NUC-3373 | 1332837-31-6

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: NUC-3373
• 英文别名: 5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl(benzoxy-L-alaninyl)]phosphate；Fosifloxuridine Nafalbenamide；benzyl (2S)-2-[[[(2R,3S,5R)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-naphthalen-1-yloxyphosphoryl]amino]propanoate
• CAS: 1332837-31-6
• 化学式: C₂₉H₂₉FN₃O₉P
• 分子量: 613.536
• InChiKey: BIOWRMNRHMERIO-ZVAHOJSLSA-N

物化性质

• 密度：
  1.47±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：100 mg/mL（162.99 mM；需要超声波）

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  43
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  153
• 氢给体数：
  3
• 氢受体数：
  11

安全信息

• 储存条件：
  -20°C，密闭保存，干燥环境

制备方法与用途

NUC-3373是一种基于磷酰胺单磷酸盐形式的5-氟-2'-脱氧尿苷前药，它可转化为活性代谢物氟尿嘧啶，并作为嘧啶核苷的抗代谢物和氟嘧啶类似物，具有潜在的抗肿瘤活性。

反应信息

• 作为反应物：
  描述：

  NUC-3373 在 水 、 三乙胺 、 氨 作用下， 以 水 、 异丙醇 为溶剂， 反应 16.0h， 以30%的产率得到5-fluoro-2'-deoxyuridine 5'-O-[(L-alaninyl)]phosphate ammonium salt
  参考文献：
  名称：

  The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5-fluoro-2′-deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes

  摘要：

  A novel phosphoramidate nucleotide prodrug of the anticancer nucleoside analogue 5-fluoro-2'-deoxyuridine (5-FdUrd) was synthesized and evaluated for its cytostatic activity. Whereas 5-FdUrd substantially lost its cytostatic potential in thymidine kinase (TK)-deficient murine leukaemia L1210 and human lymphocyte CEM cell cultures, NUC-3073 markedly kept its antiproliferative activity in TK-deficient tumour cells, and thus is largely independent of intracellular TK activity to exert its cytostatic action. NUC-3073 was found to inhibit thymidylate synthase (TS) in the TK-deficient and wild-type cell lines at drug concentrations that correlated well with its cytostatic activity in these cells. NUC-3073 does not seem to be susceptible to inactivation by catabolic enzymes such as thymidine phosphorylase (TP) and uridine phosphorylase (UP). These findings are in line with our observations that 5-FdUrd, but not NUC-3073, substantially loses its cytostatic potential in the presence of TP-expressing mycoplasmas in the tumour cell cultures. Therefore, we propose NUC-3073 as a novel 5-FdUrd phosphoramidate prodrug that (i) may circumvent potential resistance mechanisms of tumour cells (e.g. decreased TK activity) and (ii) is not degraded by catabolic enzymes such as TP which is often upregulated in tumour cells or expressed in mycoplasma-infected tumour tissue. (C) 2011 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2011.05.024
• 作为产物：
  描述：

  1-萘基二氯磷酸酯 在 叔丁基氯化镁 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 13.5h， 生成 NUC-3373
  参考文献：
  名称：

  核苷磷酸酯/酰胺衍生物及其医药用途

  摘要：

  本发明涉及式I所示的核苷磷酸酯/酰胺衍生物，及其异构体，及其非毒性药学上可接受的盐，及其溶剂合物：式I中，Nu代表如下解结构的核苷残基：R1选自碳原子数1‑5的烷基、碳原子数1‑7的环烷基、或碳原子数1‑8的芳香炕基；R2选自H或碳原子数1‑5的烷基；P原子上取代基的构型为R型或S型。

  公开号：

  CN109134568B

文献信息

• [EN] PHOSPHORAMIDATE DERIVATIVES OF 5 - FLUORO - 2 ' - DEOXYURIDINE FOR USE IN THE TREATMENT OF CANCER<br/>[FR] DÉRIVÉS PHOSPHORAMIDATES DE 5-FLUORO-2'- DÉSOXYURIDINE DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT D'UN CANCER
  申请人：NUCANA BIOMED LTD

  公开号：WO2012117246A1

  公开（公告）日：2012-09-07

  Phosphoramidate derivatives of 5-fluoro-2'-deoxyuridine are disclosed for use in the treatment of cancer, especially in the treatment of cancer where the patient shows resistance, for example, in a patient with cells with a lowered level of nucleoside transporter proteins and/or with nucleoside kinase-deficient cells and/or with mycoplasma-infected cells and/or with cells with a raised level of thymidylate synthase.

