5'-O-(DMT)-2'-N,4'-C-[(N-methoxyamino)methylene]uridine | 1091607-99-6

• 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: 5'-O-(DMT)-2'-N,4'-C-[(N-methoxyamino)methylene]uridine
• 英文别名: 1-[(1R,3R,4R,7S)-1-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-7-hydroxy-5-methoxy-2-oxa-5-azabicyclo[2.2.1]heptan-3-yl]pyrimidine-2,4-dione
• CAS: 1091607-99-6
• 化学式: C₃₂H₃₃N₃O₈
• 分子量: 587.629
• InChiKey: BGMDDWJFOULHHQ-VVFTXPSUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  43
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  5'-O-(DMT)-2'-N,4'-C-[(N-methoxyamino)methylene]uridine 、 叔丁基二甲基氯硅烷 在 咪唑 、 碳酸氢钠 作用下， 以 N,N-二甲基甲酰胺 、 水 为溶剂， 反应 24.0h， 以85.4%的产率得到5'-O-(DMT)-3'-O-(TBDMS)-2'-N,4'-C-[(N-methoxyamino)methylene]uridine
  参考文献：
  名称：

  WO2008/150729

  摘要：

  公开号：
• 作为产物：
  描述：

  2'-N,4'-C-[(N-methoxyamino)methylene]uridine 、 4,4'-双甲氧基三苯甲基氯 在 吡啶 作用下， 反应 8.0h， 以99%的产率得到5'-O-(DMT)-2'-N,4'-C-[(N-methoxyamino)methylene]uridine
  参考文献：
  名称：

  Antisense Oligonucleotides Containing Conformationally Constrained 2′,4′-(N-Methoxy)aminomethylene and 2′,4′-Aminooxymethylene and 2′-O,4′-C-Aminomethylene Bridged Nucleoside Analogues Show Improved Potency in Animal Models

  摘要：

  To identify chemistries and strategies to improve the potency of MOE second generation ASOs, we have evaluated gapmer antisense oligonucleotides containing BNAs having N-O bonds. These modifications include N-MeO-amino BNA, N-Me-aminooxy BNA, 2'4'-BNA(NC)[NMe], and 2',4'-BNA(NC) bridged nucleoside analogues. These modifications provided increased thermal stability and improved in vitro activity compared to the corresponding ASO containing the MOE modification. Additionally, ASOs containing N-MeO-amino BNA, N-Me-aminooxy BNA, and 2',4'-BNA(NC)[NMe] modifications showed improved in vivo activity (> 5-fold) compared to MOE ASO. Importantly, toxicity parameters, such as AST, ALT, liver, kidney, and body weights, were found to be normal for N-MeO-amino BNA, N-Me-aminooxy BNA, and 2'4'-BNA(NC)[NMe] ASO treated animals. The data generated in these experiments suggest that N-MeO-amino BNA, N-Me-aminooxy BNA, and 2'4'-BNA(NC)[NMe] are useful modifications for applications in both antisense and other oligonucleotide based drug discovery efforts.

  DOI：

  10.1021/jm9013295

文献信息

• WO2008/150729
  申请人：——

  公开号：——

  公开（公告）日：——
• Antisense Oligonucleotides Containing Conformationally Constrained 2′,4′-(<i>N</i>-Methoxy)aminomethylene and 2′,4′-Aminooxymethylene and 2′-<i>O</i>,4′-<i>C</i>-Aminomethylene Bridged Nucleoside Analogues Show Improved Potency in Animal Models
  作者：Thazha P. Prakash、Andrew Siwkowski、Charles R. Allerson、Michael T. Migawa、Sam Lee、Hans J. Gaus、Chris Black、Punit P. Seth、Eric E. Swayze、Balkrishen Bhat

  DOI：10.1021/jm9013295

  日期：2010.2.25

  To identify chemistries and strategies to improve the potency of MOE second generation ASOs, we have evaluated gapmer antisense oligonucleotides containing BNAs having N-O bonds. These modifications include N-MeO-amino BNA, N-Me-aminooxy BNA, 2'4'-BNA(NC)[NMe], and 2',4'-BNA(NC) bridged nucleoside analogues. These modifications provided increased thermal stability and improved in vitro activity compared to the corresponding ASO containing the MOE modification. Additionally, ASOs containing N-MeO-amino BNA, N-Me-aminooxy BNA, and 2',4'-BNA(NC)[NMe] modifications showed improved in vivo activity (> 5-fold) compared to MOE ASO. Importantly, toxicity parameters, such as AST, ALT, liver, kidney, and body weights, were found to be normal for N-MeO-amino BNA, N-Me-aminooxy BNA, and 2'4'-BNA(NC)[NMe] ASO treated animals. The data generated in these experiments suggest that N-MeO-amino BNA, N-Me-aminooxy BNA, and 2'4'-BNA(NC)[NMe] are useful modifications for applications in both antisense and other oligonucleotide based drug discovery efforts.