arabinouridine-5'-[1-naphthyl-(isopropoxy-L-alaninyl)]-phosphate | 1228437-60-2

• 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: arabinouridine-5'-[1-naphthyl-(isopropoxy-L-alaninyl)]-phosphate
• 英文别名: propan-2-yl (2S)-2-[[[(2R,3S,4S,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-naphthalen-1-yloxyphosphoryl]amino]propanoate
• CAS: 1228437-60-2
• 化学式: C₂₅H₃₀N₃O₁₀P
• 分子量: 563.501
• InChiKey: SXFWFUKFRXBBSB-PPJBUBGSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  39
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  173
• 氢给体数：
  4
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  (2S)-isopropyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate 、 阿糖尿苷 在 吡啶 、 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以22%的产率得到arabinouridine-5'-[1-naphthyl-(isopropoxy-L-alaninyl)]-phosphate
  参考文献：
  名称：

  Phosphoramidates of 2′-β-d-arabinouridine (AraU) as phosphate prodrugs; design, synthesis, in vitro activity and metabolism

  摘要：

  2'-beta-D-Arabinouridine (AraU), the uridine analogue of the anticancer agent AraC, was synthesized and evaluated for antiviral activity and cytotoxicity. In addition, a series of AraU monophosphate prodrugs in the form of triester phosphoramidates (ProTides) were also synthesized and tested against a range of viruses, leukaemia and solid tumour cell lines. Unfortunately, neither the parent compound (AraU) nor any of its ProTides showed antiviral activity, nor potent inhibitory activity against any of the cancer cell lines. Therefore, the metabolism of AraU phosphoramidates to release AraU monophosphate was investigated. The results showed carboxypeptidase Y, hog liver esterase and crude CEM tumor cell extracts to hydrolyse the ester motif of phosphoramidates with subsequent loss of the aryl group, while molecular modelling studies suggested that the AraU L-alanine aminoacyl phosphate derivative might not be a good substrate for the phosphoramidase enzyme Hint-1. These findings are in agreement with the observed disappearance of intact prodrug and concomitant appearance of the corresponding phosphoramidate intermediate derivative in CEM cell extracts without measurable formation of araU monophosphate. These findings may explain the poor antiviral/cytostatic potential of the prodrugs. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.02.059

文献信息

• Phosphoramidates of 2′-β-d-arabinouridine (AraU) as phosphate prodrugs; design, synthesis, in vitro activity and metabolism
  作者：Youcef Mehellou、Rocco Valente、Huw Mottram、Elisabeth Walsby、Kenneth I. Mills、Jan Balzarini、Christopher McGuigan

  DOI：10.1016/j.bmc.2010.02.059

  日期：2010.4

  2'-beta-D-Arabinouridine (AraU), the uridine analogue of the anticancer agent AraC, was synthesized and evaluated for antiviral activity and cytotoxicity. In addition, a series of AraU monophosphate prodrugs in the form of triester phosphoramidates (ProTides) were also synthesized and tested against a range of viruses, leukaemia and solid tumour cell lines. Unfortunately, neither the parent compound (AraU) nor any of its ProTides showed antiviral activity, nor potent inhibitory activity against any of the cancer cell lines. Therefore, the metabolism of AraU phosphoramidates to release AraU monophosphate was investigated. The results showed carboxypeptidase Y, hog liver esterase and crude CEM tumor cell extracts to hydrolyse the ester motif of phosphoramidates with subsequent loss of the aryl group, while molecular modelling studies suggested that the AraU L-alanine aminoacyl phosphate derivative might not be a good substrate for the phosphoramidase enzyme Hint-1. These findings are in agreement with the observed disappearance of intact prodrug and concomitant appearance of the corresponding phosphoramidate intermediate derivative in CEM cell extracts without measurable formation of araU monophosphate. These findings may explain the poor antiviral/cytostatic potential of the prodrugs. (C) 2010 Elsevier Ltd. All rights reserved.