1-naphthyl-(ethoxy-L-valinyl)-phosphorochloridate | 1184942-61-7

• 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: 1-naphthyl-(ethoxy-L-valinyl)-phosphorochloridate
• 英文别名: ethyl (2S)-2-[[chloro(naphthalen-1-yloxy)phosphoryl]amino]-3-methylbutanoate
• CAS: 1184942-61-7
• 化学式: C₁₇H₂₁ClNO₄P
• 分子量: 369.785
• InChiKey: CKIFZTXQZMCPKV-FXIRQEPWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 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-(ethoxy-L-valinyl)-phosphorochloridate 、 溴夫定 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 12.52h， 以9.4%的产率得到(E)-5-(2-bromovinyl)-2’-deoxyuridine-5’-[1-naphthyl(ethyloxy-L-valinyl)]phosphate
  参考文献：
  名称：

  BVdU 的 ProTides 作为潜在的抗癌剂，有效地在细胞内递送其活化的代谢物

  摘要：

  核苷是治疗癌症的主要化疗药物，但其在细胞摄取、核苷激酶介导的激活和分解代谢方面的局限性已有充分记录。被称为 ProTides 的单磷酸前核苷酸代表了一种绕过对主动转运和核苷激酶介导的激活的依赖的强大策略。在此，我们报告了 BVdU ProTides 的结构调整。制备了 46 种氨基磷酸酯，并针对三种不同的癌细胞系进行了生物学评估；鼠白血病 (L1210)、人 CD 4 + T 淋巴细胞 (CEM) 和人宫颈癌 (HeLa)。与 BVdU 相比，针对 L1210 细胞的效力增强了 20 倍。有趣的是，与无活性的母体 BVdU 相比，许多 ProTides 对 CEM 和 HeLa 细胞表现出较低的微摩尔活性。ProTides 对非致瘤性人肺成纤维细胞培养物显示出即使有可测量的毒性，也很差。报道了四对非对映异构体混合物的分离以及它们的光谱特性、生物活性和酶活化率的比较。

  DOI：

  10.1016/j.bmcl.2016.10.077
• 作为产物：
  描述：

  1-萘基二氯磷酸酯 、 L-缬氨酸乙酯盐酸盐 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以67%的产率得到1-naphthyl-(ethoxy-L-valinyl)-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

• 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.
• ProTides of BVdU as potential anticancer agents upon efficient intracellular delivery of their activated metabolites
  作者：Sahar Kandil、Jan Balzarini、Stephanie Rat、Andrea Brancale、Andrew D. Westwell、Christopher McGuigan

  DOI：10.1016/j.bmcl.2016.10.077

  日期：2016.12

  cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation and catabolism are well-documented. The monophosphate pro-nucleotides known as ProTides represents a powerful strategy for bypassing the dependence on active transport and nucleoside kinase-mediated activation. Herein, we report the structural tuning of BVdU ProTides. Forty six phosphoramidates were

  核苷是治疗癌症的主要化疗药物，但其在细胞摄取、核苷激酶介导的激活和分解代谢方面的局限性已有充分记录。被称为 ProTides 的单磷酸前核苷酸代表了一种绕过对主动转运和核苷激酶介导的激活的依赖的强大策略。在此，我们报告了 BVdU ProTides 的结构调整。制备了 46 种氨基磷酸酯，并针对三种不同的癌细胞系进行了生物学评估；鼠白血病 (L1210)、人 CD 4 + T 淋巴细胞 (CEM) 和人宫颈癌 (HeLa)。与 BVdU 相比，针对 L1210 细胞的效力增强了 20 倍。有趣的是，与无活性的母体 BVdU 相比，许多 ProTides 对 CEM 和 HeLa 细胞表现出较低的微摩尔活性。ProTides 对非致瘤性人肺成纤维细胞培养物显示出即使有可测量的毒性，也很差。报道了四对非对映异构体混合物的分离以及它们的光谱特性、生物活性和酶活化率的比较。