3'-deoxy-3'-fluoro-4-thiothymidine | 124903-20-4

• 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: 3'-deoxy-3'-fluoro-4-thiothymidine
• 英文别名: 1-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-4-thiothymine；S4FLT；1-(2,3-dideoxy-3-fluoro-β-D-ribofuranosyl)-4-thiothymine；2',3'-dideoxy-3'-fluoro-4-thiothymidine；Thymidine, 3'-deoxy-3'-fluoro-4-thio-；1-[(2R,4S,5R)-4-fluoro-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-4-sulfanylidenepyrimidin-2-one
• CAS: 124903-20-4
• 化学式: C₁₀H₁₃FN₂O₃S
• 分子量: 260.289
• InChiKey: RHBTTWULFWNOBZ-XLPZGREQSA-N

物化性质

• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  17
• 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：
  93.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3'-deoxy-3'-fluoro-4-thiothymidine 在 1H-1,2,4-三唑 、 sodium iodide 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 水 、 丙酮 为溶剂， 反应 0.25h， 生成 disodium 1-(2',3'-dideoxy-3'-fluoro-β-D-erythro-pentofuranosyl)-4-thiothymine-5'-monophosphate
  参考文献：
  名称：

  Thiated derivatives of 2′,3′-dideoxy-3′-fluorothymidine: Synthesis, in vitro anti-HIV-1 activity and interaction with recombinant drug resistant HIV-1 reverse transcriptase forms

  摘要：

  Various thiated analogues of thymine 2',3'-dideoxy-3'-fluoronucleoside (FLT) and their 5'-monophosphates and 5'-triphosphates were prepared with the use of modified multistep procedures. The thiated analogues of FLT and FLTMP were evaluated against the wild type and drug- and multidrug-resistant strains of HIV-1, using the replicative phenotyping format of the deCIPhR assay, and showed potent inhibition of drug-resistant HIV-1 strains at low cytotoxicity. Additionally, inhibition of recombinant drug resistant forms of reverse transcriptase from single and multiple HIV-1 mutants by the synthesized 5'-triphosphates was investigated. The strongest inhibition was observed for K103N and Delta 67 mutants and the most potent anti-HIV-1 activity against drug resistant strains and the lowest cytotoxicity was exerted by S(4)FLTMP and FLTMP which may be regarded as potential anti-HIV/AIDS agents. (C) 2011 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.antiviral.2011.05.012
• 作为产物：
  描述：

  1-(5-O-acetyl-2,3-dideoxy-3-fluoro-β-D-ribofuranosyl)-4-thiothymine 在 氨 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以98 mg的产率得到3'-deoxy-3'-fluoro-4-thiothymidine
  参考文献：
  名称：

  Thiated derivatives of 2′,3′-dideoxy-3′-fluorothymidine: Synthesis, in vitro anti-HIV-1 activity and interaction with recombinant drug resistant HIV-1 reverse transcriptase forms

  摘要：

  Various thiated analogues of thymine 2',3'-dideoxy-3'-fluoronucleoside (FLT) and their 5'-monophosphates and 5'-triphosphates were prepared with the use of modified multistep procedures. The thiated analogues of FLT and FLTMP were evaluated against the wild type and drug- and multidrug-resistant strains of HIV-1, using the replicative phenotyping format of the deCIPhR assay, and showed potent inhibition of drug-resistant HIV-1 strains at low cytotoxicity. Additionally, inhibition of recombinant drug resistant forms of reverse transcriptase from single and multiple HIV-1 mutants by the synthesized 5'-triphosphates was investigated. The strongest inhibition was observed for K103N and Delta 67 mutants and the most potent anti-HIV-1 activity against drug resistant strains and the lowest cytotoxicity was exerted by S(4)FLTMP and FLTMP which may be regarded as potential anti-HIV/AIDS agents. (C) 2011 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.antiviral.2011.05.012

文献信息

• Modified 2',3'-dideoxynucleosides for treatment infections caused by human immunodeficiency virus (HIV) multidrug resistant strains, method of their synthesis and the pharmaceutical agent containing these nucleosides
  申请人：Instytut Biochemii I Biofizyki Pan

  公开号：EP2402356A3

  公开（公告）日：2012-07-18

  2',3'-Dideoxy-3'-fluoro-4-thiothymidine (4-SFLT) derivatives according to the invention substituted at 5'-O position of 4-SFLT with 12-tetradodecanoyl, 12-bromododecanoyl, 12-metoxydodecanoyl, 12-ethylothiododecanoyl, 11-ethylothioundecanoyl or 12-azidodocanoyl group (represented by the symbols WA18, WA19, WA21,WA22,WA23 and WA20 in the deCIPhR™ cell system exert high antiviral activity against wild type HIV-1 strain, as well as against its drug and multidrug resistant strains, and moreover very low citotoxicity (CC50 > 200 µM) and very high selectivity. The compounds, because of lack of toxicity may be applied at all AIDS phases i.e. also them the T4 lymphocytes level in patients drops down below 200/ µL of peripheral blood. 2',3'-Dideoxy-3'-fluoro-4-thiothymidine derivatives according to the invention are synthesized by the transformation of the known compound 2',3'-dideoxy-3'-fluoro-4-thiothymidine (4-SFLT).

