phenyl (tert-butyloxy-L-alaninyl)phosphorochloridate | 220592-63-2

• 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: phenyl (tert-butyloxy-L-alaninyl)phosphorochloridate
• 英文别名: tert-butyl (2S)-2-[[chloro(phenoxy)phosphoryl]amino]propanoate
• CAS: 220592-63-2
• 化学式: C₁₃H₁₉ClNO₄P
• 分子量: 319.725
• InChiKey: XAVGOMLTCARSJX-SMNKDYLDSA-N

物化性质

• 沸点：
  385.4±44.0 °C(Predicted)
• 密度：
  1.226±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  phenyl (tert-butyloxy-L-alaninyl)phosphorochloridate 在 甲酸 、 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 21.25h， 生成 (S)-2-{[(2R,3S,4R,5R)-2-Azido-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid tert-butyl ester
  参考文献：
  名称：

  Application of the Phosphoramidate ProTide Approach to 4‘-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside

  摘要：

  We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.

  DOI：

  10.1021/jm0613370
• 作为产物：
  描述：

  苯酚 在 三乙胺 、 三氯氧磷 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 2.5h， 生成 phenyl (tert-butyloxy-L-alaninyl)phosphorochloridate
  参考文献：
  名称：

  激动素核糖苷及其蛋白激活与帕金森病相关的PTEN诱导的假定激酶1（PINK1），与线粒体去极化无关。

  摘要：

  由于PINK1功能突变的丧失导致帕金森氏病的早期发作，因此人们对发现能放大PINK1激酶活性的小分子的兴趣日益浓厚。我们在此报告了四种激动素核糖苷ProTides的设计，合成，血清稳定性和水解性。这些ProTides与激动素核糖体一起激活了独立于线粒体去极化的细胞中的PINK1。这突出了修饰的核苷及其磷酸盐前药作为神经退行性疾病治疗的潜力。

  DOI：

  10.1021/acs.jmedchem.6b01897

文献信息

• Design, synthesis, and anti-HIV activity of 2′,3′-didehydro-2′,3′-dideoxyuridine (d4U), 2′,3′-dideoxyuridine (ddU) phosphoramidate ‘ProTide’ derivatives
  作者：Youcef Mehellou、Christopher McGuigan、Andrea Brancale、Jan Balzarini

  DOI：10.1016/j.bmcl.2007.04.043

  日期：2007.7

  We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the

  我们报告2'，3'-didehydro-2'，3'-dideoxyuridine（d4U）和2'，3'-dideoxyuridine（ddU）氨基磷酸'ProTide'衍生物的合成及其对HIV-1和HIV-2的评估。此外，我们对d4U和ddU单磷酸盐进行了分子建模研究，以研究其第二次磷酸化过程。建模研究的结果提供了令人信服的证据，证明与相应的ddU氨基磷酸酯相比，d4U氨基磷酸酯缺乏抗HIV活性。
• Application of Phosphoramidate ProTide Technology Significantly Improves Antiviral Potency of Carbocyclic Adenosine Derivatives
  作者：Christopher McGuigan、Alshaimaa Hassan-Abdallah、Sheila Srinivasan、Yikang Wang、Adam Siddiqui、Susan M. Daluge、Kristjan S. Gudmundsson、Huiqiang Zhou、Ed W. McLean、Jennifer P. Peckham、Thimysta C. Burnette、Harry Marr、Richard Hazen、Lynn D. Condreay、Lance Johnson、Jan Balzarini

