1-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}uracil | 911205-91-9

• 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-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}uracil
• 英文别名: diisopropyl ((2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)methyl)phosphonate；1-[2-[[Oxido-di(propan-2-yloxy)phosphaniumyl]methoxy]ethyl]pyrimidine-2,4-dione；1-[2-[[oxido-di(propan-2-yloxy)phosphaniumyl]methoxy]ethyl]pyrimidine-2,4-dione
• CAS: 911205-91-9
• 化学式: C₁₃H₂₃N₂O₆P
• 分子量: 334.309
• InChiKey: FGIKIWYTKKSJFT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  22
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}uracil 在 四(三苯基膦)钯 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 sodium carbonate 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-[2-[Di(propan-2-yloxy)phosphorylmethoxy]ethyl]-5-(4-fluorophenyl)pyrimidine-2,4-dione
  参考文献：
  名称：

  Pd-catalyzed Suzuki–Miyaura coupling reactions in the synthesis of 5-aryl-1-[2-(phosphonomethoxy)ethyl]uracils as potential multisubstrate inhibitors of thymidine phosphorylase

  摘要：

  5-aryl-1-[2-(phosphonomethoxy)ethyl]uracils were prepared via Pd-catalyzed Suzuki-Miyaura coupling reaction of the appropriate 5-bromouracil derivative with a series of arylboronic acids followed by deprotection. These compounds were designed as potential multisubstrate inhibitors of thymidine phosphorylase based on an assumption that the potential hydrophobic effect of the aryl groups might modify the inhibitory effect towards this enzyme and they may also demonstrate cytostatic activity. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2007.02.107
• 作为产物：
  描述：

  diisopropyl 2-(chloroethoxy)methylphosphonate 在 Dowex 50 H(+) form 、 sodium hydride 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 1-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}uracil
  参考文献：
  名称：

  Syntheses of Base and Side-Chain Modified Pyrimidine 1-[2-(Phosphonomethoxy)propyl] Derivatives as Potent Inhibitors of Thymidine Phosphorylase (PD-ECGF) from SD-Lymphoma

  摘要：

  在这项研究中，我们合成了一系列嘧啶和5-乙基尿嘧啶无环核苷酸磷酸酯，其侧链带有羟甲基、甲氧基甲基、叠氮甲基、氨基甲基和（三甲基铵）甲基基团，作为胸苷磷酸酶的有效抑制剂。此外，我们特别研究了含氟衍生物的新合成，侧链含有氟甲基或三氟甲基基团，如5-乙基-1-[(S)-3-氟-2-(磷酸甲氧基)丙基]尿嘧啶（8）或5-乙基-1-[3,3,3-三氟-2-(磷酸甲氧基)丙基]尿嘧啶以及嘧啶衍生物27和28。尿嘧啶无环核苷酸磷酸酯1-{2-[(二异丙氧基磷酰基)甲氧基]乙基}尿嘧啶（12）和1-{2-[(二异丙氧基磷酰基)甲氧基]-3,3,3-三氟丙基}尿嘧啶（19）被氟化为相应的5-氟尿嘧啶衍生物。虽然5-氟尿嘧啶衍生物表现出边缘的抑制作用，但侧链含氟的嘧啶和5-乙基尿嘧啶化合物对来自大鼠自发性T细胞淋巴瘤的胸苷磷酸酶具有相当的抑制活性。

  DOI：

  10.1135/cccc20060595

文献信息

• Discovery of an Acyclic Nucleoside Phosphonate that Inhibits<i>Mycobacterium tuberculosis</i>ThyX Based on the Binding Mode of a 5-Alkynyl Substrate Analogue
  作者：Anastasia Parchina、Matheus Froeyen、Lia Margamuljana、Jef Rozenski、Steven De Jonghe、Yves Briers、Rob Lavigne、Piet Herdewijn、Eveline Lescrinier

  DOI：10.1002/cmdc.201300146

  日期：2013.8

  by the results of the modeling and NMR studies, and inspired by the success of acyclic antiviral nucleosides, compounds where a 5‐alkynyl uracyl moiety is coupled to an acyclic nucleoside phosphonate (ANP) were synthesized and evaluated. Of the compounds evaluated, sodium (6‐(5‐(3‐octanamidoprop‐1‐yn‐1‐yl)‐2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)hexyl)phosphonate (3 e) exhibited 43 % of inhibitory effect

