2-(1H-benzimidazol-1-ylmethyl)-4H-pyrido[1,2-a]pyrimidin-4-one | 1434288-23-9

• 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: 2-(1H-benzimidazol-1-ylmethyl)-4H-pyrido[1,2-a]pyrimidin-4-one
• 英文别名: 2-(1h-Benzimidazol-1-Ylmethyl)-4h-Pyrido[1,2-A]pyrimidin-4-One；2-(benzimidazol-1-ylmethyl)pyrido[1,2-a]pyrimidin-4-one
• CAS: 1434288-23-9
• 化学式: C₁₆H₁₂N₄O
• 分子量: 276.297
• InChiKey: BCWFSHAZZLFCIE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  50.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  苯并咪唑 、 2-氯甲基-4h-吡啶并[1,2-a]嘧啶-4-酮 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 以36%的产率得到2-(1H-benzimidazol-1-ylmethyl)-4H-pyrido[1,2-a]pyrimidin-4-one
  参考文献：
  名称：

  发现2-（（1 H-苯并[ d ]咪唑-1-基）甲基）-4 H-吡啶基[1,2 - a ]嘧啶-4-酮类化合物作为新型PKM2激活剂

  摘要：

  丙酮酸激酶的M2同工型是抗肿瘤治疗的新兴目标。在这封信中，我们描述了发现2-（（1 H-苯并[ d ]咪唑-1-基）甲基）-4 H-吡啶基[1,2- a ]嘧啶-4-酮的发现，这是有力且选择性的PKM2被发现具有新型结合模式的活化剂。通过计算机辅助基于结构的药物设计，将从高通量筛选中鉴定出的原始铅优化为有效系列。该系列中的代表性化合物和文献中描述的活化剂均被用作分子工具来探测PKM2活化对癌细胞的生物学作用。我们的结果表明，单独的PKM2激活不足以改变癌细胞的代谢。

  DOI：

  10.1016/j.bmcl.2013.03.090

文献信息

• IMAGING TUMOR GLYCOLYSIS BY NON-INVASIVE MEASUREMENT OF PYRUVATE KINASE M2
  申请人：The Board of Trustees of the Leland Stanford Junior University

  公开号：US20180043040A1

  公开（公告）日：2018-02-15

  The present disclosure provides a positron emission tomography (PET)-detectable 1-((2-fluoro-6-[ 18 F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([ 18 F]DASA-23) probe that can selectively bind to the pyruvate kinase variant M2 (PKM2) found in cancer cells, such as of human glioma. Given the importance of PKM2 in the regulation of tumor metabolism, there is an on-going need to non-invasively measure its expression through the development of PKM2-specific radiopharmaceuticals. Precursors useful for the synthesis of the radiolabeled [ 18 F]DASA-23-PKM2-specific probe and related compounds, and their methods of synthesis, are provided. Since the half-life of the 18 F isotope is approximately 110 min, it is advantageous for a practitioner to attach the radionuclide to the precursor shortly before administration. Therefore, a precursor compound suitable for receiving the radionuclide and capable of specifically binding to the PKM2 variant can be provided.

  本公开提供了一种正电子发射断层扫描（PET）可检测的1-（（2-氟-6-[18F]氟苯基）磺酰基）-4-（（4-甲氧基苯基）磺酰基）哌嗪（[18F]DASA-23）探针，该探针可以选择性地结合于癌细胞中发现的丙酮酸激酶变异体M2（PKM2），例如人脑胶质瘤。鉴于PKM2在肿瘤代谢调节中的重要性，需要通过开发PKM2特异性放射性药物来非侵入性地测量其表达。提供了用于合成放射性标记的[18F]DASA-23-PKM2特异性探针和相关化合物的有用前体及其合成方法。由于18F同位素的半衰期约为110分钟，因此对于从业者来说，在给药前不久将放射性核素附加到前体上是有利的。因此，可以提供一种适用于接收放射性核素并能够特异性结合于PKM2变异体的前体化合物。
• Imaging tumor glycolysis by non-invasive measurement of pyruvate kinase M2
  申请人：The Board of Trustees of the Leland Stanford Junior University

