(4‐methoxy)phenyl (methoxy‐L‐alaninyl)phosphorochloridate | 147907-38-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (4‐methoxy)phenyl (methoxy‐L‐alaninyl)phosphorochloridate
• 英文别名: p-methoxyphenyl methoxyalaninyl phosphorochloridate；methyl (2S)-2-[[chloro-(4-methoxyphenoxy)phosphoryl]amino]propanoate
• CAS: 147907-38-8
• 化学式: C₁₁H₁₅ClNO₅P
• 分子量: 307.671
• InChiKey: LWJBVFJHQLKMEM-LQABBHMDSA-N

物化性质

• 沸点：
  395.0±52.0 °C(Predicted)
• 密度：
  1.308±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  19
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  73.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (4‐methoxy)phenyl (methoxy‐L‐alaninyl)phosphorochloridate 在 4-二甲氨基吡啶 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， -40.0~20.0 ℃ 、101.33 kPa 条件下， 生成 methyl ((3-(hydroxy(methyl)amino)-3-oxopropoxy)(4-methoxyphenoxy)phosphoryl)-L-alaninate
  参考文献：
  名称：

  氟沙星及其衍生物的氨基磷酸芳基酯前药的合成及生物学评价。

  摘要：

  合成了氧氟沙星衍生物15a-b和8a-b的芳基氨基磷酸酯前药，并研究其靶向细菌的能力。在固相培养基上对耻垢分枝杆菌和大肠杆菌均未观察到生长抑制，表明细菌细胞中没有活性化合物的释放。对前药的稳定性及其在非生物和生物条件下的多酶裂解的研究表明，使用芳基氨基磷酸酯前药方法来递送非核苷酸化合物并不明显，并且可能不适用于抗菌药物。

  DOI：

  10.1016/j.bioorg.2019.103012
• 作为产物：
  描述：

  4-甲氧基苯酚 在 三乙胺 、 三氯氧磷 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 生成 (4‐methoxy)phenyl (methoxy‐L‐alaninyl)phosphorochloridate
  参考文献：
  名称：

  氟沙星及其衍生物的氨基磷酸芳基酯前药的合成及生物学评价。

  摘要：

  合成了氧氟沙星衍生物15a-b和8a-b的芳基氨基磷酸酯前药，并研究其靶向细菌的能力。在固相培养基上对耻垢分枝杆菌和大肠杆菌均未观察到生长抑制，表明细菌细胞中没有活性化合物的释放。对前药的稳定性及其在非生物和生物条件下的多酶裂解的研究表明，使用芳基氨基磷酸酯前药方法来递送非核苷酸化合物并不明显，并且可能不适用于抗菌药物。

  DOI：

  10.1016/j.bioorg.2019.103012

文献信息

• Phosphate Prodrugs Derived from <i>N</i>-Acetylglucosamine Have Enhanced Chondroprotective Activity in Explant Cultures and Represent a New Lead in Antiosteoarthritis Drug Discovery
  作者：Christopher McGuigan、Michaela Serpi、Rita Bibbo、Helen Roberts、Clare Hughes、Bruce Caterson、Ana Torrent Gibert、Carlos Raúl Alaez Verson

  DOI：10.1021/jm800594c

  日期：2008.9.25

  the phosphoramidate ProTide approach, developed by us for antiviral nucleosides, to sugar derivatives with potential chondroprotection against osteoarthritis. In particular, N-acetylglucosamine was converted to a series of 06 arylaminoacyl phosphoramidates with ester and amino acid variation. Compounds were prepared by two routes, with or without sugar protection, and were isolated as phosphate diastereoisomers

  我们报告了由我们为抗病毒核苷开发的氨基磷酸酯ProTide方法在糖衍生物中的应用，该糖衍生物具有抗骨关节炎的潜在软骨保护作用。特别地，N-乙酰氨基葡糖被转化为一系列具有酯和氨基酸变化的06个芳基氨基酰基氨基磷酸酯。通过有或没有糖保护的两种途径制备化合物，并将其分离为磷酸盐非对映异构体。测定了化合物的细胞毒性和对IL-1诱导的糖胺聚糖（GAG）从牛关节软骨体外外植体培养物中释放的抑制（即蛋白聚糖降解）。与N-乙酰氨基葡糖母体相比，某些类似物在抑制炎性细胞因子诱导的蛋白聚糖降解方面显示出显着的功效增强。
• Cytotoxic nucleoside analog compound 003 for treating cancer
  申请人：Uckun M. Fatih

  公开号：US20060046972A1

  公开（公告）日：2006-03-02

  The present invention provides pharmaceutical compositions comprising Compound 003 or metabolites thereof in combination with one or more carboxylesterase inhibitors. The invention provides methods for inhibiting cellular proliferation associated with proliferative cell disorders in a subject by administering Compound 003 or metabolites thereof. The invention also provides methods for arresting the cell cycle. Methods of inhibiting proliferation of cells for treatment of cancer by administering Compound 003 are described.