  对新抗生素的迫切需求对靶向未开发的重要细胞过程提出了挑战。胸苷酸的生物合成就是这样一种过程，因为它在DNA复制和修复中起着至关重要的作用。胸苷酸合酶（TS）催化生物合成5-三磷酸胸苷（TTP）的关键步骤，这是DNA合成和修复所需的基本组成部分。迄今为止，由于TS抑制剂对人体酶和微生物酶的特异性不足，因此仅被成功用于抗癌治疗。但是，在一系列致病细菌中发现了一个新的TS酶家族（ThyX），该家族在结构和生化上与“经典” TS（ThyA）不同，这为开发选择性ThyX抑制剂作为有效的抗菌药物提供了可能。这里，1）用结核分枝杆菌从公开的晶体结构开始，使用分子模型探索ThyX酶，并通过NMR实验进一步证实。虽然化合物1的脱氧尿酸（dUMP）部分占据了ThyX中天然底物的腔，但其余的配体（“ 5-炔基尾巴”）延伸至酶的四个亚基中的两个之间。通过置换Tyr 44.C，Tyr 108.A和Lys 165.A
• Synthesis and biological evaluation of acyclic nucleotide analogues with a furo[2,3-<i>d</i>]pyrimidin-2(3<i>H</i>)-one base
  作者：Zlatko Janeba、Antonín Holý、Radek Pohl、Robert Snoeck、Graciela Andrei、Erik De Clercq、Jan Balzarini

  DOI：10.1139/v10-054

  日期：2010.7

  As a part of a broader structure–activity relationship (SAR) study of bicyclic nucleoside analogues (BCNAs) [anti-varicella-zoster virus (anti-VZV) and anti-human cytomegalovirus (anti-HCMV) agents], a novel series of 2-(phosphonomethoxy)ethyl (PME) substituted furo[2,3-d]pyrimidin-2(3H)-ones was synthesized. The target acyclic nucleotide analogues were prepared by Sonogashira coupling of protected 5-iodo-1-[2-(phosphonomethoxy)ethyl]uracil with various 1-alkynes, followed by in situ Cu(I)-promoted intramolecular cyclization and standard removal of the isopropyl ester groups. None of the prepared PME analogues were active at subtoxic concentrations against VZV thymidine kinase competent (TK⁺), VZV thymidine kinase deficient (TK^–), HCMV, or any other viruses tested.

  作为对双环核苷类似物（BCNAs）[抗水痘-带状疱疹病毒（anti-VZV）和抗人类巨细胞病毒（anti-HCMV）药物]进行更广泛的结构-活性关系（SAR）研究的一部分，合成了一系列新型 2-（膦甲氧基）乙基（PME）取代的呋喃并[2,3-d]嘧啶-2(3H)-酮。目标无环核苷酸类似物是通过受保护的 5-碘-1-[2-（磷酰甲氧基）乙基]尿嘧啶与各种 1-炔烃的 Sonogashira 偶联，然后在原位 Cu(I)促进下进行分子内环化，并以标准方式去除异丙酯基团而制备的。所制备的 PME 类似物在亚毒性浓度下对 VZV 胸苷激酶能力（TK+）、VZV 胸苷激酶缺陷（TK-）、HCMV 或任何其他受测病毒均无活性。
• Syntheses of Pyrimidine Acyclic Nucleoside Phosphonates as Potent Inhibitors of Thymidine Phosphorylase (PD-ECGF) from SD-Lymphoma
  作者：Karel Pomeisl、Ivan Votruba、Antonín Holý、Radek Pohl

