3'-ureido-N6-(3-iodobenzyl)adenosine

• 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: 3'-ureido-N6-(3-iodobenzyl)adenosine
• 英文别名: MRS 3481；N6-(3-iodobenzyl)-9-(3-deoxy-3-ureido-B-D-ribofuranosyl)adenine；[(2S,3S,4R,5R)-4-hydroxy-2-(hydroxymethyl)-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]oxolan-3-yl]urea
• 化学式: C₁₈H₂₀IN₇O₄
• 分子量: 525.306
• InChiKey: ABGDLYABGFCQLB-CTWCOEIASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  160
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,5-di-O-acetyl-3-azido-1-(6-chloropurin-9-yl)-β-D-1,3-dideoxyribofuranose 在 咪唑 、 四丁基氟化铵 、 sodium methylate 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 68.5h， 生成 3'-ureido-N6-(3-iodobenzyl)adenosine
  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

文献信息

• Synthesis of<i>N</i>⁶-Substituted 3′-Ureidoadenosine Derivatives as Highly Potent Agonists at the Mutant A₃Adenosine Receptor
  作者：Lak Shin Jeong、Seung Ah Choe、Ae Yil Kim、Hea Ok Kim、Zhan-Guo Gao、Kenneth A. Jacobson、Moon Woo Chun、Hyung Ryong Moon

  DOI：10.1080/15257770701493161

  日期：2007.11.26

  Several N6-substituted 3 '-ureidoadenosine derivatives were efficiently synthesized starting from D-glucose for the development of H272E mutant A3 adenosine receptor (AR) agonists. Among compounds tested, 3 '-ureido-N6-(3-iodobenzyl)adenosine (2c) exhibited the highest binding affinity (Ki = 0.22 micro M) at the H272E mutant A3 AR without binding to the natural A3AR.

  从 D-葡萄糖开始有效合成了几种 N6 取代的 3'-脲基腺苷衍生物，用于开发 H272E 突变体 A3 腺苷受体 (AR) 激动剂。在测试的化合物中，3'-ureido-N6-(3-iodobenzyl)adenosine (2c) 在 H272E 突变体 A3 AR 处表现出最高的结合亲和力（Ki = 0.22 micro M），而不与天然 A3AR 结合。
• SYNTHESIS OF 3′-UREIDOADENOSINE ANALOGUES AND THEIR BINDING AFFINITY TO THE A₃ ADENOSINE RECEPTOR
  作者：Moon Woo Chun、Hyouk Woo Lee、Ae Yil Kim、Myong Jung Kim、Hea Ok Kim、Zhan-Guo Gao、Kenneth A. Jacobson、Lak Shin Jeong

  DOI：10.1081/ncn-200060079

  日期：2005.4.1

  Novel 3'-ureidoadenosine analogues were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose in order to lead to stronger hydrogen bonding at the A(3) adenosine receptor than the corresponding 3'-aminoadenosine derivatives. However, all synthesized 3'-ureidoadenosine analogues have lost their binding affinities to the all subtypes of adenosine receptors, indicating that bulky 3'-urea moiety led to conformational distortion.
• Orthogonal Activation of the Reengineered A₃ Adenosine Receptor (Neoceptor) Using Tailored Nucleoside Agonists
  作者：Zhan-Guo Gao、Heng T. Duong、Tatiana Sonina、Soo-Kyung Kim、Philippe Van Rompaey、Serge Van Calenbergh、Liaman Mamedova、Hea Ok Kim、Myong Jung Kim、Ae Yil Kim、Bruce T. Liang、Lak Shin Jeong、Kenneth A. Jacobson

  DOI：10.1021/jm050968b

  日期：2006.5.1

  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.