1-[(2R,3S,4R,5R)-3-氟-4-羟基-5-(羟基甲基)四氢呋喃-2-基]嘧啶-2-酮 | 136675-88-2

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 中文名称: 1-[(2R,3S,4R,5R)-3-氟-4-羟基-5-(羟基甲基)四氢呋喃-2-基]嘧啶-2-酮
• 中文别名: 三十三烷-1-醇
• 英文名称: 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)pyrimidin-2(1H)-one
• 英文别名: 2'-fluoro-2'-deoxyzebularine；2'-deoxy-2'-β-fluorozebularine；1-[(2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
• CAS: 136675-88-2
• 化学式: C₉H₁₁FN₂O₄
• 分子量: 230.196
• InChiKey: WQIKHPATWLOZFO-ULAWRXDQSA-N

物化性质

• 沸点：
  452.9±55.0 °C(Predicted)
• 密度：
  1.67±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  82.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-[(2R,3S,4R,5R)-3-氟-4-羟基-5-(羟基甲基)四氢呋喃-2-基]嘧啶-2-酮 、 phenyl(benzyloxy-L-alaninyl)phosphorochloridate 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 以23%的产率得到2'-deoxy-2'-β-fluorozebularine 5'-[phenyl(benzoxy-L-alaninyl)]phosphate
  参考文献：
  名称：

  Activation of p16 Gene Silenced by DNA Methylation in Cancer Cells by Phosphoramidate Derivatives of 2′-Deoxyzebularine

  摘要：

  We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2'-deoxyzebularine 5'-triphosphate (dZTP). Because 2'-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5'-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers of p16 tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma. cells.

  DOI：

  10.1021/jm8005965
• 作为产物：
  描述：

  2-脱氧-1-溴-2-氟-3,5-二苯甲酰基-alpha-D-阿拉伯呋喃糖 在 甲醇 、 氨 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 19.5h， 生成 1-[(2R,3S,4R,5R)-3-氟-4-羟基-5-(羟基甲基)四氢呋喃-2-基]嘧啶-2-酮
  参考文献：
  名称：

  2（1H）-嘧啶酮核糖苷（zebularine）及其氟化类似物的抗肿瘤特性。

  摘要：

  已合成2（1H）-嘧啶酮核糖苷（zebularine，1b）及其5-氟（6b）和2'-ara-氟（7b）类似物，并在体内作为抗肿瘤药进行了评估。Zebularine可延长ca的寿命（ILS）值。70％抵抗腹膜内（ip）鼠B16黑色素瘤，50％抵抗P388白血病。腹膜内或口服给药时，该化合物对经腹膜内或皮下植入的L1210白血病具有活性，在400 mg / kg的最佳剂量下产生的ILS值约为100％。1b对抗ara C的L1210也有活性（60％ILS）。类似的未取代的嘌呤核糖苷核苷（2）对P388白血病（60％ILS）的活性中等。尽管高剂量的2'-ara-fluorozebularine（7b）对L1210白血病的活性很小（40％ILS），但5-氟类似物6b的活性比zebularine高，并且大约为5。强效100倍。尽管6b的活性与1b的抗P388白血病的活性大致相同，但在该模型中也实现了

  DOI：

  10.1021/jm00115a017

文献信息

• USE OF COMPOSITIONS COMPRISING CldC AS RADIOSENSITIZERS IN THE TREATMENT OF NEOPLASTIC DISEASES
  申请人：Halogenetics, Inc.

  公开号：EP1156827B1

  公开（公告）日：2006-09-20
• Antitumor properties of 2(1H)-pyrimidinone riboside (zebularine) and its fluorinated analogs
  作者：John S. Driscoll、Victor E. Marquez、Jacqueline Plowman、Paul S. Liu、James A. Kelley、Joseph J. Barchi

  DOI：10.1021/jm00115a017

  日期：1991.11

  2'-ara-fluoro (7b) analogues have been synthesized and evaluated in vivo as antitumor agents. Zebularine provides increase in life span (ILS) values of ca. 70% against intraperitoneal (ip) murine B16 melanoma and 50% against P388 leukemia. This compound is active when administered either ip or orally against ip or subcutaneously implanted L1210 leukemia, producing ILS values of about 100% at an optimum

  已合成2（1H）-嘧啶酮核糖苷（zebularine，1b）及其5-氟（6b）和2'-ara-氟（7b）类似物，并在体内作为抗肿瘤药进行了评估。Zebularine可延长ca的寿命（ILS）值。70％抵抗腹膜内（ip）鼠B16黑色素瘤，50％抵抗P388白血病。腹膜内或口服给药时，该化合物对经腹膜内或皮下植入的L1210白血病具有活性，在400 mg / kg的最佳剂量下产生的ILS值约为100％。1b对抗ara C的L1210也有活性（60％ILS）。类似的未取代的嘌呤核糖苷核苷（2）对P388白血病（60％ILS）的活性中等。尽管高剂量的2'-ara-fluorozebularine（7b）对L1210白血病的活性很小（40％ILS），但5-氟类似物6b的活性比zebularine高，并且大约为5。强效100倍。尽管6b的活性与1b的抗P388白血病的活性大致相同，但在该模型中也实现了
• Activation of <i>p16</i> Gene Silenced by DNA Methylation in Cancer Cells by Phosphoramidate Derivatives of 2′-Deoxyzebularine
  作者：Christine B. Yoo、Rocco Valente、Costantino Congiatu、Federica Gavazza、Annette Angel、Maqbool A. Siddiqui、Peter A. Jones、Christopher McGuigan、Victor E. Marquez

  DOI：10.1021/jm8005965

  日期：2008.12.11

  We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2'-deoxyzebularine 5'-triphosphate (dZTP). Because 2'-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5'-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers of p16 tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma. cells.