4-fluoro-phenyl-(benzoxy-L-alaninyl)-phosphorochloridate | 840506-36-7

• 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: 4-fluoro-phenyl-(benzoxy-L-alaninyl)-phosphorochloridate
• 英文别名: p-fluorophenyl-(benzoxy-L-alaninyl)-phosphorochloridate；benzyl (2S)-2-[[chloro-(4-fluorophenoxy)phosphoryl]amino]propanoate
• CAS: 840506-36-7
• 化学式: C₁₆H₁₆ClFNO₄P
• 分子量: 371.733
• InChiKey: BTQPZUNUXLMNDF-JMSDCMLSSA-N

物化性质

• 沸点：
  459.8±55.0 °C(Predicted)
• 密度：
  1.346±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-fluoro-phenyl-(benzoxy-L-alaninyl)-phosphorochloridate 、 溴夫定 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 以64%的产率得到(E)-5-(2-bromovinyl)-2'-deoxyuridine-5'-[para-fluorophenyl-(benzoxy-L-alaninyl)]-phosphate
  参考文献：
  名称：

  Anti-cancer ProTides: tuning the activity of BVDU phosphoramidates related to thymectacin

  摘要：

  Based on our wide ranging knowledge of phosphoramidate ProTides as anti-viral agents we have tuned the lead anti-cancer agent thymectacin in the ester and amino acid regions and revealed a substantial enhancement in in vitro potency versus colon and prostate cancer cell lines. Twelve analogues have been reported, with yields of 29-78%. The compounds are fully characterised and data clearly reveal the presence of two phosphate diastereoisomers, as expected, in roughly equi-molar proportions. The compounds were evaluated in tissue culture versus three different tumour cell lines, using thymectacin as the control. It is notable that minor structural modification of the parent phenyl methoxyalaninyl structure of thymectacin leads to significant enhancements in potency. In particular, replacement of the methyl ester moiety in the lead by a benzyl ester gave a 175-fold boost in potency versus colon cancer HT115. This derivative emerges as a low micromolar inhibitor of HT115 cells and a new lead for further optimisation. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.02.041
• 作为产物：
  描述：

  4-氟苯酚 在 三乙胺 、 三氯氧磷 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 16.0h， 生成 4-fluoro-phenyl-(benzoxy-L-alaninyl)-phosphorochloridate
  参考文献：
  名称：

  Anti-cancer ProTides: tuning the activity of BVDU phosphoramidates related to thymectacin

  摘要：

  Based on our wide ranging knowledge of phosphoramidate ProTides as anti-viral agents we have tuned the lead anti-cancer agent thymectacin in the ester and amino acid regions and revealed a substantial enhancement in in vitro potency versus colon and prostate cancer cell lines. Twelve analogues have been reported, with yields of 29-78%. The compounds are fully characterised and data clearly reveal the presence of two phosphate diastereoisomers, as expected, in roughly equi-molar proportions. The compounds were evaluated in tissue culture versus three different tumour cell lines, using thymectacin as the control. It is notable that minor structural modification of the parent phenyl methoxyalaninyl structure of thymectacin leads to significant enhancements in potency. In particular, replacement of the methyl ester moiety in the lead by a benzyl ester gave a 175-fold boost in potency versus colon cancer HT115. This derivative emerges as a low micromolar inhibitor of HT115 cells and a new lead for further optimisation. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.02.041

文献信息

• The Application of Phosphoramidate Protide Technology to Acyclovir Confers Anti-HIV Inhibition
  作者：Marco Derudas、Davide Carta、Andrea Brancale、Christophe Vanpouille、Andrea Lisco、Leonid Margolis、Jan Balzarini、Christopher McGuigan

  DOI：10.1021/jm9007856

  日期：2009.9.10

  Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated, ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types-1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.
• US7951787B2
  申请人：——

  公开号：US7951787B2

  公开（公告）日：2011-05-31
• USRE47589E1
  申请人：——

  公开号：USRE47589E1

  公开（公告）日：2019-09-03
• Anti-cancer ProTides: tuning the activity of BVDU phosphoramidates related to thymectacin
  作者：Christopher McGuigan、Jean-Christophe Thiery、Felice Daverio、Wen G. Jiang、Gaynor Davies、Malcolm Mason

  DOI：10.1016/j.bmc.2005.02.041

  日期：2005.5

  Based on our wide ranging knowledge of phosphoramidate ProTides as anti-viral agents we have tuned the lead anti-cancer agent thymectacin in the ester and amino acid regions and revealed a substantial enhancement in in vitro potency versus colon and prostate cancer cell lines. Twelve analogues have been reported, with yields of 29-78%. The compounds are fully characterised and data clearly reveal the presence of two phosphate diastereoisomers, as expected, in roughly equi-molar proportions. The compounds were evaluated in tissue culture versus three different tumour cell lines, using thymectacin as the control. It is notable that minor structural modification of the parent phenyl methoxyalaninyl structure of thymectacin leads to significant enhancements in potency. In particular, replacement of the methyl ester moiety in the lead by a benzyl ester gave a 175-fold boost in potency versus colon cancer HT115. This derivative emerges as a low micromolar inhibitor of HT115 cells and a new lead for further optimisation. (c) 2005 Elsevier Ltd. All rights reserved.