N6-dimethylaminomethylene-2'-O-(N,N'-di-Boc-guanidinopropyl)-5'-O-(4,4'-dimethoxytrityl)-adenosine | 1360744-22-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: N6-dimethylaminomethylene-2'-O-(N,N'-di-Boc-guanidinopropyl)-5'-O-(4,4'-dimethoxytrityl)-adenosine
• CAS: 1360744-22-4
• 化学式: C₄₈H₆₁N₉O₁₀
• 分子量: 924.067
• InChiKey: XHOMMSPKBXAYTA-CISTVLBBSA-N

物化性质

• 密度：
  1.26±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.51
• 重原子数：
  67.0
• 可旋转键数：
  16.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  214.6
• 氢给体数：
  3.0
• 氢受体数：
  15.0

反应信息

• 作为反应物：
  描述：

  N6-dimethylaminomethylene-2'-O-(N,N'-di-Boc-guanidinopropyl)-5'-O-(4,4'-dimethoxytrityl)-adenosine 、 双(二异丙基氨基)(2-氰基乙氧基)膦 在 4,5-二氰基咪唑 作用下， 以 二氯甲烷 为溶剂， 反应 7.0h， 以84%的产率得到N6-dimethylaminomethylene-2'-O-(N,N'-di-Boc-guanidinopropyl)-5'-O-(4,4'-dimethoxytrityl)-adenosine 3'-(cyanoethyl)-N,N-diisopropyl phosphoramidite
  参考文献：
  名称：

  Synthesis of 2′-O-guanidinopropyl-modified nucleoside phosphoramidites and their incorporation into siRNAs targeting hepatitis B virus

  摘要：

  Synthetic RNAi activators have shown considerable potential for therapeutic application to silencing of pathology-causing genes. Typically these exogenous RNAi activators comprise duplex RNA of approximately 21 bp with 2 nt overhangs at the 3' ends. To improve efficacy of siRNAs, chemical modification at the 2'-OH group of ribose has been employed. Enhanced stability, gene silencing and attenuated immunostimulation have been demonstrated using this approach. Although promising, efficient and controlled delivery of highly negatively charged nucleic acid gene silencers remains problematic. To assess the potential utility of introducing positively charged groups at the 2' position, our investigations aimed at assessing efficacy of novel siRNAs containing 2'-O-guanidinopropyl (GP) moieties. We describe the formation of all four GP-modified nucleosides using the synthesis sequence of Michael addition with acrylonitrile followed by Raney-Ni reduction and guanidinylation. These precursors were used successfully to generate antihepatitis B virus (HBV) siRNAs. Testing in a cell culture model of viral replication demonstrated that the GP modifications improved silencing. Moreover, thermodynamic stability was not affected by the GP moieties and their introduction into each position of the seed region of the siRNA guide strand did not alter the silencing efficacy of the intended HBV target. These results demonstrate that modification of siRNAs with GP groups confers properties that may be useful for advancing therapeutic application of synthetic RNAi activators. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.12.024
• 作为产物：
  描述：

  2'-O-aminopropyl-3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)-adenosine 在 吡啶 、 triethylamine tris(hydrogen fluoride) 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 3.5h， 生成 N6-dimethylaminomethylene-2'-O-(N,N'-di-Boc-guanidinopropyl)-5'-O-(4,4'-dimethoxytrityl)-adenosine
  参考文献：
  名称：

  Synthesis of 2′-O-guanidinopropyl-modified nucleoside phosphoramidites and their incorporation into siRNAs targeting hepatitis B virus

  摘要：

  Synthetic RNAi activators have shown considerable potential for therapeutic application to silencing of pathology-causing genes. Typically these exogenous RNAi activators comprise duplex RNA of approximately 21 bp with 2 nt overhangs at the 3' ends. To improve efficacy of siRNAs, chemical modification at the 2'-OH group of ribose has been employed. Enhanced stability, gene silencing and attenuated immunostimulation have been demonstrated using this approach. Although promising, efficient and controlled delivery of highly negatively charged nucleic acid gene silencers remains problematic. To assess the potential utility of introducing positively charged groups at the 2' position, our investigations aimed at assessing efficacy of novel siRNAs containing 2'-O-guanidinopropyl (GP) moieties. We describe the formation of all four GP-modified nucleosides using the synthesis sequence of Michael addition with acrylonitrile followed by Raney-Ni reduction and guanidinylation. These precursors were used successfully to generate antihepatitis B virus (HBV) siRNAs. Testing in a cell culture model of viral replication demonstrated that the GP modifications improved silencing. Moreover, thermodynamic stability was not affected by the GP moieties and their introduction into each position of the seed region of the siRNA guide strand did not alter the silencing efficacy of the intended HBV target. These results demonstrate that modification of siRNAs with GP groups confers properties that may be useful for advancing therapeutic application of synthetic RNAi activators. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.12.024