thymidine 5'-phosphoramidate | 17495-16-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: thymidine 5'-phosphoramidate
• 英文别名: thymidine 5'-amidomonophosphate；3-deoxythymidine-5’-monophosphate；dTMP；thymidine-5'-O-phosphoramidate；1-[(2R,4S,5R)-5-(dihydroxyphosphinimyloxymethyl)-4-hydroxyoxolan-2-yl]-5-methylpyrimidine-2,4-dione
• CAS: 17495-16-8
• 化学式: C₁₀H₁₆N₃O₇P
• 分子量: 321.227
• InChiKey: ZBEGSMVHWDDGDJ-XLPZGREQSA-N

物化性质

• 密度：
  1.598±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  151
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  在 氨 、 水 、 Rexyn 101 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 1.5h， 以51 mg的产率得到thymidine 5'-phosphoramidate
  参考文献：
  名称：

  从固相环水杨基磷酸化试剂合成核苷单、二和三磷酰胺

  摘要：

  在碳酸钾的存在下，氯甲基聚苯乙烯树脂与 5-羟基水杨醛反应，得到聚合物结合的 2-羟基苯甲醛。随后用硼烷溶液还原产生聚合物结合的 2-羟基苯甲醇。固定化的 2-羟基苯甲醇与适当的亚磷酸酯化试剂反应生成固相环水杨基单-、二-和三亚磷酸酯化试剂，其与未保护的核苷反应，随后碘氧化、氰乙氧基脱保护和碱性裂解，分别以52-73% 的总产率提供 5'- O-核苷单-、二-和三氨基磷酸酯。

  DOI：

  10.1021/ol900320r

文献信息

• Hydrolytic reactions of 3′-N-phosphoramidate and 3′-N-thiophosphoramidate analogs of thymidylyl-3′,5′-thymidine
  作者：Mikko Ora、Merita Murtola、Sami Aho、Mikko Oivanen

  DOI：10.1039/b313470a

  日期：——

  The diastereomeric thiophosphoramidate analogs [(RP)- and (SP)-3′,5′-Tnp(s)T] 2 and the phosphoramidate analog [3′,5′-TnpT] 3 of thymidylyl-3′,5′-thymidine were prepared and their hydrolytic reactions over the pH-range 1–8 at 363.2 K were followed by RP HPLC. At pH < 6, an acid-catalyzed P–N3′ bond cleavage (first-order in [H+]) takes place with both 3′,5′-Tnp(s)T and 3′,5′-TnpT, the former being about 12 fold more stable than the latter. At pH > 4, Tnp(s)T undergoes two competing pH-independent reactions, desulfurization (yielding TnpT) and depyrimidination (cleavage of the N-glycosidic bond) the rates of which are of the same order of magnitude. Also with 3′,5′-TnpT the pH-independent depyrimidination competes with P–N3′ cleavage at pH > 5.

  硫代磷酰胺酯类似物[(RP)-和(SP)-3′,5′-Tnp(s)T]2以及磷酰胺酯类似物[3′,5′-TnpT]3的胸苷基-3′,5′-胸苷被制备出来，并在363.2 K下通过反相高效液相色谱法跟踪了它们在pH范围1至8的水解反应。在pH < 6时，酸催化的P-N3′键断裂（[H+]的一级反应）在3′,5′-Tnp(s)T和3′,5′-TnpT中都会发生，前者比后者稳定约12倍。在pH > 4时，Tnp(s)T会经历两种竞争性的pH无关反应，去硫化（生成TnpT）和去嘧啶化（N-糖苷键断裂），这两种反应的速率是同一数量级的。同样，3′,5′-TnpT在pH > 5时，pH无关的去嘧啶化与P-N3′键断裂竞争。
• Prebiotic Phosphorylation and Concomitant Oligomerization of Deoxynucleosides to form DNA
  作者：Eddy I. Jiménez、Clémentine Gibard、Ramanarayanan Krishnamurthy

  DOI：10.1002/anie.202015910

  日期：2021.5.3

  RNA and DNA replication, coupled with prebiotic co‐synthesis of deoxyribo‐ and ribo‐nucleotides, have resurrected the hypothesis of co‐emergence of RNA and DNA. As further support, we show that diamidophosphate (DAP) with 2‐aminoimidazole (amido)phosphorylates and oligomerizes deoxynucleosides to form DNA—under conditions similar to those of ribonucleosides. The pyrimidine deoxynucleoside 5′‐O‐amidophosphates

