[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(1,4,7,10,13-pentaoxacyclopentadec-2-ylmethylamino)purin-9-yl]oxolan-2-yl]methyl sulfamate | 1310342-30-3

• 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: [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(1,4,7,10,13-pentaoxacyclopentadec-2-ylmethylamino)purin-9-yl]oxolan-2-yl]methyl sulfamate
• CAS: 1310342-30-3
• 化学式: C₂₁H₃₄N₆O₁₁S
• 分子量: 578.601
• InChiKey: PAKOUDNFCOLNAK-BWZSZYTASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.2
• 重原子数：
  39
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  229
• 氢给体数：
  4
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  6-氯嘌呤核苷 在 水 、 sodium hydride 、 对甲苯磺酸 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二甲基亚砜 为溶剂， 反应 8.5h， 生成 [(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(1,4,7,10,13-pentaoxacyclopentadec-2-ylmethylamino)purin-9-yl]oxolan-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

文献信息

• Identification of NAE Inhibitors Exhibiting Potent Activity in Leukemia Cells: Exploring the Structural Determinants of NAE Specificity
  作者：Julie L. Lukkarila、Sara R. da Silva、Mohsin Ali、Vijay M. Shahani、G. Wei Xu、Judd Berman、Andrew Roughton、Sirano Dhe-Paganon、Aaron D. Schimmer、Patrick T. Gunning

  DOI：10.1021/ml2000615

  日期：2011.8.11

  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.