1-naphthyl-(benzoxy-dimethylglycinyl)-phosphorochloridate | 874362-14-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 1-naphthyl-(benzoxy-dimethylglycinyl)-phosphorochloridate
• 英文别名: 1-naphthyl (benzoxydimethylglycinyl) phosphorochloridate；1-naphthyl(benzoxydimethylglycinyl)phosphorochloridate；1-naphthyl-(benzoxy-dimethylglycinyl)phosphochloridate；Benzyl 2-[[chloro(naphthalen-1-yloxy)phosphoryl]amino]-2-methylpropanoate
• CAS: 874362-14-8
• 化学式: C₂₁H₂₁ClNO₄P
• 分子量: 417.829
• InChiKey: QKMOUJVDPIZNCQ-UHFFFAOYSA-N

物化性质

• 沸点：
  541.8±52.0 °C(Predicted)
• 密度：
  1.296±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• 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：

  1-naphthyl-(benzoxy-dimethylglycinyl)-phosphorochloridate 、 5-氟-2'-脱氧脲核苷 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 生成 5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl(benzoxy-α,α-dimethylglycine)]phosphate
  参考文献：
  名称：

  Phosphoramidate ProTides of the Anticancer Agent FUDR Successfully Deliver the Preformed Bioactive Monophosphate in Cells and Confer Advantage over the Parent Nucleoside

  摘要：

  The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependence of the current drugs on active transport and nucleoside kinase-mediated activation. They are also resistant to metabolic deactivation by phosphorolytic enzymes. We report 39 ProTides of the fluorinated pyrimidine FUDR with variation in the aryl, ester, and amino acid. regions. Notably, only certain ProTide motifs are successful in delivering the nucleoside monophosphate into intact cells. We also find that the ProTides retain activity in mycoplasma infected cells, unlike FUDR. Data suggest these compounds to be worthy of further progression.

  DOI：

  10.1021/jm200815w
• 作为产物：
  描述：

  萘酚 在 三乙胺 、 三氯氧磷 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 4.5h， 生成 1-naphthyl-(benzoxy-dimethylglycinyl)-phosphorochloridate
  参考文献：
  名称：

  NUC-7738（一种 3'-脱氧腺苷的芳氧基磷酰胺酯）的合成和表征，作为一种潜在的抗癌剂

  摘要：

  3′-脱氧腺苷（3′-dA，虫草素，1）是一种具有抗癌特性的核苷类似物，但由于其被腺苷脱氨酶（ADA）失活以及由于人类低表达而导致细胞摄取不良，其临床开发受到阻碍。平衡转运蛋白（hENT1）。在这里，我们描述了 NUC-7738 ( 7a )（一种 3'-dA 的 5'-芳氧基氨基磷酸酯前药）的合成和表征。我们的体外证据表明， 7a在一组实体和血液癌细胞系中是一种有效的抗癌药物，显示出其对白血病干细胞的优先细胞毒性作用。我们发现，与 3'-dA 不同， 7a的活性独立于 hENT1 和激酶活性。此外，它还能抵抗 ADA 代谢失活。与这些发现一致，7a显示细胞内活性代谢物 3'-脱氧腺苷三磷酸 (3'-dATP) 水平增加。从机制上讲，细胞内 3'-dATP 水平与体外效力密切相关。NUC-7738 目前正处于晚期实体瘤患者的 II 期剂量递增研究中。

  DOI：

  10.1021/acs.jmedchem.2c01348

文献信息

• [EN] SALTS OF DIPHOSPHATE PHOSPHORAMIDATE OF NUCLEOSIDES AS ANTICANCER COMPOUNDS<br/>[FR] SELS DE PHOSPHORAMIDATE DIPHOSPHATE DE NUCLÉOSIDES UTILISÉS EN TANT QUE COMPOSÉS ANTICANCÉREUX
  申请人：NUCANA PLC

  公开号：WO2019110991A1

  公开（公告）日：2019-06-13

  The present invention relates to compounds comprising a salt of a diphosphate phosphoramidate of a nucleoside drug, e.g. clofarabine. The compounds are useful in the treatment of cancer, e.g. leukemia.

  本发明涉及包括核苷药物的二磷酸磷酰胺盐化合物，例如克洛法滨。这些化合物在癌症治疗中，如白血病治疗中具有用途。
• Virtual Screening of Acyclovir Derivatives as Potential Antiviral Agents: Design, Synthesis, and Biological Evaluation of New Acyclic Nucleoside ProTides
  作者：Marco Derudas、Christophe Vanpouille、Davide Carta、Sonia Zicari、Graciela Andrei、Robert Snoeck、Andrea Brancale、Leonid Margolis、Jan Balzarini、Christopher McGuigan

  DOI：10.1021/acs.jmedchem.7b01009

  日期：2017.9.28

  anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate

  根据我们对无环鸟苷（ACV）磷酸盐前药的抗人免疫缺陷病毒（HIV）活性的发现，我们在此报告了ProTide方法应用于一系列无环核苷的用途，旨在鉴定新型和选择性抗病毒剂，特别是抗HIV代理商。本研究中使用的无环核苷类似物通过使用HIV逆转录酶（RT），腺苷酸/鸟苷酸激酶和人DNA聚合酶γ的虚拟筛选进行鉴定。总共合成了39种新的磷酸盐前药，并针对HIV-1（体外和离体人类扁桃体组织系统）和人类疱疹病毒进行了评估。几种ProTide化合物在低微摩尔范围内显示出对HIV-1的显着效力，而母体核苷则无效。另外，观察到明显抑制疱疹病毒复制。
• Novel Potential Anticancer Naphthyl Phosphoramidates of BVdU:  Separation of Diastereoisomers and Assignment of the Absolute Configuration of the Phosphorus Center
  作者：Costantino Congiatu、Andrea Brancale、Malcolm D. Mason、Wen G. Jiang、Christopher McGuigan

  DOI：10.1021/jm0509896

  日期：2006.1.1

  We have previously reported our SAR optimization of the anticancer agent thymectacin. Tuning of the parent ProTide structure initially involved the amino acid and, subsequently, the aromatic masking group on the phosphate moiety. Herein, derivatives bearing the combined modifications are reported and biological evaluation is described. Moreover, separation of the diastereoisomeric final product mixture shows a different cytostatic activity for the two diastereoisomers. Through computational and NMR studies, the absolute stereochemistry of the phosphorus center of the two diastereoisomers has been suggested.
• 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.
• Activation of <i>p16</i> Gene Silenced by DNA Methylation in Cancer Cells by Phosphoramidate Derivatives of 2′-Deoxyzebularine
  作者：Christine B. Yoo、Rocco Valente、Costantino Congiatu、Federica Gavazza、Annette Angel、Maqbool A. Siddiqui、Peter A. Jones、Christopher McGuigan、Victor E. Marquez

  DOI：10.1021/jm8005965

  日期：2008.12.11

  We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2'-deoxyzebularine 5'-triphosphate (dZTP). Because 2'-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5'-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers of p16 tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma. cells.