1-(4-(phosphonomethoxy)butyl)thymine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 1-(4-(phosphonomethoxy)butyl)thymine
• 英文别名: 4-(5-Methyl-2,4-dioxopyrimidin-1-yl)butoxymethylphosphonic acid
• 化学式: C₁₀H₁₇N₂O₆P
• 分子量: 292.229
• InChiKey: SQWFDWDJZBJOCK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  19
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  116
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (Z)-4-[(diisopropylphosphono)methoxy]-2-buten-1-ol 在 10percent Pd/C 三甲基溴硅烷 、 偶氮二甲酸二异丙酯 、 氢气 、 三苯基膦 、 甲胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、206.85 kPa 条件下， 反应 24.0h， 生成 1-(4-(phosphonomethoxy)butyl)thymine
  参考文献：
  名称：

  Design, Synthesis, and Enzymatic Evaluation of Multisubstrate Analogue Inhibitors of Escherichia coli Thymidine Phosphorylase

  摘要：

  A series of acyclic phosphonate derivatives of thymine has been synthesized and tested as multisubstrate analogue inhibitors of Escherichia colt thymidine phosphorylase. The compounds synthesized include 1-(phosphonoalkyl)thymines with six to nine methylenes (1-4, respectively); 1-[(Z)-4-phosphonomethoxy-2-butenyl]thymine (5) and its butyl and 2,3-cis-dihydroxybutyl derivatives (6 and 7, respectively); 1-[(Z)-(4-(phosphonomethoxy)methoxy)-2-butenyl]thymine (8) and also its butyl and 2,3-cis-dihydroxybutyl analogues (9 and 10); and 1-[((Z)-4-(phosphonomethoxy)-2-butenoxy)methyl]thymine(11), Evaluation of these compounds against E. coli revealed significant enzymatic inhibition by 2, 3, 4, 6, and 8 at a concentration of 1000 mu M, 3 and 4 being the most potent. Replacement of the thymine base in 3 by 6-amino-5-bromouracil and 7-deazaxanthine afforded compounds 12 and 13, which showed a pronounced improvement of TPase inhibition, comparable to 7-deazaxanthine. When inorganic phosphate was used as a variable substrate, compounds 12 and 13 displayed competitive kinetics with respect to phosphate, indicating a direct interaction of these compounds with the phosphate binding site. Also compounds 12 and 13 were found to be competitive inhibitors of TPase against thymidine as a variable substrate. These results are consistent with the compounds being multisubstrate analogue inhibitors of E. coli TPase, and they represent the first example of such TPase inhibitors.

  DOI：

  10.1021/jm9911377

文献信息

• Antiviral phosphonomethoxyalkylene purine and pyrimidine derivatives
  申请人：INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY OF THE ACADEMY OF SCIENCES OF THE CZECH REPUBLIC

  公开号：EP0269947A1

  公开（公告）日：1988-06-08

  series of compounds of Formula I are described which are useful in treating viral infections, their compositions and use. In Formula I B is a purine or pyrimidine base; alk1, alk2 and alk3 are cheical bonds or alkylene groups; Q is hydrogen or hydroxyl; and R1 -R4 are hydrogen or alkyl.

  描述了一系列可用于治疗病毒感染的式 I 化合物及其组合物和用途。 在式 I 中，B 是嘌呤或嘧啶碱；alk1、alk2 和 alk3 是螯键或亚烷基；Q 是氢或羟基；R1 -R4 是氢或烷基。
• US5650510A
  申请人：——

  公开号：US5650510A

  公开（公告）日：1997-07-22
• US5854228A
  申请人：——

  公开号：US5854228A

  公开（公告）日：1998-12-29
• Design, Synthesis, and Enzymatic Evaluation of Multisubstrate Analogue Inhibitors of <i>Escherichia </i><i>coli</i> Thymidine Phosphorylase
  作者：Antonio Esteban-Gamboa、Jan Balzarini、Robert Esnouf、Erik De Clercq、María-José Camarasa、María-Jesús Pérez-Pérez

  DOI：10.1021/jm9911377

  日期：2000.3.1

  A series of acyclic phosphonate derivatives of thymine has been synthesized and tested as multisubstrate analogue inhibitors of Escherichia colt thymidine phosphorylase. The compounds synthesized include 1-(phosphonoalkyl)thymines with six to nine methylenes (1-4, respectively); 1-[(Z)-4-phosphonomethoxy-2-butenyl]thymine (5) and its butyl and 2,3-cis-dihydroxybutyl derivatives (6 and 7, respectively); 1-[(Z)-(4-(phosphonomethoxy)methoxy)-2-butenyl]thymine (8) and also its butyl and 2,3-cis-dihydroxybutyl analogues (9 and 10); and 1-[((Z)-4-(phosphonomethoxy)-2-butenoxy)methyl]thymine(11), Evaluation of these compounds against E. coli revealed significant enzymatic inhibition by 2, 3, 4, 6, and 8 at a concentration of 1000 mu M, 3 and 4 being the most potent. Replacement of the thymine base in 3 by 6-amino-5-bromouracil and 7-deazaxanthine afforded compounds 12 and 13, which showed a pronounced improvement of TPase inhibition, comparable to 7-deazaxanthine. When inorganic phosphate was used as a variable substrate, compounds 12 and 13 displayed competitive kinetics with respect to phosphate, indicating a direct interaction of these compounds with the phosphate binding site. Also compounds 12 and 13 were found to be competitive inhibitors of TPase against thymidine as a variable substrate. These results are consistent with the compounds being multisubstrate analogue inhibitors of E. coli TPase, and they represent the first example of such TPase inhibitors.