butyl {4-[1-hydroxy-2-(4-(pyridine-4-yl)piperazin-1-yl)ethyl]phenyl}carbamate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: butyl {4-[1-hydroxy-2-(4-(pyridine-4-yl)piperazin-1-yl)ethyl]phenyl}carbamate
• 英文别名: butyl N-[4-[1-hydroxy-2-(4-pyridin-4-ylpiperazin-1-yl)ethyl]phenyl]carbamate
• 化学式: C₂₂H₃₀N₄O₃
• 分子量: 398.505
• InChiKey: JGOQMKBVPWSFJO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  77.9
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  氯甲酸丁酯 在 吡啶 、 sodium tetrahydroborate 、 溴 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 氯仿 、 丙酮 为溶剂， 反应 9.0h， 生成 butyl {4-[1-hydroxy-2-(4-(pyridine-4-yl)piperazin-1-yl)ethyl]phenyl}carbamate
  参考文献：
  名称：

  An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors

  摘要：

  Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b] pyrimido[5,4-f]azepine and two alkyl{3-/4-[-1-hydroxy-2-(4-arylpiperazin-1-yl)ethyliphenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.08.017

文献信息

• Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques
  作者：Ludmila E. Campos、Francisco M. Garibotto、Emilio Angelina、Jiri Kos、Tihomir Tomašič、Nace Zidar、Danijel Kikelj、Tomas Gonec、Pavlina Marvanova、Petr Mokry、Josef Jampilek、Sergio E. Alvarez、Ricardo D. Enriz

  DOI：10.1016/j.bioorg.2019.103125

  日期：2019.10

  The identification of the V600E activating mutation in the protein kinase BRAF in around 50% of melanoma patients has driven the development of highly potent small inhibitors (BRAFi) of the mutated protein. To date, Dabrafenib and Vemurafenib, two specific BRAFi, have been clinically approved for the treatment of metastatic melanoma. Unfortunately, after the initial response, tumors become resistant and patients develop a progressive and lethal disease, making imperative the development of new therapeutic options. The main objective of this work was to find new BRAF inhibitors with different structural scaffolds than those of the known inhibitors. Our study was carried out in different stages; in the first step we performed a virtual screening that allowed us to identify potential new inhibitors. In the second step, we synthesized and tested the inhibitory activity of the novel compounds founded. Finally, we conducted a molecular modelling study that allowed us to understand interactions at the molecular level that stabilize the formation of the different molecular complexes.Our theoretical and experimental study allowed the identification of four new structural scaffolds, which could be used as starting structures for the design and development of new inhibitors of BRAF. Our experimental data indicate that the most active compounds reduced significantly ERK1/2 phosphorylation, a measure of BRAF inhibition, and cell viability. Thus, from our theoretical and experimental results, we propose new substituted hydroxynaphthalenecarboxamides, N-(hetero)aryl-piperazinylhydroxyalkylphenylcarbamates, substituted piperazinylethanols and substituted piperazinylpropandiols as initial structures for the development of new inhibitors for BRAF. Moreover, by performing QTAIM analysis, we are able to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analysis indicates which portion of the different molecules must be changed in order to obtain an increase in the binding affinity of these new ligands.
• An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
  作者：Marcela Vettorazzi、Emilio Angelina、Santiago Lima、Tomas Gonec、Jan Otevrel、Pavlina Marvanova、Tereza Padrtova、Petr Mokry、Pavel Bobal、Lina M. Acosta、Alirio Palma、Justo Cobo、Janette Bobalova、Jozef Csollei、Ivan Malik、Sergio Alvarez、Sarah Spiegel、Josef Jampilek、Ricardo D. Enriz

  DOI：10.1016/j.ejmech.2017.08.017

  日期：2017.10

  Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b] pyrimido[5,4-f]azepine and two alkyl3-/4-[-1-hydroxy-2-(4-arylpiperazin-1-yl)ethyliphenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands. (C) 2017 Elsevier Masson SAS. All rights reserved.