3',5'-bis-O-tetrahydropyranyl-2'-O-allyl-araU | 188665-28-3

• 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: 3',5'-bis-O-tetrahydropyranyl-2'-O-allyl-araU
• 英文别名: 1-[(2R,3S,4R,5R)-4-(oxan-2-yloxy)-5-(oxan-2-yloxymethyl)-3-prop-2-enoxyoxolan-2-yl]pyrimidine-2,4-dione
• CAS: 188665-28-3
• 化学式: C₂₂H₃₂N₂O₈
• 分子量: 452.505
• InChiKey: SVBVWAYAVWOYEK-TVLUASMKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3',5'-bis-O-tetrahydropyranyl-2'-O-allyl-araU 在 ammonium hydroxide 、 Proton Sponge 、 三正丁胺 、 Dowex 1-X₂ (OH^- form) 、 三乙基碳酸氢铵缓冲液 、 对甲苯磺酸 、 N,N-二丁基丁烷-1-胺,磷酸 、 三乙胺 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 甲醇 、 乙腈 为溶剂， 反应 32.0h， 生成 2'-O-allyl-araC 5'-diphosphate
  参考文献：
  名称：

  5‘-Phosphoramidates and 5‘-Diphosphates of 2‘-O-Allyl-β-d-arabinofuranosyl- uracil, -cytosine, and -adenine:  Inhibition of Ribonucleotide Reductase

  摘要：

  Continuing our studies on ribonucleotide reductase (RNR) mechanism-based inhibitors, we have now prepared the diphosphates (DP) of 2'-O-allyl-1-beta-D-arabinofuranosyl-uracil and -cytosine and 2'-O-allyl-9-beta-D-arabinofuranosyl-adenine and evaluated their inhibitory activity against recombinant murine RNR. 2'-O-Allyl-araUDP proved to be inhibitory to RNR at an IC50 of 100 mu M, whereas 2'-O-allyl-araCDP was only marginally active (IC50 1 mM) and 2'-O-allyl-araADP was completely inactive. The susceptibility of the parent nucleosides to phosphorylation by thymidine kinase and 2'-deoxycytidine kinase was also investigated, and all nucleosides proved to be poor substrates for the above-cited kinases. Moreover, prodrugs of 2'-O-allyl-araU and -araC monophosphates, namely 2'-O-allyl-5'-(phenylethoxy-L-alanyl phosphate)-araU and -araC, were prepared and tested against tumor cell proliferation but proved to be inactive. A molecular modeling study has been conducted in order to explain our results. The data confirm that for both the natural and analogue nucleoside diphosphates, the principal determinant interaction with the active site of RNR is with the diphosphate group, which forms strong hydrogen bonds with Glu623, Thr624, Ser625, and Thr209. Our findings indicate that the poor phosphorylation may represent an explanation for the lack of marked in vitro cytostatic activity of the test compounds.

  DOI：

  10.1021/jm9807095
• 作为产物：
  描述：

  2,2'-脱水尿苷 在 氢氧化钾 、 sodium hydride 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 乙醇 、 乙腈 为溶剂， 反应 24.17h， 生成 3',5'-bis-O-tetrahydropyranyl-2'-O-allyl-araU
  参考文献：
  名称：

  5‘-Phosphoramidates and 5‘-Diphosphates of 2‘-O-Allyl-β-d-arabinofuranosyl- uracil, -cytosine, and -adenine:  Inhibition of Ribonucleotide Reductase

