3,3′-(2,2′-(phenylazanediyl)bis(ethane-2,1-diyl))bis-(4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide) | 1190761-85-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑四嗪类
• 英文名称: 3,3′-(2,2′-(phenylazanediyl)bis(ethane-2,1-diyl))bis-(4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide)
• 英文别名: 3,3'-(2,2'-(phenylazanediyl)bis(ethane-2,1-diyl))bis-(4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide)；3-[2-[N-[2-(8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3-yl)ethyl]anilino]ethyl]-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide
• CAS: 1190761-85-3
• 化学式: C₂₀H₁₉N₁₃O₄
• 分子量: 505.456
• InChiKey: ARQXOCSZPICKQJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  215
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  N,N-二甲氧基羰基乙基苯胺 在 盐酸 、 一水合肼 、 sodium nitrite 作用下， 以 二氯甲烷 、 水 、 二甲基亚砜 、 异丙醇 、 甲苯 为溶剂， 反应 74.0h， 生成 3,3′-(2,2′-(phenylazanediyl)bis(ethane-2,1-diyl))bis-(4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide)
  参考文献：
  名称：

  Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair, and p53

  摘要：

  The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR, and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bifunctional analogues are reported, and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bifunctional congener as optimized for potency, MGMT-independence, and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development, and their improved in vitro activity validates the principles on which they were designed.

  DOI：

  10.1021/jm401121k

文献信息

• Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of <i>O</i>6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair, and p53
  作者：Dimitrios Pletsas、Elrashied A. E. Garelnabi、Li Li、Roger M. Phillips、Richard T. Wheelhouse

  DOI：10.1021/jm401121k

  日期：2013.9.12

  The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR, and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bifunctional analogues are reported, and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bifunctional congener as optimized for potency, MGMT-independence, and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development, and their improved in vitro activity validates the principles on which they were designed.