3-(4-(2-(diethylamino)ethoxy)phenyl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione | 1207377-61-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 3-(4-(2-(diethylamino)ethoxy)phenyl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione
• 英文别名: 3-[4-[2-(diethylamino)ethoxy]phenyl]-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7-dione
• CAS: 1207377-61-4
• 化学式: C₁₉H₂₄N₆O₃
• 分子量: 384.438
• InChiKey: JXHDDTBSACSQBZ-UHFFFAOYSA-N

物化性质

• 沸点：
  491.5±55.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  90.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-甲基-6-(1-甲基肼基)-2,4(1H,3H)-嘧啶二酮 在 溶剂黄146 、 sodium nitrite 作用下， 以 乙醇 、 水 为溶剂， 反应 16.0h， 生成 3-(4-(2-(diethylamino)ethoxy)phenyl)-1,6-dimethylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione
  参考文献：
  名称：

  Investigation of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-diones as small molecule antagonists of β-catenin/TCF transcription

  摘要：

  Nearly all colorectal cancers (CRCs) and varied subsets of other cancers have somatic mutations leading to beta-catenin stabilization and increased beta-catenin/TCF transcriptional activity. Inhibition of stabilized beta-catenin in CRC cell lines arrests their growth and highlights the potential of this mechanism for novel cancer therapeutics. We have pursued efforts to develop small molecules that inhibit beta-catenin/TCF transcriptional activity. We used xanthothricin, a known beta-catenin/TCF antagonist of microbial origin, as a lead compound to synthesize related analogues with drug-like features such as low molecular weight and good metabolic stability. We studied a panel of six candidate Wnt/beta-catenin/Tcf-regulated genes and found that two of them (Axin2, Lgr5) were reproducibly activated (9-10 fold) in rat intestinal epithelial cells (IEC-6) following beta-catenin stabilization by Wnt-3a ligand treatment. Two previously reported beta-catenin/TCF antagonists (calphostin C, xanthothricin) and XAV939 (tankyrase antagonist) inhibited Wnt-activated genes in a dose-dependent fashion. We found that four of our compounds also potently inhibited Wnt-mediated activation in the panel of target genes. We investigated the mechanism of action for one of these (8c) and demonstrated these novel small molecules inhibit beta-catenin transcriptional activity by degrading beta-catenin via a proteasome-dependent, but GSK3 beta-, APC-, AXIN2- and beta TrCP-independent, pathway. The data indicate the compounds act at the level of beta-catenin to inhibit Wnt/beta-catenin/TCF function and highlight a robust strategy for assessing the activity of beta-catenin/TCF antagonists. (c) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.08.111

文献信息

• Pyrimidotriazinediones and Pyrimidopyrimidinediones and Methods of Using the Same
  申请人：Showalter H.D. H.

  公开号：US20110166144A1

  公开（公告）日：2011-07-07

  The present disclosure is directed to pyrimidotriazinediones and pyrimidopyrimidinediones having a formula (I), (II), or (III), or a mixture or pharmaceutically acceptable salt or hydrate thereof, and to methods of treating cancer comprising administering the same.
• [EN] PYRIMIDOTRIAZINEDIONES AND PYRIMIDOPYRIMIDINEDIONES AND METHODS OF USING THE SAME<br/>[FR] PYRIMIDOTRIAZINEDIONES ET PYRIMIDOPYRIMIDINEDIONES ET PROCÉDÉS D'UTILISATION
  申请人：UNIV MICHIGAN

  公开号：WO2010014798A2

  公开（公告）日：2010-02-04

  The present disclosure is directed to pyrimidotriazinediones and pyrimidopyrimidinediones having a formula (I), (II), or (III), or a mixture or pharmaceutically acceptable salt or hydrate thereof, and to methods of treating cancer comprising administering the same.
• Investigation of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-diones as small molecule antagonists of β-catenin/TCF transcription
  作者：Jörg Zeller、Anjanette J. Turbiak、Ian A. Powelson、Surin Lee、Duxin Sun、H.D. Hollis Showalter、Eric R. Fearon

  DOI：10.1016/j.bmcl.2013.08.111

  日期：2013.11

  Nearly all colorectal cancers (CRCs) and varied subsets of other cancers have somatic mutations leading to beta-catenin stabilization and increased beta-catenin/TCF transcriptional activity. Inhibition of stabilized beta-catenin in CRC cell lines arrests their growth and highlights the potential of this mechanism for novel cancer therapeutics. We have pursued efforts to develop small molecules that inhibit beta-catenin/TCF transcriptional activity. We used xanthothricin, a known beta-catenin/TCF antagonist of microbial origin, as a lead compound to synthesize related analogues with drug-like features such as low molecular weight and good metabolic stability. We studied a panel of six candidate Wnt/beta-catenin/Tcf-regulated genes and found that two of them (Axin2, Lgr5) were reproducibly activated (9-10 fold) in rat intestinal epithelial cells (IEC-6) following beta-catenin stabilization by Wnt-3a ligand treatment. Two previously reported beta-catenin/TCF antagonists (calphostin C, xanthothricin) and XAV939 (tankyrase antagonist) inhibited Wnt-activated genes in a dose-dependent fashion. We found that four of our compounds also potently inhibited Wnt-mediated activation in the panel of target genes. We investigated the mechanism of action for one of these (8c) and demonstrated these novel small molecules inhibit beta-catenin transcriptional activity by degrading beta-catenin via a proteasome-dependent, but GSK3 beta-, APC-, AXIN2- and beta TrCP-independent, pathway. The data indicate the compounds act at the level of beta-catenin to inhibit Wnt/beta-catenin/TCF function and highlight a robust strategy for assessing the activity of beta-catenin/TCF antagonists. (c) 2013 Elsevier Ltd. All rights reserved.