O⁶-(2,4,6-triisopropylbenzenesulfonyl)-3',5'-O-(di-tert-butylsilanediyl)guanosine | 1207452-07-0

• 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: O⁶-(2,4,6-triisopropylbenzenesulfonyl)-3',5'-O-(di-tert-butylsilanediyl)guanosine
• 英文别名: [9-[(4aR,6R,7R,7aS)-2,2-ditert-butyl-7-hydroxy-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl]-2-aminopurin-6-yl] 2,4,6-tri(propan-2-yl)benzenesulfonate
• CAS: 1207452-07-0
• 化学式: C₃₃H₅₁N₅O₇SSi
• 分子量: 689.949
• InChiKey: GKRGFAFHBIIZNX-NYBSAPDNSA-N

物化性质

• 沸点：
  803.1±75.0 °C(Predicted)
• 密度：
  1.31±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.26
• 重原子数：
  47
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  169
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  O⁶-(2,4,6-triisopropylbenzenesulfonyl)-3',5'-O-(di-tert-butylsilanediyl)guanosine 在 吡啶 、 甲酸 、 氨 、 氢气 、 caesium carbonate 、 triethylamine tris(hydrogen fluoride) 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 叔丁醇 为溶剂， 20.0 ℃ 、3.0 MPa 条件下， 反应 19.0h， 生成 N²-dimethylformamidine-2'-O-(3-(N,N'-di-tert-butoxycarbonylguanidino)propyl)-5'-O-(4,4'-dimethoxytrityl)guanosine
  参考文献：
  名称：

  Inhibition of hepatitis B virus replication in cultured cells and in vivo using 2′-O-guanidinopropyl modified siRNAs

  摘要：

  Silencing hepatitis B virus (HBV) gene expression with exogenous activators of the RNA interference (RNAi) pathway has shown promise as a new mode of treating infection with the virus. However, optimizing efficacy, specificity, pharmacokinetics and stability of RNAi activators remains a priority before clinical application of this promising therapeutic approach is realised. Chemical modification of synthetic short interfering RNAs (siRNAs) provides the means to address these goals. This study aimed to assess the benefits of incorporating nucleotides with 2'-O-guanidinopropyl (GP) modifications into siRNAs that target HBV. Single GP residues were incorporated at nucleotide positions from 2 to 21 of the antisense strand of a previously characterised effective antiHBV siRNA. When tested in cultured cells, siRNAs with GP moieties at selected positions improved silencing efficacy. Stability of chemically modified siRNAs in 80% serum was moderately improved and better silencing effects were observed without evidence for toxicity or induction of an interferon response. Moreover, partially complementary target sequences were less susceptible to silencing by siRNAs with GP residues located in the seed region. Hydrodynamic co-injection of siRNAs with a replication-competent HBV plasmid resulted in highly effective knock down of markers of viral replication in mice. Evidence for improved efficacy, reduced off target effects and good silencing in vivo indicate that GP-modifications of siRNAs may be used to enhance their therapeutic utility. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.04.073
• 作为产物：
  描述：

  2,4,6-三异丙基苯磺酰氯 、 3',5'-O-(di-tert-butylsilanediyl)guanosine 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以97%的产率得到O⁶-(2,4,6-triisopropylbenzenesulfonyl)-3',5'-O-(di-tert-butylsilanediyl)guanosine
  参考文献：
  名称：

  Facile and efficient approach for the synthesis of N2-dimethylaminomethylene-2′-O-methylguanosine

  摘要：

  A convenient method for the synthesis of N-2-dimethylaminomethylene-2'-O-methylguanosine (1), which is a useful intermediate for oligonucleotide construction, was developed. We chose the di-tert-butylsilyl group and the triisopropylbenzenesulfonyl group as sugar and base protecting groups, respectively. These protecting groups were stable during the 2'-O-methylation step with MeI and NaH. Our six-step synthesis of 1 is easy to perform using commercially available reagents, and requires only three chromatographic purifications. Compound 1 was obtained in 56% yield from guanosine. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.11.016

文献信息

• 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.