5-fluoro-3-(4-nitrobenzyl)-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione | 98653-15-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-fluoro-3-(4-nitrobenzyl)-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
• 英文别名: 5-fluoro-3-(4-nitrobenzyl)-1-tetrahydrofuran-2-ylpyrimidine-2,4(1H,3H)-dione；5-fluoro-3-[(4-nitrophenyl)methyl]-1-(oxolan-2-yl)pyrimidine-2,4-dione
• CAS: 98653-15-7
• 化学式: C₁₅H₁₄FN₃O₅
• 分子量: 335.292
• InChiKey: AFZTXICWZLCKNC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  95.7
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-fluoro-3-(4-nitrobenzyl)-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione 在 N-甲基吗啉 、 palladium 10% on activated carbon 、 氢气 、 铁粉 、 氯化铵 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 N-(4-((5-fluoro-2,6-dioxo-3-(tetrahydrofuran-2-yl)-3,6-dihydropyrimidin-1(2H)-yl)methyl)phenyl)-2,4-dihydroxy-5-isopropylbenzamide
  参考文献：
  名称：

  Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells

  摘要：

  A major cause of failure of therapy in patients with non-small cell lung cancer (NSCLC) is development of acquired drug resistance leading to tumor recurrence and disease progression. In addition to the development of new generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), different molecular targets may provide opportunities to improve the therapeutic outcomes. In this study, we utilized the core structure 5-fluorouracil (5-FU) or tegafur, a 5-FU prodrug combined through different linkers with resorcinol to generate a series of fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides which inhibit potent Heat Shock Protein 90 (HSP90). These compounds were found to show significant antiproliferative activity in colorectal cancer (CRC) HCT116 and NSCLC A549, H460, and H1975 (EGFR L858R/T790 M double mutation) cells. Compound 12c, developed by molecular docking analysis and enzymatic assays exhibits promising inhibitory activity of HSP90. This compound, 12c shows the most potent HSP90 inhibitory activity with an IC50 value of 27.8 4.4 nM, superior to that of reference compounds AUY-922 (Luminespib) and BlIB021 whose IC50 values are 43.0 0.9 nM and 56.8 4.0 nM respectively. This strong HSP90 inhibitory activity of 12c leads to rapid degradation of client proteins EGFR and Akt in NSCLC cells. In addition, 12c induces significant accumulation of a sub-G1 phase population in parallel with apoptosis by showing activated caspase-3, -8 and -9 and PARP induction. These results provide a new strategy for development of novel HSP90 inhibitors for cancer treatment. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112540
• 作为产物：
  描述：

  2-硝基苄溴 在 potassium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 5-fluoro-3-(4-nitrobenzyl)-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  （邻-和对-硝基苄氧基羰基）-5-氟尿嘧啶衍生物作为潜在的共轭生物还原烷基化剂。

  摘要：

  在三乙胺的存在下，在DMF或Me2SO中，使氯甲酸邻-或对硝基苄基酯与5-氟尿嘧啶反应，合成了一系列（邻-和对硝基苄氧基羰基）-5-氟尿嘧啶衍生物。假设这些试剂的还原活化产生反应性甲基化物和5-氟尿嘧啶，这两种成分能够通过互补抑制产生协同相互作用。在缺氧和需氧条件下，用这些试剂处理的EMT6肿瘤细胞的存活分数的测量可导致相等的细胞杀伤力，而与氧合作用的状态无关。一种合成的药物3-（对硝基苄氧基羰基）-5-氟尿嘧啶（4）在延长带有P388白血病和肉瘤180腹膜内植入物的小鼠的存活时间方面似乎优于5-氟尿嘧啶。

  DOI：

  10.1021/jm00151a014

文献信息

• Pyrimidinedione-mediated selective histone deacetylase 6 inhibitors with antitumor activity in colorectal cancer HCT116 cells
  作者：Yi-Min Liu、Hsueh-Yun Lee、Mei-Jung Lai、Shiow-Lin Pan、Hsiang-Ling Huang、Fei-Chiao Kuo、Mei-Chuan Chen、Jing-Ping Liou

  DOI：10.1039/c5ob01509j

  日期：——

  We synthesized a series of pyrimidinedione derivatives and evaluated their activities.

