{2-[(2R,3R,4R,5R)-5-(6-Benzoylamino-purin-9-yl)-3,4-dihydroxy-4-methyl-tetrahydro-furan-2-yl]-ethyl}-phosphonic acid dibenzyl ester | 851085-36-4

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 5'-脱氧核糖核苷
• 英文名称: {2-[(2R,3R,4R,5R)-5-(6-Benzoylamino-purin-9-yl)-3,4-dihydroxy-4-methyl-tetrahydro-furan-2-yl]-ethyl}-phosphonic acid dibenzyl ester
• 英文别名: N-[9-[(2R,3R,4R,5R)-5-[2-bis(phenylmethoxy)phosphorylethyl]-3,4-dihydroxy-3-methyloxolan-2-yl]purin-6-yl]benzamide
• CAS: 851085-36-4
• 化学式: C₃₃H₃₄N₅O₇P
• 分子量: 643.636
• InChiKey: JODLYMNSTHLTAM-ARRLULCRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  158
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  {2-[(2R,3R,4R,5R)-5-(6-Benzoylamino-purin-9-yl)-3,4-dihydroxy-4-methyl-tetrahydro-furan-2-yl]-ethyl}-phosphonic acid dibenzyl ester 在 palladium on activated charcoal 吡啶 、 咪唑 、 氨 、 氢气 、 苯甲基-2-磺酰三硝基三氮唑 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.0h， 生成 2,2-Dimethyl-thiopropionic acid S-(2-{{2-[(2R,3R,4R,5R)-5-(6-amino-purin-9-yl)-3-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy-4-methyl-tetrahydro-furan-2-yl]-ethyl}-[2-(2,2-dimethyl-propionylsulfanyl)-ethoxy]-phosphinoyloxy}-ethyl) ester
  参考文献：
  名称：

  Design, Synthesis, and Antiviral Activity of Adenosine 5‘-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus

  摘要：

  A series of adenosine 5'-phosphonate analogues were designed to mimic naturally occurring adenosine monophosphate. These compounds (1-5) were synthesized and evaluated in a cellular hepatitis C virus (HCV) replication assay. To improve cellular permeability and enhance the anti-HCV activity of these phosphonates, a bis(S-acyl-2-thioethyl) prodrug for compound 5 was prepared, and its cellular activity was determined. To elucidate the mechanism of action of these novel adenosine phosphonates, their diphosphate derivatives (1a-5a) were synthesized. Further nucleotide incorporation assays by HCV NS5B RNA-dependent RNA polymerase revealed that 2a and 3a can serve as chain terminators, whereas compounds 1a, 4a, and 5a are competitive inhibitors with ATP. Additional steady-state kinetic analysis determined the incorporation efficiency of 2a and 3a as well as the inhibition constants for 1a, 4a, and 5a. The structure -activity relationships among these compounds were analyzed, and the implication for nucleoside phosphonate drug design was discussed.

  DOI：

  10.1021/jm049029u
• 作为产物：
  描述：

  N⁶-benzoyl-9-[3'-O-benzoyl-5',6'-dideoxy-6'-(diphenoxyphosphinyl)-2'-C-methyl-β-D-ribohexofuranosyl]adenine 、 苯甲醇 在 sodium hydride 作用下， 以 二甲基亚砜 为溶剂， 生成 {2-[(2R,3R,4R,5R)-5-(6-Benzoylamino-purin-9-yl)-3,4-dihydroxy-4-methyl-tetrahydro-furan-2-yl]-ethyl}-phosphonic acid dibenzyl ester
  参考文献：
  名称：

  Design, Synthesis, and Antiviral Activity of Adenosine 5‘-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus

  摘要：

  A series of adenosine 5'-phosphonate analogues were designed to mimic naturally occurring adenosine monophosphate. These compounds (1-5) were synthesized and evaluated in a cellular hepatitis C virus (HCV) replication assay. To improve cellular permeability and enhance the anti-HCV activity of these phosphonates, a bis(S-acyl-2-thioethyl) prodrug for compound 5 was prepared, and its cellular activity was determined. To elucidate the mechanism of action of these novel adenosine phosphonates, their diphosphate derivatives (1a-5a) were synthesized. Further nucleotide incorporation assays by HCV NS5B RNA-dependent RNA polymerase revealed that 2a and 3a can serve as chain terminators, whereas compounds 1a, 4a, and 5a are competitive inhibitors with ATP. Additional steady-state kinetic analysis determined the incorporation efficiency of 2a and 3a as well as the inhibition constants for 1a, 4a, and 5a. The structure -activity relationships among these compounds were analyzed, and the implication for nucleoside phosphonate drug design was discussed.

  DOI：

  10.1021/jm049029u

文献信息

• Design, Synthesis, and Antiviral Activity of Adenosine 5‘-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus
  作者：Yung-hyo Koh、Jae Hoon Shim、Jim Zhen Wu、Weidong Zhong、Zhi Hong、Jean-Luc Girardet

  DOI：10.1021/jm049029u

  日期：2005.4.1

  A series of adenosine 5'-phosphonate analogues were designed to mimic naturally occurring adenosine monophosphate. These compounds (1-5) were synthesized and evaluated in a cellular hepatitis C virus (HCV) replication assay. To improve cellular permeability and enhance the anti-HCV activity of these phosphonates, a bis(S-acyl-2-thioethyl) prodrug for compound 5 was prepared, and its cellular activity was determined. To elucidate the mechanism of action of these novel adenosine phosphonates, their diphosphate derivatives (1a-5a) were synthesized. Further nucleotide incorporation assays by HCV NS5B RNA-dependent RNA polymerase revealed that 2a and 3a can serve as chain terminators, whereas compounds 1a, 4a, and 5a are competitive inhibitors with ATP. Additional steady-state kinetic analysis determined the incorporation efficiency of 2a and 3a as well as the inhibition constants for 1a, 4a, and 5a. The structure -activity relationships among these compounds were analyzed, and the implication for nucleoside phosphonate drug design was discussed.