3'-azidothymidine-5'-(p-bromophenyl)methoxyalaninyl phosphate | 220693-38-9

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 3'-azidothymidine-5'-(p-bromophenyl)methoxyalaninyl phosphate
• 英文别名: zidampidine；AZT-5'-[p-bromophenyl methoxyalaninyl phosphate]；methyl (2S)-2-[[[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-(4-bromophenoxy)phosphoryl]amino]propanoate；methyl (2S)-2-[[[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-(4-bromophenoxy)phosphoryl]amino]propanoate
• CAS: 220693-38-9
• 化学式: C₂₀H₂₄BrN₆O₈P
• 分子量: 587.324
• InChiKey: CZBHANBNVRCPMC-CXRKLNNMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  147
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  3'-azidothymidine-5'-(p-bromophenyl)methoxyalaninyl phosphate 在 Candida antarctica lipase B 作用下， 以 甲醇 、 水 为溶剂， 生成 4-溴苯酚 、 2(S)-(3-deoxy-3-azidothymidyl(hydroxy)phosphorylamino)propionic acid methyl ester
  参考文献：
  名称：

  Effect of change in nucleoside structure on the activation and antiviral activity of phosphoramidate derivatives

  摘要：

  Changing the nucleoside group of a series of phosphoramidate derivatives affects the enzyme mediated hydrolysis rate of the compounds. d4T and AZT-substituted analogs were activated by enzymes such as lipases, esterases, and proteases. On the other hand, 3dT-substituted derivatives were comparatively less prone to hydrolysis under similar experimental conditions. From the experimental results, we propose that-the most preferable nucleoside group for enzyme activation is d4T rather than AZT or 3dT. Additionally, we also observed that depending on the enzymes used the chiral selectivity of the enzymes for the phosphorus center of these phosphoramidate derivatives differed, demonstrating the importance of the nucleoside structure for this class of compounds. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.04.083
• 作为产物：
  描述：

  4-溴苯基二氯磷酸酯 在 N-甲基咪唑 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 3'-azidothymidine-5'-(p-bromophenyl)methoxyalaninyl phosphate
  参考文献：
  名称：

  Zidampidine, an aryl phosphate derivative of AZT: in vivo pharmacokinetics, metabolism, toxicity, and anti-viral efficacy against hemorrhagic fever caused by Lassa virus

  摘要：

  The pharmacokinetics, metabolism, and toxicity of Zidampidine, an aryl phosphate derivative of AZT, 3'-azidothymidine-5'-[p-bromophenyl methoxyalaninyl phosphate] were investigated in CD-1 mice. Following iv injection, Zidampidine was rapidly converted to its metabolites Ala-AZT-MP and AZT. Zidampidine was not toxic to mice at doses up to 250 mg/kg. We next examined the therapeutic effect of Zidampidine in CBA mice challenged with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or non-toxic doses of Zidampidine administered intraperitoneally 24 h prior, 1 h prior, and 24, 48, 72, and 96 h after virus inoculation. The probability of survival following the Lassa challenge was significantly improved for Zidampidine-treated mice (Kaplan Meier, Log-Rank p value < 0.0001). This pilot study provides the basis for future preclinical evaluation of Zidampidine and its potential as a new agent for the treatment of viral hemorrhagic fevers caused by Lassa virus. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.02.031

文献信息

• Aryl phosphate derivatives of d4T having anti-HIV activity
  申请人：Parker Hughes Institute

  公开号：US06350736B1

  公开（公告）日：2002-02-26

  Aryl phosphate derivatives of d4T with para-bromo substitution on the aryl group show markedly increased potency as anti-HIV agents without undesirable levels of cytotoxic activity. In particular, these derivatives are potent inhibitors of HIV reverse transcriptase. In a preferred aspect of the present invention, the phosphorus of the aryl phosphate group is further substituted with an amino acid residue that may be esterified or substituted, such as a methoxy alaninyl group.

  d4T的芳基磷酸酯衍生物，在芳基上对位溴取代，显示出明显增强的抗HIV活性，而无不良水平的细胞毒活性。特别是，这些衍生物是HIV反转录酶的强效抑制剂。在本发明的首选方面，芳基磷酸酯基的磷进一步取代为氨基酸残基，该残基可以酯化或取代，如甲氧基丙氨基基团。
• Benyumov, Alexey O.; Venkatachalam, Taracad K.; Grigoriants, Olga O., Arzneimittel-Forschung/Drug Research, 2005, vol. 55, # 2, p. 114 - 122
  作者：Benyumov, Alexey O.、Venkatachalam, Taracad K.、Grigoriants, Olga O.、Vassilev, Alexei O.、Tibbles, Heather E.、Downs, Suzanne、Dumez, Darin、Uckun, Fatih M.

  DOI：——

  日期：——
• Effect of change in nucleoside structure on the activation and antiviral activity of phosphoramidate derivatives
  作者：T.K. Venkatachalam、P. Samuel、S. Qazi、F.M. Uckun

  DOI：10.1016/j.bmc.2005.04.083

  日期：2005.9

  Changing the nucleoside group of a series of phosphoramidate derivatives affects the enzyme mediated hydrolysis rate of the compounds. d4T and AZT-substituted analogs were activated by enzymes such as lipases, esterases, and proteases. On the other hand, 3dT-substituted derivatives were comparatively less prone to hydrolysis under similar experimental conditions. From the experimental results, we propose that-the most preferable nucleoside group for enzyme activation is d4T rather than AZT or 3dT. Additionally, we also observed that depending on the enzymes used the chiral selectivity of the enzymes for the phosphorus center of these phosphoramidate derivatives differed, demonstrating the importance of the nucleoside structure for this class of compounds. (c) 2005 Elsevier Ltd. All rights reserved.
• Zidampidine, an aryl phosphate derivative of AZT: in vivo pharmacokinetics, metabolism, toxicity, and anti-viral efficacy against hemorrhagic fever caused by Lassa virus
  作者：F.M. Uckun、T.K. Venkatachalam、D. Erbeck、C.L. Chen、A.S. Petkevich、A. Vassilev

  DOI：10.1016/j.bmc.2005.02.031

  日期：2005.5

  The pharmacokinetics, metabolism, and toxicity of Zidampidine, an aryl phosphate derivative of AZT, 3'-azidothymidine-5'-[p-bromophenyl methoxyalaninyl phosphate] were investigated in CD-1 mice. Following iv injection, Zidampidine was rapidly converted to its metabolites Ala-AZT-MP and AZT. Zidampidine was not toxic to mice at doses up to 250 mg/kg. We next examined the therapeutic effect of Zidampidine in CBA mice challenged with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or non-toxic doses of Zidampidine administered intraperitoneally 24 h prior, 1 h prior, and 24, 48, 72, and 96 h after virus inoculation. The probability of survival following the Lassa challenge was significantly improved for Zidampidine-treated mice (Kaplan Meier, Log-Rank p value < 0.0001). This pilot study provides the basis for future preclinical evaluation of Zidampidine and its potential as a new agent for the treatment of viral hemorrhagic fevers caused by Lassa virus. (c) 2005 Elsevier Ltd. All rights reserved.