4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoic acid
• 英文别名: 4-(2,4,6-trioxo-tetrahydro-pyrimidin-5-ylidenehydrazino)-benzoic acid；4-(2,4,6-Trioxo-tetrahydro-pyrimidin-5-ylidenhydrazino)-benzoesaeure；4-[2-(2,4,6-trioxo-1,3-diazinan-5-ylidene)hydrazinyl]benzoic acid
• 化学式: C₁₁H₈N₄O₅
• mdl: MFCD01011562
• 分子量: 276.208
• InChiKey: YFBVHTQHOCUABL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.48
• 重原子数：
  20.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  136.96
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  巴比妥酸 、 4-肼基苯甲酸 在 盐酸 、 sodium hydroxide 、 sodium nitrite 作用下， 以 水 为溶剂， 反应 1.0h， 以67%的产率得到4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoic acid
  参考文献：
  名称：

  2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile as novel inhibitor of receptor tyrosine kinase and PI3K/AKT/mTOR signaling pathway in glioblastoma

  摘要：

  Nerve growth factor receptor (NGFR), a member of kinase protein, is emerging as an important target for Glioblastoma (GBM) treatment. Overexpression of NGFR is observed in many metastatic cancers including GBM, promoting tumor migration and invasion. Hydrazones have been reported to effectively interact with receptor tyrosine kinases (RTKs). We report herein the synthesis of 23 arylhydrazones of active methylene compounds (AHAMCs) compounds and their anti-proliferative activity against GBM cell lines, LN229 and U87. Compound 8234, 2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile, was identified as the most active anti-neoplastic compound, with the IC50 value ranging 87 mu M - 107 mu M Molecular docking simulations of the synthesized compounds into the active site of tyrosine receptor kinase A (TrkA), demonstrated a strong binding affinity with 8234 and concurs well with the obtained biological results. 8234 was found to be a negative regulator of PI3K/Akt/mTOR pathway and an enhancer of p53 expression. In addition, 8234 treated GBM cells exhibited the downregulation of cyclins, cyclin-dependent kinases and other key molecules involved in cell cycle such as CCNE, E2F, CCND, CDK6, indicating that 8234 induces cell cycle arrest at G1/S. R234 also exerted its apoptotic effects independent of caspase3/7 activity, in both cell lines. In U87 cells, 8234 induced oxidative effects whereas LN229 cells annulled oxidative stress. The study thus concludes that 8234, being a negative modulator of RTKs and cell cycle inhibitor, may represent a novel class of anti-GBM drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.01.021

文献信息

• Synthesen in der Lumiflavinreihe
  作者：P. Hemmerich、S. Fallab、H. Erlenmeyer

  DOI：10.1002/hlca.19560390511

  日期：——

  A short way for the synthesis of lumiflavin and derivatives is developed, leading to the new structural analogues 2-thiolumiflavine and 2-lumiflavimine, which exhibit interesting oxido-reductive and metal chelating properties and may be riboflavin antirnetabolites.

  开发了一种合成鲁米黄素及其衍生物的捷径，从而产生了新的结构类似物2-硫代鲁米黄素和2-鲁米拉维明，它们表现出令人感兴趣的氧化还原和金属螯合性能，并且可能是核黄素抗金属代谢物。
• Synthesis, activity evaluation, and docking analysis of barbituric acid aryl hydrazone derivatives as RSK2 inhibitors
  作者：Mengzhu Xue、Minghao Xu、Weiqiang Lu、Jin Huang、Honglin Li、Yufang Xu、Xiaofeng Liu、Zhenjiang Zhao

  DOI：10.3109/14756366.2012.681651

  日期：2013.8.1

  The 90 kDa ribosomal S6 kinases (RSKs), especially RSK2, have attracted attention for the development of new anticancer agents. Through structural optimization of the hit compound 1 from our previous study, a series of barbituric acid aryl hydrazone analogues were designed and synthesized as potential RSK2 inhibitors. The most potent one, compound 9, showed a higher activity against RSK2 with an IC50 value of 1.95 mu M. To analyze and elucidate their structure-activity relationship, the homology model of RSK2 N-terminal kinase domain was built and molecular docking simulations were performed, which provide helpful clues to design new inhibitors with desired activities.
• 2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile as novel inhibitor of receptor tyrosine kinase and PI3K/AKT/mTOR signaling pathway in glioblastoma
  作者：Anisha Viswanathan、Dinesh Kute、Aliyu Musa、Saravanan Konda Mani、Vili Sipilä、Frank Emmert-Streib、Fedor I. Zubkov、Atash V. Gurbanov、Olli Yli-Harja、Meenakshisundaram Kandhavelu

  DOI：10.1016/j.ejmech.2019.01.021

  日期：2019.3

  Nerve growth factor receptor (NGFR), a member of kinase protein, is emerging as an important target for Glioblastoma (GBM) treatment. Overexpression of NGFR is observed in many metastatic cancers including GBM, promoting tumor migration and invasion. Hydrazones have been reported to effectively interact with receptor tyrosine kinases (RTKs). We report herein the synthesis of 23 arylhydrazones of active methylene compounds (AHAMCs) compounds and their anti-proliferative activity against GBM cell lines, LN229 and U87. Compound 8234, 2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile, was identified as the most active anti-neoplastic compound, with the IC50 value ranging 87 mu M - 107 mu M Molecular docking simulations of the synthesized compounds into the active site of tyrosine receptor kinase A (TrkA), demonstrated a strong binding affinity with 8234 and concurs well with the obtained biological results. 8234 was found to be a negative regulator of PI3K/Akt/mTOR pathway and an enhancer of p53 expression. In addition, 8234 treated GBM cells exhibited the downregulation of cyclins, cyclin-dependent kinases and other key molecules involved in cell cycle such as CCNE, E2F, CCND, CDK6, indicating that 8234 induces cell cycle arrest at G1/S. R234 also exerted its apoptotic effects independent of caspase3/7 activity, in both cell lines. In U87 cells, 8234 induced oxidative effects whereas LN229 cells annulled oxidative stress. The study thus concludes that 8234, being a negative modulator of RTKs and cell cycle inhibitor, may represent a novel class of anti-GBM drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.