3-chloro-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1-oxide | 910105-60-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: 3-chloro-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1-oxide
• 英文别名: 3-chloro-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1-oxide；3-chloro-1-oxido-7,8-dihydro-6H-cyclopenta[g][1,2,4]benzotriazin-1-ium
• CAS: 910105-60-1
• 化学式: C₁₀H₈ClN₃O
• 分子量: 221.646
• InChiKey: OBJHWNJFEFPMGV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  51.2
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-chloro-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1-oxide 在 水 、 fluorine 、 乙腈 作用下， 以 二氯甲烷 为溶剂， 反应 0.17h， 生成 3-chloro-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide
  参考文献：
  名称：

  Discovery and Optimization of Benzotriazine Di-N-Oxides Targeting Replicating and Nonreplicating Mycobacterium tuberculosis

  摘要：

  Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 mu g/mL against H37Rv and a cytotoxicity (CC50) against Vero cells of 25 mu g/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.

  DOI：

  10.1021/jm300123s
• 作为产物：
  描述：

  6-硝基-2,3-二氢-1H-茚-5-胺 在 亚硝酸特丁酯 、 硫酸 、 三氯氧磷 作用下， 以 乙醚 、 水 、 叔丁醇 为溶剂， 反应 10.0h， 生成 3-chloro-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1-oxide
  参考文献：
  名称：

  Discovery and Optimization of Benzotriazine Di-N-Oxides Targeting Replicating and Nonreplicating Mycobacterium tuberculosis

  摘要：

  Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 mu g/mL against H37Rv and a cytotoxicity (CC50) against Vero cells of 25 mu g/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.

  DOI：

  10.1021/jm300123s

文献信息

• New approach of delivering cytotoxic drugs towards CAIX expressing cells: A concept of dual-target drugs
  作者：Simon J.A. van Kuijk、Nanda Kumar Parvathaneni、Raymon Niemans、Marike W. van Gisbergen、Fabrizio Carta、Daniela Vullo、Silvia Pastorekova、Ala Yaromina、Claudiu T. Supuran、Ludwig J. Dubois、Jean-Yves Winum、Philippe Lambin

  DOI：10.1016/j.ejmech.2016.10.037

  日期：2017.2

  Targeting CAIX might be a valuable approach for specific delivery of cytotoxic drugs, thereby reducing normal tissue side-effects. A series of dual-target compounds were designed and synthesized incorporating a sulfonamide, sulfamide, or sulfamate moiety combined with several different anti-cancer drugs, including the chemotherapeutic agents chlorambucil, tirapazamine, and temozolomide, two Ataxia Telangiectasia

  碳酸酐酶IX（CAIX）是一种低氧调节的肿瘤特异性蛋白质，可维持细胞的pH平衡。靶向CAIX可能是特异性递送细胞毒性药物的有价值的方法，从而减少正常组织的副作用。设计并合成了一系列双目标化合物，将磺酰胺，磺酰胺或氨基磺酸盐部分与几种不同的抗癌药物（包括化疗药苯丁酸氮芥，替拉帕明和替莫唑胺），两种共济失调毛细血管扩张症和Rad3相关蛋白抑制剂结合在一起（ ATRi）和抗糖尿病双胍剂苯乙双胍。当与放射线结合使用时，ATRi衍生物（12）是唯一在CAIX过表达细胞中优于没有CAIX表达的细胞中表现出优选功效的化合物。但是，其功效可能不仅仅取决于与CAIX的结合，因为所有描述的化合物作为碳酸酐酶抑制剂通常都表现出较低的活性。因此，没有证实双靶化合物特异性靶向表达CAIX的肿瘤细胞的假说。即使双靶标化合物仍然是一种有趣的方法，替代方案也应作为新的治疗策略进行研究。
• Benzotriazine Di-Oxide Prodrugs for Exploiting Hypoxia and Low Extracellular pH in Tumors
  作者：Michael P. Hay、Hong Nam Shin、Way Wua Wong、Wan Wan Sahimi、Aaron T.D. Vaz、Pooja Yadav、Robert F. Anderson、Kevin O. Hicks、William R. Wilson

  DOI：10.3390/molecules24142524

  日期：——

  feature of tumor microenvironments but has yet to be successfully exploited in cancer therapy. The reversal of the pH gradient across the plasma membrane in cells that regulate intracellular pH (pHi) has potential to drive the selective uptake of weak acids at low extracellular pH (pHe). Here, we investigate the dual targeting of low pHe and hypoxia, another key feature of tumor microenvironments. We prepared

  细胞外酸化是肿瘤微环境的一个重要特征，但尚未在癌症治疗中成功利用。调节细胞内 pH (pHi) 的细胞质膜 pH 梯度的逆转有可能驱动低细胞外 pH (pHe) 下弱酸的选择性摄取。在这里，我们研究了低 pHe 和缺氧的双重靶向，这是肿瘤微环境的另一个关键特征。我们通过附加链烷酸或氨基链烷酸侧链，制备了基于二氧化苯并三嗪（BTO）核的八种生物还原前药。BTO 酸在 SiHa 和 FaDu 细胞培养物中对低 pHe（pH 6.5 与 7.4，比率 2 至 5 倍）和缺氧（比率 2 至 8 倍）表现出适度的选择性。相关的中性 BTO 对酸中毒没有选择性，但比 BTO 酸具有更大的细胞毒性效力和缺氧选择性。对代表性 BTO 酸的摄取和代谢的研究证实，在低 pHe 下摄取增强，但细胞内浓度低于被动扩散的预期。此外，细胞内还原酶活性的调节和细胞排斥电子受体 WST-1 的竞争表明，BTO 酸的大部分
• Benzotriazine Oxides as Drugs Targeting Mycobacterium Tuberculosis
  申请人：Madrid Peter

  公开号：US20130150369A1

  公开（公告）日：2013-06-13

  Benzotriazine doxides are disclosed as drugs targeting mycobacterium tuberculosis , including novel compounds of formula I:

  Benzotriazine doxides被披露为针对结核分枝杆菌的药物，包括公式I的新化合物。
• Tricyclic 1,2,4-triazine oxides and compositions for therapeutic use in cancer treatments
  申请人：Auckland Uniservices Limited

  公开号：US07989451B2

  公开（公告）日：2011-08-02

  The invention relates to novel tricyclic 1,2,4-triazine-1-oxides and novel tricyclic 1,2,4-triazine-1,4-dioxides of formula I and to related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明涉及新型三环1,2,4-三嗪-1-氧化物和新型三环1,2,4-三嗪-1,4-二氧化物的公式I以及相关类似物，涉及它们的制备，以及它们作为缺氧选择性药物和放射增敏剂用于癌症治疗，无论是单独使用还是与放射治疗和/或其他抗癌药物联合使用。
• Tricyclic 1,2,4-Triazine Oxides and Compositions for Therapeutic Use in Cancer Treatments
  申请人：Hay Michael Patrick

  公开号：US20090186886A1

  公开（公告）日：2009-07-23

  The invention relates to novel tricyclic 1,2,4-triazine-1-oxides and novel tricyclic 1,2,4-triazine-1,4-dioxides of formula I and to related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明涉及新型三环1,2,4-三嗪-1-氧化物和新型三环1,2,4-三嗪-1,4-二氧化物的公式I以及相关类似物，它们的制备以及它们作为低氧选择性药物和放射增敏剂用于癌症治疗，可以单独使用或与放射线和/或其他抗癌药物联合使用。