(2S,3S,4R,5R) 3-azido-4-hydroxy-5-(6-[3-iodobenzylamino]-purin-9-yl)-tetrahydro-furan-2-carboxylic acid methylamide | 786665-99-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2S,3S,4R,5R) 3-azido-4-hydroxy-5-(6-[3-iodobenzylamino]-purin-9-yl)-tetrahydro-furan-2-carboxylic acid methylamide
• 英文别名: (2S,3S,4R,5R)-3-azido-4-hydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyloxolane-2-carboxamide
• CAS: 786665-99-4
• 化学式: C₁₈H₁₈IN₉O₃
• 分子量: 535.304
• InChiKey: SVWWALKTOHAUAD-MHMFGPJMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  31
• 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：
  129
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2S,3S,4R,5R) 3-azido-4-hydroxy-5-(6-[3-iodobenzylamino]-purin-9-yl)-tetrahydro-furan-2-carboxylic acid methylamide 在 咪唑 、 ammonium hydroxide 、 三苯基膦 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.0h， 生成 3-amino-5-(6-(3-iodobenzylamino)purin-9-yl)-4-t-butyldimethylsiloxy-tetrahydro-furan-2-carboxylic acid methyl amide
  参考文献：
  名称：

  Design and synthesis of 3′-ureidoadenosine-5′-uronamides: effects of the 3′-ureido group on binding to the A3 adenosine receptor

  摘要：

  On the basis of high binding affinity at the A(3) adenosine receptor of 3'-aminoadenosine derivatives with hydrogen bonding donor ability, novel 3'-ureidoadenosine analogues were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose in order to lead to stronger hydrogen bonding than the corresponding 3'-aminoadeno sine derivatives. However, the synthesized 3'-ureidoadenosine analogues were totally devoid of binding affinity, because 3'-urea moiety caused steric and electrostatic repulsions at the binding site of the A(3) adenosine receptor, leading to conformational distortion. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.07.042
• 作为产物：
  描述：

  1,2:5,6-di-O-isopropylidene-3-O-triflyl-α-D-glucofuranose 在 ruthenium trichloride 、 ammonium sulfate 、 sodium periodate 、 sodium azide 、 草酰氯 、 硫酸 、 溶剂黄146 、 三乙胺 、 六甲基二硅氮烷 作用下， 以 四氢呋喃 、 四氯化碳 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 128.83h， 生成 (2S,3S,4R,5R) 3-azido-4-hydroxy-5-(6-[3-iodobenzylamino]-purin-9-yl)-tetrahydro-furan-2-carboxylic acid methylamide
  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

• Design and synthesis of 3′-ureidoadenosine-5′-uronamides: effects of the 3′-ureido group on binding to the A3 adenosine receptor
  作者：Lak Shin Jeong、Myong Jung Kim、Hea Ok Kim、Zhan-Guo Gao、Soo-Kyung Kim、Kenneth A. Jacobson、Moon Woo Chun

  DOI：10.1016/j.bmcl.2004.07.042

  日期：2004.10

  On the basis of high binding affinity at the A(3) adenosine receptor of 3'-aminoadenosine derivatives with hydrogen bonding donor ability, novel 3'-ureidoadenosine analogues were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose in order to lead to stronger hydrogen bonding than the corresponding 3'-aminoadeno sine derivatives. However, the synthesized 3'-ureidoadenosine analogues were totally devoid of binding affinity, because 3'-urea moiety caused steric and electrostatic repulsions at the binding site of the A(3) adenosine receptor, leading to conformational distortion. (C) 2004 Elsevier Ltd. All rights reserved.
• Exploring human adenosine A3 receptor complementarity and activity for adenosine analogues modified in the ribose and purine moiety
  作者：Philippe Van Rompaey、Kenneth A. Jacobson、Ariel S. Gross、Zhan-Guo Gao、Serge Van Calenbergh

  DOI：10.1016/j.bmc.2004.11.044

  日期：2005.2

  In this paper we investigated the influence on affinity, selectivity and intrinsic activity upon modification of the adenosine agonist scaffold at the 3- and 5'-positions of the ribofuranosyl moiety and the 2- and N-6-positions of the purine base. This resulted in the synthesis of various analogues, that is, 3-12 and 24-33, with good hA(3)AR selectivity and moderate-to-high affinities (as in 32, K-i = 27 nM). Interesting was the ability to tune the intrinsic activity depending on the substituent introduced at the 3'-position. (C) 2004 Elsevier Ltd. All rights reserved.
• 3‘-Aminoadenosine-5‘-uronamides:  Discovery of the First Highly Selective Agonist at the Human Adenosine A₃ Receptor
  作者：Michael P. DeNinno、Hiroko Masamune、Lois K. Chenard、Kenneth J. DiRico、Cynthia Eller、John B. Etienne、Jeanene E. Tickner、Scott P. Kennedy、Delvin R. Knight、Jimmy Kong、Joseph J. Oleynek、W. Ross Tracey、Roger J. Hill

  DOI：10.1021/jm0255724

  日期：2003.1.1

  Selective adenosine A(3) agonists have potential utility for the prevention of perioperative myocardial ischemic injury. Herein, we report on the discovery and synthesis of compound 7. This amino nucleoside agonist possesses unprecedented levels of selectivity for the human adenosine A(3) receptor.
• 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.