((3aR,4R,6R,6aR)-6-(6-((furan-2-ylmethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol | 185848-23-1

• 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)-6-(6-((furan-2-ylmethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol
• CAS: 185848-23-1
• 化学式: C₁₈H₂₁N₅O₅
• 分子量: 387.395
• InChiKey: RDKBWDSCXQCJED-LSCFUAHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.44
• 重原子数：
  28.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  116.69
• 氢给体数：
  2.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  ((3aR,4R,6R,6aR)-6-(6-((furan-2-ylmethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol 在 sodium hydride 、 氨基磺酰氯 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以69%的产率得到((3aR,4R,6R,6aR)-6-(6-((furan-2-ylmethyl)amino)-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
• 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)-6-(6-((furan-2-ylmethyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[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

• Copper-Catalyzed Intramolecular Alkoxylation of Purine Nucleosides: One-Step Synthesis of 5′-<i>O</i>,8-Cyclopurine Nucleosides
  作者：Mingwu Yu、Zhiqian Wang、Junbin Hu、Shunlai Li、Hongguang Du

  DOI：10.1021/acs.joc.5b01360

  日期：2015.10.2

  A novel copper-catalyzed intramolecular dehydrogenative alkoxylation of purine nucleosides has been developed successfully, providing the 5′-O,8-cyclopurine nucleosides in one-step with a yield up to 90%. The method, which utilized an inexpensive CuCl catalyst and a di-tert-butyl peroxide (DTBP) oxidant was suitable in a broad substrate scope and proceeded well even in gram scale.

  已成功开发了一种新型的铜催化的嘌呤核苷分子内脱氢烷氧基化反应，一步即可提供5'- O，8-环嘌呤核苷，产率高达90％。该方法使用了廉价的CuCl催化剂和二叔丁基过氧化物（DTBP）氧化剂，适用于广泛的底物范围，即使以克为单位，也能很好地进行。
• [EN] ANTIVIRAL COMPOUNDS, METHODS FOR THE MANUFACTURING OF COMPOUNDS, ANTIVIRAL PHARMACEUTICAL COMPOSITION, USE OF THE COMPOUNDS AND METHOD FOR THE ORAL TREATMENT OF CORONAVIRUS INFECTION AND RELATED DISEASES THEREOF<br/>[FR] COMPOSÉS ANTIVIRAUX, PROCÉDÉS DE FABRICATION DES COMPOSÉS, COMPOSITION PHARMACEUTIQUE ANTIVIRALE, UTILISATION DES COMPOSÉS ET MÉTHODE DE TRAITEMENT PAR VOIE ORALE D'UNE INFECTION À CORONAVIRUS ET DE MALADIES ASSOCIÉES
  申请人：[en]CALIXTO, João Batista

  公开号：WO2022204777A1

  公开（公告）日：2022-10-06

  The present invention relates to antiviral compounds selected from cytokinins, their nucleosides and nucleotide analogs, and their prodrugs as inhibitors of viral RNA synthesis, or their salts, solvates, derivatives, or even combinations of aforementioned compounds, for prophylactic treatment, curative (therapeutic) or mitigative coronavirus infection, represented by human and veterinary coronavirus, SARS-CoV-2 and MHV, and for the treatment of individuals potentially exposed to COVID-19. The present invention also comprises the methods for the manufacturing of such compounds, the antiviral pharmaceutical composition containing the compounds of the invention, as well as the use of the compounds, combinations of compounds, and method for the prophylactic, curative (therapeutic) or mitigative treatment of coronavirus infection, represented by coronavirus, in especial SARS-CoV-2 and of patients with COVID-19, individual infected with SARS-CoV-2 or potentially exposed to this virus. The antiviral activity of the compounds of this invention against SARS-CoV-2 was greatly enhanced by inhibiting the 3'-5'-exonuclease. Synergistic results of the compounds according to the present invention were obtained from the combination with repurposed drugs.