1-(2'-O-allyl-β-D-arabinofuranosyl)uracil | 188665-29-4

• 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: 1-(2'-O-allyl-β-D-arabinofuranosyl)uracil
• 英文别名: 2'-O-Allyl-araU；1-[(2R,3S,4R,5R)-4-hydroxy-5-(hydroxymethyl)-3-prop-2-enoxyoxolan-2-yl]pyrimidine-2,4-dione
• CAS: 188665-29-4
• 化学式: C₁₂H₁₆N₂O₆
• 分子量: 284.269
• InChiKey: NGZRTPYYZWYZSO-CZULRBLNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  108
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(2'-O-allyl-β-D-arabinofuranosyl)uracil 在 4-二甲氨基吡啶 、 溶剂黄146 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 46.0h， 生成 2'-O-allyl-3'-O-tert-butyldimethylsilyl-5'-O-tosyl-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
• 作为产物：
  描述：

  3',5'-bis-O-tetrahydropyranyl-araU 在 甲醇 、 sodium hydride 、 对甲苯磺酸 作用下， 以 四氢呋喃 为溶剂， 生成 1-(2'-O-allyl-β-D-arabinofuranosyl)uracil
  参考文献：
  名称：

  Synthesis and antiproliferative activity of 2′-O-allyl-1-β-D-arabinofuranosyl-uracil, -cytosine and -adenine

  摘要：

  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.

  DOI：

  10.1016/s0960-894x(97)00044-9

文献信息

• Dinucleotides containing two allyl groups by combinations of allyl phosphotriesters, 5-allyl-, 2′-O-allyl- and 2′-arabino-O-allyl uridine derivatives as substrates for ring-closing metathesis
  作者：Philip Børsting、Morten Freitag、Poul Nielsen

  DOI：10.1016/j.tet.2004.09.023

  日期：2004.11

  Five different dinucleotides, each containing two allyl groups in various positions, were prepared and studied as substrates for ring-closing metathesis reactions. These dinucleotides were designed from appropriate nucleoside building blocks combining four different positions for the allyl group; the allyl phosphotriester linkage, 5-allyl-2' -deoxyuridine, and ribo- as well as arabino-configured 2'-O-allyluridine. Thus, convenient procedures for these building blocks were developed. From the dinucleotides, two new cyclic nucleotide structures were obtained; one connecting two adjacent nucleobase moieties and the other forming an unsaturated four-carbon linkage between the phosphate moiety and the adjacent pyrimidine nucleobase. The latter cyclic dinucleotide was also prepared with a saturated four-carbon linkage using a tandem ring-closing metathesis-hydrogenation procedure. This compound was found to be significantly more stable towards a nucleophilic ring-opening than its unsaturated counterpart. (C) 2004 Elsevier Ltd. All rights reserved.
• 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.