(4-((2-bromobenzyl)oxy)phenyl)methanamine

• 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: (4-((2-bromobenzyl)oxy)phenyl)methanamine
• 英文别名: [4-[(2-Bromophenyl)methoxy]phenyl]methanamine
• 化学式: C₁₄H₁₄BrNO
• 分子量: 292.175
• InChiKey: OPPSVBGGDPRHMN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  35.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (4-((2-bromobenzyl)oxy)phenyl)methanamine 在 盐酸 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 为溶剂， 反应 72.0h， 生成 3-(1-((4-((2-bromobenzyl)oxy)benzyl)amino)-2-(tert-butylamino)-2-oxoethyl)-6-chloro-1H-indole-2-carboxylic acid
  参考文献：
  名称：

  Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction

  摘要：

  Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient alpha-helical N-terminal "lid" segment of MDM2 from the proximity of the p53-complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111588
• 作为产物：
  描述：

  1-溴-2-[(4-氰基苯氧基)甲基]苯 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 生成 (4-((2-bromobenzyl)oxy)phenyl)methanamine
  参考文献：
  名称：

  1,4,5-Trisubstituted Imidazole-Based p53–MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers

  摘要：

  The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TPS3 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53-MDM2/MDMX inhibitors and conjugation with bioactive carriers.

  DOI：

  10.1021/acs.jmedchem.7b00104

文献信息

• 1,4,5-Trisubstituted Imidazole-Based p53–MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers
  作者：Aleksandra Twarda-Clapa、Sylwia Krzanik、Katarzyna Kubica、Katarzyna Guzik、Beata Labuzek、Constantinos G. Neochoritis、Kareem Khoury、Kaja Kowalska、Miroslawa Czub、Grzegorz Dubin、Alexander Dömling、Lukasz Skalniak、Tad A. Holak

  DOI：10.1021/acs.jmedchem.7b00104

  日期：2017.5.25

  The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TPS3 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53-MDM2/MDMX inhibitors and conjugation with bioactive carriers.
• Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction
  作者：Constantinos G. Neochoritis、Jack Atmaj、Aleksandra Twarda-Clapa、Ewa Surmiak、Lukasz Skalniak、Lisa-Maria Köhler、Damian Muszak、Katarzyna Kurpiewska、Justyna Kalinowska-Tłuścik、Barbara Beck、Tad A. Holak、Alexander Dömling

  DOI：10.1016/j.ejmech.2019.111588

  日期：2019.11

  Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient alpha-helical N-terminal "lid" segment of MDM2 from the proximity of the p53-complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds. (C) 2019 Elsevier Masson SAS. All rights reserved.