  公开号：US10675366B2

  公开（公告）日：2020-06-09

  The present disclosure provides a positron emission tomography (PET)-detectable 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) probe that can selectively bind to the pyruvate kinase variant M2 (PKM2) found in cancer cells, such as of human glioma. Given the importance of PKM2 in the regulation of tumor metabolism, there is an on-going need to non-invasively measure its expression through the development of PKM2-specific radiopharmaceuticals. Precursors useful for the synthesis of the radiolabeled [18F]DASA-23-PKM2-specific probe and related compounds, and their methods of synthesis, are provided. Since the half-life of the 18F isotope is approximately 110 min, it is advantageous for a practitioner to attach the radionuclide to the precursor shortly before administration. Therefore, a precursor compound suitable for receiving the radionuclide and capable of specifically binding to the PKM2 variant can be provided.

  本公开提供了一种正电子发射断层扫描（PET）可检测的1-((2-氟-6-[18F]氟苯基)磺酰基)-4-((4-甲氧基苯基)磺酰基)哌嗪（[18F]DASA-23）探针，该探针可选择性地与癌细胞（如人类胶质瘤）中的丙酮酸激酶变体M2（PKM2）结合。鉴于 PKM2 在调节肿瘤代谢中的重要性，目前需要通过开发 PKM2 特异性放射性药物来非侵入性地测量其表达。本文提供了用于合成放射性标记的[18F]DASA-23-PKM2 特异性探针和相关化合物的前体及其合成方法。由于 18F 同位素的半衰期约为 110 分钟，因此对于医生来说，在给药前不久将放射性核素附着在前体上是非常有利的。因此，可以提供一种适合接受放射性核素并能与 PKM2 变异体特异性结合的前体化合物。
• PKM2 ACTIVATORS IN COMBINATION WITH REACTIVE OXYGEN SPECIES FOR TREATMENT OF CANCER
  申请人：TOLERO PHARMACEUTICALS, INC.

  公开号：US20200237766A1

  公开（公告）日：2020-07-30

  Combination therapies for treatment of cancer are provided. The disclosed methods comprise administration of a PKM2 activator and an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells to a patient in need thereof.
• [EN] PKM2 ACTIVATORS IN COMBINATION WITH REACTIVE OXYGEN SPECIES FOR TREATMENT OF CANCER<br/>[FR] ACTIVATEURS DE PKM2 EN COMBINAISON AVEC DES ESPÈCES RÉACTIVES DE L'OXYGÈNE POUR LE TRAITEMENT DU CANCER
  申请人：TOLERO PHARMACEUTICALS INC

  公开号：WO2019075367A1

  公开（公告）日：2019-04-18

  Combination therapies for treatment of cancer are provided. The disclosed methods comprise administration of a PKM2 activator and an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells to a patient in need thereof.
• Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators
  作者：Chuangxing Guo、Angelica Linton、Mehran Jalaie、Susan Kephart、Martha Ornelas、Mason Pairish、Samantha Greasley、Paul Richardson、Karen Maegley、Michael Hickey、John Li、Xin Wu、Xiaodong Ji、Zhi Xie

  DOI：10.1016/j.bmcl.2013.03.090

  日期：2013.6

  pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design

  丙酮酸激酶的M2同工型是抗肿瘤治疗的新兴目标。在这封信中，我们描述了发现2-（（1 H-苯并[ d ]咪唑-1-基）甲基）-4 H-吡啶基[1,2- a ]嘧啶-4-酮的发现，这是有力且选择性的PKM2被发现具有新型结合模式的活化剂。通过计算机辅助基于结构的药物设计，将从高通量筛选中鉴定出的原始铅优化为有效系列。该系列中的代表性化合物和文献中描述的活化剂均被用作分子工具来探测PKM2活化对癌细胞的生物学作用。我们的结果表明，单独的PKM2激活不足以改变癌细胞的代谢。