4-amino-1-[(1S,3R,4R,7S)-7-hydroxy-1-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-3-yl]-1,2-dihydropyrimidin-2-one | 206055-69-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-amino-1-[(1S,3R,4R,7S)-7-hydroxy-1-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-3-yl]-1,2-dihydropyrimidin-2-one
• 英文别名: (1S,3R,4R,7S)-7-hydroxy-1-hydroxymethyl-3-(cytosin-1-yl)-2,5-dioxabicyclo[2.2.1]heptane；2′-O,4′-C-methylenecytidine；2'-O,4'-C-Methylenecytidine；4-amino-1-[(1S,3R,4R,7S)-7-hydroxy-1-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-3-yl]pyrimidin-2-one
• CAS: 206055-69-8
• 化学式: C₁₀H₁₃N₃O₅
• 分子量: 255.23
• InChiKey: FCMRQQIZHFHCNG-JIOCBJNQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.5
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  118
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-amino-1-[(1S,3R,4R,7S)-7-hydroxy-1-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-3-yl]-1,2-dihydropyrimidin-2-one 在 ammonium hydroxide 作用下， 以 吡啶 为溶剂， 反应 3.5h， 生成 (1S,3R,4R,7S)-3-(4-N-benzoylcytosin-1-yl)-7-hydroxy-1-hydroxymethyl-2,5-dioxabicyclo[2.2.1]heptane
  参考文献：
  名称：

  LNA（锁定核酸）：腺嘌呤，胞嘧啶，鸟嘌呤，5-甲基胞嘧啶，胸腺嘧啶和尿嘧啶双环核苷单体的合成，寡聚化和前所未有的核酸识别

  摘要：

  由2'- O，4'- C-亚甲基双环核苷单体组成的LNA（锁定核酸）被有效合成，并评估了其对六种不同核碱基（腺嘌呤，胞嘧啶，鸟嘌呤，5-甲基胞嘧啶，胸腺嘧啶）的核酸识别潜力和尿嘧啶。当评估部分或完全修饰的LNA的混合序列时，双链体对DNA和RNA的热稳定性出现了前所未有的提高（每个修饰+3至+8°C）。错配序列的研究表明，与相应的未修饰参考链相比，LNA遵循具有普遍提高的选择性的Watson-Crick碱基配对规则。

  DOI：

  10.1016/s0040-4020(98)00094-5
• 作为产物：
  描述：

  ((1R,3R,4R,7S)-3-(4-amino-2-oxopyrimidin-1(2H)-yl)-7-(benzyloxy)-2,5-dioxabicyclo[2.2.1]heptan-1-yl)methylmethanesulfonate 在 10 wt% Pd(OH)2 on carbon 、 甲酸铵 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 反应 31.0h， 生成 4-amino-1-[(1S,3R,4R,7S)-7-hydroxy-1-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-3-yl]-1,2-dihydropyrimidin-2-one
  参考文献：
  名称：

  Synthesis of 2′-O,4′-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase

  摘要：

  The synthesis of 2'-O,4'-C-methylene-bridged bicyclic guanine ribonucleosides bearing 2'-C-methyl or 5'C-methyl modifications is described. Key to the successful installation of the methyl functionality in both cases was the use of a one-pot oxidation-Grignard procedure to avoid formation of the respective unreactive hydrates prior to alkylation. The 2'-C-methyl- and 5'-C-methyl-modified bicyclic guanosines were evaluated, along with the known uracil-, cytosine-, adenine-, guanine-LNA and guanine-ENA nucleosides, as potential antiviral agents and found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay. Examination of the corresponding nucleoside triphosphates, however, against the purified HCV NS5B polymerase indicated that LNA-G and 2'-C-methyl-LNA-G are potent inhibitors of both 1b wild type and S282T mutant enzymes in vitro. Activity was further demonstrated for the LNA-G-triphosphate against HCV NS5B polymerase genotypes 1a, 2a, 3a and 4a. A phosphorylation by-pass prodrug strategy may be required to promote anti-HCV activity in the replicon assay. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.04.050

