6-[N-[(E)-[4-(3,4-dimethoxyphenyl)-2-thienyl]methyleneamino]-N-methylamino]-3-methyl-1H-pyrimidine-2,4-dione | 1448808-37-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 6-[N-[(E)-[4-(3,4-dimethoxyphenyl)-2-thienyl]methyleneamino]-N-methylamino]-3-methyl-1H-pyrimidine-2,4-dione
• 英文别名: 6-[[(E)-[4-(3,4-dimethoxyphenyl)thiophen-2-yl]methylideneamino]-methylamino]-3-methyl-1H-pyrimidine-2,4-dione
• CAS: 1448808-37-4
• 化学式: C₁₉H₂₀N₄O₄S
• 分子量: 400.458
• InChiKey: AVZZYFISIHAYEG-KEBDBYFISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-[N-[(E)-[4-(3,4-dimethoxyphenyl)-2-thienyl]methyleneamino]-N-methylamino]-3-methyl-1H-pyrimidine-2,4-dione 在 溶剂黄146 、 sodium nitrite 、 1,4-二巯基-2,3-丁二醇 作用下， 以 水 、 乙醇 为溶剂， 反应 19.0h， 以128 mg的产率得到3-[4-(3,4-dimethoxyphenyl)-2-thienyl]-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione
  参考文献：
  名称：

  Toxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II

  摘要：

  The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAP.) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.

  DOI：

  10.1021/jm400568p
• 作为产物：
  描述：

  6-氯-3-甲基尿嘧啶 以 乙醇 为溶剂， 反应 0.34h， 生成 6-[N-[(E)-[4-(3,4-dimethoxyphenyl)-2-thienyl]methyleneamino]-N-methylamino]-3-methyl-1H-pyrimidine-2,4-dione
  参考文献：
  名称：

  Toxoflavins and Deazaflavins as the First Reported Selective Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase II

  摘要：

  The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAP.) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.

  DOI：

  10.1021/jm400568p