5'-thymidyl piperidylphosphoramidic acid | 72273-07-5

• 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: 5'-thymidyl piperidylphosphoramidic acid
• 英文别名: Thymidin-5'-phosphoropiperidat；[(2R,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-piperidin-1-ylphosphinic acid
• CAS: 72273-07-5
• 化学式: C₁₅H₂₄N₃O₇P
• 分子量: 389.345
• InChiKey: PXPMPNJXHBACKD-YNEHKIRRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  129
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  5'-thymidyl piperidylphosphoramidic acid 在 4,5-二氰基咪唑 、 bis(tetrabutylammonium) hydrogen phosphate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 Natrium-2'-desoxythymidin-5'-diphosphat
  参考文献：
  名称：

  AP（V）–N活化核苷多磷酸盐合成的策略

  摘要：

  已经开发了由4，5-二氰基咪唑（DCI）促进的受保护的核苷5'-磷酸哌啶酸酯合成核苷5'-三磷酸酯（NTPs）和核苷5'-二磷酸酯（NDP）的通用且高产率的方法。31 P NMR示踪实验表明，顺序的脱保护和偶联反应非常干净。磷酸哌啶酯对DCI促进的NTP / NDP合成显示出优于常规磷酸吗啉酸酯的反应性。实验结果表明，取决于焦磷酸盐和磷酸盐的不同亲核性，DCI激活的机制对于NTP和NDP合成可能是独特的。

  DOI：

  10.1021/jo4011156
• 作为产物：
  描述：

  哌啶-1-基膦酰二氯 在 10percent Pd/C 吡啶 、 N-甲基咪唑 、 乙基溴化镁 、 氢气 作用下， 以 四氢呋喃 为溶剂， 反应 15.17h， 生成 5'-thymidyl piperidylphosphoramidic acid
  参考文献：
  名称：

  Synthesis and Biological Activity of Novel 5-Fluoro-2‘-deoxyuridine Phosphoramidate Prodrugs

  摘要：

  A series of novel haloethyl and piperidyl phosphoramidate FdUMP prodrug analogues has been synthesized, and the growth inhibitory activity of these compounds has been evaluated against L1210 mouse leukemia cells. All compounds exhibited potent inhibition of L1210 cell proliferation with IC50 values in the nanomolar range. Growth inhibition was reversed by the addition of 5 muM thymidine, suggesting a mechanism of action involving the intracellular release of FdUMP. P-31 NMR studies carried out on model haloethyl phosphoramidates confirm the release of nucleotide via cyclization of the phosphoramidate anion to the aziridinium ion intermediate followed by hydrolysis of the P-N bond. The data suggests that <50% of the prodrug is converted to FdUMP intracellularly by this pathway. Piperidyl phosphoramidate analogues are also converted to nucleotide intracellularly, presumably by the action of an endogenous phosphoramidase.

  DOI：

  10.1021/jm000301j

文献信息

• An improved P(V)-N activation strategy for the synthesis of nucleoside diphosphate 6-deoxy-l-sugars
  作者：Qi Sun、Xingjian Li、Jian Sun、Shanshan Gong、Gang Liu、Guodong Liu

  DOI：10.1016/j.tet.2013.11.059

  日期：2014.1

  Four nucleoside diphosphate 6-deoxy-(L)-sugars have been efficiently synthesized by coupling sugar-1-phosphates prepared from the H-phosphonate precursors with nucleoside 5'-phosphoropiperidates in the presence of 4,5-dicyanoimidazole (DCI) as the activator. Compared to the conventional 1H-tetrazole-promoted phosphoromorpholidate method, the new phosphoropiperidate/DCI system significantly shortened the reaction time and afforded nucleoside diphosphate sugars in excellent isolated yields. (c) 2013 Elsevier Ltd. All rights reserved.
• A P(V)–N Activation Strategy for the Synthesis of Nucleoside Polyphosphates
  作者：Qi Sun、Shanshan Gong、Jian Sun、Si Liu、Qiang Xiao、Shouzhi Pu

  DOI：10.1021/jo4011156

  日期：2013.9.6

  A general and high-yielding synthesis of nucleoside 5′-triphosphates (NTPs) and nucleoside 5′-diphosphates (NDPs) from protected nucleoside 5′-phosphoropiperidates promoted by 4,5-dicyanoimidazole (DCI) has been developed. 31P NMR tracing experiments showed that the sequential deprotection and coupling reactions were exceptionally clean. The phosphoropiperidate exhibited superior reactivity to the

  已经开发了由4，5-二氰基咪唑（DCI）促进的受保护的核苷5'-磷酸哌啶酸酯合成核苷5'-三磷酸酯（NTPs）和核苷5'-二磷酸酯（NDP）的通用且高产率的方法。31 P NMR示踪实验表明，顺序的脱保护和偶联反应非常干净。磷酸哌啶酯对DCI促进的NTP / NDP合成显示出优于常规磷酸吗啉酸酯的反应性。实验结果表明，取决于焦磷酸盐和磷酸盐的不同亲核性，DCI激活的机制对于NTP和NDP合成可能是独特的。
• Synthesis and Biological Activity of Novel 5-Fluoro-2‘-deoxyuridine Phosphoramidate Prodrugs
  作者：Caren L. Freel Meyers、Liping Hong、Carolyn Joswig、Richard F. Borch

  DOI：10.1021/jm000301j

  日期：2000.11.1

  A series of novel haloethyl and piperidyl phosphoramidate FdUMP prodrug analogues has been synthesized, and the growth inhibitory activity of these compounds has been evaluated against L1210 mouse leukemia cells. All compounds exhibited potent inhibition of L1210 cell proliferation with IC50 values in the nanomolar range. Growth inhibition was reversed by the addition of 5 muM thymidine, suggesting a mechanism of action involving the intracellular release of FdUMP. P-31 NMR studies carried out on model haloethyl phosphoramidates confirm the release of nucleotide via cyclization of the phosphoramidate anion to the aziridinium ion intermediate followed by hydrolysis of the P-N bond. The data suggests that <50% of the prodrug is converted to FdUMP intracellularly by this pathway. Piperidyl phosphoramidate analogues are also converted to nucleotide intracellularly, presumably by the action of an endogenous phosphoramidase.