文献信息

• A Simplified and Efficient Route to 2‘-<i>O</i>, 4‘-<i>C</i>-Methylene-Linked Bicyclic Ribonucleosides (Locked Nucleic Acid)
  作者：Alexei A. Koshkin、Jef Fensholdt、Henrik M. Pfundheller、Christian Lomholt

  DOI：10.1021/jo010732p

  日期：2001.12.1

  can be prepared from D-glucose in multigram scale. Four different nucleobases were stereoselectively coupled to 8 using a modified Vorbrüggen procedure to give the corresponding 4'-C-branched nucleoside derivatives. Subsequent ring closing furnished the protected LNA nucleosides. The 5'-O-mesyl groups were efficiently displaced by nucleophilic substitution using sodium benzoate. Saponification of the

  描述了一种合成锁核酸（LNA）单体的新型有效方法。通过聚合合成制备了含有胸腺嘧啶，4-N-乙酰基和4-N-苯甲酰基胞嘧啶，6-N-苯甲酰腺嘌呤和2-N-异丁酰鸟嘌呤作为核碱基的LNA 5'，3'-二醇。该方法基于使用常见的糖中间体1,2-二-O-乙酰基-3-O-苄基-4-C-甲磺酰氧基甲基-5-O-甲磺酰-D-赤型戊呋喃糖（8）可以从D-葡萄糖以克数制得。使用改良的Vorbrüggen程序将四个不同的核碱基立体选择性地偶联到8个核碱基上，得到相应的4'-C-支链核苷衍生物。随后的闭环提供了受保护的LNA核苷。使用苯甲酸钠通过亲核取代有效地置换了5'-O-甲磺酰基。将5'-苯甲酸酯皂化，然后催化除去3'-O-苄基，得到游离的LNA二醇。腺苷和胞苷的环外氨基被选择性地酰化，得到4-N-乙酰基或4-N-苯甲酰基-LNA-C和6-N-苯甲酰基-LNA-A。在制备2-N-异丁酰基-LNA-G期间，鸟
• Oligonucleotide analogues
  申请人：Wengel Jesper

  公开号：US20050287566A1

  公开（公告）日：2005-12-29

  The present invention relates to novel bicyclic and tricyclic nucleoside and nucleotide analogues as well as to oligonucleotides comprising such elements. The nucleotide analogues, LNAs (Locked Nucleoside Analogues), are able to provide valuable improvements to oligonucleotides with respect to affinity and specificity towards complementary RNA and DNA oligomers. The novel type of LNA modified oligonucleotides, as well as the LNAs as such, are useful in a wide range of diagnostic applications as well as therapeutic applications. Among these can be mentioned antisense applications, PCR applications, strand displacement oligomers, as substrates for nucleic acid polymerases, as nucleotide based drugs, etc. The present invention also relates to such applications.

  本发明涉及新型的双环和三环核苷酸和核苷酸类似物，以及包含这些元素的寡核苷酸。这些核苷酸类似物，即锁定核苷酸类似物（LNAs），能够为寡核苷酸提供与互补RNA和DNA寡聚物的亲和力和特异性方面的有价值的改进。这种新型的LNA修饰的寡核苷酸以及LNA本身在广泛的诊断应用和治疗应用中非常有用。其中包括反义应用、PCR应用、链置换寡聚物、作为核酸聚合酶的底物、作为基于核苷酸的药物等。本发明还涉及这些应用。
• OLIGONUCLEOTIDE ANALOGUES
  申请人：Wengel Jesper

  公开号：US20100279895A1

  公开（公告）日：2010-11-04

  The present invention relates to novel bicyclic and tricyclic nucleoside and nucleotide analogues as well as to oligonucleotides comprising such elements. The nucleotide analogues, LNAs (Locked Nucleoside Analogues), are able to provide valuable improvements to oligonucleotides with respect to affinity and specificity towards complementary RNA and DNA oligomers. The novel type of LNA modified oligonucleotides, as well as the LNAs as such, are useful in a wide range of diagnostic applications as well as therapeutic applications. Among these can be mentioned antisense applications, PCR applications, strand displacement oligomers, as substrates for nucleic acid polymerases, as nucleotide based drugs, etc. The present invention also relates to such applications.

