| 1337926-44-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• CAS: 1337926-44-9
• 化学式: C₁₁H₁₅FN₂O₅
• 分子量: 274.249
• InChiKey: WHDZAEQAHKWECS-FNCVBFRFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.52
• 重原子数：
  19.0
• 可旋转键数：
  2.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  104.55
• 氢给体数：
  3.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  在 吡啶 、 N-甲基咪唑 、 四氮唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 1,5-anhydro-4-O-(cyanoethoxydiisopropylaminophosphinyl)-2,3-dideoxy-6-O-(4,4'-dimethoxytrityl)-3-fluoro-2-(thymin-1-yl)-D-mannitol
  参考文献：
  名称：

  Synthesis, Improved Antisense Activity and Structural Rationale for the Divergent RNA Affinities of 3′-Fluoro Hexitol Nucleic Acid (FHNA and Ara-FHNA) Modified Oligonucleotides

  摘要：

  The synthesis, biophysical, structural, and biological properties of both isomers of 3'-fluoro hexitol nucleic acid (FHNA and Ara-FHNA) modified oligonucleotides are reported. Synthesis of the FHNA and Ara-FHNA thymine phosphoramidites was efficiently accomplished starting from known sugar precursors. Optimal RNA affinities were observed with a 3'-fluorine atom and nucleobase in a trans-diaxial orientation. The Ara-FHNA analog with an equatorial fluorine was found to be destabilizing. However, the magnitude of destabilization was sequence-dependent. Thus, the loss of stability is sharply reduced when Ara-FHNA residues were inserted at pyrimidine-purine (Py-Pu) steps compared to placement within a stretch of pyrimidines (Py-Py). Crystal structures of A-type DNA duplexes modified with either monomer provide a rationalization for the opposing stability effects and point to a steric origin of the destabilization caused by the Ara-FHNA analog. The sequence dependent effect can be explained by the formation of an internucleotide C-F center dot center dot center dot H-C pseudo hydrogen bond between F3' of Ara-FHNA and C8-H of the nucleobase from the 3'-adjacent adenosine that is absent at Py-Py steps. In animal experiments, FHNA-modified antisense oligonudeotides formulated in saline showed a potent downregulation of gene expression in liver tissue without producing hepatotoxicity. Our data establish FHNA as a useful modification for antisense therapeutics and also confirm the stabilizing influence of F(Py)center dot center dot center dot H-C(Pu) pseudo hydrogen bonds in nucleic acid structures.

  DOI：

  10.1021/ja207086x
• 作为产物：
  描述：

  2,4,6-tri-O-acetyl-1,5-anhydro-3-deoxy-3-fluoro-D-glucitol 在 吡啶 、 20% palladium hydroxide on charcoal 、 氢气 、 potassium carbonate 、 对甲苯磺酸 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 甲醇 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.5h， 生成
  参考文献：
  名称：

  Synthesis, Improved Antisense Activity and Structural Rationale for the Divergent RNA Affinities of 3′-Fluoro Hexitol Nucleic Acid (FHNA and Ara-FHNA) Modified Oligonucleotides

  摘要：

  The synthesis, biophysical, structural, and biological properties of both isomers of 3'-fluoro hexitol nucleic acid (FHNA and Ara-FHNA) modified oligonucleotides are reported. Synthesis of the FHNA and Ara-FHNA thymine phosphoramidites was efficiently accomplished starting from known sugar precursors. Optimal RNA affinities were observed with a 3'-fluorine atom and nucleobase in a trans-diaxial orientation. The Ara-FHNA analog with an equatorial fluorine was found to be destabilizing. However, the magnitude of destabilization was sequence-dependent. Thus, the loss of stability is sharply reduced when Ara-FHNA residues were inserted at pyrimidine-purine (Py-Pu) steps compared to placement within a stretch of pyrimidines (Py-Py). Crystal structures of A-type DNA duplexes modified with either monomer provide a rationalization for the opposing stability effects and point to a steric origin of the destabilization caused by the Ara-FHNA analog. The sequence dependent effect can be explained by the formation of an internucleotide C-F center dot center dot center dot H-C pseudo hydrogen bond between F3' of Ara-FHNA and C8-H of the nucleobase from the 3'-adjacent adenosine that is absent at Py-Py steps. In animal experiments, FHNA-modified antisense oligonudeotides formulated in saline showed a potent downregulation of gene expression in liver tissue without producing hepatotoxicity. Our data establish FHNA as a useful modification for antisense therapeutics and also confirm the stabilizing influence of F(Py)center dot center dot center dot H-C(Pu) pseudo hydrogen bonds in nucleic acid structures.

  DOI：

  10.1021/ja207086x