  摘要：

  Continuing our studies on ribonucleotide reductase (RNR) mechanism-based inhibitors, we have now prepared the diphosphates (DP) of 2'-O-allyl-1-beta-D-arabinofuranosyl-uracil and -cytosine and 2'-O-allyl-9-beta-D-arabinofuranosyl-adenine and evaluated their inhibitory activity against recombinant murine RNR. 2'-O-Allyl-araUDP proved to be inhibitory to RNR at an IC50 of 100 mu M, whereas 2'-O-allyl-araCDP was only marginally active (IC50 1 mM) and 2'-O-allyl-araADP was completely inactive. The susceptibility of the parent nucleosides to phosphorylation by thymidine kinase and 2'-deoxycytidine kinase was also investigated, and all nucleosides proved to be poor substrates for the above-cited kinases. Moreover, prodrugs of 2'-O-allyl-araU and -araC monophosphates, namely 2'-O-allyl-5'-(phenylethoxy-L-alanyl phosphate)-araU and -araC, were prepared and tested against tumor cell proliferation but proved to be inactive. A molecular modeling study has been conducted in order to explain our results. The data confirm that for both the natural and analogue nucleoside diphosphates, the principal determinant interaction with the active site of RNR is with the diphosphate group, which forms strong hydrogen bonds with Glu623, Thr624, Ser625, and Thr209. Our findings indicate that the poor phosphorylation may represent an explanation for the lack of marked in vitro cytostatic activity of the test compounds.

  DOI：

  10.1021/jm9807095

文献信息

• Synthesis and antiproliferative activity of 2′-O-allyl-1-β-D-arabinofuranosyl-uracil, -cytosine and -adenine
  作者：Stefano Manfredini、Pier Giovanni Baraldi、Rita Bazzanini、Daniele Simoni、Jan Balzarini、Erik De Clercq

  DOI：10.1016/s0960-894x(97)00044-9

  日期：1997.2

  With the aim to design potential inhibitors of ribonucleotide reductase (RR), 2'-O-allyl-beta-D-arabinofuranosyl-uracil (4), -cytosine (7) and -adenosine (10) were prepared and evaluated for their cytostatic activity against Molt4/C8, CEM and L1210 cell lines. Although our preliminary data do not allow to assess if RR is the intracellular target, the results point to differences in the (anti)metabolic behavior of these compounds. This study also offers a general synthesis of 2'-O-allyl-beta-D-arabinofuranosyl nucleosides for potential applications in the preparation of 2'-O-allyl-beta-D-oligoarabino nucleotides. (C) 1997, Elsevier Science Ltd.
• 5‘-Phosphoramidates and 5‘-Diphosphates of 2‘-<i>O</i>-Allyl-β-<scp>d</scp>-arabinofuranosyl- uracil, -cytosine, and -adenine:  Inhibition of Ribonucleotide Reductase
  作者：Stefano Manfredini、Pier Giovanni Baraldi、Elisa Durini、Silvia Vertuani、Jan Balzarini、Erik De Clercq、Anna Karlsson、Valentina Buzzoni、Lars Thelander

  DOI：10.1021/jm9807095

  日期：1999.8.1

  Continuing our studies on ribonucleotide reductase (RNR) mechanism-based inhibitors, we have now prepared the diphosphates (DP) of 2'-O-allyl-1-beta-D-arabinofuranosyl-uracil and -cytosine and 2'-O-allyl-9-beta-D-arabinofuranosyl-adenine and evaluated their inhibitory activity against recombinant murine RNR. 2'-O-Allyl-araUDP proved to be inhibitory to RNR at an IC50 of 100 mu M, whereas 2'-O-allyl-araCDP was only marginally active (IC50 1 mM) and 2'-O-allyl-araADP was completely inactive. The susceptibility of the parent nucleosides to phosphorylation by thymidine kinase and 2'-deoxycytidine kinase was also investigated, and all nucleosides proved to be poor substrates for the above-cited kinases. Moreover, prodrugs of 2'-O-allyl-araU and -araC monophosphates, namely 2'-O-allyl-5'-(phenylethoxy-L-alanyl phosphate)-araU and -araC, were prepared and tested against tumor cell proliferation but proved to be inactive. A molecular modeling study has been conducted in order to explain our results. The data confirm that for both the natural and analogue nucleoside diphosphates, the principal determinant interaction with the active site of RNR is with the diphosphate group, which forms strong hydrogen bonds with Glu623, Thr624, Ser625, and Thr209. Our findings indicate that the poor phosphorylation may represent an explanation for the lack of marked in vitro cytostatic activity of the test compounds.