  DOI：10.1080/15257770701508679

  日期：2007.11.26

  In the present study, we synthesized a series of pyrimidine acyclic nucleoside phosphonates bearing a number of substituents in C-5 position of uracil moiety and in the N-1-side chain. In addition, we have investigated in particular the novel syntheses of fluorinated derivatives substituted in the N-1-side chain and uracil C-5 position because fluorine-containing substituents are often powerful modifiers of chemical and biological properties. The obtained compounds exhibit a considerable inhibitory potency of thymidine phosphorylase from SD-lymphoma. In contrast, the synthesized phosphonates are not efficient inhibitors of E. coli and human thymidine phosphorylase.
• Syntheses of Base and Side-Chain Modified Pyrimidine 1-[2-(Phosphonomethoxy)propyl] Derivatives as Potent Inhibitors of Thymidine Phosphorylase (PD-ECGF) from SD-Lymphoma
  作者：Karel Pomeisl、Ivan Votruba、Antonín Holý、Radek Pohl

  DOI：10.1135/cccc20060595

  日期：——

  In this study we synthesized a series of thymine and 5-ethyluracil acyclic nucleoside phosphonates bearing hydroxymethyl, methoxymethyl, azidomethyl, aminomethyl and (trimethylammonio)methyl group in side chain as potent inhibitors of thymidine phosphorylase. In addition, we investigated in particular the novel syntheses of fluorinated derivatives containing fluoromethyl or trifluoromethyl groups in side chain such as 5-ethyl- 1-[(S)-3-fluoro-2-(phosphonomethoxy)propyl]uracil (8) or 5-ethyl-1-[3,3,3-trifluoro-2-(phosphonomethoxy)propyl]uracil and thymine derivatives 27 and 28. Uracil acyclic nucleoside phosphonates 1-2-[(diisopropoxyphosphoryl)methoxy]ethyl}uracil (12) and 1-2-[(diisopropoxyphosphoryl)methoxy]-3,3,3-trifluoropropyl}uracil (19) were fluorinated to corresponding 5-fluorouracil derivatives. While the 5-fluorouracil derivatives exhibit a marginal inhibitory effect, thymine and 5-ethyluracil compound with fluorine in side chains possess considerable inhibitory potency toward thymidine phosphorylase from rat spontaneous T-cell lymphoma.

  在这项研究中，我们合成了一系列嘧啶和5-乙基尿嘧啶无环核苷酸磷酸酯，其侧链带有羟甲基、甲氧基甲基、叠氮甲基、氨基甲基和（三甲基铵）甲基基团，作为胸苷磷酸酶的有效抑制剂。此外，我们特别研究了含氟衍生物的新合成，侧链含有氟甲基或三氟甲基基团，如5-乙基-1-[(S)-3-氟-2-(磷酸甲氧基)丙基]尿嘧啶（8）或5-乙基-1-[3,3,3-三氟-2-(磷酸甲氧基)丙基]尿嘧啶以及嘧啶衍生物27和28。尿嘧啶无环核苷酸磷酸酯1-2-[(二异丙氧基磷酰基)甲氧基]乙基}尿嘧啶（12）和1-2-[(二异丙氧基磷酰基)甲氧基]-3,3,3-三氟丙基}尿嘧啶（19）被氟化为相应的5-氟尿嘧啶衍生物。虽然5-氟尿嘧啶衍生物表现出边缘的抑制作用，但侧链含氟的嘧啶和5-乙基尿嘧啶化合物对来自大鼠自发性T细胞淋巴瘤的胸苷磷酸酶具有相当的抑制活性。
• Pd-catalyzed Suzuki–Miyaura coupling reactions in the synthesis of 5-aryl-1-[2-(phosphonomethoxy)ethyl]uracils as potential multisubstrate inhibitors of thymidine phosphorylase
  作者：Karel Pomeisl、Antonín Holý、Radek Pohl

  DOI：10.1016/j.tetlet.2007.02.107

  日期：2007.4

  5-aryl-1-[2-(phosphonomethoxy)ethyl]uracils were prepared via Pd-catalyzed Suzuki-Miyaura coupling reaction of the appropriate 5-bromouracil derivative with a series of arylboronic acids followed by deprotection. These compounds were designed as potential multisubstrate inhibitors of thymidine phosphorylase based on an assumption that the potential hydrophobic effect of the aryl groups might modify the inhibitory effect towards this enzyme and they may also demonstrate cytostatic activity. (c) 2007 Elsevier Ltd. All rights reserved.