N2-isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-O-propargyl guanosine | 171486-53-6

• 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: N2-isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-O-propargyl guanosine
• 英文别名: 5'-O-[Bis(4-methoxyphenyl)phenylmethyl]-N-(2-methyl-1-oxopropyl)-2'-O-2-propyn-1-yl-Guanosine；N-[9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxy-3-prop-2-ynoxyoxolan-2-yl]-6-oxo-1H-purin-2-yl]-2-methylpropanamide
• CAS: 171486-53-6
• 化学式: C₃₈H₃₉N₅O₈
• 分子量: 693.756
• InChiKey: ZTBYTNLGRCUAEU-BEGXHNNXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  51
• 可旋转键数：
  13
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  155
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N2-isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-O-propargyl guanosine 、 乙酰丙酸酐 在 吡啶 作用下， 反应 16.0h， 生成
  参考文献：
  名称：

  Convenient Synthesis of a Propargylated Cyclic (3′-5′) Diguanylic Acid and Its “Click” Conjugation to a Biotinylated Azide

  摘要：

  The ribonucleoside building block, N(2)-isobutyryl-2'-O-propargyl-3'-O-levulinyl guanosine, was prepared from commercial N(2)-isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-O-propargyl guanosine in a yield of 91%. The propargylated guanylyl(3'-5')guanosine phosphotriester was synthesized from the reaction of N(2)-isobutyryl-2'-O-propargyl-3'-O-levulinyl guanosine with N(2)-isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-O-tert-butyldimethylsilyl-3'-O-[(2-cyanoethyl)-N, N-diisopropylaminophosphinyl] guanosine and isolated in a yield of 88% after P(III) oxidation, 3'-/5'-deprotection, and purification. The propargylated guanylyl(3'-5')guanosine phosphotriester was phosphitylated using 2-cyanoethyl tetraisopropylphosphordiamidite and 1H-tetrazole and was followed by an in situ intramolecular cyclization to give a propargylated c-di-GMP triester, which was isolated in a yield of 40% after P(III) oxidation and purification. Complete N-deacylation of the guanine bases and removal of the 2-cyanoethyl phosphate protecting groups from the propargylated c-di-GMP triester were performed by treatment with aqueous ammonia at ambient temperature. The final 2'-desilylation reaction was effected by exposure to triethylammonium trihydrofluoride affording the desired propargylated c-di-GMP diester, the purity of which exceeded 95%. Biotinylation of the propargylated c-di-GMP diester was easily accomplished through its cycloaddition reaction with a biotinylated azide derivative under click conditions to produce the biotinylated c-di-GMP conjugate of interest in an isolated yield of 62%.

  DOI：

  10.1021/bc1003857
• 作为产物：
  描述：

  5’-O-DMT-N2-isobutyrylguanosine 、 3-溴丙炔 在 四丁基溴化铵 、 二正丁基氧化锡 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以45 g的产率得到N2-isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-O-propargyl guanosine
  参考文献：
  名称：

  [EN] LIGAND-MODIFIED DOUBLE-STRANDED NUCLEIC ACIDS
  [FR] ACIDES NUCLÉIQUES DOUBLE BRIN MODIFIÉS PAR UN LIGAND

  摘要：

  该发明提供了包括具有感链或反义链的5'延伸以及进一步包括与配体结合的多个核苷酸的双链核酸分子，以及使用这些双链核酸分子的方法。其中，感链形成四环的配体修饰寡聚物提供了新的强效和稳定的RNA干扰剂。这些双链核酸分子是使用包括配体修饰单体、核苷酸类似物单体、修饰核苷酸单体等的多个核苷酸合成的，使用标准的核苷酸合成方法和系统。

  公开号：

  WO2016100401A1

文献信息

• Versatile Site-Specific Conjugation of Small Molecules to siRNA Using Click Chemistry
  作者：Takeshi Yamada、Chang Geng Peng、Shigeo Matsuda、Haripriya Addepalli、K. Narayanannair Jayaprakash、Md. Rowshon Alam、Kathy Mills、Martin A. Maier、Klaus Charisse、Mitsuo Sekine、Muthiah Manoharan、Kallanthottathil G. Rajeev

  DOI：10.1021/jo101761g

  日期：2011.3.4

  We have previously demonstrated that conjugation of small molecule ligands to small interfering RNAs (siRNAs) and anti-microRNAs results in functional siRNAs and antagomirs in vivo. Here we report on the development of an efficient chemical strategy to make oligoribonucleotide-ligand conjugates using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) or click reaction. Three click reaction approaches were evaluated for their feasibility and suitability for high-throughput synthesis: the CuAAC reaction at the monomer level prior to oligonucleotide synthesis, the solution-phase postsynthetic "click conjugation", and the "click conjugation" on an immobilized and cornpletely protected alkyne-oligonucleotide scaffold. Nucleosides bearing 5'-alkyne moieties were used for conjugation to the 5'-end of the oligonucleotide. Previously described 2'- and 3'-O-propargylated nucleosides were prepared to introduce the alkyne moiety to the 3' and 5' termini and to the internal positions of the scaffold. Azido-functionalized ligands bearing lipophilic long chain alkyls, cholesterol, oligoamine, and carbohydrate were utilized to study the effect of physicochemical characteristics of the incoming azide on click conjugation to the alkyne-oligonucleotide scaffold in solution and on immobilized solid support. We found that microwave-assisted click conjugation of azido-functionalized ligands to a fully protected solid-support bound alkyne-oligonucleotide prior to deprotection was the most efficient "click conjugation" strategy for site-specific, high-throughput oligonucleotide conjugate synthesis tested. The siRNA conjugates synthesized using this approach effectively silenced expression of a luciferase gene in a stably transformed HeLa cell line.
• Ligand-Modified Double-Stranded Nucleic Acids
  申请人：Dicerna Pharmaceuticals, Inc.

