12-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide | 1610978-70-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 12-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide
• CAS: 1610978-70-5
• 化学式: C₂₂H₁₉N₅O₃
• 分子量: 401.425
• InChiKey: HLWKVUFQFSYKFH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  94.1
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氯烟酸 在 盐酸 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 82.25h， 生成 12-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethyl]-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide
  参考文献：
  名称：

  Design, Synthesis, and Structure–Activity Relationships of Pyridoquinazolinecarboxamides as RNA Polymerase I Inhibitors

  摘要：

  RNA polymerase I (Pol I) is a dedicated polymerase that transcribes the 45S ribosomal (r) RNA precursor. The 45S rRNA precursor is subsequently processed into the mature 5.8S, 18S, and 28S rRNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. On the basis of the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides have been evaluated as inhibitors of Pol I and activators of the destruction of RPA194, the Poll large catalytic subunit protein. Structure-activity relationships in assays of nucleolar stress and cell viability demonstrate key pharmacophores and their physicochemical properties required for potent activation of Pol I stress and cytotoxidty. This work identifies a set of bioactive compounds that potently cause RPA194 degradation that function in a tightly constrained chemical space. This work has yielded novel derivatives that contribute to the development of Pol I inhibitory cancer therapeutic strategies.

  DOI：

  10.1021/jm5004842

文献信息

• [EN] COMPOUNDS WHICH INHIBIT RNA POLYMERASE, COMPOSITIONS INCLUDING SUCH COMPOUNDS, AND THEIR USE<br/>[FR] COMPOSÉS QUI INHIBENT L'ARN POLYMÉRASE, COMPOSITIONS COMPRENANT DE TELS COMPOSÉS, ET LEUR UTILISATION
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2015143293A1

  公开（公告）日：2015-09-24

  RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.

  RNA聚合酶I（Pol I）是专门用于转录47S核糖体RNA前体的聚合酶，随后将其加工成成熟的5.8S、18S和28S核糖体RNA，并在核仁中组装成核糖体。Pol I活性在人类癌症中常常失调。基于引物分子BMH-21的发现，合成了一系列吡啶喹唑啉羧酰胺作为Pol I的抑制剂和RPA194的破坏激活剂，RPA194是Pol I的大催化亚基蛋白。本发明确定了一组生物活性化合物，包括纯化的立体异构体，它们能够有效地导致RPA194的降解，这些化合物在一个严格受限制的化学空间中发挥作用。还提供了包括这些化合物的药物组合物及其在癌症和其他与Pol I相关疾病中的用途。
• Compounds which inhibit RNA polymerase, compositions including such compounds, and their use
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US11001581B2

  公开（公告）日：2021-05-11

  RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.

  RNA 聚合酶 I（Pol I）是一种专用聚合酶，用于转录 47S 核糖体 RNA 前体，随后加工成成熟的 5.8S、18S 和 28S 核糖体 RNA，并在核仁中组装成核糖体。在人类癌症中，Pol I 的活性通常会发生失调。在发现先导分子 BMH-21 的基础上，合成了一系列吡啶喹唑啉羧酰胺，作为 Pol I 的抑制剂和破坏 Pol I 大催化亚基蛋白 RPA194 的激活剂。本发明确定了一组生物活性化合物，包括纯化的立体异构体，它们能有效地导致 RPA194 降解，并在严格限制的化学空间中发挥作用。本发明还提供了包含这些化合物的药物组合物及其在癌症和其他 Pol I 相关疾病中的用途。
• COMPOUNDS WHICH INHIBIT RNA POLYMERASE, COMPOSITIONS INCLUDING SUCH COMPOUNDS, AND THEIR USE
  申请人：The Johns Hopkins University

  公开号：EP3119781A1

  公开（公告）日：2017-01-25
• COMBINATORY TREATMENT STRATEGIES OF CANCER BASED ON RNA POLYMERASE I INHIBITION
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US20190247397A1

  公开（公告）日：2019-08-15

  Disclosed herein are compositions comprising a combination of at least one Pol I inhibitor, and at least one autophagy inhibiting compound, and/or at least one ACAT1 inhibiting compound, and/or at least one PARP inhibiting compound and their use in treating cancers and other related neoplastic diseases and which may also include additional chemotherapeutic agents.
• [EN] COMBINATORY TREATMENT STRATEGIES OF CANCER BASED ON RNA POLYMERASE I INHIBITION<br/>[FR] STRATÉGIES DE TRAITEMENTS COMBINÉS DU CANCER BASÉES SUR L'INHIBITION DE L'ARN POLYMÉRASE I
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2018057834A1

  公开（公告）日：2018-03-29

  Disclosed herein are compositions comprising a combination of at least one Pol I inhibitor, and at least one autophagy inhibiting compound, and/or at least one ACAT1 inhibiting compound, and/or at least one PARP inhibiting compound and their use in treating cancers and other related neoplastic diseases and which may also include additional chemotherapeutic agents.