1-[(2R,4S,5S)-4-azido-5-[(4-oxo-1,3,2-benzodioxaphosphinin-2-yl)oxymethyl]oxolan-2-yl]-5-methylpyrimidine-2,4-dione | 136049-69-9

• 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-[(2R,4S,5S)-4-azido-5-[(4-oxo-1,3,2-benzodioxaphosphinin-2-yl)oxymethyl]oxolan-2-yl]-5-methylpyrimidine-2,4-dione
• CAS: 136049-69-9
• 化学式: C₁₇H₁₆N₅O₇P
• 分子量: 433.317
• InChiKey: UYZQHKBUYXDOCZ-QOPOODTQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  118
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  1-[(2R,4S,5S)-4-azido-5-[(4-oxo-1,3,2-benzodioxaphosphinin-2-yl)oxymethyl]oxolan-2-yl]-5-methylpyrimidine-2,4-dione 在 borane-N,N-diisopropylethylamine complex 、 三正丁胺 、 水 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 3'-azido-3'-deoxythymidine 5'-α-PI-borano-β,γ-(difluoromethylene)triphosphate
  参考文献：
  名称：

  AZT 5'-三磷酸酯模拟物的合成及其对HIV-1逆转录酶的抑制作用。

  摘要：

  为寻找活性核苷5'-三磷酸模拟物，我们合成了一系列AZT三磷酸模拟物（AZT P3Ms），并评估了它们对HIV-1逆转录酶的抑制作用以及它们在胎牛血清和CEM细胞提取物中的稳定性。AZT与2-氯-4H-1,3,2-苯并二氧杂磷酰基-4-酮反应，然后用焦磷酸盐类似物处理亚磷酸酯中间体2，得到环状三磷酸酯中间体4b-4f，将其进行硼化并随后进行硼化水解得到AZT5'-α-硼烷-β，γ-桥修饰的三磷酸酯6b-6f，产率中等至良好。环状中间体4d与碘反应，然后用一系列亲核试剂处理，得到AZT5'-β，γ-二氟亚甲基-γ-取代的三磷酸酯（7b-7i）。几种不同类型的AZT P3M，包括α-P-硫代（或二硫代）和β，γ-二氟亚甲基（13,14），α，β-二氟亚甲基和γ-P-甲基（或苯基）（15,16），以及还合成了α-硼烷-β，γ-二氟亚甲基和γ-O-甲基/苯基（11,12）。使用荧光测定法和以聚（A

  DOI：

  10.1021/jm040116w
• 作为产物：
  描述：

  2-氯-1,3,2-苯并二氧磷杂环己烷-4-酮 、 齐多夫定 在 吡啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 1-[(2R,4S,5S)-4-azido-5-[(4-oxo-1,3,2-benzodioxaphosphinin-2-yl)oxymethyl]oxolan-2-yl]-5-methylpyrimidine-2,4-dione
  参考文献：
  名称：

  AZT 5'-三磷酸酯模拟物的合成及其对HIV-1逆转录酶的抑制作用。

  摘要：

  为寻找活性核苷5'-三磷酸模拟物，我们合成了一系列AZT三磷酸模拟物（AZT P3Ms），并评估了它们对HIV-1逆转录酶的抑制作用以及它们在胎牛血清和CEM细胞提取物中的稳定性。AZT与2-氯-4H-1,3,2-苯并二氧杂磷酰基-4-酮反应，然后用焦磷酸盐类似物处理亚磷酸酯中间体2，得到环状三磷酸酯中间体4b-4f，将其进行硼化并随后进行硼化水解得到AZT5'-α-硼烷-β，γ-桥修饰的三磷酸酯6b-6f，产率中等至良好。环状中间体4d与碘反应，然后用一系列亲核试剂处理，得到AZT5'-β，γ-二氟亚甲基-γ-取代的三磷酸酯（7b-7i）。几种不同类型的AZT P3M，包括α-P-硫代（或二硫代）和β，γ-二氟亚甲基（13,14），α，β-二氟亚甲基和γ-P-甲基（或苯基）（15,16），以及还合成了α-硼烷-β，γ-二氟亚甲基和γ-O-甲基/苯基（11,12）。使用荧光测定法和以聚（A

