1-[(2R,3R,4S,5R)-5-(azidomethyl)-3-hydroxy-4-phenylmethoxy-5-(phenylmethoxymethyl)oxolan-2-yl]-3-[(4-methoxyphenyl)methyl]pyrimidine-2,4-dione | 1361928-07-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-[(2R,3R,4S,5R)-5-(azidomethyl)-3-hydroxy-4-phenylmethoxy-5-(phenylmethoxymethyl)oxolan-2-yl]-3-[(4-methoxyphenyl)methyl]pyrimidine-2,4-dione
• CAS: 1361928-07-5
• 化学式: C₃₂H₃₃N₅O₇
• 分子量: 599.643
• InChiKey: XLSRFWCKBFNIFJ-FHRWSLRQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  44
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  1-[(2R,3R,4S,5R)-5-(azidomethyl)-3-hydroxy-4-phenylmethoxy-5-(phenylmethoxymethyl)oxolan-2-yl]-3-[(4-methoxyphenyl)methyl]pyrimidine-2,4-dione 在 20% palladium hydroxide on charcoal 、 氢气 、 甲酸铵 、 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 9.08h， 生成
  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
• 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 、 三氟甲磺酸 、 sodium methylate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 13.5h， 生成 1-[(2R,3R,4S,5R)-5-(azidomethyl)-3-hydroxy-4-phenylmethoxy-5-(phenylmethoxymethyl)oxolan-2-yl]-3-[(4-methoxyphenyl)methyl]pyrimidine-2,4-dione
  参考文献：
  名称：

  4′-C-乙酰胺甲基-2′-O-甲氧基乙基核酸修饰可提高小干扰 RNA 的热稳定性、核酸酶抗性、效力和 hAgo2 结合

  摘要：

  在本研究中，我们设计了4′- C-乙酰胺甲基-2′- O-甲氧基乙基(4′- C -ACM-2′- O -MOE)尿苷和胸苷修饰，旨在测试它们在小干扰RNA中的作用。热熔解研究表明，在 DNA 双链体中掺入单个 4'- C -ACM-2'- O -MOE 修饰会降低热稳定性。相反，当在 DNA:RNA 杂交体和 siRNA 中引入修饰时，观察到热稳定性增加。 DNA双链体的热失稳归因于不利的熵，这在一定程度上主要由焓因子补偿。在 3' 特异性核酸外切酶、蛇毒磷酸二酯酶 (SVPD) 存在下，dT 20 寡核苷酸 3' 末端倒数第二个位置上的单个 4'- C -ACM-2'- O -MOE 胸苷修饰显示出显着的修饰作用。与包括 2'- O -Me、2'- O -MOE 和 2'-F 在内的单体修饰相比，稳定性更高。在基因沉默研究中，我们发现过客链3'突出端的4'- C -ACM-2'- O

  DOI：

  10.1021/acs.joc.3c02506

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.
• 4′-<i>C</i>-Acetamidomethyl-2′-<i>O</i>-methoxyethyl Nucleic Acid Modifications Improve Thermal Stability, Nuclease Resistance, Potency, and hAgo2 Binding of Small Interfering RNAs
  作者：Sumit Gangopadhyay、Gourav Das、Shalini Gupta、Atanu Ghosh、Siddharam Shivappa Bagale、Pritam Kumar Roy、Mahitosh Mandal、S. Harikrishna、Surajit Sinha、Kiran R. Gore

  DOI：10.1021/acs.joc.3c02506

  日期：2024.3.15

  that our modification could induce prolonged gene silencing due to improved metabolic stability. Molecular modeling studies revealed that the introduction of the 4′-C-ACM-2′-O-MOE modification at the 3′-end of the siRNA guide strand helps to anchor the strand within the PAZ domain of the hAgo2 protein. The overall results indicate that the 4′-C-ACM-2′-O-MOE uridine and thymidine modifications are promising

  在本研究中，我们设计了4′- C-乙酰胺甲基-2′- O-甲氧基乙基(4′- C -ACM-2′- O -MOE)尿苷和胸苷修饰，旨在测试它们在小干扰RNA中的作用。热熔解研究表明，在 DNA 双链体中掺入单个 4'- C -ACM-2'- O -MOE 修饰会降低热稳定性。相反，当在 DNA:RNA 杂交体和 siRNA 中引入修饰时，观察到热稳定性增加。 DNA双链体的热失稳归因于不利的熵，这在一定程度上主要由焓因子补偿。在 3' 特异性核酸外切酶、蛇毒磷酸二酯酶 (SVPD) 存在下，dT 20 寡核苷酸 3' 末端倒数第二个位置上的单个 4'- C -ACM-2'- O -MOE 胸苷修饰显示出显着的修饰作用。与包括 2'- O -Me、2'- O -MOE 和 2'-F 在内的单体修饰相比，稳定性更高。在基因沉默研究中，我们发现过客链3'突出端的4'- C -ACM-2'- O