N*6*-Cyclopropyl-N*2*-(4-morpholin-4-yl-phenyl)-9H-purine-2,6-diamine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: N*6*-Cyclopropyl-N*2*-(4-morpholin-4-yl-phenyl)-9H-purine-2,6-diamine
• 英文别名: 6-N-cyclopropyl-2-N-(4-morpholin-4-ylphenyl)-7H-purine-2,6-diamine
• 化学式: C₁₈H₂₁N₇O
• 分子量: 351.411
• InChiKey: YIHIFTKWCROQBT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  91
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-氟-6-氯嘌呤 在 N,N-二异丙基乙胺 作用下， 以 乙醇 、 正丁醇 为溶剂， 反应 48.0h， 生成 N*6*-Cyclopropyl-N*2*-(4-morpholin-4-yl-phenyl)-9H-purine-2,6-diamine
  参考文献：
  名称：

  “Reversine” and Its 2-Substituted Adenine Derivatives as Potent and Selective A₃ Adenosine Receptor Antagonists

  摘要：

  The dedifferentiation agent "reversine" [2-(4-morpholinoanilino)-N-6-cyclohexyladenine 2] was found to be a moderately potent antagonist for the human A(3) adenosine receptor (AR) with a K-i value of 0.66 mu M. This result prompted an exploration of the structure-activity relationship of related derivatives, synthesized via sequential substitution of 6-chloro-2-fluoropurine with selected nucleophiles. Optimization of substituents at these two positions identified 2-(phenylamino)-N6-cyclohexyladenine (12), 2-(phenylamino)-N-6-cycloheptyladenine (19), and 2-phenylamino-N-6-endo-norbornyladenine (21) as potent A(3) AR ligands with K-i values of 51, 42, and 37 nM, respectively, with 30-200-fold selectivity in comparison to A(1) and A(2A) ARs. The most selective A(3) AR antagonist (> 200-fold) was 2-(phenyloxy)-N-6-cyclohexyladenine (22). 9-Methylation of 12, but not 19, was well-tolerated in A(3) AR binding. Extension of the 2-phenylamino group to 2-benzyl- and 2-(2-phenylethylamino) reduced affinity. In the series of 2-(phenylamino), 2-(phenyloxy), and 2-(phenylthio) substitutions, the order of affinity at the A(3) AR was oxy >= amino > thio. Selected derivatives, including reversine (K-B value of 466 nM via Schild analysis), competitively antagonized the functional effects of a selective A(3) AR agonist, i.e., inhibition of forskolin-stimulated cAMP production in stably transfected Chinese hamster ovary (CHO) cells. These results are in agreement with other studies suggesting the presence of a lipophilic pocket in the AR binding site that is filled by moderately sized cycloalkyl rings at the N-6 position of both adenine and adenosine derivatives. Thus, the compound series reported herein comprise an important new series of selective A(3) AR antagonists. We were unable to reproduce the dedifferentiation effect of reversine, previously reported, or to demonstrate any connection between A(3) AR antagonist effects and dedifferentiation.

  DOI：

  10.1021/jm050221l

文献信息

• “Reversine” and Its 2-Substituted Adenine Derivatives as Potent and Selective A₃ Adenosine Receptor Antagonists
  作者：Melissa Perreira、Jian-kang Jiang、Athena M. Klutz、Zhan-Guo Gao、Asher Shainberg、Changrui Lu、Craig J. Thomas、Kenneth A. Jacobson

  DOI：10.1021/jm050221l

  日期：2005.7.1

  The dedifferentiation agent "reversine" [2-(4-morpholinoanilino)-N-6-cyclohexyladenine 2] was found to be a moderately potent antagonist for the human A(3) adenosine receptor (AR) with a K-i value of 0.66 mu M. This result prompted an exploration of the structure-activity relationship of related derivatives, synthesized via sequential substitution of 6-chloro-2-fluoropurine with selected nucleophiles. Optimization of substituents at these two positions identified 2-(phenylamino)-N6-cyclohexyladenine (12), 2-(phenylamino)-N-6-cycloheptyladenine (19), and 2-phenylamino-N-6-endo-norbornyladenine (21) as potent A(3) AR ligands with K-i values of 51, 42, and 37 nM, respectively, with 30-200-fold selectivity in comparison to A(1) and A(2A) ARs. The most selective A(3) AR antagonist (> 200-fold) was 2-(phenyloxy)-N-6-cyclohexyladenine (22). 9-Methylation of 12, but not 19, was well-tolerated in A(3) AR binding. Extension of the 2-phenylamino group to 2-benzyl- and 2-(2-phenylethylamino) reduced affinity. In the series of 2-(phenylamino), 2-(phenyloxy), and 2-(phenylthio) substitutions, the order of affinity at the A(3) AR was oxy >= amino > thio. Selected derivatives, including reversine (K-B value of 466 nM via Schild analysis), competitively antagonized the functional effects of a selective A(3) AR agonist, i.e., inhibition of forskolin-stimulated cAMP production in stably transfected Chinese hamster ovary (CHO) cells. These results are in agreement with other studies suggesting the presence of a lipophilic pocket in the AR binding site that is filled by moderately sized cycloalkyl rings at the N-6 position of both adenine and adenosine derivatives. Thus, the compound series reported herein comprise an important new series of selective A(3) AR antagonists. We were unable to reproduce the dedifferentiation effect of reversine, previously reported, or to demonstrate any connection between A(3) AR antagonist effects and dedifferentiation.