N-(2,5-dihydroxyphenyl)-2-(phenylthio)acetamide

• 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: N-(2,5-dihydroxyphenyl)-2-(phenylthio)acetamide
• 英文别名: N-(2,5-dihydroxyphenyl)-2-phenylsulfanylacetamide
• 化学式: C₁₄H₁₃NO₃S
• 分子量: 275.328
• InChiKey: CQPMMJZXMHQKJO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  94.9
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氯-N-(2,5-二甲氧基苯基)乙酰胺 在 三溴化硼 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 14.0h， 生成 N-(2,5-dihydroxyphenyl)-2-(phenylthio)acetamide
  参考文献：
  名称：

  Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells

  摘要：

  Some cancers, like acute myeloid leukemia (AML), use reactive oxygen species to endogenously activate cell proliferation and angiogenic signaling cascades. Thus many cancers display increases in reactive oxygen like hydrogen peroxide concentrations. To translate this finding into a therapeutic strategy we designed new hydrogen peroxide-activated agents with two key molecular pharmacophores. The first pharmacophore is a peroxide-acceptor and the second is a pendant amine. The acceptor is an N-(2,5-dihydroxyphenyl) acetamide susceptible to hydrogen peroxide oxidation. We hypothesized that selectivity between AML and normal cells could be achieved by tuning the pendant amine. Synthesis and testing of fourteen compounds that differed at the pendent amine led to the identification of an agent (14) with 2 mu M activity against AML cancer cells and an eleven fold-lower activity in healthy CD34+ blood stem cells. Interestingly, analysis shows that upon oxidation the pendant amine cyclizes, ejecting water, with the acceptor to give a bicyclic compound capable of reacting with nucleophiles. Preliminary mechanistic investigations show that AML cells made from addition of two oncogenes (NrasG12D and MLL-AF9) increase the ROS-status, is initially an anti-oxidant as hydrogen peroxide is consumed to activate the pro-drug, and cells respond by upregulating electrophilic defense as visualized by Western blotting of KEAP1. Thus, using this chemical approach we have obtained a simple, potent, and selective ROS-activated anti-AML agent. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.10.029

文献信息

• A Ligand-Based Virtual Screening Approach to Identify Small Molecules as hERG Channel Activators
  作者：Elisa Giacomini、Rosa Buonfiglio、Matteo Masetti、Yuhong Wang、Gea-Ny Tseng、Marinella Roberti、Maurizio Recanatini

  DOI：10.2174/1386207318666150305121841

  日期：2015.4.23

  The hERG potassium channel is currently emerging as a potential target for the treatment of some forms of arrhythmias or to contrast an unintentional channel block caused by drugs. Despite its therapeutic relevance, so far only few compounds are described as able to enhance channel function by potentiating hERG currents. This gap is also related to the lack of hERG crystal structure which strongly limits the possibility to employ structure-based techniques in the search and design of novel activators. To overcome this limitation, in the present work, a ligand-based virtual screening was performed using as separate search queries two conformations of NS1643, the most deeply investigated and better characterized hERG activator. The library of compounds resulting from the virtual screening was then clustered based on recurring chemical features, and 5 hits were selected to be evaluated for their ability to enhance hERG current in vitro. Compound 3 showed a good activating effect, also displaying a mechanism of action similar to that of NS1643. Moreover, the most interesting compounds were further investigated by synthesizing in a parallel fashion some analogs, with the aim to get insights about structure-activity relationships.

  hERG 钾通道目前正成为治疗某些形式心律失常或对比药物引起的无意通道阻滞的潜在靶点。尽管它具有治疗意义，但迄今为止，只有极少数化合物能通过增强 hERG 电流来增强通道功能。这一空白也与缺乏 hERG 晶体结构有关，这极大地限制了采用基于结构的技术寻找和设计新型激活剂的可能性。为了克服这一限制，本研究利用 NS1643 的两种构象作为单独的搜索查询，进行了基于配体的虚拟筛选，NS1643 是研究最深入、特征最明显的 hERG 激活剂。然后，根据重复出现的化学特征对虚拟筛选出的化合物库进行聚类，选出 5 个命中化合物，对其体外增强 hERG 电流的能力进行评估。化合物 3 表现出良好的激活效果，其作用机制也与 NS1643 相似。此外，通过平行合成一些类似物，对最有趣的化合物进行了进一步研究，目的是深入了解其结构与活性的关系。
• Hydrogen Peroxide-Activated Compounds as Selective Anti-Cancer Therapeutics
  申请人：UNIVERSITY OF CINCINNATI

  公开号：US20160318849A1

  公开（公告）日：2016-11-03

  Provided are compounds according to the following Formula I: The Formula I compounds are activated in the presence of hydrogen peroxide and are therefore selective anti-cancer therapeutics for cancers associated with elevated reactive oxygen species (ROS). Also provided are methods and pharmaceutical compositions for treating cancers associated with increased ROS.
• Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells
  作者：Anish K. Vadukoot、Safnas F. AbdulSalam、Mark Wunderlich、Eboni D. Pullen、Julio Landero-Figueroa、James C. Mulloy、Eddie J. Merino

  DOI：10.1016/j.bmc.2014.10.029

  日期：2014.12

  Some cancers, like acute myeloid leukemia (AML), use reactive oxygen species to endogenously activate cell proliferation and angiogenic signaling cascades. Thus many cancers display increases in reactive oxygen like hydrogen peroxide concentrations. To translate this finding into a therapeutic strategy we designed new hydrogen peroxide-activated agents with two key molecular pharmacophores. The first pharmacophore is a peroxide-acceptor and the second is a pendant amine. The acceptor is an N-(2,5-dihydroxyphenyl) acetamide susceptible to hydrogen peroxide oxidation. We hypothesized that selectivity between AML and normal cells could be achieved by tuning the pendant amine. Synthesis and testing of fourteen compounds that differed at the pendent amine led to the identification of an agent (14) with 2 mu M activity against AML cancer cells and an eleven fold-lower activity in healthy CD34+ blood stem cells. Interestingly, analysis shows that upon oxidation the pendant amine cyclizes, ejecting water, with the acceptor to give a bicyclic compound capable of reacting with nucleophiles. Preliminary mechanistic investigations show that AML cells made from addition of two oncogenes (NrasG12D and MLL-AF9) increase the ROS-status, is initially an anti-oxidant as hydrogen peroxide is consumed to activate the pro-drug, and cells respond by upregulating electrophilic defense as visualized by Western blotting of KEAP1. Thus, using this chemical approach we have obtained a simple, potent, and selective ROS-activated anti-AML agent. (C) 2014 Elsevier Ltd. All rights reserved.