3-amino-1,2,4-benzotriazine 4-oxide | 251322-95-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三嗪类
• 英文名称: 3-amino-1,2,4-benzotriazine 4-oxide
• 英文别名: 1,2,4-benzotriazin-3-amine 4-oxide；1-desoxytirapazamine；desoxytirapazamine；4-oxy-benzo[1,2,4]triazin-3-ylamine；3-Aminobenzo-1,2,4-triazin-4N-dioxid；3-Aminobenzo-1,2,4-triazin-4-N-oxid
• CAS: 251322-95-9
• 化学式: C₇H₆N₄O
• 分子量: 162.151
• InChiKey: DHWGBBRCMYLEFU-UHFFFAOYSA-N

物化性质

• 沸点：
  433.4±28.0 °C(Predicted)
• 密度：
  1.58±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.15
• 重原子数：
  12.0
• 可旋转键数：
  0.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  78.74
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  乙酸酐 、 3-amino-1,2,4-benzotriazine 4-oxide 反应 3.0h， 以90%的产率得到3-acetamido-1,2,4-benzotriazine 4-oxide
  参考文献：
  名称：

  3-Amino-1,2,4-benzotriazine 4-Oxide:  Characterization of a New Metabolite Arising from Bioreductive Processing of the Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)

  摘要：

  Tirapazamine (1) is a promising antitumor agent that selectively causes DNA damage in hypoxic tumor cells, following one-electron bioreductive activation. Surprisingly, after more than 10 years of study, the products arising from bioreductive metabolism of tirapazamine have not, been completely characterized. The two:previously characterized metabolites are 3-amino-1,2,4-benzotriazine 1-oxide (3) and 3-amino-1,2,4-benzotriazine (5). In this work, 3-amino-1,2,4-benzotriazine 4-oxide (4) is identified for the first time as a product resulting from:one-electron activation of the antitumor agent tirapazamine by the enzymes xanthine/xanthine oxidase and NADPH:cytochrome P450 oxidoreductase. As part of this work, the novel N-oxide (4) was unambiguously synthesized and characterized using NMR spectroscopy, UV-vis spectroscopy, LC/MS, and X-ray crystallography. Under conditions where the parent drug tirapazamine is enzymatically activated, the metabolite 4 is produced but readily undergoes further]reduction to the benzotriazine (5). Thus, under circumstances where extensive reductive metabolism occurs, the yield of the 4-oxide: (4) decreases. In contrast, the isomeric two-electron; reduction product 3-amino-1,2,4-benzotriazine 1-oxide (3) does not readily undergo enzymatic reduction and, therefore, is found as a major bioreductive metabolite under all conditions. Finally, the ability of the 4-oxide metabolite (4) to participate in tirapazamine-mediated; DNA damage is considered.

  DOI：

  10.1021/jo001232j
• 作为产物：
  描述：

  替拉扎明 在 sodium dithionite 、 过氧化乙酸叔丁酯 、 双氧水 作用下， 以 乙醇 、 水 、 溶剂黄146 为溶剂， 反应 3.5h， 生成 3-amino-1,2,4-benzotriazine 4-oxide
  参考文献：
  名称：

  3-Amino-1,2,4-benzotriazine 4-Oxide:  Characterization of a New Metabolite Arising from Bioreductive Processing of the Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)

  摘要：

  Tirapazamine (1) is a promising antitumor agent that selectively causes DNA damage in hypoxic tumor cells, following one-electron bioreductive activation. Surprisingly, after more than 10 years of study, the products arising from bioreductive metabolism of tirapazamine have not, been completely characterized. The two:previously characterized metabolites are 3-amino-1,2,4-benzotriazine 1-oxide (3) and 3-amino-1,2,4-benzotriazine (5). In this work, 3-amino-1,2,4-benzotriazine 4-oxide (4) is identified for the first time as a product resulting from:one-electron activation of the antitumor agent tirapazamine by the enzymes xanthine/xanthine oxidase and NADPH:cytochrome P450 oxidoreductase. As part of this work, the novel N-oxide (4) was unambiguously synthesized and characterized using NMR spectroscopy, UV-vis spectroscopy, LC/MS, and X-ray crystallography. Under conditions where the parent drug tirapazamine is enzymatically activated, the metabolite 4 is produced but readily undergoes further]reduction to the benzotriazine (5). Thus, under circumstances where extensive reductive metabolism occurs, the yield of the 4-oxide: (4) decreases. In contrast, the isomeric two-electron; reduction product 3-amino-1,2,4-benzotriazine 1-oxide (3) does not readily undergo enzymatic reduction and, therefore, is found as a major bioreductive metabolite under all conditions. Finally, the ability of the 4-oxide metabolite (4) to participate in tirapazamine-mediated; DNA damage is considered.

  DOI：

  10.1021/jo001232j

文献信息

• Benzoazine mono-N-oxides and benzoazine 1,4 dioxides and compositions therefrom for the therapeutic use in cancer treatments
  申请人：Auckland Uniservices Limited

  公开号：EP1468688A2

  公开（公告）日：2004-10-20

  The present invention relates to a synergetistic composition comprising one or more benzoazine-mono-N-oxides, and one or more benzoazine 1,4 dioxides for use in cancer therapy. The invention also provides a range of novel 1,2,4 benzoazine-mono-N-oxides and related analogues. These can be used as potentiators of the cytotoxicity of existing anticancer drugs and therapies for cancer treatment.

