2,2-二羟基甲基-1-氮杂双环[2.2.2]辛-3-酮 | 5608-24-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 奎宁环
• 中文名称: 2,2-二羟基甲基-1-氮杂双环[2.2.2]辛-3-酮
• 英文名称: prima-1
• 英文别名: 2,2-bis(hydroxymethyl)quinuclidin-3-one；2,2-bis(hydroxymethyl)-1-azabicyclo[2.2.2]octan-3-one
• CAS: 5608-24-2
• 化学式: C₉H₁₅NO₃
• mdl: MFCD04974196
• 分子量: 185.223
• InChiKey: RFBVBRVVOPAAFS-UHFFFAOYSA-N

物化性质

• 熔点：
  146-147 °C
• 沸点：
  353.7±17.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)
• 溶解度：
  H2O：>10mg/mL
• 稳定性/保质期：

  遵照规定使用和储存，则不会发生分解。

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.888
• 拓扑面积：
  60.8
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 危险类别码：
  R22,R43
• 安全说明：
  S36,S37
• 危险标志：
  GHS07,GHS08
• 危险性描述：
  H302,H334
• 危险性防范说明：
  P261,P342 + P311
• 包装等级：
  III
• 危险类别：
  6.1
• 危险品运输编号：
  2811
• 储存条件：
  存放在阴凉干燥处即可。

制备方法与用途

生物活性

PRIMA-1（2,2-二羟甲基-3-喹诺丁酮）是p53突变体的重活化剂。在携带p53突变的人类肿瘤中，它能诱导细胞凋亡并抑制肿瘤生长。

靶点

Target	Value
Mutant p53	()

体外研究

PRIMA-1在p53突变体中转化为一种能够与硫醇基团形成加合物的化合物。通过修饰p53突变体的硫醇基团，PRIMA-1能够恢复其肿瘤抑制活性。PRIMA-1能抑制胰腺癌细胞的生长、诱导细胞周期停滞以及减少DNA合成。它选择性地诱导表达p53突变体的胰腺癌细胞凋亡和死亡，并激活p53依赖性的凋亡途径。PRIMA-1增强化疗药物对p53突变胰腺癌细胞的毒性作用，且在急性早幼粒细胞性白血病来源的NB4细胞中表现出显著抗白血病活性。PRIMA-1诱导的凋亡遵循时间依赖性和剂量依赖性模式，并与caspase-9、caspase-7的激活和PARP断裂相关联。此外，PRIMA-1对正常人外周血单核细胞没有显著凋亡效应。

体内研究

在小鼠中静脉注射PRIMA-1并未引起明显的行为学或体重变化差异（与对照组相比）。在小鼠肿瘤模型中，PRIMA-1表现出抗肿瘤活性，并依赖于p53突变体的存在。

反应信息

• 作为反应物：
  描述：

  2,2-二羟基甲基-1-氮杂双环[2.2.2]辛-3-酮 在 lithium aluminium tetrahydride 作用下， 以60%的产率得到2,2-Bis-methylol-3-chinuclidinol
  参考文献：
  名称：

  Structure–activity studies of quinuclidinone analogs as anti-proliferative agents in lung cancer cell lines

  摘要：

  We have synthesized and tested novel quinuelidinone analogs to assay the effects on H1299 lung cancer cell lines alone or with gamma-radiation. We have found two series of quinuclidinone analogs that act as anti-cancer agents. Of these, four interesting analogs significantly decreased cell viability in H1299 lung cancer cell lines. Two derivatives decreased cell proliferation in a dose-dependent fashion alone or in the presence of gamma-radiation. Radiosensitization increased when derivative treatment preceded radiation treatment for both derivatives. These preliminary studies show an evidence for both additive and synergistic cytotoxicity for treatment of lung cancer by these novel quinuclidinone analogs. (C) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.11.085
• 作为产物：
  描述：

  3-奎宁环酮 、 聚合甲醛 在 potassium carbonate 作用下， 以45%的产率得到2,2-二羟基甲基-1-氮杂双环[2.2.2]辛-3-酮
  参考文献：
  名称：

  Structure–activity studies of quinuclidinone analogs as anti-proliferative agents in lung cancer cell lines

  摘要：

  We have synthesized and tested novel quinuelidinone analogs to assay the effects on H1299 lung cancer cell lines alone or with gamma-radiation. We have found two series of quinuclidinone analogs that act as anti-cancer agents. Of these, four interesting analogs significantly decreased cell viability in H1299 lung cancer cell lines. Two derivatives decreased cell proliferation in a dose-dependent fashion alone or in the presence of gamma-radiation. Radiosensitization increased when derivative treatment preceded radiation treatment for both derivatives. These preliminary studies show an evidence for both additive and synergistic cytotoxicity for treatment of lung cancer by these novel quinuclidinone analogs. (C) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.11.085

文献信息

• [EN] AZABICYCLOOCTAN-3-ONE DERIVATIVES AND USE THEREOF<br/>[FR] DERIVE D'AZABICYCLOOCTANE-3-ONE ET UTILISATION CORRESPONDANTE
  申请人：APREA AB

  公开号：WO2005090341A1

  公开（公告）日：2005-09-29

  Compounds of Formula (I) processes for preparing them, pharmaceutical compositions comprising them. The use of compounds of formula (I) for hyperproliferative diseases, e.g. cancer as well as autoimmune diseases and heart diseases.