  DOI：

  10.1021/jm040116w

文献信息

• 2′,3′-Dideoxynucleoside 5′-β,γ-(Difluoromethylene) Triphosphates With α-<i>P</i>-Thio or α-<i>P</i>-Seleno Modifications: Synthesis and Their Inhibition of HIV-1 Reverse Transcriptase
  作者：Nicholas A. Boyle、Patrick Fagan、Jennifer L. Brooks、Marija Prhavc、John Lambert、P. Dan Cook

  DOI：10.1080/15257770500267055

  日期：2005.9.1

  Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-R-p-borano-beta,gamma-(difluoromethylene) triphosphate (5'-alpha BCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT.([1,2]) Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma-(difluoromethylene) triphosphate mimics with either a non-bridging alpha-P-thio (5'-alpha SCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene) triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (K-i = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.
• Synthesis of boranoate, selenoate, and thioate analogs of AZTp4A and Ap4A
  作者：Qianwei Han、Stefan G. Sarafianos、Eddy Arnold、Michael A. Parniak、Barbara L. Gaffney、Roger A. Jones

  DOI：10.1016/j.tet.2009.07.079

  日期：2009.9

  We report efficient, one-flask procedures for the synthesis of a family of 14 analogs of AZTp(4)A and Ap(4)A containing BH3, S, or Se, along with two bisphosphonate analogs of Ap(4)A. These compounds should slow unwanted enzymatic hydrolysis and have the potential to create unique binding interactions in biochemical and structural Studies of the excision reaction responsible for resistance of HIV-1 to AZT, as well as assist in drug design. (C) 2009 Elsevier Ltd. All rights reserved.
• Synthesis of nucleoside 5'-O-(1,3-dithiotriphosphates) and 5'-O-(1,1-dithiotriphosphates)
  作者：Janos Ludwig、Fritz Eckstein

  DOI：10.1021/jo00005a023

  日期：1991.3

  The synthesis of 3'-deoxy-3'-azidothymidine 5'-O-(1,3-dithiotriphosphate) (5) as the first example of a nucleoside 5'-O-(1,3-dithiotriphosphate) is described. 2-Chloro-4H-1,3,2-benzodioxaphosphorin-4-one phosphitylates the 5'-hydroxy group of 3'deoxy-3'-azidothymidine to form intermediate 1. Reaction of 1 with thiopyrophosphate (9) and sulfur results in the formation of an unseparable mixture of 3'-deoxy-3'-azidothymidine 5'-O-(1,3-dithiotriphosphate) (5) and 3'-deoxy-3'-azidothymidine 5'-O-(1,2-dithiotriphosphate) (3). Selective hydrolysis of 5 allows isolation of 3. However, reaction of 1 with P1-O-(cyanoethyl)-P1-thiopyrophosphate (8) and sulfur produced the diastereomers of 5 in good yield. Compound 8 is prepared by reaction of 3-hydroxyproprionitrile with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one, pyrophosphate, and sulfur to yield 10, which is ring opened to 8 by reaction with ethylenediamine. Hydrolysis of this compound leads to 9. An alternative route to nucleoside 5'-O-(1,3-dithiotriphosphates) consists of reacting a nucleoside 5'-O-(1-thiocyclotriphosphate) such as 13 with Li2S. This reaction, when performed in pyridine/dioxane, leads to a mixture of the nucleoside 5'-O-(1,3-dithiotriphosphate) and the nucleoside 5'-O-(1,1-dithiotriphosphate). The latter is the only nucleotide product when the reaction is carried out in DMF.
• Synthesis of AZTp_Sp_CX2pp_SA and AZTp_Sp_CX2pp_SAZT:  Hydrolysis-Resistant Potential Inhibitors of the AZT Excision Reaction of HIV-1 RT
  作者：Qianwei Han、Stefan G. Sarafianos、Eddy Arnold、Michael A. Parniak、Barbara L. Gaffney、Roger A. Jones

  DOI：10.1021/ol7023746

  日期：2007.12.1

  We report an efficient, one-flask route for synthesis of AZTp(S)p(CX2)pp(s)A and AZTp(S)p(CX2)pp(s)AZT, where X = H and X = F. This route makes use of the differential susceptibility to oxidation of H-phosohonate mono- and diesters, to allow a series of sequential reactions without requiring isolation of intermediates. These compounds are hydrolysis-resistant versions of the AZTppppA that results from excision of AZT by AZT-resistant HIV reverse transcriptase (RT). This family of compounds may therefore be useful in further study of the AZT excision reaction, as well as in drug design.