MRS 3767 | 863202-25-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: MRS 3767
• 英文别名: N6-cyclohexyl-N2-phenyl-9H-purine-2,6-diamine；N*6*-Cyclohexyl-N*2*-phenyl-9H-purine-2,6-diamine；6-N-cyclohexyl-2-N-phenyl-7H-purine-2,6-diamine
• CAS: 863202-25-9
• 化学式: C₁₇H₂₀N₆
• 分子量: 308.386
• InChiKey: FDFMDLSSHFEJOS-UHFFFAOYSA-N

物化性质

• 沸点：
  634.7±58.0 °C(Predicted)
• 密度：
  1.343±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  78.5
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  MRS 3767 、 碘甲烷 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以95%的产率得到N*6*-Cyclohexyl-9-methyl-N*2*-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
• 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 63.0h， 生成 MRS 3767
  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

• Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells
  作者：Bartolomeo Bosco、Andrea Defant、Andrea Messina、Tania Incitti、Denise Sighel、Angela Bozza、Yari Ciribilli、Alberto Inga、Simona Casarosa、Ines Mancini

  DOI：10.3390/molecules23081996

  日期：——

  Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine

  Reversine 是一种有效的抗肿瘤 2,6-二氨基取代的嘌呤，可作为极光激酶抑制剂并干扰癌细胞周期进程。在这项研究中，我们描述了三个通过对接计算设计的可逆相关分子，它们在位置 2 和 6 的二氨基单元中呈现结构修饰。我们研究了这些分子之一的最稳定的质子互变异构体的构象，N6-环己基-N6-甲基-N2-苯基-7H-嘌呤-2,6-二胺 (3)，通过密度泛函理论 (DFT) 在气相、水和氯仿中计算，最后一种溶剂被认为可以深入了解核磁共振分析中的广泛信号。在所有情况下，HN(9) 互变异构体比 HN(7) 形式更稳定，但最稳定的构象在不同的​​溶剂中发生了变化。在 MCF-7 乳腺癌和 HCT116 结肠直肠癌细胞系上对分子 1-3 进行了评估，结果表明，虽然细胞毒性比逆转素小，但它们仍会导致细胞周期停滞在 G2/M 期和多倍体。与在所有使用的细胞系中在 G2/M 期产生明显细胞周期停滞的逆转素不同，类似浓度的
• “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.