adefovir monophosphate | 129556-87-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: adefovir monophosphate
• 英文别名: PMEA monophosphate；2-(6-aminopurin-9-yl)ethoxymethyl-phosphonooxyphosphinic acid
• CAS: 129556-87-2
• 化学式: C₈H₁₃N₅O₇P₂
• 分子量: 353.168
• InChiKey: VQIHLCFUFNQXPS-UHFFFAOYSA-N

物化性质

• 沸点：
  726.3±70.0 °C(Predicted)
• 密度：
  2.12±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  183
• 氢给体数：
  4
• 氢受体数：
  11

制备方法与用途

一磷酸阿德福韦是一种抗病毒药物，属于无环核苷膦酸盐（ANP）类似物，能够对抗乙型肝炎病毒（HBV）、疱疹病毒以及人类免疫缺陷病毒（HIV）。它是一种口服的无环核苷酸类似物逆转录酶抑制剂(ntRTI)，通过阻断逆转录酶来治疗乙型肝炎。需要注意的是，阿德福韦酯对HIV-1无效。

反应信息

• 作为反应物：
  描述：

  adefovir monophosphate 在 磷酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 生成 adefovir phosphonoimidazolide
  参考文献：
  名称：

  克服蛋白质/药物偶联物生产中的反应中间物的水解不稳定性：无环核苷膦酸酯与模型载体蛋白的偶联

  摘要：

  获得性免疫缺陷综合症（艾滋病）仍然是最严重的公共卫生挑战之一，也是某些人群死亡的重要原因。尽管在过去的二十年中开发了大量的抗逆转录病毒药物，但是小分子疗法无法针对HIV储库直接构成了对其有效利用的重大障碍。实际上，在缺乏靶向递送的有效手段的情况下实现所需的治疗结果必须依靠剂量增加，剂量增加经常引起严重的毒性。该问题可以通过将抗逆转录病毒药物与内源性蛋白质结合来解决，该内源性蛋白质被HIV储库（例如巨噬细胞）特异性识别用于内在化和分解代谢。但是，结合了多种抗逆转录病毒药物（无环核苷膦酸酯，诸如阿德福韦，替诺福韦和西多福韦的阿德福韦酯（例如阿德福韦膦酰咪唑啉）在水性环境中迅速降解，这对蛋白质具有挑战性。这项工作中引入的一种新颖的合成策略通过模拟其代谢途径的第一步（磷酸化），克服了阿德福韦活化形式的不稳定性，使其对蛋白质的伯胺基具有很高的反应性，同时不易被阿德福韦氧化。遇水水解。使用模型蛋白证明

  DOI：

  10.1021/acs.molpharmaceut.7b00410
• 作为产物：
  描述：

  阿德福韦 在 mitochondrial AMP kinase from L₁₂₁₀ cells (EC 2.7.4.3) 作用下， 生成 adefovir monophosphate
  参考文献：
  名称：

  Phosphorylation of Purine (Phosphonomethoxy)alkyl Derivatives by Mitochondrial AMP Kinase (AK2 Type) from L1210 Cells

  摘要：

  研究了对L1210细胞中线粒体AMP激酶（AK2型）的嘌呤（磷甲氧基）烷基衍生物的底物活性。纯化几乎纯度接近的天然AMP激酶是一种分子量为26kDa的单体。纯化的AMP激酶特异性地对天然腺嘌呤核苷酸（AMP和dAMP）作为磷酸受体，但对核苷酸5'-三磷酸作为磷酸供体具有广泛的特异性。除了腺嘌呤无环核苷酸类似物外，该酶还能磷酸化含有2,6-二氨基嘌呤基团的类似衍生物。动力学数据表明，这些无环核苷酸磷酸酯对AK2同功酶的底物活性按顺序降低为（S）-HPMPA >（R）-PMPA > PMEA > PMEDAP >（S）-PMPDAP >（R）-PMPDAP >>（S）-PMPA。无环核苷酸类似物对AK2同功酶不表现出任何抑制活性。

