phenyl (benzoxyL-leucinyl) phosphorochloridate | 840506-65-2

• 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 (benzoxyL-leucinyl) phosphorochloridate
• 英文别名: benzyl (chloro(phenoxy)phosphoryl)-L-leucinate；phenyl-(benzyloxy-L-leucinyl) phosphorochloridate；L-leucine benzyl ester phosphororchloridate；benzyl (2S)-2-[[chloro(phenoxy)phosphoryl]amino]-4-methylpentanoate
• CAS: 840506-65-2
• 化学式: C₁₉H₂₃ClNO₄P
• 分子量: 395.823
• InChiKey: QUCYHEOSJYWYIQ-MDYZWHIJSA-N

物化性质

• 沸点：
  487.8±47.0 °C(Predicted)
• 密度：
  1.230±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  26
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.32
• 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 (benzoxyL-leucinyl) phosphorochloridate 在 palladium 10% on activated carbon 、 叔丁基氯化镁 、 氢气 作用下， 以 四氢呋喃 、 乙醇 、 乙酸乙酯 为溶剂， 反应 14.5h， 生成
  参考文献：
  名称：

  Targeting GNE Myopathy: A Dual Prodrug Approach for the Delivery of N-Acetylmannosamine 6-Phosphate

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.9b00833
• 作为产物：
  描述：

  L-亮氨酸苄基酯 、 二氯磷酸苯酯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.25h， 以99%的产率得到phenyl (benzoxyL-leucinyl) phosphorochloridate
  参考文献：
  名称：

  Targeting GNE Myopathy: A Dual Prodrug Approach for the Delivery of N-Acetylmannosamine 6-Phosphate

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.9b00833

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。
• [EN] PHOSPHORODIAMIDATES AND OTHER PHOSPHORUS DERIVATIVES OF FINGOLIMOD AND RELATED S1 P RECEPTOR MODULATORS<br/>[FR] PHOSPHORODIAMIDATES ET AUTRES DÉRIVÉS DE PHOSPHORE DE FINGOLIMOD ET MODULATEURS DE RÉCEPTEUR S1 P ASSOCIÉS
  申请人：UNIV COLLEGE CARDIFF CONSULTANTS LTD

  公开号：WO2019064012A1

  公开（公告）日：2019-04-04

  Compounds of general formula (I): (Formula I)) wherein R1, Q, R3, R4, R5, R6, R7 and Ar1 are as defined herein are inhibitors of class I histone deacetylases and are of use in the treatment of lysosomal storage disorders, especially Niemann-Pick type C disease, as well as other lysosomal storage disorders, defective autophagy, accumulation of free cholesterol and mycobacterial diseases.

  通式（I）的化合物：（式I）其中R1、Q、R3、R4、R5、R6、R7和Ar1的定义如下，是类I组蛋白去乙酰化酶的抑制剂，可用于治疗溶酶体贮积症，特别是尼曼-匹克C型疾病，以及其他溶酶体贮积症、缺陷自噬、游离胆固醇积累和分枝杆菌病。
• [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。
• Phosphorodiamidates and other phosphorus derivatives of fingolimod and related S1P receptor modulators
  申请人：UNIVERSITY COLLEGE CARDIFF CONSULTANTS LTD

  公开号：US11078221B2

  公开（公告）日：2021-08-03

  Compounds of general formula (I): (Formula I)) wherein R1, Q, R3, R4, R5, R6, R7 and Ar1 are as defined herein are inhibitors of class I histone deacetylases and are of use in the treatment of lysosomal storage disorders, especially Niemann-Pick type C disease, as well as other lysosomal storage disorders, defective autophagy, accumulation of free cholesterol and mycobacterial diseases.

  通式(I)的化合物：(式 I)) 其中 R1、Q、R3、R4、R5、R6、R7 和 Ar1 如本文所定义，是 I 类组蛋白去乙酰化酶的抑制剂，可用于治疗溶酶体贮积症，尤其是 C 型尼曼-皮克病，以及其他溶酶体贮积症、自噬缺陷、游离胆固醇积累和霉菌病。
• Phosphoramidate ProTides of the Anticancer Agent FUDR Successfully Deliver the Preformed Bioactive Monophosphate in Cells and Confer Advantage over the Parent Nucleoside
  作者：Christopher McGuigan、Paola Murziani、Magdalena Slusarczyk、Blanka Gonczy、Johan Vande Voorde、Sandra Liekens、Jan Balzarini

  DOI：10.1021/jm200815w

  日期：2011.10.27

  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.