3-乙基-6-(2-甲氧基乙氧基)-1,2,4-苯并三嗪1-氧化物 | 1001430-78-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 3-乙基-6-(2-甲氧基乙氧基)-1,2,4-苯并三嗪1-氧化物
• 英文名称: 3-ethyl-6-(2-methoxyethoxy)-1,2,4-benzotriazine 1-oxide
• 英文别名: 3-Ethyl-6-(2-methoxyethoxy)-1-oxido-1,2,4-benzotriazin-1-ium
• CAS: 1001430-78-9
• 化学式: C₁₂H₁₅N₃O₃
• 分子量: 249.269
• InChiKey: BHJRRUDCLDARTQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  69.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-乙基-6-(2-甲氧基乙氧基)-1,2,4-苯并三嗪1-氧化物 在 双氧水 、 三氟乙酸酐 作用下， 以 二氯甲烷 为溶剂， 以32%的产率得到3-Ethyl-6-(2-methoxyethoxy)-1-oxido-1,2,4-benzotriazin-4-ium 4-oxide
  参考文献：
  名称：

  Hypoxia-Selective 3-Alkyl 1,2,4-Benzotriazine 1,4-Dioxides: The Influence of Hydrogen Bond Donors on Extravascular Transport and Antitumor Activity

  摘要：

  Tirapazamine (TPZ) and related 1,2,4-benzotriazine 1,4 dioxides (BTOs) are selectively toxic under hypoxia, but their ability to kill hypoxic cells in tumors is generally limited by their poor extravascular transport. Here we show that removing hydrogen bond donors by replacing the 3-NH2 group of TPZ with simple alkyl groups increased their tissue diffusion coefficients as measured in multicellular layer cultures. This advantage was largely retained using solubilizing 3-alkylaminoalkyl substituents provided these were sufficiently lipophilic at pH 7.4. The high reduction potentials of such compounds resulted in rates of metabolism too high for optimal penetration into hypoxic tissue, but electron-donating 6- and 7-substituents moderated metabolism. Pharmacokinetic/pharmacodynamic model-guided screening was used to select BTOs with optimal extravascular transport and hypoxic cytotoxicity properties for evaluation against HT29 human tumor xenografts in combination with radiation. This identified four novel 3-alkyl BTOs providing greater clonogenic killing of hypoxic cells than TPZ at equivalent host toxicity, with the 6-morpholinopropyloxy-BTO 22 being 3-fold more active.

  DOI：

  10.1021/jm701037w
• 作为产物：
  描述：

  3-ethyl-6-fluoro-1,2,4-benzotriazine 1-oxide 、 乙二醇甲醚 在 sodium hydride 作用下， 反应 3.0h， 以72%的产率得到3-乙基-6-(2-甲氧基乙氧基)-1,2,4-苯并三嗪1-氧化物
  参考文献：
  名称：

  Hypoxia-Selective 3-Alkyl 1,2,4-Benzotriazine 1,4-Dioxides: The Influence of Hydrogen Bond Donors on Extravascular Transport and Antitumor Activity

  摘要：

  Tirapazamine (TPZ) and related 1,2,4-benzotriazine 1,4 dioxides (BTOs) are selectively toxic under hypoxia, but their ability to kill hypoxic cells in tumors is generally limited by their poor extravascular transport. Here we show that removing hydrogen bond donors by replacing the 3-NH2 group of TPZ with simple alkyl groups increased their tissue diffusion coefficients as measured in multicellular layer cultures. This advantage was largely retained using solubilizing 3-alkylaminoalkyl substituents provided these were sufficiently lipophilic at pH 7.4. The high reduction potentials of such compounds resulted in rates of metabolism too high for optimal penetration into hypoxic tissue, but electron-donating 6- and 7-substituents moderated metabolism. Pharmacokinetic/pharmacodynamic model-guided screening was used to select BTOs with optimal extravascular transport and hypoxic cytotoxicity properties for evaluation against HT29 human tumor xenografts in combination with radiation. This identified four novel 3-alkyl BTOs providing greater clonogenic killing of hypoxic cells than TPZ at equivalent host toxicity, with the 6-morpholinopropyloxy-BTO 22 being 3-fold more active.

  DOI：

  10.1021/jm701037w