(3S,7aS)-3-benzyl-tetrahydro-7a-phenylpyrrolo[2,1-b]-oxazol-5(6H)-one | 1431509-15-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (3S,7aS)-3-benzyl-tetrahydro-7a-phenylpyrrolo[2,1-b]-oxazol-5(6H)-one
• 英文别名: (3S,7aS)-3-benzyl-7a-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one；(3s,7As)-3-benzyl-tetrahydro-7a-phenylpyrrolo[2,1-b]oxazol-5(6h)-one；(3S,7aS)-3-benzyl-7a-phenyl-2,3,6,7-tetrahydropyrrolo[2,1-b][1,3]oxazol-5-one
• CAS: 1431509-15-7
• 化学式: C₁₉H₁₉NO₂
• 分子量: 293.365
• InChiKey: WKTSEXAVCHEDBV-HKUYNNGSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  L-苯丙氨醇 、 3-苯丙烯溴酸酯 以 甲苯 为溶剂， 反应 16.0h， 以82%的产率得到(3S,7aS)-3-benzyl-tetrahydro-7a-phenylpyrrolo[2,1-b]-oxazol-5(6H)-one
  参考文献：
  名称：

  优化双环内酰胺衍生物作为NMDA受体拮抗剂。

  摘要：

  N-甲基-d-天冬氨酸（NMDA）受体对于中枢神经系统（CNS）的正常功能至关重要，并在记忆和学习中发挥重要作用。这些受体的过度激活导致与主要神经系统疾病（如帕金森氏病，阿尔茨海默氏病，精神分裂症和癫痫病）相关的神经元丢失。在这项研究中，22种新型对映体纯双环内酰胺被设计，合成和评估为NMDA受体拮抗剂。大多数新化合物显示出NMDA受体拮抗作用，最有前途的化合物显示的IC50值与美金刚（在临床上用于治疗阿尔茨海默氏病的NMDA受体拮抗剂）的美金刚有相同的数量级。进一步的生物学评估表明，该化合物具有大脑通透性（通过体外测定法测定），并且无肝毒性。所有这些结果表明，（3S，7aS）-7a-（4-氯苯基）-3-（4-羟基苄基）四氢吡咯并[2,1-b]恶唑-5（6H）-one（化合物5 b）是潜在的NMDA受体过度激活相关的病理治疗的候选药物。

  DOI：

  10.1002/cmdc.201700037

文献信息

• Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53–MDM2 interaction
  作者：Joana Soares、Nuno A.L. Pereira、Ângelo Monteiro、Mariana Leão、Cláudia Bessa、Daniel J.V.A. dos Santos、Liliana Raimundo、Glória Queiroz、Alessandra Bisio、Alberto Inga、Clara Pereira、Maria M.M. Santos、Lucília Saraiva

