phenyl (benzyloxy-D-alaninyl)phosphorochloridate

• 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 (benzyloxy-D-alaninyl)phosphorochloridate
• 英文别名: phenyl(benzyloxy-D-alaninyl)phosphorochloridate；phenyl-(benzoxy-D-alaninyl)-phosphorochloridate；phenyl-(benzyloxy-L-alaninyl)-phosphorochloridate；benzyl (2R)-2-[[chloro(phenoxy)phosphoryl]amino]propanoate
• 化学式: C₁₆H₁₇ClNO₄P
• 分子量: 353.742
• InChiKey: AOZOBLLGZPZKKD-JHQYKTOJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.19
• 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 (benzyloxy-D-alaninyl)phosphorochloridate 、 8-氯腺嘌呤核苷 在 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 0.17h， 以11%的产率得到5’-([(benzyloxy-D-alanin-N-yl)phenyl]phosphatyl)-8-chloroadenosine
  参考文献：
  名称：

  [EN] ADENOSINE DERIVATIVES FOR USE IN THE TREATMENT OF CANCER
  [FR] DÉRIVÉS DE L'ADÉNOSINE UTILISABLES DANS LE TRAITEMENT DU CANCER

  摘要：

  本发明涉及化学式（I）所定义的化合物，其制备以及在癌症治疗中的应用。

  公开号：

  WO2017207989A1
• 作为产物：
  描述：

  D-丙氨酸苄酯对甲苯磺酸盐 、 二氯磷酸苯酯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以84%的产率得到phenyl (benzyloxy-D-alaninyl)phosphorochloridate
  参考文献：
  名称：

  The Application of Phosphoramidate Protide Technology to Acyclovir Confers Anti-HIV Inhibition

  摘要：

  Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated, ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types-1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.

  DOI：

  10.1021/jm9007856

文献信息

• ProTides of N-(3-(5-(2′-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents
  作者：Christopher McGuigan、Marco Derudas、Blanka Gonczy、Karen Hinsinger、Sahar Kandil、Fabrizio Pertusati、Michaela Serpi、Robert Snoeck、Graciela Andrei、Jan Balzarini、Timothy D. McHugh、Arundhati Maitra、Ernest Akorli、Dimitrios Evangelopoulos、Sanjib Bhakta

  DOI：10.1016/j.bmc.2014.02.056

  日期：2014.5

  flavin-dependent thymidylate synthase X (ThyX), rare in eukaryotes and completely absent in humans, is crucial in the metabolism of thymidine (a DNA precursor) in many microorganisms including several human pathogens. Conserved in mycobacteria, including Mycobacterium leprae, and Mycobacterium tuberculosis, it represents a prospective anti-mycobacterial therapeutic target. In a M. tuberculosis ThyX-enzyme

  黄素依赖性胸苷酸合酶 X (ThyX) 在真核生物中很少见，在人类中完全不存在，它在许多微生物（包括几种人类病原体）中的胸苷（一种 DNA 前体）代谢中至关重要。它保存在分枝杆菌中，包括麻风分枝杆菌和结核分枝杆菌，代表了一种前瞻性的抗分枝杆菌治疗靶点。在结核分枝杆菌ThyX 酶抑制试验中，N-(3-(5-(2'-deoxyuridine-5'-phosphate))prop-2-ynyl)octanamide 据报道是最有效和选择性的 5-取代 2'-脱氧尿苷单磷酸类似物。在这项研究中，我们使用 ProTide 技术掩盖了该化合物磷酸盐部分的两个电荷，以增加其亲脂性，然后允许渗透通过复杂的分枝杆菌细胞壁。化学合成了一系列N -(3-(5-(2'-deoxyuridine))prop-2-ynyl)octanamide 氨基磷酸酯，并评估了它们作为潜在抗结核药的生物活性。除分枝杆菌外，几种 DNA
• Phosphoramidates of 2′-β-d-arabinouridine (AraU) as phosphate prodrugs; design, synthesis, in vitro activity and metabolism
  作者：Youcef Mehellou、Rocco Valente、Huw Mottram、Elisabeth Walsby、Kenneth I. Mills、Jan Balzarini、Christopher McGuigan

  DOI：10.1016/j.bmc.2010.02.059

  日期：2010.4

  2'-beta-D-Arabinouridine (AraU), the uridine analogue of the anticancer agent AraC, was synthesized and evaluated for antiviral activity and cytotoxicity. In addition, a series of AraU monophosphate prodrugs in the form of triester phosphoramidates (ProTides) were also synthesized and tested against a range of viruses, leukaemia and solid tumour cell lines. Unfortunately, neither the parent compound (AraU) nor any of its ProTides showed antiviral activity, nor potent inhibitory activity against any of the cancer cell lines. Therefore, the metabolism of AraU phosphoramidates to release AraU monophosphate was investigated. The results showed carboxypeptidase Y, hog liver esterase and crude CEM tumor cell extracts to hydrolyse the ester motif of phosphoramidates with subsequent loss of the aryl group, while molecular modelling studies suggested that the AraU L-alanine aminoacyl phosphate derivative might not be a good substrate for the phosphoramidase enzyme Hint-1. These findings are in agreement with the observed disappearance of intact prodrug and concomitant appearance of the corresponding phosphoramidate intermediate derivative in CEM cell extracts without measurable formation of araU monophosphate. These findings may explain the poor antiviral/cytostatic potential of the prodrugs. (C) 2010 Elsevier Ltd. All rights reserved.
• Application of the Phosphoramidate ProTide Approach to 4‘-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside
  作者：Plinio Perrone、Giovanna M. Luoni、Mary Rose Kelleher、Felice Daverio、Annette Angell、Sinead Mulready、Costantino Congiatu、Sonal Rajyaguru、Joseph A. Martin、Vincent Levêque、Sophie Le Pogam、Isabel Najera、Klaus Klumpp、David B. Smith、Christopher McGuigan

  DOI：10.1021/jm0613370

  日期：2007.4.1

  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.
• The application of phosphoramidate ProTide technology to the potent anti-HCV compound 4′-azidocytidine (R1479)
  作者：Christopher McGuigan、Mary Rose Kelleher、Plinio Perrone、Sinead Mulready、Giovanna Luoni、Felice Daverio、Sonal Rajyaguru、Sophie Le Pogam、Isabel Najera、Joseph A. Martin、Klaus Klumpp、David B. Smith

  DOI：10.1016/j.bmcl.2009.05.099

  日期：2009.8

  We report the design, synthesis and evaluation of a family of ca 50 phosphoramidate ProTides of the potent anti-HCV compound 4 '-azidocytidine (R1479), with variation on the ester, amino acid and aryl moiety of the ProTide. Sub-mu M inhibitors of HCV emerge. The compounds are all non-cytotoxic in the replicon assay. We herein report detailed SARs for each of the regions of the ProTide. (C) 2009 Elsevier Ltd. All rights reserved.
• The Application of Phosphoramidate Protide Technology to Acyclovir Confers Anti-HIV Inhibition
  作者：Marco Derudas、Davide Carta、Andrea Brancale、Christophe Vanpouille、Andrea Lisco、Leonid Margolis、Jan Balzarini、Christopher McGuigan

  DOI：10.1021/jm9007856

  日期：2009.9.10

  Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated, ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types-1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.