  5-氟-2'-脱氧尿苷的磷酰胺酸衍生物被揭示用于治疗癌症，特别是在治疗患者出现抗药性的情况下，例如，在具有降低核苷转运蛋白水平和/或核苷激酶缺陷细胞和/或受到支原体感染细胞和/或具有升高脱氧胸苷酸合成酶水平的细胞的患者。
• PHOSPHORAMIDATE DERIVATIVES OF 5 - FLUORO - 2` - DEOXYURIDINE FOR USE IN THE TREATMENT OF CANCER
  申请人：McGuigan Christopher

  公开号：US20140057866A1

  公开（公告）日：2014-02-27

  Phosphoramidate derivatives of 5-fluoro-2′-deoxyuridine are disclosed for use in the treatment of cancer, especially in the treatment of cancer where the patient shows resistance, for example, in a patient with cells with a lowered level of nucleoside transporter proteins and/or with nucleoside kinase-deficient cells and/or with mycoplasma-infected cells and/or with cells with a raised level of thymidylate synthase.

  本发明公开了用于治疗癌症的5-氟-2'-脱氧尿嘧啶的磷酰胺衍生物，特别是用于治疗患有耐药性的癌症的情况，例如，在患有核苷转运蛋白水平降低的细胞、核苷激酶缺陷细胞、支原体感染细胞或胸苷酸合成酶水平升高的细胞的患者中。
• Phosphoramidate derivatives of 5-fluoro-2′-deoxyuridine for use in the treatment of cancer
  申请人：McGuigan Christopher

  公开号：US08933053B2

  公开（公告）日：2015-01-13

  Phosphoramidate derivatives of 5-fluoro-2′-deoxyuridine are disclosed for use in the treatment of cancer, especially in the treatment of cancer where the patient shows resistance, for example, in a patient with cells with a lowered level of nucleoside transporter proteins and/or with nucleoside kinase-deficient cells and/or with mycoplasma-infected cells and/or with cells with a raised level of thymidylate synthase.

  本发明公开了5-氟-2'-脱氧尿嘧啶的磷酰胺衍生物，用于治疗癌症，特别是用于治疗患者表现出耐药性的癌症，例如在具有降低核苷转运蛋白水平和/或核苷激酶缺陷细胞和/或支原体感染细胞和/或胸腺嘧啶酸合成酶升高水平的细胞的患者中。
• Phosphoramidate ProTides of the Anticancer Agent FUDR Successfully Deliver the Preformed Bioactive Monophosphate in Cells and Confer Advantage over the Parent Nucleoside
  作者：Christopher McGuigan、Paola Murziani、Magdalena Slusarczyk、Blanka Gonczy、Johan Vande Voorde、Sandra Liekens、Jan Balzarini

  DOI：10.1021/jm200815w

  日期：2011.10.27

  The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependence of the current drugs on active transport and nucleoside kinase-mediated activation. They are also resistant to metabolic deactivation by phosphorolytic enzymes. We report 39 ProTides of the fluorinated pyrimidine FUDR with variation in the aryl, ester, and amino acid. regions. Notably, only certain ProTide motifs are successful in delivering the nucleoside monophosphate into intact cells. We also find that the ProTides retain activity in mycoplasma infected cells, unlike FUDR. Data suggest these compounds to be worthy of further progression.
• 核苷磷酸酯/酰胺衍生物及其医药用途
  申请人：北京美倍他药物研究有限公司

  公开号：CN109134568B

  公开（公告）日：2022-11-22

  本发明涉及式I所示的核苷磷酸酯/酰胺衍生物，及其异构体，及其非毒性药学上可接受的盐，及其溶剂合物：式I中，Nu代表如下解结构的核苷残基：R1选自碳原子数1‑5的烷基、碳原子数1‑7的环烷基、或碳原子数1‑8的芳香炕基；R2选自H或碳原子数1‑5的烷基；P原子上取代基的构型为R型或S型。