((3aR,4R,6R,6aR)-6-(6-(isopropylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate | 1052239-40-3

• 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-(isopropylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate
• 英文别名: N6-isopropyl-2',3'-O-isopropylidene-5'-O-(sulfamoyl)adenosine
• CAS: 1052239-40-3
• 化学式: C₁₆H₂₄N₆O₆S
• 分子量: 428.469
• InChiKey: YCIQVHLWABFRSU-SDBHATRESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.28
• 重原子数：
  29.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.69
• 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-(isopropylamino)-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50%的产率得到((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(isopropylamino)-9H-purin-9-yl)tetrahydrofuran-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：

  6-氯-9-beta-D-(2,3-异亚丙基)呋喃核糖基嘌呤 在 sodium hydride 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二甲基亚砜 为溶剂， 反应 4.17h， 生成 ((3aR,4R,6R,6aR)-6-(6-(isopropylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-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

文献信息

• Inhibition of Siderophore Biosynthesis in <i>Mycobacterium tuberculosis</i> with Nucleoside Bisubstrate Analogues: Structure−Activity Relationships of the Nucleobase Domain of 5′-<i>O</i>-[<i>N</i>-(Salicyl)sulfamoyl]adenosine
  作者：João Neres、Nicholas P. Labello、Ravindranadh V. Somu、Helena I. Boshoff、Daniel J. Wilson、Jagadeshwar Vannada、Liqiang Chen、Clifton E. Barry、Eric M. Bennett、Courtney C. Aldrich

  DOI：10.1021/jm800567v

  日期：2008.9.11

  5'-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure-activity relationship

  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。