((3aR,4R,6R,6aR)-6-(6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate | 1052239-45-8

• 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: ((3aR,4R,6R,6aR)-6-(6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate
• 英文别名: N6-cyclopentyl-2',3'-O-isopropylidene-5'-O-(sulfamoyl)adenosine
• CAS: 1052239-45-8
• 化学式: C₁₈H₂₆N₆O₆S
• 分子量: 454.507
• InChiKey: MGVJYTLCNZWPEL-LSCFUAHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.82
• 重原子数：
  31.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  152.71
• 氢给体数：
  2.0
• 氢受体数：
  11.0

反应信息

• 作为反应物：
  描述：

  ((3aR,4R,6R,6aR)-6-(6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate 在 水 、 三氟乙酸 、 ammonium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 1.0h， 以60%的产率得到((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl sulfamate
  参考文献：
  名称：

  Identification of NAE Inhibitors Exhibiting Potent Activity in Leukemia Cells: Exploring the Structural Determinants of NAE Specificity

  摘要：

  MLN4924 is a selective inhibitor of the NEDD8-activating enzyme (NAE) and has advanced into clinical trials for the treatment of both solid and hematological malignancies. In contrast, the structurally similar compound 1 (developed by Millennium: The Takeda Oncology Company) is a pan inhibitor of the El enzymes NAE, ubiquitin activating enzyme (UAE), and SUMO-activating enzyme (SAE) and is currently viewed as unsuitable for clinical use given its broad spectrum of El inhibition. Here, we sought to understand the determinants of NAE selectivity. A series of compound 1 analogues were synthesized through iterative functionalization of the purine C6 position and evaluated for NAE specificity. Optimal NAE specificity was achieved through substitution with primary N-alkyl groups, while bulky or secondary N-alkyl substituents were poorly tolerated. When assessed in vitro, inhibitors reduced the growth and viability of malignant K562 leukemia cells. Through this study, we have successfully identified a series of sub-10 nM NAE-specific inhibitors and thereby highlighted the functionalities that promote NAE selectivity.

  DOI：

  10.1021/ml2000615
• 作为产物：
  描述：

  2',3'-isopropylidene-N⁶-cyclopentyladenosine 在 sodium hydride 、 氨基磺酰氯 作用下， 以 四氢呋喃 、 乙二醇二甲醚 为溶剂， 反应 16.5h， 以78%的产率得到((3aR,4R,6R,6aR)-6-(6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate
  参考文献：
  名称：

  用核苷双底物类似物抑制结核分枝杆菌中的铁载体生物合成：5'-O-[N-（水杨酰基）氨磺酰基]腺苷核碱基结构域的构效关系。

  摘要：

  5'-O-[N-(水杨基)氨磺酰基]腺苷 (Sal-AMS) 是一类新型抗结核药物的原型，可抑制参与分枝杆菌素生物合成的称为 MbtA 的芳酸腺苷酸化酶 (AAAE)。在此，我们报告了一系列全面系统的类似物的基于结构的设计、合成、生化和生物学评估，探索了 Sal-AMS 嘌呤核碱基结构域的构效关系。值得注意的是，2-苯基-Sal-AMS 衍生物 26 表现出异常有效的抗结核活性，在 0.049 microM 的缺铁条件下具有 MIC99，而 N-6-环丙基-Sal-AMS 16 导致提高的效力和 64-增强铁缺乏条件下相对于铁充足条件下的活性，与设计的作用机制一致的表型。

  DOI：

  10.1021/jm800567v