  我们合成了一系列吡啶二酮衍生物并评估了它们的活性。

• 替加氟衍生物及其用途
  申请人：聊城大学

  公开号：CN113980005A

  公开（公告）日：2022-01-28

  本发明提供一种一种替加氟衍生物及其在制备抗肿瘤药物中的用途，具有下述通式(I)。硝基还原酶介导的替加氟衍生物的降解研究表明该替加氟衍生物在硝基还原酶条件下能够很好降解生成替加氟，体内实验表明该替加氟衍生物具有较好的抗肿瘤活性，且毒副作用小于替加氟和氟尿嘧啶
• Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells
  作者：Wei-Cheng Wu、Yi-Min Liu、Yu-Hsuan Liao、Kai-Cheng Hsu、Ssu-Ting Lien、I-Chung Chen、Mei-Jung Lai、Yu-Hsuan Li、Shiow-Lin Pan、Mei-Chuan Chen、Jing-Ping Liou

  DOI：10.1016/j.ejmech.2020.112540

  日期：2020.10

  A major cause of failure of therapy in patients with non-small cell lung cancer (NSCLC) is development of acquired drug resistance leading to tumor recurrence and disease progression. In addition to the development of new generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), different molecular targets may provide opportunities to improve the therapeutic outcomes. In this study, we utilized the core structure 5-fluorouracil (5-FU) or tegafur, a 5-FU prodrug combined through different linkers with resorcinol to generate a series of fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides which inhibit potent Heat Shock Protein 90 (HSP90). These compounds were found to show significant antiproliferative activity in colorectal cancer (CRC) HCT116 and NSCLC A549, H460, and H1975 (EGFR L858R/T790 M double mutation) cells. Compound 12c, developed by molecular docking analysis and enzymatic assays exhibits promising inhibitory activity of HSP90. This compound, 12c shows the most potent HSP90 inhibitory activity with an IC50 value of 27.8 4.4 nM, superior to that of reference compounds AUY-922 (Luminespib) and BlIB021 whose IC50 values are 43.0 0.9 nM and 56.8 4.0 nM respectively. This strong HSP90 inhibitory activity of 12c leads to rapid degradation of client proteins EGFR and Akt in NSCLC cells. In addition, 12c induces significant accumulation of a sub-G1 phase population in parallel with apoptosis by showing activated caspase-3, -8 and -9 and PARP induction. These results provide a new strategy for development of novel HSP90 inhibitors for cancer treatment. (C) 2020 Elsevier Masson SAS. All rights reserved.
• (o- and p-Nitrobenzyloxycarbonyl)-5-fluorouracil derivatives as potential conjugated bioreductive alkylating agents
  作者：Tai Shun Lin、Lin Wang、Ippolito Antonini、Lucille A. Cosby、David A. Shiba、D. Lynn Kirkpatrick、Alan C. Sartorelli

  DOI：10.1021/jm00151a014

  日期：1986.1

  A series of (o- and p-nitrobenzyloxycarbonyl)-5-fluorouracil derivatives were synthesized by reacting o- or p-nitrobenzyl chloroformate with 5-fluorouracil in the presence of triethylamine in DMF or Me2SO. The reductive activation of these agents was hypothesized to generate a reactive methide and 5-fluorouracil, two components that are capable of synergistic interaction through complementary inhibition

  在三乙胺的存在下，在DMF或Me2SO中，使氯甲酸邻-或对硝基苄基酯与5-氟尿嘧啶反应，合成了一系列（邻-和对硝基苄氧基羰基）-5-氟尿嘧啶衍生物。假设这些试剂的还原活化产生反应性甲基化物和5-氟尿嘧啶，这两种成分能够通过互补抑制产生协同相互作用。在缺氧和需氧条件下，用这些试剂处理的EMT6肿瘤细胞的存活分数的测量可导致相等的细胞杀伤力，而与氧合作用的状态无关。一种合成的药物3-（对硝基苄氧基羰基）-5-氟尿嘧啶（4）在延长带有P388白血病和肉瘤180腹膜内植入物的小鼠的存活时间方面似乎优于5-氟尿嘧啶。