((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate | 1151528-53-8

• 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: ((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate
• 英文别名: [(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-4,4-difluoro-3-hydroxyoxolan-2-yl]methyl 4-methylbenzenesulfonate
• CAS: 1151528-53-8
• 化学式: C₁₆H₁₇F₂N₃O₆S
• 分子量: 417.39
• InChiKey: FSKFESHBGYLNIA-MRVWCRGKSA-N

物化性质

• 沸点：
  622.0±65.0 °C(Predicted)
• 密度：
  1.63±0.1 g/cm3(Predicted)
• 溶解度：
  二氯甲烷、甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  140
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(2-氨基-乙基)-吡咯烷-2-酮 、 ((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以53%的产率得到2',2'-Difluoro-5'-[[2-(2-oxopyrrolizino)ethyl]amino]-2',5'-dideoxycytidine
  参考文献：
  名称：

  The identification of novel 5′-amino gemcitabine analogs as potent RRM1 inhibitors

  摘要：

  The ribonucleotide reductase (RNR) enzyme is a heteromer of RRM1 and RRM2 subunits. The active enzyme catalyzes de novo reduction of ribonucleotides to generate deoxyribonucleotides (dNTPs), which are required for DNA replication and DNA repair processes. Complexity in the generation of physiologically relevant, active RRM1/RRM2 heterodimers was perceived as limiting to the identification of selective RRM1 inhibitors by high-throughput screening of compound libraries and led us to seek alternative methods to identify lead series. In short, we found that gemcitabine, as its diphosphate metabolite, represents one of the few described active site inhibitors of RRM1. We herein describe the identification of novel 5'-amino gemcitabine analogs as potent RRM1 inhibitors through in-cell phenotypic screening. (c) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.02.007
• 作为产物：
  描述：

  盐酸吉西他滨 在 吡啶 、 咪唑 、 4-二甲氨基吡啶 、 四丁基氟化铵 、 氨 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.5h， 生成 ((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-3-hydroxytetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate
  参考文献：
  名称：

  5'-氨基-2'，5'-二脱氧-2'，2'-二氟胞苷衍生物的合成作为新型抗癌核苷类似物

  摘要：

  为了鉴定抗癌核苷类似物，已经合成了新型的5'-氨基-2'，5'-二脱氧-2'，2'-二氟胞苷衍生物。设计并实施了几种合成路线，这些路线依靠S N 2置换或还原胺化来提供所需的衍生物。

  DOI：

  10.1016/j.tetlet.2013.11.018

文献信息

• [EN] NOVEL MODULATORS OF CELL CYCLE CHECKPOINTS AND THEIR USE IN COMBINATION WITH CHECKPOINT KINASE INHIBITORS<br/>[FR] NOUVEAUX MODULATEURS DE POINTS DE CONTRÔLE DU CYCLE CELLULAIRE ET LEUR UTILISATION EN COMBINAISON AVEC DES INHIBITEURS DE KINASE DE POINT DE CONTRÔLE
  申请人：SCHERING CORP

  公开号：WO2009061781A1

  公开（公告）日：2009-05-14

  In its many embodiments, the present invention provides a novel class of pyrimidine analogs of formula (V) as targeted mechanism-based modulators of cell cycle checkpoints. Cancers and/or malignancies can be treated by administration of a cell cycle checkpoint modulator of the invention. Also discussed are suitable combinations of the cell cycle checkpoint modulator with a checkpoint kinase inhibitor to produce synergistic apoptosis in cancer cells. The invention includes methods of treating cancers by administering the combination of the cell cycle checkpoint modulator and the checkpoint kinase inhibitor, pharmaceutical compositions comprising the activator as well as the combination and pharmaceutical kits.

  在其多种实施方式中，本发明提供了一类新型的嘧啶类似物，其化学式为（V），作为细胞周期检查点的靶向机制调节剂。可以通过给予本发明的细胞周期检查点调节剂来治疗癌症和/或恶性肿瘤。还讨论了适当的细胞周期检查点调节剂与检查点激酶抑制剂的组合，以在癌细胞中产生协同凋亡。该发明包括通过给予细胞周期检查点调节剂和检查点激酶抑制剂的组合来治疗癌症的方法，以及包含激活剂以及该组合的药物组合和药物配套工具。
• [EN] SALT OF TRIPHOSPHATE PHOSPHORAMIDATES OF NUCLEOTIDES AS ANTICANCER COMPOUNDS<br/>[FR] SEL DE PHOSPHORAMIDATES DE TRIPHOSPHATE DE NUCLÉOTIDES EN TANT QUE COMPOSÉS ANTICANCÉREUX
  申请人：NUCANA PLC

  公开号：WO2020201751A1

  公开（公告）日：2020-10-08

  The present invention relates to salts of triphosphate phosphoramidates which are useful in the treatment of cancer.

  本发明涉及三磷酸三酯磷酰胺盐，可用于癌症治疗。
• NOVEL MODULATORS OF CELL CYCLE CHECKPOINTS AND THEIR USE IN COMBINATION WITH CHECKPOINT KINASE INHIBITORS
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2217611B1

  公开（公告）日：2013-07-31
• SALT OF TRIPHOSPHATE PHOSPHORAMIDATES OF NUCLEOTIDES AS ANTICANCER COMPOUNDS
  申请人：Nucana PLC

  公开号：EP3947408A1

  公开（公告）日：2022-02-09
• The identification of novel 5′-amino gemcitabine analogs as potent RRM1 inhibitors
  作者：Marc A. Labroli、Michael P. Dwyer、Ruichao Shen、Janeta Popovici-Muller、Qinglin Pu、Daniel Wyss、Mark McCoy、Dianah Barrett、Nicole Davis、Wolfgang Seghezzi、Frances Shanahan、Lorena Taricani、Maribel Beaumont、Maria-Christina Malinao、David Parry、Timothy J. Guzi

  DOI：10.1016/j.bmc.2014.02.007

  日期：2014.4

  The ribonucleotide reductase (RNR) enzyme is a heteromer of RRM1 and RRM2 subunits. The active enzyme catalyzes de novo reduction of ribonucleotides to generate deoxyribonucleotides (dNTPs), which are required for DNA replication and DNA repair processes. Complexity in the generation of physiologically relevant, active RRM1/RRM2 heterodimers was perceived as limiting to the identification of selective RRM1 inhibitors by high-throughput screening of compound libraries and led us to seek alternative methods to identify lead series. In short, we found that gemcitabine, as its diphosphate metabolite, represents one of the few described active site inhibitors of RRM1. We herein describe the identification of novel 5'-amino gemcitabine analogs as potent RRM1 inhibitors through in-cell phenotypic screening. (c) 2014 Elsevier Ltd. All rights reserved.