2-chloro-N⁶-(3-iodobenzyl)-9-(3-azido-2,5-di-O-t-butyldimethylsilyl-3-deoxy-β-D-ribofuranosyl)adenine | 889126-13-0

• 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-chloro-N⁶-(3-iodobenzyl)-9-(3-azido-2,5-di-O-t-butyldimethylsilyl-3-deoxy-β-D-ribofuranosyl)adenine
• 英文别名: 9-[(2R,3R,4R,5S)-4-azido-3-[tert-butyl(dimethyl)silyl]oxy-5-[[tert-butyl(dimethyl)silyl]oxymethyl]oxolan-2-yl]-2-chloro-N-[(3-iodophenyl)methyl]purin-6-amine
• CAS: 889126-13-0
• 化学式: C₂₉H₄₄ClIN₈O₃Si₂
• 分子量: 771.249
• InChiKey: UGMQHWDBSJWRCQ-YWDMUFDYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.68
• 重原子数：
  44
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  97.7
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-chloro-N⁶-(3-iodobenzyl)-9-(3-azido-2,5-di-O-t-butyldimethylsilyl-3-deoxy-β-D-ribofuranosyl)adenine 在 三苯基膦 、 ammonium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以94%的产率得到2-chloro-N⁶-(3-iodobenzyl)-9-(3-amino-2,5-di-O-t-butyldimethylsilyl-3-deoxy-β-D-ribofuranosyl)adenine
  参考文献：
  名称：

  Orthogonal Activation of the Reengineered A₃ Adenosine Receptor (Neoceptor) Using Tailored Nucleoside Agonists

  摘要：

  An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor ( neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A(3) adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3' : amino, aminomethyl, azido, guanidino, ureido; and at 5' : uronamido, azidodeoxy. N-6-Variations included 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N-6-3-iodobenzyl-3'-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC50 = 0.18 mu M) or phospholipase D in chick primary cardiomyocytes, both mediated by a mutant ( H272E), but not the wild-type, A(3)AR. The affinity enhancements for 10 and the corresponding 3'-acetamidomethyl analogue 6 were > 100-fold and > 20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A(3)AR (EC50 of 1.0 mu M), but had no effect on the H272E mutant A(3)AR (100 mu M). Compound 10 was inactive at human A(1), A(2A), and A(2B)ARs. The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene.

  DOI：

  10.1021/jm050968b
• 作为产物：
  描述：

  在 吡啶 、 咪唑 、 ammonium sulfate 、 三乙胺 、 六甲基二硅氮烷 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 78.33h， 生成 2-chloro-N⁶-(3-iodobenzyl)-9-(3-azido-2,5-di-O-t-butyldimethylsilyl-3-deoxy-β-D-ribofuranosyl)adenine
  参考文献：
  名称：

  Orthogonal Activation of the Reengineered A₃ Adenosine Receptor (Neoceptor) Using Tailored Nucleoside Agonists

  摘要：

  An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor ( neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A(3) adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3' : amino, aminomethyl, azido, guanidino, ureido; and at 5' : uronamido, azidodeoxy. N-6-Variations included 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N-6-3-iodobenzyl-3'-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC50 = 0.18 mu M) or phospholipase D in chick primary cardiomyocytes, both mediated by a mutant ( H272E), but not the wild-type, A(3)AR. The affinity enhancements for 10 and the corresponding 3'-acetamidomethyl analogue 6 were > 100-fold and > 20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A(3)AR (EC50 of 1.0 mu M), but had no effect on the H272E mutant A(3)AR (100 mu M). Compound 10 was inactive at human A(1), A(2A), and A(2B)ARs. The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene.

  DOI：

  10.1021/jm050968b