[4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-butoxymethoxymethyl]-phosphonic acid diisopropyl ester | 265323-00-0

• 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: [4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-butoxymethoxymethyl]-phosphonic acid diisopropyl ester
• 英文别名: 1-[4-[Di(propan-2-yloxy)phosphorylmethoxymethoxy]butyl]-5-methylpyrimidine-2,4-dione
• CAS: 265323-00-0
• 化学式: C₁₇H₃₁N₂O₇P
• 分子量: 406.416
• InChiKey: SZSZKBDRUJPXRF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  27
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  [4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-butoxymethoxymethyl]-phosphonic acid diisopropyl ester 在 2,6-二甲基吡啶 、 三甲基溴硅烷 作用下， 以 二氯甲烷 为溶剂， 反应 18.0h， 生成 [4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-butoxymethoxymethyl]-phosphonic acid
  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
• 作为产物：
  描述：

  (Z)-1-benzoxy-4-(acetoxy)methoxy-2-butene 在 10percent Pd/C 偶氮二甲酸二异丙酯 、 TMSTf 、 氢气 、 三苯基膦 、 甲胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 乙腈 为溶剂， 20.0 ℃ 、206.85 kPa 条件下， 反应 10.0h， 生成 [4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-butoxymethoxymethyl]-phosphonic acid diisopropyl ester
  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

• 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.