  DOI：10.1021/jm060776w

  日期：2006.11.30

  phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes

  我们报告了氨基磷酸酯原核苷酸（ProTide）技术在抗病毒剂碳环L-d4A（L-Cd4A）中的应用。L-Cd4A的苯基甲基丙氨酸基母体ProTide是通过格利雅（Grignard）介导的磷酰氯反应制备的，得到的化合物具有显着改善的抗HIV（2600倍）和HBV活性。我们描述了ProTide的芳基，酯和氨基酸区域的修饰，以及这些变化如何影响抗病毒活性和代谢稳定性。注意到针对HIV和HBV的SAR分别且不同。另外，由D-核苷D-Cd4A和双脱氧类似物L-CddA和D-CddA制备ProTide。与母体药物相比，这些化合物显示出更适度的效能改善。综上所述，当将ProTide方法应用于L-Cd4A时，在体外的效价提高了9000倍，非常成功，抗HIV的能力提高了。为了临床前候选人的选择，我们使用食蟹猴肝脏和肠道S9馏分进行了代谢稳定性研究。
• Synthesis and Biological Evaluation of (<i>E</i>)-4-Hydroxy-3-methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cell Immune Responses
  作者：Martin S. Davey、Roshni Malde、Rory C. Mykura、Alfie T. Baker、Taher E. Taher、Cécile S. Le Duff、Benjamin E. Willcox、Youcef Mehellou

  DOI：10.1021/acs.jmedchem.7b01824

  日期：2018.3.8

  The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This

  芳氧基三酯氨基磷酸酯前药方法已成功用于药物发现中。在这里，我们描述了这种前药技术在磷酸抗原HMBPP的单磷酸酯衍生物及其类似物中的首次应用。这些前药中的一些表现出Vγ9/Vδ2T细胞的特异性和有效激活，然后能够体外裂解膀胱癌细胞。这项工作凸显了这种前药技术在发现新型免疫疗法中的前景。
• Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
  作者：Qin Xu、Taher E. Taher、Elizabeth Ashby、Maria Sharif、Benjamin E. Willcox、Youcef Mehellou

  DOI：10.1002/cmdc.202100198

  日期：2021.8.5

  and DMAPP monophosphates. As the IPP monophosphate aryloxy triester phosphoramidates showed favorable stability, they were subsequently investigated for their ability to activate Vγ9/Vδ2 T cells and they showed promising activation of this subset of T cells. Together, these findings represent the first report of IPP and DMAPP monophosphate prodrugs and the ability of IPP aryloxy triester phosphoramidate

  异戊烯焦磷酸酯 (IPP) 和焦磷酸二甲基烯丙酯 (DMAPP) 的单磷酸酯衍生物的芳氧基三酯氨基磷酸酯前药被合成为可改善细胞摄取的亲脂性衍生物。尽管 IPP 和 DMAPP 的结构相似，但注意到它们的氨基磷酸酯前药在水环境中表现出不同的稳定性，我们表明这是由于 IPP 和 DMAPP 单磷酸盐骨架中烯丙基键的位置。由于 IPP 单磷酸芳氧基三酯氨基磷酸酯显示出良好的稳定性，因此随后研究了它们激活 Vγ9/Vδ2 T 细胞的能力，并显示出对该 T 细胞亚群的有希望的激活。一起，
• Facile synthesis of the NNRTI microbicide MC-1220 and synthesis of its phosphoramidate prodrugs
  作者：Yasser M. Loksha、Erik B. Pedersen、Paolo La Colla、Roberta Loddo

  DOI：10.1039/c5ob02055g

  日期：——

  A facile and novel synthetic route to MC-1220 was achieved by condensation of 4,6-dichloro-N,N-5-trimethylpyrimidin-2-amine (1) with the sodium salt of 2,6-difluorophenylacetonitrile, followed by methylation and strong acidic hydrolysis. The prodrugs of MC-1220 were synthesized by reaction of chlorophosphoramidate derivatives (7a–e) or α-acetobromoglucose with the sodium salt of MC-1220. The stability

  通过将4,6-二氯-N，N -5-三甲基嘧啶-2-胺（1）与2,6-二氟苯基乙腈的钠盐缩合，然后甲基化和强酸水解。MC-1220的前药是通过氯磷酸氨基酯衍生物（7a–e）或α-乙酰溴葡萄糖与MC-1220的钠盐反应合成的。事实证明，氨基磷酸酯前药的稳定性和抗HIV-1活性与母体药物MC-1220相当。