  化合物的公式（I）及其制备方法，包括它们的药物组合物。化合物的公式（I）用于治疗高增殖性疾病，例如癌症以及自身免疫疾病和心脏疾病。
• [EN] OPTICAL IMAGING CONTRAST AGENTS FOR IMAGING LUNG CANCER<br/>[FR] AGENTS DE CONTRASTE D'IMAGERIE OPTIQUE POUR L'IMAGERIE DU CANCER DU POUMON
  申请人：AMERSHAM HEALTH AS

  公开号：WO2005058370A1

  公开（公告）日：2005-06-30

  The invention provides contrast agents for optical imaging of lung cancer in patients. The contrast agents may be used in diagnosis of lung cancer, for follow up of progress in disease development, for follow up of treatment of lung cancer and for surgical guidance. Further, the invention provides methods for optical imaging of lung cancer in patients.

  该发明提供了用于患者肺癌光学成像的对比剂。这些对比剂可用于肺癌的诊断，用于随访疾病发展进展，用于随访肺癌治疗以及用于手术引导。此外，该发明还提供了患者肺癌光学成像的方法。
• [EN] OPTICAL IMAGING CONTRAST AGENTS<br/>[FR] AGENTS DE CONTRASTE POUR IMAGERIE OPTIQUE
  申请人：AMERSHAM HEALTH AS

  公开号：WO2005058371A1

  公开（公告）日：2005-06-30

  The invention provides contrast agents for optical imaging of oesophageal cancer and Barrett's oesophagus in patients. The contrast agents may be used in diagnosis of oesophageal cancer and Barrett's oesophagus, for follow up of progress in disease development, for follow up of treatment of oesophageal cancer and Barrett's oesophagus and for surgical guidance. Further, the invention provides methods for optical imaging of oesophageal cancer and Barrett's oesophagus in patients.

  该发明提供了用于患者食管癌和巴雷特食管的光学成像对比剂。这些对比剂可用于诊断食管癌和巴雷特食管，用于随访疾病进展情况，用于随访食管癌和巴雷特食管的治疗以及用于手术指导。此外，该发明提供了在患者中光学成像食管癌和巴雷特食管的方法。
• [EN] NOVEL COMPOUNDS FOR USE IN TREATING OR PREVENTING CANCEROUS DISEASES<br/>[FR] NOUVEAUX COMPOSÉS UTILISABLES DANS LE TRAITEMENT OU LA PRÉVENTION DE MALADIES CANCÉREUSES
  申请人：BIOMEDICAL RES FOUND OF THE ACAD OF ATHENS

  公开号：WO2017005919A1

  公开（公告）日：2017-01-12

  The invention relates to new compounds of formula (I) that are useful in medicine, specifically in treating or preventing cancerous diseases in a mammal, to pharmaceutical compositions comprising such compounds, optionally together with other pharmaceutically active compounds, or to pharmaceutical formulations comprising such compounds or pharmaceutical compositions. The invention further relates to methods of making these compounds.

  本发明涉及公式（I）的新化合物，该化合物在医学上具有用途，特别是在哺乳动物中治疗或预防癌症性疾病，以及包含这些化合物的药物组合物，可选地与其他药物活性化合物一起，或包含这些化合物或药物组合物的药物制剂。本发明还涉及制备这些化合物的方法。
• Optical Imaging Contrast Agents For Imaging Lung Cancer
  申请人：Klaveness Jo

  公开号：US20070212305A1

  公开（公告）日：2007-09-13

  The invention provides contrast agents for optical imaging of lung cancer in patients. The contrast agents may be used in diagnosis of lung cancer, for follow up of progress in disease development, for follow up of treatment of lung cancer and for surgical guidance. Further, the invention provides methods for optical imaging of lung cancer in patients.

  这项发明提供了用于患者肺癌光学成像的对比剂。这些对比剂可用于肺癌的诊断，用于随访疾病进展，用于随访肺癌治疗以及用于手术指导。此外，该发明还提供了用于患者肺癌光学成像的方法。