1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-(trifluromethyl)uracil | 114652-80-1

• 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: 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-(trifluromethyl)uracil
• 英文别名: 2'-deoxy-2'-fluoro-1-β-D-arabinofuranosyl-5-trifluoromethyluracil；1-((2R,3S,4R,5R)-3-Fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione；1-[(2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)pyrimidine-2,4-dione
• CAS: 114652-80-1
• 化学式: C₁₀H₁₀F₄N₂O₅
• 分子量: 314.193
• InChiKey: CYCXYYQOQWCVSL-BYPJNBLXSA-N

物化性质

• 密度：
  1.72±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  99.1
• 氢给体数：
  3
• 氢受体数：
  9

制备方法与用途

2′-脱氧-2′-氟-5-三氟甲基阿糖胞苷是一种胸苷类似物，能在复制的DNA中产生插入活性，并可用于标记细胞及追踪DNA合成过程。

反应信息

• 作为反应物：
  描述：

  乙酸酐 、 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-(trifluromethyl)uracil 在 吡啶 作用下， 反应 4.0h， 以79%的产率得到1-(3,5-di-O-acetyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-(trifluromethyl)uracil
  参考文献：
  名称：

  Nucleosides. 150. Synthesis and some biological properties of 5-monofluoromethyl, 5-difluoromethyl, and 5-trifluoromethyl derivatives of 2'-deoxyuridine and 2'-deoxy-2'-fluoro-.beta.-D-arabinofuranosyluracil

  摘要：

  A new synthesis of 5-(monofluoromethyl)- and 5-(difluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F-FMAU and F2-FMAU) is reported. 3',5'-Di-O-(tert-butyldiphenyl)silylated thymidine or FMAU was photochemically brominated with NBS to the corresponding alpha-monobromide, which was hydrolyzed to the 5-hydroxymethyl derivative. Further oxidation of the latter with MnO2 afforded the 5-formyluracil nucleoside. Treatment of these nucleosides with DAST in CH2Cl2 gave the protected alpha-fluorinated nucleosides. Desiylation with TBAF afforded the desired free nucleosides. Also, 5-(trifluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F3-FMAU) was synthesized by copper-catalyzed trifluoromethylation of 5-iodo-2'-fluoro-ara-U (FIAU). These new nucleosides were studied in comparison with the corresponding 2'-deoxy-erythro-pentofuranosyl derivatives, for their inhibitory activity against cellular thymidylate synthase (TS) and [3H]TdR incorporation into DNA, cytotoxicity against HL-60 cells, and antiviral activity against herpes simplex types 1 and 2 (HSV-1 and -2). F2-TDR and F3-TDR strongly inhibited TS and were also quite cytotoxic and antiherpetic, whereas FTDR was only active in the antiviral assay. In the 2'-fluoroarabino series, fluorine substitution at the alpha-methyl function did not alter significantly the antiherpetic activity. Although FMAU and F-FMAU did not inhibit TS to any significant extent, F2-FMAU and F3-FMAU were weakly inhibitory. The latter nucleosides did not inhibit [3H]TDR incorporation into DNA, while all the other alpha-fluorinated thymine nucleosides inhibited the incorporation of radioactivity of [3H]TDR into DNA to various extents. F2-FMAU and F3-FMAU were about 2 orders of magnitude less cytotoxic against HL-60 cells than were F2-TDR and F3-TDR. The results strongly suggest that in both the 2'-deoxy-2'-fluoroarabino and the 2'-deoxy-erythro-pentofurano series the cytotoxic action of the alpha,alpha-difluoro and alpha,alpha,alpha-trifluoro derivatives may involve the inhibition of TS. The synthesis of [2-14C]F2-FMAU, as an experimental imaging agent, is also described. Unfortunately, the highly selective uptake of the labeled compound within infected brain regions previously noted with [2-14C]FMAU was not detected with the derivative [2-14C]F2-FMAU.

