2'-O-allyl-3'-O-tert-butyldimethylsilyl-araA | 245078-10-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 2'-O-allyl-3'-O-tert-butyldimethylsilyl-araA
• 英文别名: [(2R,3R,4S,5R)-5-(6-aminopurin-9-yl)-3-[tert-butyl(dimethyl)silyl]oxy-4-prop-2-enoxyoxolan-2-yl]methanol
• CAS: 245078-10-8
• 化学式: C₁₉H₃₁N₅O₄Si
• 分子量: 421.572
• InChiKey: JVZYCCFITHXXNR-LJGDNWOOSA-N

物化性质

• 沸点：
  564.7±60.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.26
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2'-O-allyl-3'-O-tert-butyldimethylsilyl-araA 在 4-二甲氨基吡啶 、 Dowex AG 50W-X₂ (Na⁺ form) 、 氢氟酸 、 tris(tetra-n-butylammonium) hydrogen pyrophosphate 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 68.0h， 生成 2'-O-allyl-araA 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：

  阿糖腺苷 在 sodium hydride 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 90.25h， 生成 2'-O-allyl-3'-O-tert-butyldimethylsilyl-araA
  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

• 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.