Paclitaxel via STAT3-Dependent MDR1 and MRP1 Downregulation in Chemoresistant Lung Cancer Cells
  作者：Liyan Ji、Xi Liu、Shuwei Zhang、Shunan Tang、Simin Yang、Shasha Li、Xiaoxiao Qi、Siwang Yu、Linlin Lu、Xiangbao Meng、Zhongqiu Liu

  DOI：10.3390/molecules22111822

  日期：——

  Multidrug resistance (MDR) is a major cause of the inefficacy and poor response to paclitaxel-based chemotherapy. The combination of conventional cytotoxic drugs has been a plausible strategy for overcoming paclitaxel resistance. Herein, we investigated the cytotoxic effects and underlying mechanism of LSS-11, a novel naphthalimide derivative-based topoisomerase inhibitor, in paclitaxel-resistant A549 (A549/T) lung cancer cells. LSS-11 enhanced cell death in A549/T cells by inducing apoptosis through increasing the DR5 protein level and PARP1 cleavage. Importantly, LSS-11 dose-dependently reduced STAT3 phosphorylation and downregulated its target genes MDR1 and MRP1, without affecting P-gp transport function. Chromatin coimmunoprecipitation (ChIP) assay further revealed that LSS-11 hindered the binding of STAT3 to the MDR1 and MRP1 promoters. Additionally, pharmacological inhibition of p-STAT3 by sulforaphane downregulated MDR1 and MRP1, resulting in A549/T cell death by triggering apoptosis. Collectively, our data show that LSS-11 is a potent naphthalimide-based chemosensitizer that could enhance cell death in paclitaxel-resistant lung cancer cells through the DR5/PARP1 pathway and STAT3/MDR1/MRP1 STAT3 inhibition.

  多药耐药性（MDR）是导致紫杉醇类化疗无效和反应不佳的主要原因。常规细胞毒性药物的组合是克服紫杉醇耐药性的可行策略。在此，我们研究了新型萘酰亚胺衍生物拓扑异构酶抑制剂LSS-11对紫杉醇耐药A549（A549/T）肺癌细胞的细胞毒性作用和潜在机制。LSS-11通过增加DR5蛋白水平和PARP1裂解诱导细胞凋亡，从而增强A549/T细胞的细胞死亡。重要的是，LSS-11剂量依赖性地降低了STAT3磷酸化并下调了其靶基因MDR1和MRP1，而不会影响P-gp的转运功能。染色质共免疫沉淀（ChIP）分析进一步表明，LSS-11阻碍了STAT3与MDR1和MRP1启动子的结合。此外，萝卜硫素对p-STAT3的药理抑制下调了MDR1和MRP1，通过触发细胞凋亡导致A549/T细胞死亡。总之，我们的数据表明，LSS-11是一种有效的萘酰亚胺类化学增敏剂，可通过DR5/PARP1途径和STAT3/MDR1/MRP1 STAT3抑制增强紫杉醇耐药肺癌细胞的细胞死亡。