  DOI：

  10.1021/jm00403a026
• 作为产物：
  描述：

  非阿尿苷 在 吡啶 、 铜 、 溶剂黄146 作用下， 以 六甲基磷酰三胺 为溶剂， 反应 44.17h， 生成 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-(trifluromethyl)uracil
  参考文献：
  名称：

  Nucleosides. 150. Synthesis and some biological properties of 5-monofluoromethyl, 5-difluoromethyl, and 5-trifluoromethyl derivatives of 2'-deoxyuridine and 2'-deoxy-2'-fluoro-.beta.-D-arabinofuranosyluracil

  摘要：

  A new synthesis of 5-(monofluoromethyl)- and 5-(difluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F-FMAU and F2-FMAU) is reported. 3',5'-Di-O-(tert-butyldiphenyl)silylated thymidine or FMAU was photochemically brominated with NBS to the corresponding alpha-monobromide, which was hydrolyzed to the 5-hydroxymethyl derivative. Further oxidation of the latter with MnO2 afforded the 5-formyluracil nucleoside. Treatment of these nucleosides with DAST in CH2Cl2 gave the protected alpha-fluorinated nucleosides. Desiylation with TBAF afforded the desired free nucleosides. Also, 5-(trifluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F3-FMAU) was synthesized by copper-catalyzed trifluoromethylation of 5-iodo-2'-fluoro-ara-U (FIAU). These new nucleosides were studied in comparison with the corresponding 2'-deoxy-erythro-pentofuranosyl derivatives, for their inhibitory activity against cellular thymidylate synthase (TS) and [3H]TdR incorporation into DNA, cytotoxicity against HL-60 cells, and antiviral activity against herpes simplex types 1 and 2 (HSV-1 and -2). F2-TDR and F3-TDR strongly inhibited TS and were also quite cytotoxic and antiherpetic, whereas FTDR was only active in the antiviral assay. In the 2'-fluoroarabino series, fluorine substitution at the alpha-methyl function did not alter significantly the antiherpetic activity. Although FMAU and F-FMAU did not inhibit TS to any significant extent, F2-FMAU and F3-FMAU were weakly inhibitory. The latter nucleosides did not inhibit [3H]TDR incorporation into DNA, while all the other alpha-fluorinated thymine nucleosides inhibited the incorporation of radioactivity of [3H]TDR into DNA to various extents. F2-FMAU and F3-FMAU were about 2 orders of magnitude less cytotoxic against HL-60 cells than were F2-TDR and F3-TDR. The results strongly suggest that in both the 2'-deoxy-2'-fluoroarabino and the 2'-deoxy-erythro-pentofurano series the cytotoxic action of the alpha,alpha-difluoro and alpha,alpha,alpha-trifluoro derivatives may involve the inhibition of TS. The synthesis of [2-14C]F2-FMAU, as an experimental imaging agent, is also described. Unfortunately, the highly selective uptake of the labeled compound within infected brain regions previously noted with [2-14C]FMAU was not detected with the derivative [2-14C]F2-FMAU.

  DOI：

  10.1021/jm00403a026

文献信息

• Synthesis and Evaluation of [¹⁸F] Labeled Pyrimidine Nucleosides for Positron Emission Tomography Imaging of Herpes Simplex Virus 1 Thymidine Kinase Gene Expression
  作者：Nagavarakishore Pillarsetty、Shangde Cai、Lyudmila Ageyeva、Ronald D. Finn、Ronald G. Blasberg

  DOI：10.1021/jm0512847

  日期：2006.8.1

  Synthesis of three novel 2'-deoxy-2'-[F-18]fluoro-1-beta-D-arabinofuranosyluracil derivatives [F-18] FPAU, [F-18]-FBrVAU, and [F-18] FTMAU is reported. The compounds were synthesized by coupling of 1-bromo-2-deoxy-2- fluoro sugars with corresponding silylated uracil derivatives. In vitro cell uptake indicated that all three compounds are taken up selectively in RG2TK+ cells with negligible uptake in RG2 cells. The results indicate that [F-18]FBrVAU and [F-18]FTMAU have better uptake profiles in comparison to [F-18]FPAU and have potential as PET probes for imaging HSV1-tk gene expression.
• SMEE, DONALD F.;CHERNOW, MARLENE;KRAFT, MONICA;OKAMOTO, PATRICIA M.;PRISB+, NUCLEOSIDES AND NUCLEOTIDES, 7,(1988) N 2, 155-165
  作者：SMEE, DONALD F.、CHERNOW, MARLENE、KRAFT, MONICA、OKAMOTO, PATRICIA M.、PRISB+

