p-nitrophenyl 5'-thymidine monophosphate | 2304-08-7

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷酸
• 英文名称: p-nitrophenyl 5'-thymidine monophosphate
• 英文别名: p-Nph-5'-TMP；pNP-TMP；TMP-pNP；thymidine 5'-monophosphate p-nitrophenyl ester；thymidine 5'-monophosphate para-nitrophenyl ester；p-nitrophenyl 5′-thymidine monophosphate；p-nitrophenyl thymidine 5'-monophosphate；thymidine monophosphate para-nitrophenol；[(2R,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl (4-nitrophenyl) hydrogen phosphate
• CAS: 2304-08-7
• 化学式: C₁₆H₁₈N₃O₁₀P
• 分子量: 443.307
• InChiKey: RWOAVOYBVRQNIZ-BFHYXJOUSA-N

物化性质

• 密度：
  1.597±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  180
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  p-nitrophenyl 5'-thymidine monophosphate 在 ectonucleotide pyrophosphatase/phosphodiesterase-1 、 calcium chloride 、 magnesium chloride 作用下， 生成 4-硝基苯酚阴离子
  参考文献：
  名称：

  Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification

  摘要：

  Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) converts extracellular nucleotides into inorganic pyrophosphate, whereas its close relative NPP2/autotaxin hydrolyzes lysophospholipids. NPP1 regulates calcification in mineralization-competent tissues, and a lack of NPP1 function underlies calcification disorders. Here, we show that NPP1 forms homodimers via intramembrane disulfide bonding, but is also processed intracellularly to a secreted monomer. The structure of secreted NPP1 reveals a characteristic bimetallic active site and a nucleotide-binding groove, but it lacks the lipid-binding pocket and open tunnel present in NPP2. A loop adjacent to the nucleotide-binding site, which is disordered in NPP2, is well ordered in NPP1 and might promote nucleotide binding. Remarkably, the N-terminal somatomedin B-like domains of NPP1, unlike those in NPP2, are flexible and do not contact the catalytic domain. Our results provide a structural basis for the nucleotide pyrophosphatase activity of NPP1 and help to understand how disease-causing mutations may affect NPP1 structure and function.

  DOI：

  10.1016/j.str.2012.09.001
• 作为产物：
  描述：

  双(对硝基苯基)磷酸酯 在 环丁砜 、 potassium phosphate 、 N,N'-二环己基碳二亚胺 作用下， 反应 16.5h， 生成 p-nitrophenyl 5'-thymidine monophosphate
  参考文献：
  名称：

  Bis(m-nitrophenyl) and bis(p-nitrophenyl) esters and the phosphorodiamidate of thymidine 5'-phosphate as potential sources of intracellular thymidine 5'-phosphate in mouse cells in culture

  摘要：

  Thymidine 5'-phosphate (TMP) derivatives with masked phosphate groups were synthesized in tritiated form from [methyl-3H]thymidine. They were of interest as models for 5' nucleotide derivatives that might be able to permeate mammalian cells and then liberate intracellular antimetabolite 5' nucleotides by loss of the masking groups. Mouse L fibroblasts were grown in vitro in the presence of 1 mM 5'-amino-5'-deoxythymidine, which was found to suppress greater than 99% of cellular thymidine kinase activity while inhibiting the rate of cell division by only 30%. The TMP derivatives were less effective than thymidine in labeling the deoxyribonucleic acid (DNA) of the L cells. The labeling was inhibited 95-99% by 5'-amino-5'-deoxythymidine, indicating that it represented incorporation into DNA of [3H]thymidine formed from degradation of the test compounds. No evidence was obtained that the compounds acted as sources of intracellular TMP by cell permeation followed by loss of phosphate blocking groups. Similar studies yielded no evidence that the bis(m-nitrophenyl) ester of TMP produced intracellular TMP by that route in the LM(TK-) strain of L cells that are genetically deficient in thymidine kinase.

