(3S,7aR)-7a-methyl-3-(phenylmethyl)perhydropyrrolo[2,1-b][1,3]oxazol-5-one | 353751-78-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (3S,7aR)-7a-methyl-3-(phenylmethyl)perhydropyrrolo[2,1-b][1,3]oxazol-5-one
• 英文别名: (3S,7aR)-3-benzyl-tetrahydro-7a-methylpyrrolo[2,1-b]-oxazol-5(6H)-one；(3S,7aR)-3-benzyl-7a-methyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one；(3s,7Ar)-3-benzyl-tetrahydro-7a-methylpyrrolo[2,1-b]oxazol-5(6h)-one；(3S,7aR)-3-benzyl-7a-methyl-2,3,6,7-tetrahydropyrrolo[2,1-b][1,3]oxazol-5-one
• CAS: 353751-78-7
• 化学式: C₁₄H₁₇NO₂
• 分子量: 231.294
• InChiKey: KDRXMJHXWCDZCK-GXTWGEPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3S,7aR)-7a-methyl-3-(phenylmethyl)perhydropyrrolo[2,1-b][1,3]oxazol-5-one 在 双氧水 、 溶剂黄146 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正庚烷 为溶剂， 反应 16.0h， 生成 (3S,7aR)-7a-methyl-3-(phenylmethyl)-2,3,5,7a-tetrahydropyrrolo[2,1-b][1,3]oxazol-5-one
  参考文献：
  名称：

  Stereoselective synthesis of the pyrroloisoquinoline ring system

  摘要：

  在本文中，我们报告了通过应用 N-酰亚胺化学，从容易获得的非外消旋手性模板出发，对吡咯异喹啉环系统进行简便和立体选择性研究的方法。环化反应的立体化学结果是通过 NOE 和 X 射线晶体学确定的。我们还通过去除环化反应产物中的羟甲基助剂，证明了新方法的合成潜力。

  DOI：

  10.1039/b105402n
• 作为产物：
  描述：

  L-苯丙氨醇 、 5-氧代己酸 以 甲苯 为溶剂， 反应 48.0h， 以73%的产率得到(3S,7aR)-7a-methyl-3-(phenylmethyl)perhydropyrrolo[2,1-b][1,3]oxazol-5-one
  参考文献：
  名称：

  Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53–MDM2 interaction

  摘要：

  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.

  DOI：

  10.1016/j.ejps.2014.10.006

文献信息

• 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.
• 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.
• Stereoselective synthesis of the pyrroloisoquinoline ring system
  作者：Steven M. Allin、Stella L. James、William P. Martin、Timothy A. D. Smith、Mark R. J. Elsegood

  DOI：10.1039/b105402n

  日期：2001.11.15

  In this paper we report a facile and stereoselective approach to the pyrroloisoquinoline ring system through the application of N-acyliminium chemistry from readily available non-racemic chiral templates. The stereochemical outcome of the cyclisation reactions has been determined by NOE and X-ray crystallography. We also demonstrate the synthetic potential of our new approach through removal of the pendant hydroxymethyl auxiliary from a product of cyclisation.

  在本文中，我们报告了通过应用 N-酰亚胺化学，从容易获得的非外消旋手性模板出发，对吡咯异喹啉环系统进行简便和立体选择性研究的方法。环化反应的立体化学结果是通过 NOE 和 X 射线晶体学确定的。我们还通过去除环化反应产物中的羟甲基助剂，证明了新方法的合成潜力。