[(2R,3S,4S,5S)-2-(2,4-dioxopyrimidin-1-yl)-5-[(methylideneamino)oxymethyl]-4-(naphthalen-2-ylmethoxy)-5-(naphthalen-2-ylmethoxymethyl)oxolan-3-yl] methanesulfonate | 1207867-66-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [(2R,3S,4S,5S)-2-(2,4-dioxopyrimidin-1-yl)-5-[(methylideneamino)oxymethyl]-4-(naphthalen-2-ylmethoxy)-5-(naphthalen-2-ylmethoxymethyl)oxolan-3-yl] methanesulfonate
• CAS: 1207867-66-0
• 化学式: C₃₄H₃₃N₃O₉S
• 分子量: 659.717
• InChiKey: IHQBNTBEDLIDDW-SGLIHVKSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  47
• 可旋转键数：
  13
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  150
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  [(2R,3S,4S,5S)-2-(2,4-dioxopyrimidin-1-yl)-5-[(methylideneamino)oxymethyl]-4-(naphthalen-2-ylmethoxy)-5-(naphthalen-2-ylmethoxymethyl)oxolan-3-yl] methanesulfonate 在 4-甲基苯磺酸吡啶 、 sodium cyanoborohydride 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以84%的产率得到1-[(1R,5S,7R,8S)-2-methyl-8-(naphthalen-2-ylmethoxy)-5-(naphthalen-2-ylmethoxymethyl)-3,6-dioxa-2-azabicyclo[3.2.1]octan-7-yl]pyrimidine-2,4-dione
  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
• 作为产物：
  描述：

  1-[(2R,3S,4S,5S)-3-hydroxy-5-[(methylideneamino)oxymethyl]-4-(naphthalen-2-ylmethoxy)-5-(naphthalen-2-ylmethoxymethyl)oxolan-2-yl]pyrimidine-2,4-dione 、 甲基磺酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以86%的产率得到[(2R,3S,4S,5S)-2-(2,4-dioxopyrimidin-1-yl)-5-[(methylideneamino)oxymethyl]-4-(naphthalen-2-ylmethoxy)-5-(naphthalen-2-ylmethoxymethyl)oxolan-3-yl] methanesulfonate
  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

• 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.