  DOI：

  10.1135/cccc20001653

文献信息

• Metabolic pathways for activation of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human lymphoid cells
  作者：B L Robbins、J Greenhaw、M C Connelly、A Fridland

  DOI：10.1128/aac.39.10.2304

  日期：1995.10

  9-(2-Phosphonylmethoxyethyl)adenine (PMEA), the acyclic phosphonate analog of adenine monophosphate, is a promising antiviral drug with activity against herpesviruses, Epstein-Barr virus, and retroviruses, including the human immunodeficiency virus. In order to be active, it must be converted to the diphosphate derivative, the putative inhibitor of viral DNA polymerases. The metabolic pathway responsible for activation of PMEA is unclear. The metabolism of PMEA was investigated in human T-lymphoid cells (CEMss) and a PMEA-resistant subline (CEMss(r-1)) with a partial deficiency in adenylate kinase activity. Experiments with [3H]PMEA showed that extracts of CEMss phosphorylated PMEA to its mono- and diphosphate in the presence of ATP as the phosphate donor. No other nucleotides or 5-phosphoribosyl pyrophosphate displayed appreciable activity as a phosphate donor. Subcellular fractionation experiments showed that CEMss cells contained two nucleotide kinase activities, one in mitochondria and one in the cytosol, which phosphorylated PMEA. The PMEA-resistant CEMss mutant proved to have a deficiency in the mitochondrial adenylate kinase activity, indicating that this enzyme was important in the phosphorylation of PMEA. Other effective antiviral purine phosphonate derivatives of PMEA showed a profile of phosphorylating activity similar to that of PMEA. By comparison, phosphorylation of the pyrimidine analog (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine proceeded by an enzyme present in the cytosol. We conclude from these studies that adenylate kinase which has been localized in the intermembrane space of mitochondria is the major route for PMEA phosphorylation in CEMss cells but that another hitherto unidentified enzyme(s) present in the cytosol may contribute to the anabolism of the phosphonates.

  9-(2-膦酰基甲氧基乙基)腺嘌呤（PMEA）是单磷酸腺嘌呤的无环膦酸盐类似物，是一种很有前途的抗病毒药物，对疱疹病毒、爱泼斯坦-巴氏病毒和逆转录病毒（包括人类免疫缺陷病毒）具有活性。为了发挥活性，它必须转化为二磷酸衍生物，即病毒 DNA 聚合酶的假定抑制剂。激活 PMEA 的代谢途径尚不清楚。我们在人类 T 淋巴细胞（CEMss）和部分缺乏腺苷酸激酶活性的抗 PMEA 亚系（CEMss(r-1)）中研究了 PMEA 的代谢。用[3H]PMEA进行的实验表明，在有ATP作为磷酸供体的情况下，CEMss的提取物能将PMEA磷酸化成其一磷酸酯和二磷酸酯。没有其他核苷酸或 5-磷酸核糖基焦磷酸盐作为磷酸供体显示出明显的活性。亚细胞分馏实验表明，CEMss 细胞含有两种核苷酸激酶活性，一种在线粒体中，另一种在细胞质中，它们都能使 PMEA 磷酸化。耐 PMEA 的 CEMss 突变体被证明缺乏线粒体腺苷酸激酶活性，这表明这种酶在 PMEA 磷酸化过程中非常重要。PMEA 的其他有效抗病毒嘌呤膦酸盐衍生物显示出与 PMEA 相似的磷酸化活性。相比之下，嘧啶类似物(S)-1-(3-羟基-2-膦酰甲氧基丙基)胞嘧啶的磷酸化是由存在于细胞质中的一种酶进行的。我们从这些研究中得出结论，已定位在线粒体膜间隙的腺苷酸激酶是 CEMss 细胞中 PMEA 磷酸化的主要途径，但细胞质中存在的另一种（多种）迄今尚未确定的酶可能有助于膦酸盐的合成代谢。
• Substituted Phosphate Esters of Nucleoside Phosphonates
  申请人：Hostetler Karl Y.