  本发明涉及新型的双环和三环核苷酸和核苷酸类似物，以及包含这些元素的寡核苷酸。这些核苷酸类似物，即LNAs（锁定核苷酸类似物），能够为寡核苷酸提供与互补RNA和DNA寡聚物相比亲和力和特异性的有价值的改进。这种新型的LNA修饰的寡核苷酸以及LNAs本身在广泛的诊断应用和治疗应用中都有用途。其中可以提到反义应用、PCR应用、链位移寡聚物、作为核酸聚合酶底物、作为核苷酸基药物等。本发明还涉及这些应用。
• Oligonucleotide Analogues
  申请人：WENGEL Jesper

  公开号：US20110245327A1

  公开（公告）日：2011-10-06

  The present invention relates to novel bicyclic and tricyclic nucleoside and nucleotide analogues as well as to oligonucleotides comprising such elements. The nucleotide analogues, LNAs ( L ocked N ucleoside A nalogues), are able to provide valuable improvements to oligonucleotides with respect to affinity and specificity towards complementary RNA and DNA oligomers. The novel type of LNA modified oligonucleotides, as well as the LNAs as such, are useful in a wide range of diagnostic applications as well as therapeutic applications. Among these can be mentioned antisense applications, PCR applications, strand displacement oligomers, as substrates for nucleic acid polymerases, as nucleotide based drugs, etc. The present invention also relates to such applications.

  本发明涉及新型的双环和三环核苷酸和核苷酸类似物，以及包含这些元素的寡核苷酸。核苷酸类似物，即锁定核苷酸类似物（LNAs），能够为寡核苷酸提供有价值的改进，使其对互补的RNA和DNA寡聚体具有更高的亲和力和特异性。这种新型的LNA修饰的寡核苷酸以及LNAs本身在广泛的诊断应用和治疗应用中都很有用。其中包括反义应用、PCR应用、链置换寡聚体、作为核酸聚合酶的底物、作为基于核苷酸的药物等。本发明还涉及这些应用。
• Bi-cyclic nucleoside, nucleotide and oligonucleoide analogues
  申请人：Exiqon A/S

  公开号：EP1557424A1

  公开（公告）日：2005-07-27

  The present invention relates to novel bicyclic and tricyclic nucleoside analogues as well as to oligonucleotides comprising such elements. The nucleotide analogues, LNAs (Locked Nucleoside Analogues), are able to provide valuable improvements to oligonucleotides with respect to affinity and specificity towards complementary RNA and DNA oligomers. The novel type of LNA modified oligonucleotides, as well as the LNAs as such, are useful in a wide range of diagnostic applications as well as therapeutic applications. Among these can be mentioned antisense applications, PCR applications, strand displacement oligomers, as substrates for nucleic acid polymerises, as nucleotide based drugs, etc. The present invention also relates to such applications.

  本发明涉及新型双环和三环核苷类似物以及包含此类元素的寡核苷酸。这种核苷酸类似物 LNA（锁定核苷酸类似物）能够在对互补 RNA 和 DNA 寡聚体的亲和性和特异性方面对寡核苷酸进行有价值的改进。新型 LNA 修饰寡核苷酸以及 LNA 本身可用于广泛的诊断和治疗应用。其中包括反义应用、PCR 应用、链置换寡聚体、核酸聚合底物、核苷酸类药物等。本发明也涉及此类应用。