  本发明涉及一种协同组合物，包括一种或多种苯并噁唑-单-N-氧化物，以及一种或多种苯并噁唑1,4-二氧化物，用于癌症治疗。 该发明还提供了一系列新颖的1,2,4苯并噁唑-单-N-氧化物及相关类似物。这些可以用作增强现有抗癌药物的细胞毒性和癌症治疗的治疗剂。
• Synthesis, crystal structure and calculation of oxides of 2-methylamino-3-methyl quinoxaline
  作者：Rui Wang、Min Zhang、Wenfeng Wang、Xucheng Wang、Yaofeng Yuan、Junjian Li

  DOI：10.1016/j.molstruc.2020.128826

  日期：2020.12

  Abstract Monoxide and dioxide of animo quinoxaline were synthesized and characterized by 1H NMR, 13C NMR and HRMS. The result shows that monoxide is main product. 1H NMR analysis, quantum calculation and crystal structure all indicate that the monoxide is 4-oxide structure but not 1-oxide structure. The subsequent discussions of electronic effect and steric effect of 1-oxide and 4-oxide support the

  摘要 合成了氨基喹喔啉的一氧化物和二氧化物，并用1H NMR、13C NMR和HRMS进行了表征。结果表明，一氧化碳是主要产物。1H NMR分析、量子计算和晶体结构均表明该一氧化物为4-氧化物结构而不是1-氧化物结构。随后对1-氧化物和4-氧化物的电子效应和空间效应的讨论支持了4-氧化物为主导产物的结论，这与1H NMR分析和晶体结构一致。最后，计算出的结构与本文的晶体结构吻合较好，说明本文计算结果是可信的。
• Time-Resolved Spectroscopy of the Excited Singlet States of Tirapazamine and Desoxytirapazamine
  作者：Xiaofeng Shi、James S. Poole、Ijeoma Emenike、Gotard Burdzinski、Matthew S. Platz

  DOI：10.1021/jp0457040

  日期：2005.3.1

  Laser flash photolysis (LFP, 400 nm excitation) of the anti-cancer drug tirapazamine (TPZ) in acetonitrile produces the singlet excited-state S-1 with lambda(max) = 544 nm. The lifetime of this state is 130 ps, in good agreement with the reported fluorescence lifetime. The excited state is reduced to the corresponding radical anion by KSCN or KI. The spectrum of the radical anion is in good agreement with previously reported pulse radiolysis studies and time-dependent density functional theory (TD-DFT) calculations. LFP of desoxytirapazamine (dTPZ) also produces the first excited singlet state, S1. The fluorescence quantum yield and lifetime (5.4 ns) of the dTPZ singlet excited state are both much greater than the corresponding values of TPZ. This is explained by DFT calculations that predict that cyclization of TPZ to form an oxaziridine is thermodynamically facile but that cyclization of dTPZ to form an oxadiaziridine is not. Thus, the S-1 state of TPZ has a short lifetime and low fluorescence quantum yield due to ready cyclization whereas the cyclization of the S-1 state of dTPZ is unimportant and does not limit either the fluorescence quantum yield or the fluorescence lifetime. This conclusion is confirmed by studies of dTPZ', an isomer of dTPZ containing the C=N-O moiety which has a low quantum yield and short fluorescence lifetime similar to that of TPZ.
• 3-Amino-1,2,4-benzotriazine 4-Oxide:  Characterization of a New Metabolite Arising from Bioreductive Processing of the Antitumor Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)
  作者：Tarra Fuchs、Goutam Chowdhury、Charles L. Barnes、Kent S. Gates

  DOI：10.1021/jo001232j

  日期：2001.1.1

  Tirapazamine (1) is a promising antitumor agent that selectively causes DNA damage in hypoxic tumor cells, following one-electron bioreductive activation. Surprisingly, after more than 10 years of study, the products arising from bioreductive metabolism of tirapazamine have not, been completely characterized. The two:previously characterized metabolites are 3-amino-1,2,4-benzotriazine 1-oxide (3) and 3-amino-1,2,4-benzotriazine (5). In this work, 3-amino-1,2,4-benzotriazine 4-oxide (4) is identified for the first time as a product resulting from:one-electron activation of the antitumor agent tirapazamine by the enzymes xanthine/xanthine oxidase and NADPH:cytochrome P450 oxidoreductase. As part of this work, the novel N-oxide (4) was unambiguously synthesized and characterized using NMR spectroscopy, UV-vis spectroscopy, LC/MS, and X-ray crystallography. Under conditions where the parent drug tirapazamine is enzymatically activated, the metabolite 4 is produced but readily undergoes further]reduction to the benzotriazine (5). Thus, under circumstances where extensive reductive metabolism occurs, the yield of the 4-oxide: (4) decreases. In contrast, the isomeric two-electron; reduction product 3-amino-1,2,4-benzotriazine 1-oxide (3) does not readily undergo enzymatic reduction and, therefore, is found as a major bioreductive metabolite under all conditions. Finally, the ability of the 4-oxide metabolite (4) to participate in tirapazamine-mediated; DNA damage is considered.