((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol | 223761-85-1

• 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)-2,2-dimethyl-6-(6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol
• 英文别名: [(3aR,4R,6R,6aR)-2,2-dimethyl-4-[6-(oxan-4-ylamino)purin-9-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methanol
• CAS: 223761-85-1
• 化学式: C₁₈H₂₅N₅O₅
• 分子量: 391.427
• InChiKey: WSQLTCRIOYLHOH-LSCFUAHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol 在 水 、 sodium hydride 、 三氟乙酸 作用下， 以 四氢呋喃 为溶剂， 反应 4.5h， 生成 ((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(tetrahydro-2H-pyran-4-ylamino)-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-氯嘌呤核苷 在 对甲苯磺酸 、 N,N-二异丙基乙胺 作用下， 以 二甲基亚砜 为溶剂， 反应 3.67h， 生成 ((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol
  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

• ADENOSINE A1-RECEPTOR AGONISTS
  申请人：GLAXO GROUP LIMITED

  公开号：EP1027363A2

  公开（公告）日：2000-08-16
• US6407076B1
  申请人：——

  公开号：US6407076B1

  公开（公告）日：2002-06-18
• [EN] CHEMICAL COMPOUNDS<br/>[FR] COMPOSES CHIMIQUES
  申请人：——

  公开号：WO1999024450A2

  公开（公告）日：1999-05-20

  [EN] A compound of formula (I) wherein R<2> represents C1-3 alkyl, halogen or hydrogen; R<3> represents a fluorinated straight or branched alkyl group of 1-6 carbon atoms; and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof. These compounds are agonists of the Adenosine A1 receptor.
  [FR] L'invention concerne un composé représenté par la formule (I), dans laquelle R<2> représente alkyle C1-3, halogène ou hydrogène; R<3> représente un groupe alkyle fluoré droit ou ramifié comportant de 1 à 6 atomes de carbone. L'invention concerne également des sels et des solvates, en particulier des sels et des solvates physiologiquement acceptables, dudit composé. Ces composés sont des agonistes du récepteur A1 de l'adénosine.