N6-dimethylaminomethylene-3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)-adenosine | 864837-24-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: N6-dimethylaminomethylene-3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)-adenosine
• 英文别名: 6-N-dimethylaminomethylene-3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)adenosine；N'-[9-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]purin-6-yl]-N,N-dimethylmethanimidamide
• CAS: 864837-24-1
• 化学式: C₂₅H₄₄N₆O₅Si₂
• 分子量: 564.833
• InChiKey: JEGWVDULQOATPW-PTGPVQHPSA-N

物化性质

• 沸点：
  604.5±65.0 °C(Predicted)
• 密度：
  1.24±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.26
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N6-dimethylaminomethylene-3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)-adenosine 在 吡啶 、 4,5-二氰基咪唑 、 氨 、 氢气 、 caesium carbonate 、 一水合肼 、 triethylamine tris(hydrogen fluoride) 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 叔丁醇 为溶剂， 20.0 ℃ 、3.0 MPa 条件下， 反应 17.5h， 生成 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：

  N⁶-Dimethylaminomethylen-adenosin 、 1,3二氯-1,1,3,3-四异丙基二硅氧烷 在 吡啶 作用下， 反应 24.0h， 以95%的产率得到N6-dimethylaminomethylene-3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)-adenosine
  参考文献：
  名称：

  2'-O-修饰的腺苷结构单元的合成及其在RNA干扰中的应用。

  摘要：

  RNA干扰已被认为是控制基因功能的强大工具，并已通过敲低mRNA用于基因沉默。化学修饰的RNA，尤其是2'-O-修饰，成功地改善了其理化和药学特性，例如稳定性，核酸酶抗性和递送。在这里，我们报告合成具有不同2'链修饰的氨基乙基和胍基乙基的腺苷结构单元，并表明它们与RNAi功能兼容。它们延长了血清中siRNA的半衰期，表明这些修饰可以增强siRNA在体内的药代动力学特性并降低其活性。

  DOI：

  10.1016/j.bmc.2007.09.019

文献信息

• 2'-HYDROXYL-MODIFIED RIBONUCLEOSIDE DERIVATIVE
  申请人：TOKYO INSTITUTE OF TECHNOLOGY

  公开号：EP2006293B1

  公开（公告）日：2016-08-24
• Synthesis of 2′-O-modified adenosine building blocks and application for RNA interference
  作者：Dalibor Odadzic、Jesper B. Bramsen、Romualdas Smicius、Claus Bus、Jørgen Kjems、Joachim W. Engels

  DOI：10.1016/j.bmc.2007.09.019

  日期：2008.1

  gene function and has been used for gene silencing by knocking down mRNA. Chemically modified RNAs, especially 2'-O-modification, successfully improved their physicochemical and pharmaceutical properties such as stability, nuclease resistance and delivery. Here, we report the synthesis of adenosine building blocks with different 2'-tethered modifications like aminoethyl and guanidinoethyl and show that

  RNA干扰已被认为是控制基因功能的强大工具，并已通过敲低mRNA用于基因沉默。化学修饰的RNA，尤其是2'-O-修饰，成功地改善了其理化和药学特性，例如稳定性，核酸酶抗性和递送。在这里，我们报告合成具有不同2'链修饰的氨基乙基和胍基乙基的腺苷结构单元，并表明它们与RNAi功能兼容。它们延长了血清中siRNA的半衰期，表明这些修饰可以增强siRNA在体内的药代动力学特性并降低其活性。
• Synthesis of 2′-O-guanidinopropyl-modified nucleoside phosphoramidites and their incorporation into siRNAs targeting hepatitis B virus
  作者：Jolanta Brzezinska、Jennifer D’Onofrio、Maximilian C.R. Buff、Justin Hean、Abdullah Ely、Musa Marimani、Patrick Arbuthnot、Joachim W. Engels

  DOI：10.1016/j.bmc.2011.12.024

  日期：2012.2

  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.