((2R,3R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate | 1062136-15-5

• 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: ((2R,3R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate
• 英文别名: 2',2'-difluorodeoxyuridine triphosphate；dF-dUTP；2',2'-Difluorodeoxyuridine 5'-triphosphate；[[(2R,3R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4,4-difluoro-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate
• CAS: 1062136-15-5
• 化学式: C₉H₁₃F₂N₂O₁₄P₃
• 分子量: 504.125
• InChiKey: ZSLPPDIWQJYAFN-QPPQHZFASA-N

物化性质

• 密度：
  2.07±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -4.9
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  239
• 氢给体数：
  6
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  (2R,3R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl acetate 在 吡啶 、 2-氯-1,3,2-苯并二氧磷杂环己烷-4-酮 、 三正丁胺 、 tri-n-butylamine pyrophosphate 、 碘 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 水 为溶剂， 反应 0.5h， 以10%的产率得到((2R,3R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate
  参考文献：
  名称：

  发现β-d-2'-deoxy-2'-二氯尿苷核苷酸前药作为丙型肝炎病毒复制的有效抑制剂

  摘要：

  索非布韦的发现从根本上改变了丙型肝炎的治疗，核苷/潮 NS5B 抑制剂现在被视为与其他直接作用抗病毒药物联合治疗的关键成分之一。作为我们确定新的 HCV 复制核苷抑制剂计划的一部分，我们现在希望报告 β- d的发现-2'-脱氧-2'-二氯尿苷核苷酸前药作为 HCV 复制的有效抑制剂。尽管早已认识到胞苷类似物通过胞苷脱氨酶的作用代谢为胞苷和三磷酸尿苷，但通常认为尿苷类似物仅产生三磷酸尿苷。对我们新发现的尿苷前药以及索非布韦的细胞内代谢的详细研究现已揭示了尿苷和三磷酸胞苷的形成。这不仅发生在细胞系的体外，而且在狗口服给药后也发生在体内。

  DOI：

  10.1016/j.bmcl.2017.05.075

文献信息

• Facile Small Scale Synthesis of Nucleoside 5′-Phosphate Mixtures
  作者：Robert S. Jansen、Hilde Rosing、Jan HM Schellens、Jos H. Beijnen

  DOI：10.1080/15257770903451546

  日期：2010.1

  phosphorylate small amounts of nucleosides (0.05 μmol) into mixtures of their 5′-mono-, di-, and triphosphates in a one-pot reaction. The nucleosides were first converted into their dichlorophosphates using a large excess (15–18 equivalents) of phosphorous oxychloride in trimethylphosphate. The large excess resulted in good dichlorophosphate yields (46–76%) for the four nucleosides tested. Upon the addition

  我们提出了一种简便的方法，可以在一锅反应中将少量的核苷（0.05μmol）磷酸化为5'-单-，二-和三磷酸的混合物。首先使用磷酸三甲酯中大量过量的氯氧化磷（15-18当量）将核苷转化为其二氯磷酸酯。大量过量导致所测试的四种核苷的二氯磷酸酯收率良好（46–76％）。在将磷酸三丁铵与另外的三丁胺（均20当量）一起加入后，将二氯磷酸酯转化为含有等量的单磷酸酯，二磷酸酯和三磷酸酯的混合物。所提出的方法已成功地应用于合成稳定同位素标记的核苷酸的混合物，该混合物可用作定量质谱分析中的内标。
• Exploring the Potent Inhibition of CTP Synthase by Gemcitabine-5′-Triphosphate
  作者：Gregory D. McCluskey、Samy Mohamady、Scott D. Taylor、Stephen L. Bearne

  DOI：10.1002/cbic.201600405

  日期：2016.12.2

  Fluorinated nucleotides: Gemcitabine‐5′‐triphosphate, a metabolite of the anticancer drug gemcitabine, is a potent competitive inhibitor of the chemotherapeutic target CTP synthase (CTPS). CTPS can use the corresponding 2′,2′‐difluoro derivative of UTP as a substrate, thus furnishing a mechanism for regenerating the active drug in vivo.

  氟化核苷酸：吉西他滨-5'-三磷酸，抗癌药吉西他滨的代谢产物，是化疗靶标CTP合酶（CTPS）的有效竞争性抑制剂。CTPS可以使用相应的UTP 2'，2'-二氟衍生物作为底物，从而提供了一种在体内再生活性药物的机制。
• Nucleotides for the treatment of liver cancer
  申请人：IDENIX PHARMACEUTICALS LLC

  公开号：US10030044B2

  公开（公告）日：2018-07-24

  Provided herein are compounds, compositions and methods for the treatment of liver cancer such as hepatocellular carcinoma, cholangiocarcinoma, or biliary tract cancer. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-cancer agents. In certain embodiments, the compounds are nucleoside analogs of Formula I: (I); or a pharmaceutically acceptable salt thereof, wherein Base, Z1, Z2, Z3, Z4, V, W, X, Ar, R1 and R2 are as described herein.

  本文提供了用于治疗肝癌（如肝细胞癌、胆管癌或胆道癌）的化合物、组合物和方法。 在某些实施方案中，公开了核苷衍生物的化合物和组合物，可单独或与其他抗癌剂联合使用。 在某些实施方案中，所述化合物为式I的核苷类似物：(I)；或其药学上可接受的盐，其中Base、Z1、Z2、Z3、Z4、V、W、X、Ar、R1和R2如本文所述。
• NUCLEOTIDES FOR THE TREATMENT OF LIVER CANCER
  申请人：IDENIX PHARMACEUTICALS LLC

  公开号：US20170029456A1

  公开（公告）日：2017-02-02

  Provided herein are compounds, compositions and methods for the treatment of liver cancer such as hepatocellular carcinoma, cholangiocarcinoma, or biliary tract cancer. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-cancer agents. In certain embodiments, the compounds are nucleoside analogs of Formula I: (I); or a pharmaceutically acceptable salt thereof, wherein Base, Z 1 , Z 2 , Z 3 , Z 4 , V, W, X, Ar, R 1 and R 2 are as described herein.
• [EN] NUCLEOTIDES FOR THE TREATMENT OF LIVER CANCER<br/>[FR] NUCLÉOTIDES POUR LE TRAITEMENT DU CANCER DU FOIE
  申请人：IDENIX PHARMACEUTICALS INC

  公开号：WO2015081133A2

  公开（公告）日：2015-06-04

  Provided herein are compounds, compositions and methods for the treatment of liver cancer such as hepatocellular carcinoma, cholangiocarcinoma, or biliary tract cancer. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-cancer agents. In certain embodiments, the compounds are nucleoside analogs of Formula I: (I); or a pharmaceutically acceptable salt thereof, wherein Base, Z1, Z2, Z3, Z4, V, W, X, Ar, R1 and R2 are as described herein.