3-(4-methoxyphenyl)-6-methyl-1-phenylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione | 1146960-08-8

• 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-methoxyphenyl)-6-methyl-1-phenylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione
• 英文别名: 3-(4-Methoxyphenyl)-6-methyl-1-phenylpyrimido[5,4-e][1,2,4]triazine-5,7-dione；3-(4-methoxyphenyl)-6-methyl-1-phenylpyrimido[5,4-e][1,2,4]triazine-5,7-dione
• CAS: 1146960-08-8
• 化学式: C₁₉H₁₅N₅O₃
• 分子量: 361.36
• InChiKey: JAIGDRNZUDSMNO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  86.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(4-methoxyphenyl)-6-methyl-1-phenylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione 在 三溴化硼 、 caesium carbonate 作用下， 以 乙醇 、 二氯甲烷 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 29.0h， 生成 3-[4-(2-(dimethylamino)ethoxy)phenyl]-6-methyl-1-phenyl-1H-pyrimido[5,4-e][1,2,4]triazine-5,7-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
• 作为产物：
  描述：

  6-(2-(4-methoxybenzylidene)-1-phenylhydrazinyl)-3-methyl-5-nitropyrimidine-2,4(1H,3H)-dione 在 氯化铵 、 锌 作用下， 以 乙醇 、 水 为溶剂， 以78%的产率得到3-(4-methoxyphenyl)-6-methyl-1-phenylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione
  参考文献：
  名称：

  N1-(取代)-嘧啶[5,4-e]-1,2,4-三嗪-5,7(1H,6H)-二酮的新合成

  摘要：

  N 1 -(取代)-嘧啶基[5,4- e ]-1,2,4-三嗪-5,7(1 H ,6 H ) -二酮的新合成，它们是天然产物毒素黄素的类似物，被报道。预先形成的烷基或芳基腙与 6-氯-3-甲基-5-硝基尿嘧啶的缩合可通过三步法有效地提供嘧啶并三嗪二酮，从而拓宽了 R 1取代基的范围。

  DOI：

  10.1016/j.tetlet.2009.02.084

文献信息

• A New Route to Substituted Pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones and Facile Extension to 5,7(6H,8H) Isomers
  作者：H. Showalter、Anjanette Turbiak

  DOI：10.1055/s-0029-1217030

  日期：2009.12

  pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones is outlined. The synthesis proceeds via pre-formed hydrazone intermediates, which are then condensed with an activated chlorouracil to build up the entire molecular framework, followed by a reductive ring closure to provide the parent series. The route has been extended to the isomeric pyrimido[5,4-e]-1,2,4-triazine-5,7(6H,8H)-dione class via the use of methylhydrazine

  概述了取代嘧啶并[5,4-e]-1,2,4-三嗪-5,7(1H,6H)-二酮的新途径。合成通过预先形成的腙中间体进行，然后将其与活化的氯尿嘧啶缩合以建立整个分子框架，然后进行还原闭环以提供母体系列。通过使用甲基肼作为肼替代物，该路线已扩展到异构嘧啶并[5,4-e]-1,2,4-三嗪-5,7(6H,8H)-二酮类，然后进行区域特异性烷基化具有一系列烷基和烷芳基取代基的 N(8)-H 嘧啶并三嗪二酮。这种新方法允许在 N(1)、C(3) 和 N(8) 位置生成各种具有可变替换的化合物，用于具有证明药理活性的杂环支架。
• 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.
• A novel synthesis of N1-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones
  作者：Anjanette J. Turbiak、H.D. Hollis Showalter

  DOI：10.1016/j.tetlet.2009.02.084

  日期：2009.4

  A new synthesis of N1-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, which are analogues of the natural product toxoflavin, is reported. Condensation of preformed alkyl or aryl hydrazones with 6-chloro-3-methyl-5-nitrouracil efficiently provides pyrimidotriazinediones in a three-step process that broadens the scope of R1 substituents.

  N 1 -(取代)-嘧啶基[5,4- e ]-1,2,4-三嗪-5,7(1 H ,6 H ) -二酮的新合成，它们是天然产物毒素黄素的类似物，被报道。预先形成的烷基或芳基腙与 6-氯-3-甲基-5-硝基尿嘧啶的缩合可通过三步法有效地提供嘧啶并三嗪二酮，从而拓宽了 R 1取代基的范围。