2(S)-(hydroxy(3-deoxy-3-azidothymidyl)phosphorylamino)-3-(3-indolyl)propionic acid methyl ester | 168478-36-2

• 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)-(hydroxy(3-deoxy-3-azidothymidyl)phosphorylamino)-3-(3-indolyl)propionic acid methyl ester
• 英文别名: [(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methoxy-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-methoxy-2-oxo-ethyl]phosphonamidic acid；[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-N-[(2S)-3-(1H-indol-3-yl)-1-methoxy-1-oxopropan-2-yl]phosphonamidic acid
• CAS: 168478-36-2
• 化学式: C₂₂H₂₆N₇O₈P
• 分子量: 547.464
• InChiKey: XIUIJLHMXJPJKE-INDMIFKZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  38
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  174
• 氢给体数：
  4
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  2(S)-(hydroxy(3-deoxy-3-azidothymidyl)phosphorylamino)-3-(3-indolyl)propionic acid methyl ester 、 甲胺 以 甲醇 为溶剂， 反应 120.0h， 以100%的产率得到3'-azido-2'-deoxythymidine-5'-methylamino-L-tryptophanylphosphoramidate
  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：

  L-色氨酸甲酯 在 1,2,3,4,5,6,7,8-八硫杂环辛烷 、 Oxone 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 吡啶 、 乙腈 为溶剂， 反应 3.0h， 生成 2(S)-(hydroxy(3-deoxy-3-azidothymidyl)phosphorylamino)-3-(3-indolyl)propionic acid methyl ester
  参考文献：
  名称：

  Conjugation of amino acid O-methyl esters with AZT-5′-O-phosphorothioate and phosphorodithioate

  摘要：

  Based upon 1,3,2-oxathia(-dithia)phospholane chemistry, 5'-O-derivatisation of AZT with the O-methyl esters of L-phenylalanine and L-tryptophan was performed and the corresponding 5'-aminoacidophosphoramidothioates or phosphoramidodithioates of AZT were obtained in satisfactory yield. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4039(00)01635-x

文献信息

• Probing the Mechanism of Action and Decomposition of Amino Acid Phosphomonoester Amidates of Antiviral Nucleoside Prodrugs
  作者：Edward J. McIntee、Rory P. Remmel、Raymond F. Schinazi、Timothy W. Abraham、Carston R. Wagner

  DOI：10.1021/jm960694f

  日期：1997.10.1

  are internalized by lymphocytes to the same extent as AZT by a nonsaturable process. In lymphocytes, the amino acid carbomethoxy ester phosphomonoester amidates of AZT are not significantly metabolized to either AZT or the mono-, di-, or triphosphate of AZT. The amount of active anabolite, AZT-5'-triphosphate, formed in PBMCs incubated with the AZT phosphomonoester amidates 3 and 4 was 2- and 3-fold less

  结构相似的3'-叠氮基3'-脱氧胸苷（AZT）氨基磷酸酯1-6和3'-氟-3'-的外周血单核细胞（PBMC）的分解途径和体外抗HIV-1活性据报道脱氧胸苷（FLT）氨基磷酸酯7-10。AZT氨基磷酸酯在高达100 microM的浓度下对CEM细胞无细胞毒性，而FLT氨基磷酸酯9和10的CC50值分别为95.6和35.1 microM。在高达100 microM的浓度下，所有10种化合物对PBMC均无细胞毒性，并有效抑制病毒复制。特别地，AZT磷酸单酯酰胺化物4显示出与亲本核苷类似物AZT相当的抗病毒活性。对氨基酸碳甲氧基酯磷酸单酯酰胺化物的机理研究表明，它们的分解途径不同于核苷酸前药的氨基酸碳甲氧基酯芳基磷酸二酯酰胺化物的分解途径。AZT磷酸单酯酰胺化物通过不饱和过程被淋巴细胞内化到与AZT相同的程度。在淋巴细胞中，AZT的氨基酸碳甲氧基酯磷酸单酯酰胺化物不会显着代谢为AZT或AZT的单磷
• 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.
• A Phosphoramidite-Based Synthesis of Phosphoramidate Amino Acid Diesters of Antiviral Nucleosides
  作者：Timothy W. Abraham、Carston R. Wagner

  DOI：10.1080/15257779408010671

  日期：1994.9

  A general synthetic procedure is presented for the preparation of 5'-amino acid phosphoramidates of zidovudine (AZT), 3'-deoxy-2',3'-didehydrothymidine (D4T), and 3'-fluoro-3'-deoxythymidine (FLT) from their corresponding phosphoramidites. These water soluble amino acid phosphoramidates are more non-polar than the parent nucleoside and exhibit high stability in aqueous media.
• 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.
• Conjugation of amino acid O-methyl esters with AZT-5′-O-phosphorothioate and phosphorodithioate
  作者：Janina Baraniak、Renata Kaczmarek、Wojciech J. Stec

  DOI：10.1016/s0040-4039(00)01635-x

  日期：2000.11

  Based upon 1,3,2-oxathia(-dithia)phospholane chemistry, 5'-O-derivatisation of AZT with the O-methyl esters of L-phenylalanine and L-tryptophan was performed and the corresponding 5'-aminoacidophosphoramidothioates or phosphoramidodithioates of AZT were obtained in satisfactory yield. (C) 2000 Elsevier Science Ltd. All rights reserved.