2'-O-benzyl-5'-O-[bis(4-methoxyphenyl)(phenyl)methyl]inosine | 1338796-57-8

• 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: 2'-O-benzyl-5'-O-[bis(4-methoxyphenyl)(phenyl)methyl]inosine
• 英文别名: 9-[(2R,3R,4R,5R)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxy-3-phenylmethoxyoxolan-2-yl]-1H-purin-6-one
• CAS: 1338796-57-8
• 化学式: C₃₈H₃₆N₄O₇
• 分子量: 660.726
• InChiKey: CZYQRPITUZZKMT-SPBWOXKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  49
• 可旋转键数：
  12
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2'-O-benzyl-5'-O-[bis(4-methoxyphenyl)(phenyl)methyl]inosine 、 chloro-(2-cyanoethyl)-diisopropylaminophosphane 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 以78%的产率得到2'-O-benzyl-5'-O-[bis(4-methoxyphenyl)(phenyl)methyl]-3'-O-[(2-cyanoethoxy)(dipropan-2-ylamino)phosphanyl]inosine
  参考文献：
  名称：

  Nucleoside Optimization for RNAi: A High-Throughput Platform

  摘要：

  The RNA induced silencing complex (RISC) contains at its core the endonuclease Argonaute (Ago) that allows for guide strand (GS)-mediated sequence-specific cleavage of the target mRNA. Functionalization of the sugar/phosphodiester backbone of the GS, which is in direct contact with Ago, presents a logical opportunity to affect RISC's activity. A systematic evaluation of modified nucleosides requires the synthesis of phosphoramidites corresponding to all four canonical bases (A, U, C, and G) and their sequential evaluation at each position along the 21-nucleotide-long GS. With the use of a platform approach, the sequential replacement of canonical bases with inosine greatly simplifies the problem and defines a new activity baseline toward which the col-responding sugar-modified inosines are compared. This approach was validated using 2'-O-benzyl modification, which demonstrated that positions 5, 8, 15, and 19 can accommodate this large group. Application of this high-throughput methodology now allows for hypothesis-driven rational design of highly potent, immunologically silent and stable siRNAs suitable for therapeutic applications.

  DOI：

  10.1021/ja2068774
• 作为产物：
  描述：

  3',5'-O-(di-tert-butylsilanylidene)inosine 在 吡啶 、 三乙烯二胺 、 4-二甲氨基吡啶 、 potassium fluoride 、 四丁基氟化铵 、 sodium methylate 、 2-叔丁基亚氨基-2-二乙基氨基-1,3-二甲基全氢-1,3,2-二氮杂磷 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 10.67h， 生成 2'-O-benzyl-5'-O-[bis(4-methoxyphenyl)(phenyl)methyl]inosine
  参考文献：
  名称：

  Nucleoside Optimization for RNAi: A High-Throughput Platform

  摘要：

  The RNA induced silencing complex (RISC) contains at its core the endonuclease Argonaute (Ago) that allows for guide strand (GS)-mediated sequence-specific cleavage of the target mRNA. Functionalization of the sugar/phosphodiester backbone of the GS, which is in direct contact with Ago, presents a logical opportunity to affect RISC's activity. A systematic evaluation of modified nucleosides requires the synthesis of phosphoramidites corresponding to all four canonical bases (A, U, C, and G) and their sequential evaluation at each position along the 21-nucleotide-long GS. With the use of a platform approach, the sequential replacement of canonical bases with inosine greatly simplifies the problem and defines a new activity baseline toward which the col-responding sugar-modified inosines are compared. This approach was validated using 2'-O-benzyl modification, which demonstrated that positions 5, 8, 15, and 19 can accommodate this large group. Application of this high-throughput methodology now allows for hypothesis-driven rational design of highly potent, immunologically silent and stable siRNAs suitable for therapeutic applications.

  DOI：

  10.1021/ja2068774

文献信息

• Method For Rapidly Evaluating Performance Of Short Interfering RNA With Novel Chemical Modifications
  申请人：Butora Gabor

  公开号：US20120252027A1

  公开（公告）日：2012-10-04

  It is an object of the instant invention to provide a method for the rapid evaluation of novel sugar modifications to be used in siRNA synthesis including the rapid evaluation of chemical modification patterns within the siRNA to effectuate increased stability and ultimately increased efficacy of a siRNA therapeutic. It is a further object of the instant invention to provide novel nucleosides useful for siRNA therapy.

  本发明的目的是提供一种用于快速评估新型糖基修饰的方法，以用于siRNA合成，包括快速评估siRNA中的化学修饰模式，以实现siRNA的稳定性增加和最终疗效增加。本发明的另一个目的是提供用于siRNA治疗的新型核苷酸。
• METHOD FOR RAPIDLY EVALUATING PERFORMANCE OF SHORT INTERFERING RNA WITH NOVEL CHEMICAL MODIFICATIONS
  申请人：SIRNA THERAPEUTICS, INC.

  公开号：US20150132761A1

  公开（公告）日：2015-05-14

  It is an object of the instant invention to provide a method for the rapid evaluation of novel sugar modifications to be used in siRNA synthesis including the rapid evaluation of chemical modification patterns within the siRNA to effectuate increased stability and ultimately increased efficacy of a siRNA therapeutic. It is a further object of the instant invention to provide novel nucleosides useful for siRNA therapy.

  本发明的目的是提供一种用于快速评估新型糖基修饰用于siRNA合成的方法，包括快速评估siRNA中的化学修饰模式，以实现增加稳定性和最终增加siRNA治疗的功效。本发明的另一个目的是提供用于siRNA治疗的新型核苷酸。
• Method for rapidly evaluating performance of short interfering RNA with novel chemical modifications
  申请人：Butora Gabor

  公开号：US08877439B2

  公开（公告）日：2014-11-04

  It is an object of the instant invention to provide a method for the rapid evaluation of novel sugar modifications to be used in siRNA synthesis including the rapid evaluation of chemical modification patterns within the siRNA to effectuate increased stability and ultimately increased efficacy of a siRNA therapeutic. It is a further object of the instant invention to provide novel nucleosides useful for siRNA therapy.

  本发明的目的是提供一种用于快速评估新型糖基修饰的方法，用于siRNA合成，包括快速评估siRNA中的化学修饰模式，以实现增加稳定性并最终增加siRNA治疗的功效。本发明的另一个目的是提供用于siRNA治疗的新型核苷酸。
• A METHOD FOR RAPIDLY EVALUATING PERFORMANCE OF SHORT INTERFERING RNA WITH NOVEL CHEMICAL MODIFICATIONS
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2513337A1

  公开（公告）日：2012-10-24
• US8877439B2
  申请人：——

  公开号：US8877439B2

  公开（公告）日：2014-11-04