  公开号：US20090156545A1

  公开（公告）日：2009-06-18

  Compounds and compositions are provided for treatment, prevention, or amelioration of a variety of medical disorders associated with viral infections and/or cell proliferation. The compounds provided herein are obtained by attaching the phosphonate nucleoside of interest to alkyloxyalkyl-phosphate or alkyl-phosphate in a phosphate-phosphono anhydride linkage to provide a modified nucleoside phosphonate drug.

  本文提供了用于治疗、预防或改善与病毒感染和/或细胞增殖有关的各种医学疾病的化合物和组合物。所提供的化合物是通过将感兴趣的膦酸核苷连接到烷氧基烷基磷酸酯或烷基磷酸酯中的磷酸酯-膦酸酐连接处，从而提供一种修饰的核苷酸膦酸药物获得的。
• Acyclic Phosphonate Nucleotides and Human Adenylate Kinases: Impact of a Borano Group on α-P Position
  作者：D. Topalis、K. Alvarez、K. Barral、H. Munier-Lehmann、B. Schneider、M. Véron、C. Guerreiro、L. Mulard、C. El-Amri、B. Canard、D. Deville-Bonne

  DOI：10.1080/15257770801941952

  日期：2008.4.4

  Adenylate kinases are involved in the activation of antiviral drugs such as the acyclic phosphonates analogs PMEA and (R)PMPA. We examine the in vitro phosphorylation of PMEA and PMPA bearing a borano- or a H- group on the phosphorus atom. The alpha-borano or alpha-H on PMEA and PMPA were detrimental to the activity of recombinant human AMP kinases 1 and 2. Docking PMEA to the active site of AMP kinase 1 indicated that the borano group may prevent two conserved critical Arg interactions with the -phosphate, resulting in substrate bad positioning.
• Effective metabolism and long intracellular half life of the anti-Hepatitis B agent adefovir in hepatic cells
  作者：Adrian S. Ray、Jennifer E. Vela、Loren Olson、Arnold Fridland

  DOI：10.1016/j.bcp.2004.07.010

  日期：2004.11

  Adefovir dipivoxil (ADV) is esterolytically cleaved to the 2-deoxyadenosine monophosphate (dAMP) analog adefovir, subsequent phosphorylation leads to the formation of the anti-Hepatitis B virus (HBV) agent adefovir-DP. To better understand the mechanism of action of ADV, metabolism studies were done in Hep G2, Huh-7 and primary human hepatocytes. Separation of radiolabeled adefovir metabolites after incubation in Hep G2 cells suggested that adefovir in its mono- and di-phosphorylated forms are the only metabolites formed from adefovir. Incubation of 10 muM adefovir with hepatic cell lines and fresh monolayers of primary human hepatocytes from two donors and analysis of intracellular metabolites by liquid chromatography coupled to tandem mass sepctrometery resulted in adefovir-DP levels of approximately 10 pmol/million cells. Adefovir was more efficiently phosphorylated in primary hepatocytes than cell lines with adefovir-DP accounting for 44% versus 26% of total intracellular adefovir after 24 h. Egress studies showed adefovir-DP to have a half-life of 33 +/- 3 h, 10 +/- 1 h, 48 +/- 3 h and 33 +/- 2 h in Hep G2, Huh-7, and primary hepatocytes from two separate donors, respectively. The markedly shorter half-life in Huh-7 cells was inferred to be transport dependent based on its sensitivity to the transport inhibitor MK-571. Effective phosphorylation coupled with a long intracellular half-life and small competing dATP pool sizes in primary hepatocytes forms the cellular metabolic basis for the efficacy of adefovir dipivoxil in the treatment of chronic hepatitis B. (C) 2004 Elsevier Inc. All rights reserved.
• HOLY, ANTONIN;ROSENBERG, IVAN, COLLECT. CZECHOSL. CHEM. COMMUN., 52,(1987) N 11, 2801-2809
  作者：HOLY, ANTONIN、ROSENBERG, IVAN

  DOI：——

  日期：——