  本发明的2',3'-二脱氧-3'-氟-4-硫代胸腺嘧啶（4-SFLT）衍生物，在4-SFLT的5'-O位置用12-四十二碳酰基、12-溴十二碳酰基、12-甲氧基十二碳酰基、12-乙基硫代十二碳酰基、11-乙基硫代十一碳酰基或12-叠氮十二碳酰基（在deCIPhR™细胞系统中用符号WA18、WA19、WA21、WA22、WA23和WA20表示）进行取代，对野生型HIV-1株以及其耐药和多药耐药株具有高抗病毒活性，并且细胞毒性非常低（CC50> 200 µM）和选择性非常高。由于缺乏毒性，这些化合物可应用于所有艾滋病阶段，即使在患者的T4淋巴细胞水平降至每个外周血液中的200 / µL以下。根据本发明的2',3'-二脱氧-3'-氟-4-硫代胸腺嘧啶衍生物是通过转化已知化合物2',3'-二脱氧-3'-氟-4-硫代胸腺嘧啶（4-SFLT）合成的。
• Substituierte Pyrimidinnucleoside, Verfahren zu ihrer Herstellung und sie enthaltende pharmazeutische Mittel
  申请人：MATTHES, Eckart, Dr.

  公开号：EP0355031A2

  公开（公告）日：1990-02-21

  Es werden neue, gegen durch Viren bzw. Retroviren verur­sachte Infektionen wirksame, substituierte Pyrimidin­nucleoside der Formel I, II und III in der bedeuten: R¹ Wasserstoff, Halogen, Azido, aliphatisches Alkyl mit 1 bis 5 Kohlenstoffatomen, vorzugsweise mit 1 bis 3 Kohlenstoffatomen, oder Alkenyl mit 2 bis 5 Kohlen­stoffatomen, R² Wasserstoff, Thio, Thiomethyl, Hydroxylamino oder Alkylamino, R³ Hydroxyl, O-Acetyl, O-Palmitoyl, O-Alkoxycarbonyl, Mono-, Di-, oder Triphosphorsäure, -alkaliphosphat, -ammoniumphosphat oder -alkylammoniumphosphat oder eine Vorstufe für die Hydroxylgruppe, und sie enthaltende pharmazeutische Mittel beschrieben. Ein besonders geeigneter Wirkstoff ist 1-(2,3-Didesoxy-3-­fluor-ß-D-ribofuranosyl)-4-thiothymin.

  式 I、II 和 III 的新取代嘧啶核苷 其中 R¹ 氢、卤素、叠氮、含 1 至 5 个碳原子（最好含 1 至 3 个碳原子）的脂肪族烷基或含 2 至 5 个碳原子的烯基、 R²氢、硫代、硫代甲基、羟基氨基或烷基氨基、 R³ 羟基、O-乙酰基、O-棕榈酰基、O-烷氧羰基、单磷酸、二磷酸或三磷酸、磷酸二氢钾、磷酸铵或磷酸烷基铵或羟基的前体、 以及含有它们的药物组合物。 一种特别合适的活性成分是 1-(2,3-二脱氧-3-氟-ß-D-呋喃核糖基)-4-硫代氨基甲烷。
• Synthesis, Biological Properties and Anti-HIV-1 Activity of New Pyrimidine P₁,P₂-Dinucleotides
  作者：A. Miazga、P. Ziemkowski、M. A. Siwecka、A. Lipniacki、A. Piasek、T. Kulikowski

  DOI：10.1080/15257771003738642

  日期：2010.6.10

  New homo- and hetero-P1,P2-dinucleotides were prepared with the use of multistep procedures starting from the monophosphates of 3'-fluoro-2-thiothymidine, 3'-fluoro-4-thiothymidine, AZT and 1-[(2-hydroxyethoxy)-methyl-5-propyl-6-phenylselenenyl]uracil. Anti-HIV properties of the synthesized P1,P2-dinucleotides were evaluated against laboratory syncytia inducing strain HIV-1 in CEM-T4 cells. Anti-HIV activities were in the range of 5-45 nM, and therapeutic indexes were higher than 4666-14000. Interactions of the above mentioned compounds with recombinant HIV-1 reverse transcriptase were also investigated. The obtained results point to reverse transcriptase inhibition, with somewhat lower inhibitory activity than that of their parental nucleoside-5'-triphosphates. Compound 6 may be regarded as a potent anti-HIV/AIDS drug.
• US5496935A
  申请人：——

  公开号：US5496935A

  公开（公告）日：1996-03-05
• Thiated derivatives of 2′,3′-dideoxy-3′-fluorothymidine: Synthesis, in vitro anti-HIV-1 activity and interaction with recombinant drug resistant HIV-1 reverse transcriptase forms
  作者：Agnieszka Miazga、François Hamy、Séverine Louvel、Thomas Klimkait、Zofia Pietrusiewicz、Anna Kurzyńska-Kokorniak、Marek Figlerowicz、Patrycja Wińska、Tadeusz Kulikowski

  DOI：10.1016/j.antiviral.2011.05.012

  日期：2011.10

  Various thiated analogues of thymine 2',3'-dideoxy-3'-fluoronucleoside (FLT) and their 5'-monophosphates and 5'-triphosphates were prepared with the use of modified multistep procedures. The thiated analogues of FLT and FLTMP were evaluated against the wild type and drug- and multidrug-resistant strains of HIV-1, using the replicative phenotyping format of the deCIPhR assay, and showed potent inhibition of drug-resistant HIV-1 strains at low cytotoxicity. Additionally, inhibition of recombinant drug resistant forms of reverse transcriptase from single and multiple HIV-1 mutants by the synthesized 5'-triphosphates was investigated. The strongest inhibition was observed for K103N and Delta 67 mutants and the most potent anti-HIV-1 activity against drug resistant strains and the lowest cytotoxicity was exerted by S(4)FLTMP and FLTMP which may be regarded as potential anti-HIV/AIDS agents. (C) 2011 Elsevier B.V. All rights reserved.