  公开号：US20170305956A1

  公开（公告）日：2017-10-26

  The invention provides for double stranded nucleic acid molecules comprising a 5′ extension of the sense or antisense strand and further comprising a plurality of nucleotides that are conjugated to a ligand and methods of using the double-stranded nucleic acid molecules. Ligand-modified oligomers where the sense stands form a tetraloop provide new potent and stable RNA interference agents. These dsNA molecules are synthesized using a plurality of nucleotides that include ligand-modified monomers, nucleotide analog monomers, modified nucleotide monomers and the like, using standard nucleotide synthetic methods and systems.
• LIGAND-MODIFIED DOUBLE-STRANDED NUCLEIC ACIDS
  申请人：Dicerna Pharmaceuticals, Inc.

  公开号：US20200031862A1

  公开（公告）日：2020-01-30

  The invention provides for double stranded nucleic acid molecules comprising a 5′ extension of the sense or antisense strand and further comprising a plurality of nucleotides that are conjugated to a ligand and methods of using the double-stranded nucleic acid molecules. Ligand-modified oligomers where the sense stands form a tetraloop provide new potent and stable RNA interference agents. These dsNA molecules are synthesized using a plurality of nucleotides that include ligand-modified monomers, nucleotide analog monomers, modified nucleotide monomers and the like, using standard nucleotide synthetic methods and systems.
• [EN] LIGAND-MODIFIED DOUBLE-STRANDED NUCLEIC ACIDS<br/>[FR] ACIDES NUCLÉIQUES DOUBLE BRIN MODIFIÉS PAR UN LIGAND
  申请人：DICERNA PHARMACEUTICALS INC

  公开号：WO2016100401A1

  公开（公告）日：2016-06-23

  The invention provides for double stranded nucleic acid molecules comprising a 5 'extension of the sense or antisense strand and further comprising a plurality of nucleotides that are conjugated to a ligand and methods of using the double-stranded nucleic acid molecules. Ligand-modified oligomers where the sense stands form a tetraloop provide new potent and stable RNA interference agents. These dsNA molecules are synthesized using a plurality of nucleotides that include ligand-modified monomers, nucleotide analog monomers, modified nucleotide monomers and the like, using standard nucleotide synthetic methods and systems.

  该发明提供了包括具有感链或反义链的5'延伸以及进一步包括与配体结合的多个核苷酸的双链核酸分子，以及使用这些双链核酸分子的方法。其中，感链形成四环的配体修饰寡聚物提供了新的强效和稳定的RNA干扰剂。这些双链核酸分子是使用包括配体修饰单体、核苷酸类似物单体、修饰核苷酸单体等的多个核苷酸合成的，使用标准的核苷酸合成方法和系统。
• Convenient Synthesis of a Propargylated Cyclic (3′-5′) Diguanylic Acid and Its “Click” Conjugation to a Biotinylated Azide
  作者：Andrzej Grajkowski、Jacek Cieślak、Alexei Gapeev、Christian Schindler、Serge L. Beaucage

  DOI：10.1021/bc1003857

  日期：2010.11.17

  The ribonucleoside building block, N(2)-isobutyryl-2'-O-propargyl-3'-O-levulinyl guanosine, was prepared from commercial N(2)-isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-O-propargyl guanosine in a yield of 91%. The propargylated guanylyl(3'-5')guanosine phosphotriester was synthesized from the reaction of N(2)-isobutyryl-2'-O-propargyl-3'-O-levulinyl guanosine with N(2)-isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-O-tert-butyldimethylsilyl-3'-O-[(2-cyanoethyl)-N, N-diisopropylaminophosphinyl] guanosine and isolated in a yield of 88% after P(III) oxidation, 3'-/5'-deprotection, and purification. The propargylated guanylyl(3'-5')guanosine phosphotriester was phosphitylated using 2-cyanoethyl tetraisopropylphosphordiamidite and 1H-tetrazole and was followed by an in situ intramolecular cyclization to give a propargylated c-di-GMP triester, which was isolated in a yield of 40% after P(III) oxidation and purification. Complete N-deacylation of the guanine bases and removal of the 2-cyanoethyl phosphate protecting groups from the propargylated c-di-GMP triester were performed by treatment with aqueous ammonia at ambient temperature. The final 2'-desilylation reaction was effected by exposure to triethylammonium trihydrofluoride affording the desired propargylated c-di-GMP diester, the purity of which exceeded 95%. Biotinylation of the propargylated c-di-GMP diester was easily accomplished through its cycloaddition reaction with a biotinylated azide derivative under click conditions to produce the biotinylated c-di-GMP conjugate of interest in an isolated yield of 62%.