1-{2'-O-methyl-3'-O-[2-cyanoethoxy(diisopropylamino)phosphino]-4'-C-trifluoroacetylaminomethyl-5'-(4,4'-dimethoxytrityl)-β-D-ribofuranosyl}uracil | 1361928-14-4

• 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: 1-{2'-O-methyl-3'-O-[2-cyanoethoxy(diisopropylamino)phosphino]-4'-C-trifluoroacetylaminomethyl-5'-(4,4'-dimethoxytrityl)-β-D-ribofuranosyl}uracil
• 英文别名: N-[[(2R,3S,4R,5R)-2-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-3-[2-cyanoethoxy-[di(propan-2-yl)amino]phosphanyl]oxy-5-(2,4-dioxopyrimidin-1-yl)-4-methoxyoxolan-2-yl]methyl]-2,2,2-trifluoroacetamide
• CAS: 1361928-14-4
• 化学式: C₄₃H₅₁F₃N₅O₁₀P
• 分子量: 885.874
• InChiKey: MUDYFQMPXUREAE-QTJOZJJWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  62
• 可旋转键数：
  20
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  170
• 氢给体数：
  2
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  5-azido-3-O-benzyl-4-C-[(benzyloxy)methyl]-5-deoxy-1,2-O-isopropylidene-β-L-lyxofuranose 在 N,O-双三甲硅基乙酰胺 、 ammonium cerium (IV) nitrate 、 三氟甲磺酸 、 palladium 10% on activated carbon 、 水 、 氢气 、 sodium methylate 、 sodium hydride 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 N,N-二异丙基乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 吡啶 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 溶剂黄146 、 乙腈 为溶剂， 反应 116.08h， 生成 1-{2'-O-methyl-3'-O-[2-cyanoethoxy(diisopropylamino)phosphino]-4'-C-trifluoroacetylaminomethyl-5'-(4,4'-dimethoxytrityl)-β-D-ribofuranosyl}uracil
  参考文献：
  名称：

  Synthesis, Gene Silencing, and Molecular Modeling Studies of 4′-C-Aminomethyl-2′-O-methyl Modified Small Interfering RNAs

  摘要：

  The linear syntheses of 4'-C-aminomethyl-2'-O-methyl uridine and cytidine nucleoside phosphoramidites were achieved using glucose as the starting material. The modified RNA building blocks were incorporated into small interfering RNAs (siRNAs) by employing solid phase RNA synthesis. Thermal melting studies showed that the modified siRNA duplexes exhibited slightly lower T-m (similar to 1 degrees C/modification) compared to the unmodified duplex. Molecular dynamics simulations revealed that the 4'-C-aminomethyl-2'-O-methyl modified nucleotides adopt South-type conformation in a siRNA duplex, thereby altering the stacking and hydrogen-bonding interactions. These modified siRNAs were also evaluated for their gene silencing efficiency in HeLa cells using a luciferase-based reporter assay. The results indicate that the modifications are well tolerated in various positions of the passenger strand and at the 3' end of the guide strand but are less tolerated in the seed region of the guide strand. The modified siRNAs exhibited prolonged stability in human serum compared to unmodified siRNA. This work has implications for the use of 4'-C-aminomethyl-2'-O-methyl modified nucleotides to overcome some of the challenges associated with the therapeutic utilities of siRNAs.

  DOI：

  10.1021/jo202666m

文献信息

• Synthesis, Gene Silencing, and Molecular Modeling Studies of 4′-<i>C</i>-Aminomethyl-2′-<i>O</i>-methyl Modified Small Interfering RNAs
  作者：Kiran R. Gore、Ganesh N. Nawale、S. Harikrishna、Vinita G. Chittoor、Sushil Kumar Pandey、Claudia Höbartner、Swati Patankar、P. I. Pradeepkumar

  DOI：10.1021/jo202666m

  日期：2012.4.6

  The linear syntheses of 4'-C-aminomethyl-2'-O-methyl uridine and cytidine nucleoside phosphoramidites were achieved using glucose as the starting material. The modified RNA building blocks were incorporated into small interfering RNAs (siRNAs) by employing solid phase RNA synthesis. Thermal melting studies showed that the modified siRNA duplexes exhibited slightly lower T-m (similar to 1 degrees C/modification) compared to the unmodified duplex. Molecular dynamics simulations revealed that the 4'-C-aminomethyl-2'-O-methyl modified nucleotides adopt South-type conformation in a siRNA duplex, thereby altering the stacking and hydrogen-bonding interactions. These modified siRNAs were also evaluated for their gene silencing efficiency in HeLa cells using a luciferase-based reporter assay. The results indicate that the modifications are well tolerated in various positions of the passenger strand and at the 3' end of the guide strand but are less tolerated in the seed region of the guide strand. The modified siRNAs exhibited prolonged stability in human serum compared to unmodified siRNA. This work has implications for the use of 4'-C-aminomethyl-2'-O-methyl modified nucleotides to overcome some of the challenges associated with the therapeutic utilities of siRNAs.