2(S)-(3-deoxy-3-azidothymidyl(hydroxy)phosphorylamino)-3-methylbutyric acid methyl ester | 244127-83-1

• 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: 2(S)-(3-deoxy-3-azidothymidyl(hydroxy)phosphorylamino)-3-methylbutyric acid methyl ester
• 英文别名: (S)-2-{[3-Azido-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydrofuran-2-ylmethoxy]-hydroxyphosphorylamino}-3-methyl-butyric acid methyl ester；[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-N-[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl]phosphonamidic acid
• CAS: 244127-83-1
• 化学式: C₁₆H₂₅N₆O₈P
• 分子量: 460.384
• InChiKey: DUACTXDTZCRIFM-LOWDOPEQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  158
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  甲胺 、 2(S)-(3-deoxy-3-azidothymidyl(hydroxy)phosphorylamino)-3-methylbutyric acid methyl ester 以 甲醇 为溶剂， 反应 120.0h， 以65%的产率得到(2-methyl-1(S)-methylcarbamoylpropyl)phosphoramidic acid momo(3-deoxy-3-azidothymidyl)ester
  参考文献：
  名称：

  Synthesis, in Vitro Anti-Breast Cancer Activity, and Intracellular Decomposition of Amino Acid Methyl Ester and Alkyl Amide Phosphoramidate Monoesters of 3‘-Azido-3‘-deoxythymidine (AZT)

  摘要：

  We report the synthesis and anticancer activity of a series of AZT phosphoramidate monoesters containing amino acid methyl ester (3a-11a) and N-alkyl amide (3b-11b, 9c-9f) moieties. The aromatic amino acid methyl esters were found to be more cytotoxic than the aliphatic analogues toward MCF-7 cells (human pleural effusion breast adenocarcinoma cell line). A marked stereochemical preference for the L-amino acid stereochemistry was also observed in MCF-7 cells. There was no consistent enhancement of cytotoxicity of the methyl amides over the corresponding methyl esters. AZT and the two AZT aromatic amino acid methyl ester phosphoramidates 8a and 9a were found to be more cytotoxic toward MCF-7 cells than to CEM cells (human T-cell lymphoblastic leukemia). The selective cytotoxicity toward MCF-7 cells may be associated with greater intracellular levels of phosphoramidate monoester and/or phosphorylated AZT.

  DOI：

  10.1021/jm000110g
• 作为产物：
  描述：

  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)-3-methylbutyric 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

文献信息

• Synthesis, in Vitro Anti-Breast Cancer Activity, and Intracellular Decomposition of Amino Acid Methyl Ester and Alkyl Amide Phosphoramidate Monoesters of 3‘-Azido-3‘-deoxythymidine (AZT)
  作者：Vidhya V. Iyer、George W. Griesgraber、Matthew R. Radmer、Edward J. McIntee、Carston R. Wagner

  DOI：10.1021/jm000110g

  日期：2000.6.1

  We report the synthesis and anticancer activity of a series of AZT phosphoramidate monoesters containing amino acid methyl ester (3a-11a) and N-alkyl amide (3b-11b, 9c-9f) moieties. The aromatic amino acid methyl esters were found to be more cytotoxic than the aliphatic analogues toward MCF-7 cells (human pleural effusion breast adenocarcinoma cell line). A marked stereochemical preference for the L-amino acid stereochemistry was also observed in MCF-7 cells. There was no consistent enhancement of cytotoxicity of the methyl amides over the corresponding methyl esters. AZT and the two AZT aromatic amino acid methyl ester phosphoramidates 8a and 9a were found to be more cytotoxic toward MCF-7 cells than to CEM cells (human T-cell lymphoblastic leukemia). The selective cytotoxicity toward MCF-7 cells may be associated with greater intracellular levels of phosphoramidate monoester and/or phosphorylated AZT.
• 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.