2-{6-Amino-2-[2-(4-methoxy-phenyl)-ethylamino]-purin-9-yl}-5-hydroxymethyl-tetrahydro-furan-3,4-diol | 124499-07-6

• 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-{6-Amino-2-[2-(4-methoxy-phenyl)-ethylamino]-purin-9-yl}-5-hydroxymethyl-tetrahydro-furan-3,4-diol
• 英文别名: (2R,3R,4S,5R)-2-[6-amino-2-[2-(4-methoxyphenyl)ethylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol
• CAS: 124499-07-6
• 化学式: C₁₉H₂₄N₆O₅
• 分子量: 416.437
• InChiKey: KPVFQOIXIGJFNL-SCFUHWHPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  161
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  6-氯鸟嘌呤核苷 在 copper(l) iodide 、 氨 、 碘 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 、 乙二醇甲醚 为溶剂， 反应 42.5h， 生成 2-{6-Amino-2-[2-(4-methoxy-phenyl)-ethylamino]-purin-9-yl}-5-hydroxymethyl-tetrahydro-furan-3,4-diol
  参考文献：
  名称：

  Adenosine Analogues as Inhibitors of Trypanosoma brucei Phosphoglycerate Kinase:  Elucidation of a Novel Binding Mode for a 2-Amino-N⁶-Substituted Adenosine

  摘要：

  As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N-6-, 2-amino-N-6-, and N-2-substituted adenosine analogues were synthesized and tested to establish structure-activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for NG-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N-6-[2 "-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 muM. 2-[[2 "-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 muM. To explore the potential of an additive effect that having the N-6 and N-2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N-6,N-2-disubstituted adenosine analogues to yield N-6-(2 " -phenylethyl)-2-[(2 " -phenylethyl)amino]adenosine (69) as a 30 muM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 Angstrom X-ray structure of a T, brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this "flipped and rotated" binding mode.

  DOI：

  10.1021/jm000287a

文献信息

• Highly selective adenosine A2 receptor agonists in a series of N-alkylated 2-aminoadenosines
  作者：John E. Francis、Randy L. Webb、Geetha R. Ghai、Alan J. Hutchison、Michael A. Moskal、Reynalda DeJesus、Rina Yokoyama、Stephen L. Rovinski、Nicolina Contardo

  DOI：10.1021/jm00112a035

  日期：1991.8

  with the moderately A2 receptor selective adenosine agonist 2-anilinoadenosine (CV-1808). High selectivity combined with significant affinity at the A2 receptor in rat membranes was observed for those amines bearing a two-carbon chain to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethylamino)adenosine (3d), a 14-fold A2 selective compound, was modified by introduction of a variety

  制备了多种2-取代的氨基腺苷与中度A2受体选择性腺苷激动剂2-苯胺基腺苷（CV-1808）进行比较。对于那些带有连接了芳基，杂芳基或脂环族部分的双碳链的胺，观察到了高选择性以及对大鼠膜上A2受体的显着亲和力。通过在苯环和侧链中引入各种取代基，对14倍的A2选择性化合物2-（2-苯乙氨基）腺苷（3d）进行了修饰。这些变化中的一些导致改善的A2亲和力和增加的选择性。用环己烯基取代苯基部分产生210倍选择性激动剂3ag（CGS 22989），而环己基类似物3af（CGS 22492）在A2位点具有530倍选择性。
• Certain 2-substituted adenosine derivatives
  申请人：CIBA-GEIGY AG

  公开号：EP0323807A2

  公开（公告）日：1989-07-12

  Disclosed are 2-substituted adenosine derivatives of the formula wherein R represents a substituted amino grouping as defined in the specification, which are therapeutically effective adenosine-2 (A-2) agonists. They are prepared by methods known per se.

  公开了式中的 2-取代腺苷衍生物 其中 R 代表说明书中定义的取代氨基，是治疗有效的腺苷-2（A-2）激动剂。它们是通过本身已知的方法制备的。
• Adenosine Analogues as Inhibitors of <i>Trypanosoma </i><i>b</i><i>rucei </i>Phosphoglycerate Kinase:  Elucidation of a Novel Binding Mode for a 2-Amino-N⁶-Substituted Adenosine
  作者：Jerome C. Bressi、Jungwoo Choe、Melinda T. Hough、Frederick S. Buckner、Wesley C. Van Voorhis、Christophe L. M. J. Verlinde、Wim G. J. Hol、Michael H. Gelb

  DOI：10.1021/jm000287a

  日期：2000.11.1

  As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N-6-, 2-amino-N-6-, and N-2-substituted adenosine analogues were synthesized and tested to establish structure-activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for NG-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N-6-[2 "-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 muM. 2-[[2 "-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 muM. To explore the potential of an additive effect that having the N-6 and N-2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N-6,N-2-disubstituted adenosine analogues to yield N-6-(2 " -phenylethyl)-2-[(2 " -phenylethyl)amino]adenosine (69) as a 30 muM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 Angstrom X-ray structure of a T, brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this "flipped and rotated" binding mode.