3-(4-methoxyphenyl)-6-methylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione

• 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-methylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione
• 英文别名: 3-(4-Methoxyphenyl)-6-methylpyrimido[5,4-E][1,2,4]triazine-5,7(6H,8H)-dione；3-(4-methoxyphenyl)-6-methyl-8H-pyrimido[5,4-e][1,2,4]triazine-5,7-dione
• 化学式: C₁₃H₁₁N₅O₃
• 分子量: 285.262
• InChiKey: IWFHUQMQPDIHEG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  97.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(4-methoxyphenyl)-6-methylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione 在 乙醇 、 sodium hydroxide 、 盐酸 作用下， 以 乙醇 、 水 为溶剂， 以60%的产率得到3-(4-methoxyphenyl)-5-methyl-5H-imidazo[4,5-e][1,2,4]triazin-6(7H)-one
  参考文献：
  名称：

  转化黄素和Reumycins（7-Azapteridines）合成6-氮杂嘌呤及其细胞毒性

  摘要：

  本文介绍了一种可靠且简便的合成6-氮杂uri啶酮，1,5-二甲基-1 H-咪唑并[4,5- e ] [1,2,4]三嗪-6（5 H）-ones和5-甲基-5 H-咪唑并[4,5- e ] [1,2,4]三嗪-6（7 H）-一，通过在10-70°C或回流下用10％氢氧化钠或乙醇乙醇溶液处理毒素黄素和瑞霉素，然后通过空气脱羧和氧化以及苯甲酸类型重排。此外，将产生的6-氮杂嘌呤在10％乙醇氢氧化钠中加热，得到具有1-甲基脲的相应的1-甲基-5,6-二氧代-1,4,5,6-四氢-1,2,4-三嗪。还研究了6-氮杂嘌呤类药物对CCRF-HSB-2（人类T细胞急性淋巴母细胞性白血病）和KB（人类口腔表皮样癌）细胞系的抗肿瘤活性，其中某些化合物显示出预期的抗肿瘤活性。

  DOI：

  10.1071/ch14425
• 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 17.0h， 生成 3-(4-methoxyphenyl)-6-methylpyrimido[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

• 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。
• YONEDA F.; KAWAMURA M.; NAGAMATSU T.; KURETANI K.; HOSHI A.; IOQO M., HETEROCYCLES, 1976, 4, NO 9, 1503-1508
  作者：YONEDA F.、 KAWAMURA M.、 NAGAMATSU T.、 KURETANI K.、 HOSHI A.、 IOQO M.

  DOI：——

  日期：——
• YONEDA FUMIO; NOGUCHI MITSUKO; NODA MITSUE; NITTA YOSHIHIRO, CHEM. AND PHARM. BULL., 1078, 62, NO 10, 3154-3160
  作者：YONEDA FUMIO、 NOGUCHI MITSUKO、 NODA MITSUE、 NITTA YOSHIHIRO

  DOI：——

  日期：——
• 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.
• Synthesis of 6-Azapurines by Transformation of Toxoflavins and Reumycins (7-Azapteridines) and their Cytotoxicities
  作者：Jun Ma、Fumio Yoneda、Tomohisa Nagamatsu

  DOI：10.1071/ch14425

  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 and 5-methyl-5H-imidazo[4,5-e][1,2,4]triazin-6(7H)-ones, by treatment of toxoflavins and reumycins with 10 % aqueous or ethanolic sodium hydroxide at 5–70°C or reflux, followed by decarboxylation and oxidation by air along with a benzilic acid type rearrangement. Furthermore

  本文介绍了一种可靠且简便的合成6-氮杂uri啶酮，1,5-二甲基-1 H-咪唑并[4,5- e ] [1,2,4]三嗪-6（5 H）-ones和5-甲基-5 H-咪唑并[4,5- e ] [1,2,4]三嗪-6（7 H）-一，通过在10-70°C或回流下用10％氢氧化钠或乙醇乙醇溶液处理毒素黄素和瑞霉素，然后通过空气脱羧和氧化以及苯甲酸类型重排。此外，将产生的6-氮杂嘌呤在10％乙醇氢氧化钠中加热，得到具有1-甲基脲的相应的1-甲基-5,6-二氧代-1,4,5,6-四氢-1,2,4-三嗪。还研究了6-氮杂嘌呤类药物对CCRF-HSB-2（人类T细胞急性淋巴母细胞性白血病）和KB（人类口腔表皮样癌）细胞系的抗肿瘤活性，其中某些化合物显示出预期的抗肿瘤活性。