1-[(3'S,5'R,6'R)-5'-O-[(4,4'-dimethoxytriphenyl)methyl]-6'-[(hexadecoxycarbonyl)methyl]-2'-deoxy-3',5'-ethano-5',6'-methano-β-D-ribofuranosyl]thymine | 1374576-36-9

• 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-[(3'S,5'R,6'R)-5'-O-[(4,4'-dimethoxytriphenyl)methyl]-6'-[(hexadecoxycarbonyl)methyl]-2'-deoxy-3',5'-ethano-5',6'-methano-β-D-ribofuranosyl]thymine
• CAS: 1374576-36-9
• 化学式: C₅₂H₆₈N₂O₉
• 分子量: 865.12
• InChiKey: PMHFHNWVOGGVOD-ZCYSSYJQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.84
• 重原子数：
  63.0
• 可旋转键数：
  25.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  138.31
• 氢给体数：
  2.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  1-[(3'S,5'R,6'R)-5'-O-[(4,4'-dimethoxytriphenyl)methyl]-6'-[(hexadecoxycarbonyl)methyl]-2'-deoxy-3',5'-ethano-5',6'-methano-β-D-ribofuranosyl]thymine 、 2-氰乙基N,N-二异丙基氯亚磷酰胺 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以89%的产率得到1-[(3'S,5'R,6'S)-5'-O-[(4,4'-dimethoxytriphenyl)methyl]-6'-[(hexadecoxycarbonyl)methyl]-3'-O-[(2-cyanoethoxy)-diisopropylaminophosphanyl]-2'-deoxy-3',5'-ethano-5',6'-methano-β-D-ribofuranosyl]thymine
  参考文献：
  名称：

  Synthesis, Pairing, and Cellular Uptake Properties of C(6′)-Functionalized Tricyclo-DNA

  摘要：

  Tricyclo-DNA (tc-DNA) is a promising candidate for oligonucleotide-based therapeutic applications exhibiting increased affinity to RNA and increased resistance to nucleases. However, as many other oligonucleotide analogs, tc-DNA does not readily cross cell membranes. We wished to address this issue by preparing a prodrug of tc-DNA containing a metabolically labile group at C(6) that promotes cellular uptake. Two monomeric nucleoside building blocks bearing an ester function at C(6') (tc(ee)-T and tc(hd)-T) were synthesized starting from a known C(6') functionalized bicyclic sugar unit to which the cyclopropane ring was introduced via carbene addition. NIS-mediated nucleosidation of the corresponding glycal with in situ persilylated thymine afforded the beta-iodonucleoside exclusively that was dehalogenated via radical reduction. Diversity in the ester function was obtained by hydrolysis and reesterification. The two nucleosides were subsequently incorporated into DNA or tc-DNA by standard phosphoramidite chemistry. The reactivity of the ester function during oligonudeotide deprotection was explored and the corresponding C(6') amide, carboxylic acid, or unchanged ester functions were obtained, depending on the deprotection conditions. Compared to unmodified DNA, these tc-DNA derivatives increased the stability of duplexes investigated with Delta T-m/mod of +0.4 to +2.0 degrees C. The only destabilizing residue was tc(hd)-T, most likely due to self aggregation of the lipophilic side chains in the single stranded oligonucleotide. A decamer containing five tc(hd)-T residues was readily taken up by HeLa and HEK 293T cells without the use of a transfection agent.

  DOI：

  10.1021/jo300648u
• 作为产物：
  描述：

  1-[(3'S,5'R,6'S)-3'-O-trimethylsilyl-5'-O-(tert-butyldimethylsilyl)-6'-[(ethoxycarbonyl)methyl]-2'-deoxy-3',5'-ethano-5',6'-methano-β-D-ribofuranosyl]thymine 在 吡啶 、 乙醇 、 氢氟酸 、 1,2-二氯乙烷 、 potassium hydroxide 作用下， 以 二氯甲烷 为溶剂， 生成 1-[(3'S,5'R,6'R)-5'-O-[(4,4'-dimethoxytriphenyl)methyl]-6'-[(hexadecoxycarbonyl)methyl]-2'-deoxy-3',5'-ethano-5',6'-methano-β-D-ribofuranosyl]thymine
  参考文献：
  名称：

  Tricyclic nucleosides and oligomeric compounds prepared therefrom

  摘要：

  本发明提供了新颖的三环核苷和由此制备的寡聚合物化合物。将一种或多种三环核苷并入寡聚合物化合物中，预计会增强寡聚合物化合物的一种或多种性质。这种寡聚合物化合物也可以包含在双链组合物中。在某些实施方式中，本文提供的寡聚合物化合物预计会与靶RNA的部分杂交，导致靶RNA的正常功能丧失。

  公开号：

  EP2639238A1