3'-azido-3'-deoxy-5'-phosphoromorpholidate-thymidine | 106060-91-7

• 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'-azido-3'-deoxy-5'-phosphoromorpholidate-thymidine
• 英文别名: [(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-morpholin-4-ylphosphinic acid
• CAS: 106060-91-7
• 化学式: C₁₄H₂₁N₆O₇P
• 分子量: 416.331
• InChiKey: MUGLMDDFDZLPJZ-QJPTWQEYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  132
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  tris(tributylammonium) myristoyl pyrophosphate 、 3'-azido-3'-deoxy-5'-phosphoromorpholidate-thymidine 在 camphor-10-sulfonic acid 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 tetradecanoyl 3'-azido-3'-deoxy-5'-thymidinyltriphosphate
  参考文献：
  名称：

  Potential Lipophilic Nucleotide Prodrugs:  Synthesis, Hydrolysis, and Antiretroviral Activity of AZT and d4T Acyl Nucleotides

  摘要：

  Three general methods for the synthesis of acyl nucleotides (mono-, di-, and triphosphates) have been developed and applied to different HIV inhibitors. These new types of compounds, where a fatty acid moiety is linked to the nucleotide phosphate chain by an acyl phosphate bond, were designed as lipophilic prodrugs of HIV inhibitors metabolites. Acyl nucleoside monophosphates la,b were prepared by acylation of the corresponding nucleoside monophosphates. Acyl nucleoside diphosphates 2a-c and 3a,b were synthesized directly from the free nucleosides using DCC activation of acyl pyrophosphates. Acyl nucleoside triphosphates 4a-c and 5a were obtained using phosphoromorpholidate chemistry and acyl pyrophosphates as nucleophiles. Hydrolysis of acyl nucleotides liberated the corresponding nucleotides by selective cleavage of the acyl phosphate bond, with half lives ranging from 51 to 185 h at 37 degrees C in triethylammonium acetate buffer pH 7.0. Their antiretroviral activity, measured by the inhibition of cytopathogenicity and reverse transcriptase activity in the cultures supernatants, did not reveal any differences between an acyl nucleotide and its corresponding nucleotide. These results are explained in term of rapid aminolysis of the acyl phosphate bond in culture media.

  DOI：

  10.1021/jo951354p
• 作为产物：
  描述：

  齐多夫定 在 磷酸三甲酯 、 N,N'-二环己基碳二亚胺 、 三氯氧磷 作用下， 以 水 、 叔丁醇 为溶剂， 反应 3.0h， 生成 3'-azido-3'-deoxy-5'-phosphoromorpholidate-thymidine
  参考文献：
  名称：

  将天然和非天然核苷三磷酸导入细菌的工具

  摘要：

  三磷酸核苷在生物学中发挥着核心作用，但研究这些作用的努力已被证明是困难的，因为细胞中三磷酸的水平受到严格调控，而且单个三磷酸可能难以标记或修饰。此外，许多合成生物学工作都集中在开发在细胞环境中发挥特定功能的非天然三磷酸核苷。一般而言，将所需的三磷酸盐直接引入细胞的一般手段将促进这两种努力。以前，我们证明了来自三角褐指藻 (PtNTT2) 的核苷三磷酸转运蛋白在大肠杆菌中的重组表达，其功能是导入添加到培养基中的三磷酸。在这里，为了探索这种方法的普遍性和实用性，我们报告了 PtNTT2 的构效关系研究。我们使用传统的竞争性摄取抑制分析来表征核碱基、糖和三磷酸修饰的影响，然后开发 LC-MS/MS 分析以直接测量修饰对导入的影响。最后，我们使用转运蛋白导入放射性标记或 2'-氟修饰的三磷酸，并量化它们与 DNA 和 RNA 的结合。结果证明了 PtNTT2 介导的天然或修饰的三磷酸核苷导入对于不

  DOI：

  10.1021/jacs.7b11404

文献信息

• Nucleoside Conjugates. 15. Synthesis and Biological Activity of Anti-HIV Nucleoside Conjugates of Ether and Thioether Phospholipids
  作者：Chung I. Hong、Alexander Nechaev、Alan J. Kirisits、Rakesh Vig、Charles R. West、Konstantine K. Manouilov、Chung K. Chu

  DOI：10.1021/jm950620o

  日期：1996.1.1

  A series of the anti-HIV nucleoside conjugates of either (1-O-alkyl) and thioether (1-S-alkyl) lipids linked by a pyrophosphate diester bond has been synthesized as micelle-forming prodrugs of the nucleosides to improve their therapeutic efficiency. These include AZT 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (1), 3'-azido-2',3'-dideoxyuridine 5'-diphosphate-rac-1-S-octadecyl-2-

  已合成了一系列通过焦磷酸二酯键连接的（1-O-烷基）和硫醚（1-S-烷基）脂质的抗HIV核苷共轭物，作为核苷的胶束形成前药，以提高其治疗效率。这些包括AZT 5'-二磷酸-rac-1-S-十八烷基-2-O-棕榈酰-1-硫甘油（1），3'-叠氮基2'，3'-二脱氧尿苷5'-二磷酸-rac-1- S-十八烷基-2-O-棕榈酰基-1-硫甘油（2）2'，3'-二脱氧胞苷5'-二磷酸-rac-1-S-十八烷基-2-O-棕榈酰基-1-硫甘油（3）和AZT 5'-二磷酸酯-rac-1-O-十四烷基-2-O-棕榈酰甘油（4）。缀合物通过超声处理形成胶束（平均直径范围为6.8-55.5 nm）。结合物1可以保护80％的HIV感染CEM细胞（低至0.58 microM），并由于普遍的细胞毒性而在180 microM时失去保护，而结合物在100 microM时开始显示出细胞毒性。药代动力学研究表明，偶联物1和2
• Phosphorodiamides as Prodrugs for Antiviral Nucleosides
  作者：Alexander V. Shipitsyn、Natalya F. Zakirova、Evgeny F. Belanov、Tatyana R. Pronyaeva、Nina V. Fedyuk、Marina K. Kukhanova、Andrey G. Pokrovsky

  DOI：10.1081/ncn-120022696

  日期：2003.10

  New phosphorodiamides of modified nucleoside monophosphates were synthesized and their antiviral properties were evaluated.
• Rational design of a new series of pronucleotide
  作者：Thierry Beltran、David Egron、Alain Pompon、Isabelle Lefebvre、Christian Périgaud、Gilles Gosselin、Anne-Marie Aubertin、Jean-Louis Imbach

  DOI：10.1016/s0960-894x(01)00299-2

  日期：2001.7

  A new pronucleotide series is described involving a two-step degradation process mediated by. respectively, carboxylesterase and phosphoramidase. Taking AZT as nucleosidyl moiety, it is shown that most of the compounds inhibit HIV replication in TK- cell line, which proves 5'-AZTMP delivery. (C) 2001 Elsevier Science Ltd. All rights reserved.