phenyl (benzyloxy-L-valinyl)phosphorochloridate | 926308-97-6

• 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-L-valinyl)phosphorochloridate
• 英文别名: benzyl (2S)-2-[[chloro(phenoxy)phosphoryl]amino]-3-methylbutanoate
• CAS: 926308-97-6
• 化学式: C₁₈H₂₁ClNO₄P
• 分子量: 381.796
• InChiKey: JZYZQWFXDZMNTH-LFUZPPSTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 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-L-valinyl)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 benzyl N-[{1-((2R,3S,4R,5R)-5-azido-tetrahydro-3,4-dihydroxy-5-(hydroxymethyl)furan-2-yl)pyrimidine-2,4(1H,3H)-dione} (phenoxy)-phosphoryl]-L-valinate
  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：

  L-缬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77%的产率得到phenyl (benzyloxy-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

• [EN] MONOSACCHARIDE PHOSPHORAMIDATE PRODRUGS<br/>[FR] PROMÉDICAMENTS À BASE DE PHOSPHORAMIDATE DE MONOSACCHARIDE
  申请人：CERECOR INC

  公开号：WO2019118486A1

  公开（公告）日：2019-06-20

  The present disclosure provides monosaccharide phosphoramidate prodrugs of monosaccharide monophosphates. The present disclosure further provides methods of treating diseases of conditions such as congenital disorders of glycosylation comprising administering the monosaccharide phosphoramidate prodrugs of the present disclosure to a patient in need thereof.

  本公开提供了单糖磷酰胺酯前药，用于单糖单磷酸。本公开还提供了治疗糖基化先天性疾病等疾病或症状的方法，包括向需要的患者施用本公开的单糖磷酰胺酯前药。
• 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
• [EN] ADENOSINE DERIVATIVES FOR USE IN THE TREATMENT OF CANCER<br/>[FR] DÉRIVÉS DE L'ADÉNOSINE UTILISABLES DANS LE TRAITEMENT DU CANCER
  申请人：NUCANA BIOMED LTD

  公开号：WO2017207989A1

  公开（公告）日：2017-12-07

  The present invention relates to chemical compounds of formula (I) as defined in the amended claims, their preparation and their use in the treatment of cancer.

  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。
• Targeting GNE Myopathy: A Dual Prodrug Approach for the Delivery of <i>N</i>-Acetylmannosamine 6-Phosphate
  作者：Chiara Morozzi、Jana Sedláková、Michaela Serpi、Marialuce Avigliano、Rosangela Carbajo、Lucia Sandoval、Yadira Valles-Ayoub、Patrick Crutcher、Stephen Thomas、Fabrizio Pertusati

  DOI：10.1021/acs.jmedchem.9b00833

  日期：2019.9.12

  ProTides comprise an important class of prodrugs currently marketed and developed as antiviral and anticancer therapies. The ProTide technology employs phosphate masking groups capable of providing more favorable druglike properties and an intracellular activation mechanism for enzyme-mediated release of a nucleoside monophosphate. Herein, we describe the application of phosphoramidate chemistry to 1,3,4-O-acetylated N-acetylmannosamine (Ac(3)ManNAc) to deliver ManNAc-6-phosphate (ManNAc-6-P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG) caused by mutations in GNE that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac(3)ManNAc-6-phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug 12b showed rapid activation in a carboxylesterase (CPY) enzymatic assay and favorable ADME properties, while also being more effective than ManNAc at increasing sialic acid levels in GNE-deficient cell lines. These results provide a potential platform to address substrate deficiencies in GNE myopathy and other CDGs.
• 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.