  本发明提供了一种制剂，包括化合物003或其代谢物与一种或多种羧酯酶抑制剂的组合。本发明提供了一种通过给予化合物003或其代谢物来抑制与增殖性细胞疾病相关的细胞增殖的方法。本发明还提供了一种阻止细胞周期的方法。本发明还描述了通过给予化合物003来抑制癌细胞增殖的治疗癌症的方法。
• The Presence of Substituents on the Aryl Moiety of the Aryl Phosphoramidate Derivative of d4T Enhances Anti-HIV Efficacy in Cell Culture:  A Structure−Activity Relationship
  作者：Adam Q. Siddiqui、Carlo Ballatore、Christopher McGuigan、Erik De Clercq、Jan Balzarini

  DOI：10.1021/jm9803931

  日期：1999.2.1

  used to establish the stability of the compounds to enzymatic degradation. While there was no apparent correlation between in vitro activity and half-life of enzymatic degradation, there was a close correlation between compound lipophilicity, determined by octanol/water partition coefficient, and in vitro potency. We suggest that substitutions made to the aryl moiety of the aryl phosphoramidate of d4T

  合成了抗HIV药物d4T的新的取代芳基氨基磷酸酯衍生物，作为膜溶性细胞内前药，用于游离的生物活性磷酸盐，从而建立化合物结构与体外抗病毒活性之间的关系。相对于亲本核苷，大多数化合物表现出体外效力的提高，并且与d4T不同，它们在胸苷激酶缺陷型细胞中均保留了全部活性。带有对氯芳基（8e）的化合物在体外表达纳摩尔活性，相对于未取代的氨基磷酸酯而言，活性提高了14倍（与d4T相比，提高了100倍）。使用猪肝酯酶的测定用于建立化合物对酶促降解的稳定性。虽然在体外活性和酶促降解的半衰期之间没有明显的相关性，但由辛醇/水分配系数确定的化合物亲脂性与体外效能之间却有着密切的相关性。我们建议对d4T的氨基磷酸氨基磷酸酯的芳基部分进行取代，从而导致亲脂性增强，这可能通过被动扩散增加前药的细胞摄取，从而导致前药浓度降低时抗病毒效力的表达。
• Phosphoramidate Prodrugs of 2′-<i>C</i>-Methylcytidine for Therapy of Hepatitis C Virus Infection
  作者：Cristina Gardelli、Barbara Attenni、Monica Donghi、Malte Meppen、Barbara Pacini、Steven Harper、Annalise Di Marco、Fabrizio Fiore、Claudio Giuliano、Vincenzo Pucci、Ralph Laufer、Nadia Gennari、Isabella Marcucci、Joseph F. Leone、David B. Olsen、Malcolm MacCoss、Michael Rowley、Frank Narjes

  DOI：10.1021/jm900447q

  日期：2009.9.10

  The application of a phosphoramidate prodrug approach to 2'-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2'-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2'-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.
• Phosphoramidate and phosphate prodrugs of (−)-β-d-(2R,4R)-dioxolane-thymine: Synthesis, anti-HIV activity and stability studies
  作者：Yuzeng Liang、Janarthanan Narayanasamy、Raymond F. Schinazi、Chung K. Chu

  DOI：10.1016/j.bmc.2005.11.008

  日期：2006.4

  A series of phosphoramidate and phosphate prodrugs of DOT were synthesized via dichlorophosphate or H-phosphonate chemistry and evaluated for their anti-HIV activity against LAI M 184V mutants in PBM cells as well as for their cytotoxicity. The antiviral and cytotoxic profiles of the prodrugs were compared with that of the parent compound (DOT), and it was found that four aryl phosphoramidates 5, 18, 20, and 26 showed a significant enhancement (8- to 12-fold) in anti-HIV activity without cytotoxicity. Chemical stability of these prodrugs was evaluated in phosphate buffer at pH values of biological relevance (i.e., pH 2.0 and 7.4). Enzymatic hydrolysis was also studied in esterase or lipase in buffer solution. Chemical stability studies indicate that the phosphoramidates have good chemical stability at pH 2.0 and at pH 7.4 phosphate buffer. Phosphoramidate prodrugs were hydrolyzed in vitro by esterase or lipase and found to be better substrates for lipases than for esterases. 1,3-Diol cyclic phosphates showed potent anti-HIV activity without increasing the cytotoxicity compared with that of DOT and have good chemical and enzymatic stability. Long-chain lipid phosphates, although showed potent anti-HIV activity, exhibited increased cytotoxicity. (c) 2005 Elsevier Ltd. All rights reserved.