  DOI：

  10.1021/jm00378a036

文献信息

• Evidence for Direct Attack by Hydroxide in Phosphodiester Hydrolysis
  作者：Adam G. Cassano、Vernon E. Anderson、Michael E. Harris

  DOI：10.1021/ja020823j

  日期：2002.9.1

  deuterium isotope effects (D2Ok), ionic strength effects, and 18O isotope effects on the solvent nucleophile (18knuc). The D2Ok for hydroxide-catalyzed phosphodiester hydrolysis is slightly inverse (0.9 +/- 0.1), suggesting that a proton transfer does not occur in the transition state. A significant alpha effect is observed with hydroperoxide, demonstrating that oxyanions can act as nucleophiles in the reaction

  由于其在生物学中的重要性，磷酸二酯水解一直是深入研究的主题。尽管对磷酸二酯裂解机制进行了大量重要分析，但对这些反应中的亲核试剂知之甚少。为了确定氢氧化物在 thymidine-5'-p-nitrophenyl phosphate 的水解中是作为亲核试剂还是一般碱，我们确定了溶剂氘同位素效应 (D2Ok)、离子强度效应和 18O 同位素对溶剂亲核试剂 (18knuc ）。氢氧化物催化的磷酸二酯水解的 D2Ok 略微相反 (0.9 +/- 0.1)，表明在过渡态中不会发生质子转移。使用氢过氧化物观察到显着的 α 效应，表明氧阴离子可以在反应中充当亲核试剂。此外，氢氧化物和氢过氧化物催化的离子强度依赖性无法区分，表明它们以相同的机制起作用。最后，氢氧化物催化反应的 18knuc 为 1.068 +/- 0.007，远远超过水和氢氧化物之间的平衡 18O 同位素效应（1.040 +/- 0.003
• [EN] NUCLEOSIDE 5'-PHOSPHOROTHIOATE ANALOGUES AND USES THEREOF<br/>[FR] ANALOGUES DE NUCLÉOSIDE 5'-PHOSPHOROTHIOATE ET LEURS UTILISATIONS
  申请人：UNIV BAR ILAN

  公开号：WO2013132489A1

  公开（公告）日：2013-09-12

  The invention provides particular mono- and dinucleoside 5'-phosphorothioate analogues, more particularly mono- or di- adenosine or uridine 5'-di- or tri- phosphorothioate analogues in which at least one of the bridging oxygen atoms of the phosphorothioate is replaced by a group such as -CH2-, and at least one of the non- bridging atoms or negatively-charged atoms of the phosphorothioate is either a sulfur atom or a sulfur ion; and pharmaceutical compositions thereof. These compounds are useful for treatment of neurodegenerative diseases or disorders such as Alzheimer's disease.

  该发明提供了特定的单核苷酸和二核苷酸5'-磷硫酸酯类似物，更具体地说是单腺苷或尿苷5'-二磷硫酸酯类似物或三磷硫酸酯类似物，其中磷硫酸酯的桥氧原子之一被类似于-CH2-的基团取代，并且磷硫酸酯的非桥接原子或负电荷原子之一是硫原子或硫离子；以及其药物组合物。这些化合物可用于治疗神经退行性疾病或障碍，如阿尔茨海默病。
• [EN] HIGHLY SELECTIVE AND POTENT NPP1 INHIBITORS BASED ON URIDINE-5'-P,-DITHIOPHOSPHATE ANALOGUES<br/>[FR] INHIBITEURS DE NPP1 HAUTEMENT SÉLECTIFS ET PUISSANTS À BASE D'ANALOGUES D'URIDINE-5'-P,-DITHIOPHOSPHATE
  申请人：UNIV BAR ILAN

  公开号：WO2020212995A1

  公开（公告）日：2020-10-22

  The invention relates to a novel highly selective and potent NPP1 inhibitors, compositions comprising such, and their use as pharmaceuticals.

  该发明涉及一种新型高度选择性和强效的NPP1抑制剂，包括这种抑制剂的组合物以及它们作为药物的使用。
• RAZZELL; KHORANA, Journal of Biological Chemistry, 1959, vol. 234, # 8, p. 2105 - 2113
  作者：RAZZELL、KHORANA

  DOI：——

  日期：——
• Moffatt, Biochemical Preparations, 1961, vol. 8, p. 100
  作者：Moffatt

  DOI：——

  日期：——