6-(2-(4-methoxybenzylidene)-1-methylhydrazinyl)-3-methylpyrimidine-2,4(1H,3H)-dione | 42748-18-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 6-(2-(4-methoxybenzylidene)-1-methylhydrazinyl)-3-methylpyrimidine-2,4(1H,3H)-dione
• 英文别名: 6-[[(4-methoxyphenyl)methylideneamino]-methylamino]-3-methyl-1H-pyrimidine-2,4-dione
• CAS: 42748-18-5
• 化学式: C₁₄H₁₆N₄O₃
• 分子量: 288.306
• InChiKey: COYKSOPJHLZTBA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  74.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-(2-(4-methoxybenzylidene)-1-methylhydrazinyl)-3-methylpyrimidine-2,4(1H,3H)-dione 在 caesium carbonate 、 溶剂黄146 、 硫酸二甲酯 、 sodium nitrite 作用下， 以 水 、 丙酮 为溶剂， 反应 3.0h， 生成 3 - ( 4 - Methoxyphenyl ) - fervenulin
  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-氯-3-甲基尿嘧啶 以 乙醇 为溶剂， 反应 5.0h， 生成 6-(2-(4-methoxybenzylidene)-1-methylhydrazinyl)-3-methylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  一类蛋白质二硫键异构酶抑制剂治疗胶质母细胞瘤的发现和机理研究

  摘要：

  蛋白质二硫键异构酶（PDI）在胶质母细胞瘤（脑癌的最具侵略性形式）中过表达，并且折叠负责该疾病进展和传播的新生蛋白质。在这里，我们描述了一种新型的纳摩尔PDI抑制剂，嘧啶三嗪二酮35G8，在一组人胶质母细胞瘤细胞系中具有毒性。我们对1 000 000种化合物的不同子集进行了中通量20000化合物筛查，以鉴定具有细胞毒性的小分子。对细胞毒性化合物进行了PDI抑制作用的筛选，并且从筛选物中发现35G8是PDI最具细胞毒性的抑制剂。新生RNA的溴尿苷标记和测序（Bru-seq）表明35G8诱导类似核因子2（Nrf2）的抗氧化反应，内质网（ER）应激反应和自噬。具体而言，35G8上调了血红素加氧酶1和溶质载体家族7成员11（SLC7A11）的转录和蛋白质表达，并抑制了PDI靶基因，如硫氧还蛋白相互作用蛋白1（TXNIP）和早期生长反应1（EGR1）。有趣的是，35G8诱导的细胞死亡不是通过细胞凋亡

  DOI：

  10.1002/cmdc.201700629

文献信息

• Microwave-assisted synthesis of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione libraries: derivatives of toxoflavin
  作者：Nick Todorovic、Andrew Giacomelli、John A. Hassell、Christopher S. Frampton、Alfredo Capretta

  DOI：10.1016/j.tetlet.2010.09.044

  日期：2010.11

  The parallel synthesis of a library of toxoflavin derivatives is described. The microwave-assisted approach involves the de novo generation of the heterocyclic scaffold and allows for facile introduction of a variety of fragments.

  描述了一种平行合成的毒素类黄素衍生物的文库。微波辅助方法涉及从头产生杂环支架，并允许容易地引入各种片段。
• The Facile Synthesis of 6-Azapurines by Transformation of Toxoflavins (7-Azapteridines)
  作者：Tomohisa Nagamatsu、Jun Ma、Fumio Yoneda

  DOI：10.3987/com-08-s(f)111

  日期：——

  - This paper describes a reliable and facile synthesis of 6-azapurines (1,5-dimethyl-1H-imidazo[4,5-e][1,2,4]triazin-6(5H)-ones) by treatment of toxoflavins (7-azapteridines) with 10% aqueous sodium hydroxide at 5-25 °C along with a benzilic acid type rearrangement, followed by decarboxylation and oxidation by air. Furthermore, heating the 6-azapurines in 10% ethanolic sodium hydroxides afforded the

  - 本文描述了通过处理毒黄素可靠而简便地合成 6-氮杂嘌呤 (1,5-dimethyl-1H-imidazo[4,5-e][1,2,4]triazin-6(5H)-ones) (7-azapteridines) 与 10% 氢氧化钠水溶液在 5-25 °C 下进行苯甲酸型重排，然后通过空气进行脱羧和氧化。此外，在 10% 乙醇氢氧化钠中加热 6-氮杂嘌呤，得到相应的 1,2,4-三嗪-5,6(1H,4H)-二酮，这是由 6-氮杂嘌呤的咪唑环裂变引起的。
• 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.
• Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma
  作者：Anahita Kyani、Shuzo Tamura、Suhui Yang、Andrea Shergalis、Soma Samanta、Yuting Kuang、Mats Ljungman、Nouri Neamati

  DOI：10.1002/cmdc.201700629

  日期：2018.1.22

  Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium‐throughput 20 000‐compound screen of a diverse

  蛋白质二硫键异构酶（PDI）在胶质母细胞瘤（脑癌的最具侵略性形式）中过表达，并且折叠负责该疾病进展和传播的新生蛋白质。在这里，我们描述了一种新型的纳摩尔PDI抑制剂，嘧啶三嗪二酮35G8，在一组人胶质母细胞瘤细胞系中具有毒性。我们对1 000 000种化合物的不同子集进行了中通量20000化合物筛查，以鉴定具有细胞毒性的小分子。对细胞毒性化合物进行了PDI抑制作用的筛选，并且从筛选物中发现35G8是PDI最具细胞毒性的抑制剂。新生RNA的溴尿苷标记和测序（Bru-seq）表明35G8诱导类似核因子2（Nrf2）的抗氧化反应，内质网（ER）应激反应和自噬。具体而言，35G8上调了血红素加氧酶1和溶质载体家族7成员11（SLC7A11）的转录和蛋白质表达，并抑制了PDI靶基因，如硫氧还蛋白相互作用蛋白1（TXNIP）和早期生长反应1（EGR1）。有趣的是，35G8诱导的细胞死亡不是通过细胞凋亡