  最近展示的 RNA-DNA 嵌合体 (RDNA) 使 RNA 和 DNA 复制成为可能，再加上脱氧核糖和核糖核苷酸的益生元共合成，重新提出了 RNA 和 DNA 共生的假设。作为进一步的支持，我们表明二酰胺磷酸酯 (DAP) 与 2-氨基咪唑（酰胺基）磷酸化并寡聚化脱氧核苷以形成 DNA——在与核糖核苷相似的条件下。嘧啶脱氧核苷 5'-O-氨基磷酸酯以良好的 (≈60%) 产率形成。有趣的是，嘧啶脱氧核苷（酸）苷的存在增加了嘌呤脱氧核苷酸的产量（≈20%）。同时，观察到寡聚化 (≈18–31%) 主要是 3',5'-磷酸二酯 DNA 键和一些 (<5%) 焦磷酸盐。
• Phosphoramidates and methods therefor
  申请人：——

  公开号：US20020004594A1

  公开（公告）日：2002-01-10

  Novel phosphoramidate derivatives of hydroxy functional or amino functional compounds, including amino acids, peptides, peptidomimetics and nucleotide analogs, are described. The compounds enable enhanced intracellular delivery of drugs as their corresponding phosphate esters or amides. Described phosphoramidate compounds exhibit antiproliferative activity. Pharmaceutical formulations are provided for treatment of cancers.

  描述了羟基功能或氨基功能化合物的新型磷酰胺衍生物，包括氨基酸、肽、肽类似物和核苷酸类似物。这些化合物能够通过它们的相应磷酸酯或酰胺实现药物的增强细胞内递送。所述的磷酰胺化合物表现出抗增殖活性。提供了用于治疗癌症的药物配方。
• Methods and compositions for detecting a drug resistant EGFR mutant
  申请人：Memorial Sloan-Kettering Cancer Center

  公开号：EP2505591A1

  公开（公告）日：2012-10-03

  Polymerase chain reaction primers and methods directed to detecting the EGFR mutant C→T at the position corresponding to base 2369 of EGFR cDNA. The invention provides a PCR primer that hybridizes under suitable PCR conditions to a polynucleotide sequence 5' in each respective strand to a mutation of an EGFR gene that encodes a substitution of threonine by methionine at position 790 of the EGFR polypeptide. The invention also provides a PCR primer hybridizes to a sequence that includes a mutant T at the position corresponding to base 2369 of EGFR cDNA but not to a second EGFR polynucleotide containing a wild type C. The invention provides several methods and kits for detecting a mutant epidermal growth factor receptor (EGFR) gene in a sample comprising probing the sample with a means for selectively detecting a nucleotide sequence comprising a mutant T at the position corresponding to base 2369 of EGFR cDNA, and identifying that the base at said position is T. These methods and kits are also useful to predict resistance to the therapeutic effects of gefitinib or erlotinib in a subject suffering from or suspected of having a cancer.

  聚合酶链反应引物和检测表皮生长因子受体（EGFR）突变体C→T的方法，该突变体位于与表皮生长因子受体（EGFR）cDNA的碱基2369相对应的位置。本发明提供了一种 PCR 引物，该引物在适当的 PCR 条件下与 EGFR 基因突变 5'的多核苷酸序列杂交，该突变编码 EGFR 多肽 790 位上的苏氨酸被蛋氨酸取代。本发明还提供了一种 PCR 引物，它与在表皮生长因子受体 cDNA 碱基 2369 对应位置包括突变 T 的序列杂交，但不与含有野生型 C 的第二个表皮生长因子受体多核苷酸杂交。本发明提供了几种检测样品中突变表皮生长因子受体（EGFR）基因的方法和试剂盒，包括用一种方法探测样品，该方法可选择性地检测与 EGFR cDNA 碱基 2369 相对应的位置上包含突变 T 的核苷酸序列，并确定所述位置上的碱基为 T。
• Nucleoside phosphoramidates and nucleoside phosphoramidases
  申请人：Wagner R. Carston

  公开号：US20060014193A1

  公开（公告）日：2006-01-19

  The invention provides isolated nucleic acid sequences encoding polypeptides having nucleoside phosphoramidase activity, and methods of screening for nucleoside phosphoramidate compounds that are cleaved by a phosphoramidase or for phosphoramidases that are able to cleave phosphoramidate compounds. The invention also provides methods of delivering a nucleoside monophosphate.

  本发明提供了编码具有核苷磷酸酰胺酶活性的多肽的分离核酸序列，以及筛选可被磷酸酰胺酶裂解的核苷磷酸酰胺化合物或能够裂解磷酸酰胺化合物的磷酸酰胺酶的方法。本发明还提供了提供单磷酸核苷的方法。