(2S,2'S)-diethyl 2,2'-{[({[(R)-1-(2,6-diamino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphoryl]bis(azanediyl)}dipropanoate | 1333497-47-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,2'S)-diethyl 2,2'-{[({[(R)-1-(2,6-diamino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphoryl]bis(azanediyl)}dipropanoate
• 英文别名: ethyl (2S)-2-[[[(1R)-2-(2,6-diaminopurin-9-yl)-1-methyl-ethoxy]methyl-[[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate；ethyl (2S)-2-[[[(2R)-1-(2,6-diaminopurin-9-yl)propan-2-yl]oxymethyl-[[(2S)-1-ethoxy-1-oxopropan-2-yl]amino]phosphoryl]amino]propanoate
• CAS: 1333497-47-4
• 化学式: C₁₉H₃₃N₈O₆P
• 分子量: 500.495
• InChiKey: NGEBJPHURYWXGV-AGIUHOORSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  34
• 可旋转键数：
  15
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  199
• 氢给体数：
  4
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  (R)-9-(2-hydroxypropyl)-2,6-diaminopurine 在 吡啶 、 2,2'-二硫二吡啶 、 N,N-二甲基甲酰胺二甲基缩醛 、 三苯基膦 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 72.25h， 生成 (2S,2'S)-diethyl 2,2'-{[({[(R)-1-(2,6-diamino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphoryl]bis(azanediyl)}dipropanoate
  参考文献：
  名称：

  9-[2-(R)-(Phosphonomethoxy)propyl]-2,6-diaminopurine (R)-PMPDAP and its prodrugs: Optimized preparation, including identification of by-products formed, and antiviral evaluation in vitro

  摘要：

  New large-scale synthetic approach to antiretroviral agent 9-[2-(R)-(phosphonomethoxy) propyl]-2,6-diaminopurine, (R)-PMPDAP, was developed. Reaction of (R)-propanediol carbonate with 2,6-diaminopurine afforded exclusively (R)-9-(2-hydroxypropyl)-2,6-diaminopurine which was subsequently used for introduction of a phosphonomethyl residue using TsOCH2P(O)(OiPr)(2) or BrCH2P(O)(OiPr)(2) followed by deprotection of ester groups. All minor ingredients and by-products formed during the process were identified and further studied. The final product was obtained in high yield and its high enantiomeric purity (>99%) was confirmed by chiral capillary electrophoretic analysis using beta-cyclodextrin as a chiral selector. Antiretroviral activity data of (R)-PMPDAP and its diverse prodrugs against HIV and FIV were investigated. Akin to (R)-PMPDAP, both prodrugs inhibit FIV replication in a selective manner. Compared to the parent molecule, the amidate prodrug was 10-fold less active against FIV in cell culture, whereas the alkoxyalkyl ester prodrug was 200-fold more potent in inhibiting FIV replication in vitro. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.12.044

文献信息

• A novel and efficient one-pot synthesis of symmetrical diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates and evaluation of their biological activities
  作者：Petr Jansa、Ondřej Baszczyňski、Martin Dračínský、Ivan Votruba、Zdeněk Zídek、Gina Bahador、George Stepan、Tomas Cihlar、Richard Mackman、Antonín Holý、Zlatko Janeba

  DOI：10.1016/j.ejmech.2011.05.040

  日期：2011.9

  bis-amidates in excellent yields (83–98%) and purity. The methodology has been applied to the synthesis of the potent anticancer agent GS-9219, and symmetrical bis-amidates of other biologically active phosphonic acids. Anti-HIV, antiproliferative, and immunomodulatory activities of the compounds are discussed including the bis-amidate prodrugs 14 and 17 that exhibited anti-HIV activity at submicromolar

  报道了一种从游离膦酸或膦酸酯二酯开始一锅合成无环核苷膦酸酯的二酰胺（双酰胺）前体药物的新颖有效的方法。膦酸酯二酯通过其双（三甲基甲硅烷基）酯的方法非常方便，消除了膦酸的分离和繁琐的纯化，并以极佳的收率（83-98％）和纯度提供了相应的双氨基酸酯。该方法已应用于有效的抗癌药GS-9219以及其他具有生物活性的膦酸的对称双氨基酸盐的合成。讨论了该化合物的抗HIV，抗增殖和免疫调节活性，包括双氨基酸盐前药14和17 在亚微摩尔浓度下表现出抗HIV活性，且细胞毒性最小。