  DOI：——

  日期：——
• MATULIC-ADAMIC, JASENKA;TAKAHASHI, KIYOBUMI;CHOU, TING-CHAO;GADLER, HAKAN+, J. MED. CHEM., 31,(1988) N 8, C. 1642-1647
  作者：MATULIC-ADAMIC, JASENKA、TAKAHASHI, KIYOBUMI、CHOU, TING-CHAO、GADLER, HAKAN+

  DOI：——

  日期：——
• Nucleosides. 150. Synthesis and some biological properties of 5-monofluoromethyl, 5-difluoromethyl, and 5-trifluoromethyl derivatives of 2'-deoxyuridine and 2'-deoxy-2'-fluoro-.beta.-D-arabinofuranosyluracil
  作者：Jasenka Matulic-Adamic、Kiyobumi Takahashi、Ting Chao Chou、Hakan Gadler、Richard W. Price、Kyoichi A. Watanabe、A. R. Venugopala Reddy、Thomas I. Kalman

  DOI：10.1021/jm00403a026

  日期：1988.8

  A new synthesis of 5-(monofluoromethyl)- and 5-(difluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F-FMAU and F2-FMAU) is reported. 3',5'-Di-O-(tert-butyldiphenyl)silylated thymidine or FMAU was photochemically brominated with NBS to the corresponding alpha-monobromide, which was hydrolyzed to the 5-hydroxymethyl derivative. Further oxidation of the latter with MnO2 afforded the 5-formyluracil nucleoside. Treatment of these nucleosides with DAST in CH2Cl2 gave the protected alpha-fluorinated nucleosides. Desiylation with TBAF afforded the desired free nucleosides. Also, 5-(trifluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F3-FMAU) was synthesized by copper-catalyzed trifluoromethylation of 5-iodo-2'-fluoro-ara-U (FIAU). These new nucleosides were studied in comparison with the corresponding 2'-deoxy-erythro-pentofuranosyl derivatives, for their inhibitory activity against cellular thymidylate synthase (TS) and [3H]TdR incorporation into DNA, cytotoxicity against HL-60 cells, and antiviral activity against herpes simplex types 1 and 2 (HSV-1 and -2). F2-TDR and F3-TDR strongly inhibited TS and were also quite cytotoxic and antiherpetic, whereas FTDR was only active in the antiviral assay. In the 2'-fluoroarabino series, fluorine substitution at the alpha-methyl function did not alter significantly the antiherpetic activity. Although FMAU and F-FMAU did not inhibit TS to any significant extent, F2-FMAU and F3-FMAU were weakly inhibitory. The latter nucleosides did not inhibit [3H]TDR incorporation into DNA, while all the other alpha-fluorinated thymine nucleosides inhibited the incorporation of radioactivity of [3H]TDR into DNA to various extents. F2-FMAU and F3-FMAU were about 2 orders of magnitude less cytotoxic against HL-60 cells than were F2-TDR and F3-TDR. The results strongly suggest that in both the 2'-deoxy-2'-fluoroarabino and the 2'-deoxy-erythro-pentofurano series the cytotoxic action of the alpha,alpha-difluoro and alpha,alpha,alpha-trifluoro derivatives may involve the inhibition of TS. The synthesis of [2-14C]F2-FMAU, as an experimental imaging agent, is also described. Unfortunately, the highly selective uptake of the labeled compound within infected brain regions previously noted with [2-14C]FMAU was not detected with the derivative [2-14C]F2-FMAU.