3-Amino-6-chloro-1,4-dioxidoquinoxaline-1,4-diium-2-carbonitrile | 51420-55-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 3-Amino-6-chloro-1,4-dioxidoquinoxaline-1,4-diium-2-carbonitrile
• 英文别名: 3-amino-6-chloro-1,4-dioxidoquinoxaline-1,4-diium-2-carbonitrile
• CAS: 51420-55-4
• 化学式: C₉H₅ClN₄O₂
• 分子量: 236.617
• InChiKey: UNLGQXDHHSXMIT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  101
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  N-(4-氯-2-硝基苯基)乙酰胺 在 盐酸 、 sodium azide 、 硫酸 、 sodium acetate 、 三乙胺 、 sodium nitrite 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 26.5h， 生成 3-Amino-6-chloro-1,4-dioxidoquinoxaline-1,4-diium-2-carbonitrile
  参考文献：
  名称：

  Hypoxia-Selective Agents Derived from Quinoxaline 1,4-Di-N-oxides

  摘要：

  Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy. The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells. Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substituents in the 6- and/or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells. Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced. Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxides have reduction potentials significantly more positive than Tirapazamine (E(pc)-0.90 V). The most potent cytotoxins to cells in culture were the 6,7,-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine. The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity. Four of the compounds, 6e, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro. In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine. This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.

  DOI：

  10.1021/jm00010a023

文献信息

• New Amide Derivatives of Quinoxaline 1,4-di-N-Oxide with Leishmanicidal and Antiplasmodial Activities
  作者：Carlos Barea、Adriana Pabón、Silvia Pérez-Silanes、Silvia Galiano、German Gonzalez、Antonio Monge、Eric Deharo、Ignacio Aldana

  DOI：10.3390/molecules18044718

  日期：——

  Malaria and leishmaniasis are two of the World’s most important tropical parasitic diseases. Continuing with our efforts to identify new compounds active against malaria and leishmaniasis, twelve new 1,4-di-N-oxide quinoxaline derivatives were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against Plasmodium falciparum FCR-3 strain, Leishmania infantum and Leishmania amazonensis. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. The results obtained indicate that a cyclopentyl derivative had the best antiplasmodial activity (2.9 µM), while a cyclohexyl derivative (2.5 µM) showed the best activity against L. amazonensis, and a 3-chloropropyl derivative (0.7 µM) showed the best results against L. infantum. All these compounds also have a Cl substituent in the R7 position.

  疟疾和利什曼病是世界上最重要的两种热带寄生虫病。为了继续寻找对疟疾和利什曼病有活性的新化合物，我们合成了 12 种新的 1,4- 二-N-氧化喹喔啉衍生物，并评估了它们对恶性疟原虫 FCR-3 株、婴儿利什曼原虫和亚马逊利什曼原虫的体外抗疟和抗利什曼活性。此外，还评估了它们对 VERO 细胞（正常猴肾细胞）的毒性。结果表明，环戊基衍生物的抗疟活性最好（2.9 µM），环己基衍生物对亚马逊利什曼病的活性最好（2.5 µM），3-氯丙基衍生物对婴儿利什曼病的活性最好（0.7 µM）。所有这些化合物的 R7 位都有一个 Cl 取代基。
• Effect of complexation of 3-aminoquinoxaline-2-carbonitrile 1,4-dioxides with palladium and copper on their anti-T. cruzi activity
  作者：Diego Benítez、María L. Lavaggi、Dinorah Gambino、María H. Torre、Hugo Cerecetto、Mercedes González

  DOI：10.1007/s00044-011-9660-y

  日期：2012.7

  Pd(II) and Cu(II) complexes of 3-aminoquinoxaline-2-carbonitrile 1,4-dioxides were prepared in order to improve the anti-Trypanosoma cruzi activity of these ligands. The in vitro evaluations demonstrated that the metal complexation modified the activity of the ligands in different manners. Except for one compound, complexation with palladium increased the trypanosomicidal activity 20-80-times. Besides, copper also modified favorably the activity, however, the copper compounds resulted less active than the palladium ones, at the studied doses.
• Borah, Harsha Narayan; Boruah, Romesh Chandra; Sandhu, Jagir Singh, Heterocycles, 1984, vol. 22, # 10, p. 2323 - 2325
  作者：Borah, Harsha Narayan、Boruah, Romesh Chandra、Sandhu, Jagir Singh

  DOI：——

  日期：——
• Hypoxia-Selective Agents Derived from Quinoxaline 1,4-Di-N-oxides
  作者：Antonio Monge、Juan A. Palop、Adela Lopez de Cerain、Virginia Senador、Francisco J. Martinez、Yolanda Sainz、Susana Narro、Estrella Garcia、Carlos de Miguel

  DOI：10.1021/jm00010a023

  日期：1995.5

  Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy. The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells. Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substituents in the 6- and/or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells. Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced. Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxides have reduction potentials significantly more positive than Tirapazamine (E(pc)-0.90 V). The most potent cytotoxins to cells in culture were the 6,7,-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine. The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity. Four of the compounds, 6e, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro. In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine. This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.