1-(5-(hydroxymethyl)-4-(4-(((2-oxo-2H-chromen-6-yl)oxy)-methyl)-1H-1,2,3-triazol-1-yl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 1-(5-(hydroxymethyl)-4-(4-(((2-oxo-2H-chromen-6-yl)oxy)-methyl)-1H-1,2,3-triazol-1-yl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
• 英文别名: 1-(4-(4-((2-oxo-2H-chromen-6-yloxy)methyl)-1H-1,2,3-triazol-1-yl)-tetrahydro-5-(hydroxymethyl)furan-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione；1-[5-(Hydroxymethyl)-4-[4-[(2-oxochromen-6-yl)oxymethyl]triazol-1-yl]oxolan-2-yl]-5-methylpyrimidine-2,4-dione
• 化学式: C₂₂H₂₁N₅O₇
• 分子量: 467.438
• InChiKey: CZGFBOOZLDNOSG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  145
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  6-羟基香豆素 在 铜 、 四甲基氯化铵 、 potassium carbonate 作用下， 以 水 、 N,N-二甲基甲酰胺 、 甲苯 、 叔丁醇 为溶剂， 反应 5.0h， 生成 1-(5-(hydroxymethyl)-4-(4-(((2-oxo-2H-chromen-6-yl)oxy)-methyl)-1H-1,2,3-triazol-1-yl)tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Azidothymidine “Clicked” into 1,2,3-Triazoles: First Report on Carbonic Anhydrase–Telomerase Dual-Hybrid Inhibitors

  摘要：

  Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality. Telomerase inhibitors (i.e., azidothymidine) can represent promising antitumor agents, although showing high toxicity when administered alone. Better outcomes were observed within a multipharmacological approach instead. In this context, we exploited the validated antitumor targets carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII to attain the first proof of concept on CA-telomerase dual-hybrid inhibitors. Compounds 1b, 7h, 8b, and 11b showed good in vitro inhibition potency against the CAs IX and XII, with K-I values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC(50 )values ranging from 5.2 to 9.1 mu M). High-resolution X-ray crystallography on selected derivatives in the adduct with hCA II as a model study allowed to determine their binding modes and thus to set the structural determinants necessary for further development of compounds selectively targeting the tumoral cells.

  DOI：

  10.1021/acs.jmedchem.0c00636

文献信息

• [EN] CARBONIC ANHYDRASE INHIBITORS WITH ANTIMETASTATIC ACTIVITY<br/>[FR] INHIBITEURS D'ANHYDRASE CARBONIQUE PRÉSENTANT UNE ACTIVITÉ ANTIMÉTASTATIQUE
  申请人：METASIGNAL THERAPEUTICS INC

  公开号：WO2012070024A1

  公开（公告）日：2012-05-31

  Compositions for the treatment of cancer comprising coumarin and thiocoumarin derivatives of Formulas I- XII are disclosed. Said derivatives preferentially inhibit carbonic anhydrase IX and XII (which are associated with hypoxic and metastatic tumours) over inhibiting carbonic anhydrase I and II activity. The compositions therefore are suited for treatment of hypoxic or metastatic cancers due to this selective mechanism of action.

  本发明揭示了用于治疗癌症的组合物，包括公开的具有I-XII式的香豆素和硫代香豆素衍生物。所述衍生物优先抑制与低氧和转移性肿瘤相关的碳酸酐酶IX和XII，而不是抑制碳酸酐酶I和II的活性。因此，这些组合物由于这种选择性作用机制而适用于治疗低氧或转移性癌症。
• CARBONIC ANHYDRASE INHIBITORS WITH ANTIMETASTATIC ACTIVITY
  申请人：Supuran Claudiu

  公开号：US20140148400A1

  公开（公告）日：2014-05-29

  Derivatized coumarin-based pharmaceutical compositions and methods to use them are provided. The compositions are characterized in that they inhibit the activity of tumor-related CAIX and CAXII to a greater degree than they inhibit the activity of CAI and CAII. The compositions can be used to suppress tumor growth and/or suppress tumor metastases in a mammal.

  提供了衍生香豆素类制药组合物及其使用方法。这些组合物的特征在于它们抑制肿瘤相关的CAIX和CAXII的活性，而不是CAI和CAII的活性。这些组合物可用于抑制哺乳动物中的肿瘤生长和/或抑制肿瘤转移。
• CARBONIC ANHYDRASE IX-RELATED MARKERS AND USE THEREOF
  申请人：SignalChem Lifesciences Corporation

  公开号：EP2771488B1

  公开（公告）日：2018-03-28
• Azidothymidine “Clicked” into 1,2,3-Triazoles: First Report on Carbonic Anhydrase–Telomerase Dual-Hybrid Inhibitors
  作者：Emanuela Berrino、Andrea Angeli、Dmitry D. Zhdanov、Anna P. Kiryukhina、Andrea Milaneschi、Alessandro De Luca、Murat Bozdag、Simone Carradori、Silvia Selleri、Gianluca Bartolucci、Thomas S. Peat、Marta Ferraroni、Claudiu T. Supuran、Fabrizio Carta

  DOI：10.1021/acs.jmedchem.0c00636

  日期：2020.7.9

  Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality. Telomerase inhibitors (i.e., azidothymidine) can represent promising antitumor agents, although showing high toxicity when administered alone. Better outcomes were observed within a multipharmacological approach instead. In this context, we exploited the validated antitumor targets carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII to attain the first proof of concept on CA-telomerase dual-hybrid inhibitors. Compounds 1b, 7h, 8b, and 11b showed good in vitro inhibition potency against the CAs IX and XII, with K-I values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC(50 )values ranging from 5.2 to 9.1 mu M). High-resolution X-ray crystallography on selected derivatives in the adduct with hCA II as a model study allowed to determine their binding modes and thus to set the structural determinants necessary for further development of compounds selectively targeting the tumoral cells.