  DOI：10.1016/j.ejps.2014.10.006

  日期：2015.1

  One of the most appealing targets for anticancer treatment is the p53 tumor suppressor protein. In half of human cancers, this protein is inactivated due to endogenous negative regulators such as MDM2. Actually, restoring the p53 activity, particularly through the inhibition of its interaction with MDM2, is considered a valuable therapeutic strategy against cancers with a wild-type p53 status. In this work, we report the synthesis of nine enantiopure phenylalaninol-derived oxazolopyrrolidone lactams and the evaluation of their biological effects as p53-MDM2 interaction inhibitors. Using a yeast-based screening assay, two oxazoloisoindolinones, compounds 1b and 3a, were identified as potential p53-MDM2 interaction inhibitors. The molecular mechanism of oxazoloisoindolinone 3a was further validated in human colon adenocarcinoma HCT116 cells with wild-type p53 (HCT116 p53(+/+)) and in its isogenic derivative without p53 (HCT116 p53(-/-)). Indeed, using these cells, we demonstrated that oxazoloisoindolinone 3a exhibited a p53-dependent in vitro antitumor activity through induction of G0/G1-phase cell cycle arrest and apoptosis. The selective activation of a p53-apoptotic pathway by oxazoloisoindolinone 3a was further supported by the occurrence of PARP cleavage only in p53-expressing HCT116 cells. Moreover, oxazoloisoindolinone 3a led to p53 protein stabilization and to the up-regulation of p53 transcriptional activity with increased expression levels of several p53 target genes, as p21(WAF1/CIP1), MDM2, BAX and PUMA, in p53(+/+) but not in p53(-/-) HCT116 cells. Additionally, the ability of oxazoloisoindolinone 3a to block the p53-MDM2 interaction in HCT116 p53(+/+) cells was confirmed by co-immunoprecipitation. Finally, the molecular docking analysis of the interactions between the synthesized compounds and MDM2 revealed that oxazoloisoindolinone 3a binds to MDM2. Altogether, this work adds, for the first time, the oxazoloisoindolinone scaffold to the list of chemotypes activators of a wild-type p53-pathway with promising antitumor activity. Moreover, it may open the way to the development of a new class of p53-MDM2 interaction inhibitors. (C) 2014 Elsevier B.V. All rights reserved.
• Synthesis of phenylalaninol-derived oxazolopyrrolidone lactams and evaluation as NMDA receptor antagonists
  作者：Nuno A. L. Pereira、Francesc X. Sureda、Mireia Turch、Mercedes Amat、Joan Bosch、Maria M. M. Santos

  DOI：10.1007/s00706-012-0880-8

  日期：2013.4

  N-Methyl-d-aspartate (NMDA) receptor antagonists are known to rescue neuronal cell death caused by excessive activation of glutamate receptors. This phenomenon, known as excitotoxicity, is implicated in the pathogenesis of several neurodegenerative disorders including ischemia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. Unfortunately, some NMDA receptor antagonists have shown discouraging results when tested in clinical trials. However, recent advances in the physiology and pharmacology of the NMDA receptor have kept interest alive in modulating NMDA receptors for therapeutic intervention. We present here the synthesis of a small library of phenylalaninol-derived oxazolopyrrolidone lactams and their evaluation as NMDA receptor antagonists. The compounds were easily synthesized in yields up to 92 %. In addition, one of the compounds has a 50 % inhibitory concentration (IC (50)) of 62 mu M and offers potential to develop more potent NMDA receptor antagonists.
• Optimization of Bicyclic Lactam Derivatives as NMDA Receptor Antagonists
  作者：Margarida Espadinha、Jorge Dourado、Rocio Lajarin-Cuesta、Clara Herrera-Arozamena、Lidia M. D. Gonçalves、María Isabel Rodríguez-Franco、Cristobal de los Rios、Maria M. M. Santos

  DOI：10.1002/cmdc.201700037

  日期：2017.4.6

  for the normal function of the central nervous system (CNS), and play an important role in memory and learning. Over-activation of these receptors leads to neuronal loss associated with major neurological disorders such as Parkinson's disease, Alzheimer's disease, schizophrenia, and epilepsy. In this study, 22 novel enantiopure bicyclic lactams were designed, synthesized, and evaluated as NMDA receptor

  N-甲基-d-天冬氨酸（NMDA）受体对于中枢神经系统（CNS）的正常功能至关重要，并在记忆和学习中发挥重要作用。这些受体的过度激活导致与主要神经系统疾病（如帕金森氏病，阿尔茨海默氏病，精神分裂症和癫痫病）相关的神经元丢失。在这项研究中，22种新型对映体纯双环内酰胺被设计，合成和评估为NMDA受体拮抗剂。大多数新化合物显示出NMDA受体拮抗作用，最有前途的化合物显示的IC50值与美金刚（在临床上用于治疗阿尔茨海默氏病的NMDA受体拮抗剂）的美金刚有相同的数量级。进一步的生物学评估表明，该化合物具有大脑通透性（通过体外测定法测定），并且无肝毒性。所有这些结果表明，（3S，7aS）-7a-（4-氯苯基）-3-（4-羟基苄基）四氢吡咯并[2,1-b]恶唑-5（6H）-one（化合物5 b）是潜在的NMDA受体过度激活相关的病理治疗的候选药物。