phenyl (ethyloxy-N-methyl-glycinyl)phosphorochloridate

• 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: phenyl (ethyloxy-N-methyl-glycinyl)phosphorochloridate
• 英文别名: Ethyl 2-[[chloro(phenoxy)phosphoryl]-methylamino]acetate
• 化学式: C₁₁H₁₅ClNO₄P
• 分子量: 291.671
• InChiKey: IGJRJTBZPHCEOX-UHFFFAOYSA-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：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  phenyl (ethyloxy-N-methyl-glycinyl)phosphorochloridate 在 甲酸 、 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 21.25h， 生成 ({[(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-phosphoryl}-methyl-amino)-acetic acid ethyl 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

文献信息

• The application of phosphoramidate ProTide technology to the potent anti-HCV compound 4′-azidocytidine (R1479)
  作者：Christopher McGuigan、Mary Rose Kelleher、Plinio Perrone、Sinead Mulready、Giovanna Luoni、Felice Daverio、Sonal Rajyaguru、Sophie Le Pogam、Isabel Najera、Joseph A. Martin、Klaus Klumpp、David B. Smith

  DOI：10.1016/j.bmcl.2009.05.099

  日期：2009.8

  We report the design, synthesis and evaluation of a family of ca 50 phosphoramidate ProTides of the potent anti-HCV compound 4 '-azidocytidine (R1479), with variation on the ester, amino acid and aryl moiety of the ProTide. Sub-mu M inhibitors of HCV emerge. The compounds are all non-cytotoxic in the replicon assay. We herein report detailed SARs for each of the regions of the ProTide. (C) 2009 Elsevier Ltd. All rights reserved.
• 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.