2'-O-(2-cyanoethyl)-N⁴-(dimethylaminomethylene)-3',5'-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)cytidine | 864837-16-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2'-O-(2-cyanoethyl)-N⁴-(dimethylaminomethylene)-3',5'-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)cytidine
• 英文别名: N4-dimethylaminomethylene-2'-O-cyanoethyl-3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)-cytidine；N'-[1-[(6aR,8R,9R,9aR)-9-(2-cyanoethoxy)-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]-2-oxopyrimidin-4-yl]-N,N-dimethylmethanimidamide
• CAS: 864837-16-1
• 化学式: C₂₇H₄₇N₅O₆Si₂
• 分子量: 593.871
• InChiKey: DFSATIFQTDPYLR-VNSJUHMKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.62
• 重原子数：
  40
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  118
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2'-O-(2-cyanoethyl)-N⁴-(dimethylaminomethylene)-3',5'-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)cytidine 在 氨 、 氢气 、 一水合肼 作用下， 以 甲醇 为溶剂， 20.0 ℃ 、3.0 MPa 条件下， 反应 2.0h， 生成 2'-O-aminopropyl-3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)-cytidine
  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：

  N4-dimethylaminomethylene-3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)-cytidine 、 丙烯腈 在 caesium carbonate 作用下， 以 叔丁醇 为溶剂， 反应 2.5h， 以86%的产率得到2'-O-(2-cyanoethyl)-N⁴-(dimethylaminomethylene)-3',5'-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)cytidine
  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

文献信息

• Solution phase synthesis of short oligoribonucleotides on a precipitative tetrapodal support
  作者：Alejandro Gimenez Molina、Amit M Jabgunde、Pasi Virta、Harri Lönnberg

  DOI：10.3762/bjoc.10.237

  日期：——

  An effective method for the synthesis of short oligoribonucleotides in solution has been elaborated. Novel 2'-O-(2-cyanoethyl)-5'-O-(1-methoxy-1-methylethyl) protected ribonucleoside 3'-phosphoramidites have been prepared and their usefulness as building blocks in RNA synthesis on a soluble support has been demonstrated. As a proof of concept, a pentameric oligoribonucleotide, 3'-UUGCA-5', has been

  已经阐述了一种在溶液中合成短寡核糖核苷酸的有效方法。已制备了新型 2'-O-(2-氰乙基)-5'-O-(1-甲氧基-1-甲基乙基) 保护的核糖核苷 3'-亚磷酰胺，它们作为可溶载体上 RNA 合成的构建块的有用性已被证实证明了。作为概念证明，在沉淀四足四（4-叠氮甲基苯基）季戊四醇载体上制备了五聚寡核糖核苷酸 3'-UUGCA-5'。3'-末端核苷通过 Cu(I) 促进的 1,3-偶极环加成以 3'-O-(4-戊炔酰基) 衍生物的形式偶联到载体上。用 1.5 当量的积木进行偶联。在每个偶联循环中，小分子试剂和副产物通过从 MeOH 中的两次定量沉淀去除，一个在氧化之后，第二个在 5'-脱保护之后。链组装完成后，用三乙胺、氨和 TBAF 处理以高产率释放五聚体。
• 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.