benzyl N-[{1-[(3aR,4R,6R,6aS)-4-azido-tetrahydro-4-(hydroxymethyl)-2,2-cyclopentylfuro[3,4-d][1,3]dioxol-6-yl]pyrimidine-2,4(1H,3H)-dione} (phenoxy)-phosphoryl]-L-alaninate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: benzyl N-[{1-[(3aR,4R,6R,6aS)-4-azido-tetrahydro-4-(hydroxymethyl)-2,2-cyclopentylfuro[3,4-d][1,3]dioxol-6-yl]pyrimidine-2,4(1H,3H)-dione} (phenoxy)-phosphoryl]-L-alaninate
• 英文别名: 2',3'-O,O-cyclopentylidene-4'-azidouridine 5'-O-[phenyl(benzyloxy-L-alaninyl)] phosphate；benzyl (2S)-2-[[[(3aS,4R,6R,6aR)-4-azido-6-(2,4-dioxopyrimidin-1-yl)spiro[6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxole-2,1'-cyclopentane]-4-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• 化学式: C₃₀H₃₃N₆O₁₀P
• 分子量: 668.6
• InChiKey: TUHQTMMSDGPDGX-DKNSJBSBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  47
• 可旋转键数：
  13
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  165
• 氢给体数：
  2
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  benzyl N-[{1-[(3aR,4R,6R,6aS)-4-azido-tetrahydro-4-(hydroxymethyl)-2,2-cyclopentylfuro[3,4-d][1,3]dioxol-6-yl]pyrimidine-2,4(1H,3H)-dione} (phenoxy)-phosphoryl]-L-alaninate 在 甲酸 作用下， 反应 4.0h， 以55%的产率得到(S)-2-{[(2R,3S,4R,5R)-2-Azido-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid benzyl ester
  参考文献：
  名称：

  Application of the Phosphoramidate ProTide Approach to 4‘-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside

  摘要：

  We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.

  DOI：

  10.1021/jm0613370
• 作为产物：
  描述：

  2',3'-O,O-cyclopentylidene-4'-azidouridine 、 phenyl(benzyloxy-L-alaninyl)phosphorochloridate 在 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 17.25h， 以49%的产率得到benzyl N-[{1-[(3aR,4R,6R,6aS)-4-azido-tetrahydro-4-(hydroxymethyl)-2,2-cyclopentylfuro[3,4-d][1,3]dioxol-6-yl]pyrimidine-2,4(1H,3H)-dione} (phenoxy)-phosphoryl]-L-alaninate
  参考文献：
  名称：

  Application of the Phosphoramidate ProTide Approach to 4‘-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside

  摘要：

  We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.

  DOI：

  10.1021/jm0613370

文献信息

• Application of the Phosphoramidate ProTide Approach to 4‘-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside
  作者：Plinio Perrone、Giovanna M. Luoni、Mary Rose Kelleher、Felice Daverio、Annette Angell、Sinead Mulready、Costantino Congiatu、Sonal Rajyaguru、Joseph A. Martin、Vincent Levêque、Sophie Le Pogam、Isabel Najera、Klaus Klumpp、David B. Smith、Christopher McGuigan

  DOI：10.1021/jm0613370

  日期：2007.4.1

  We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.