2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(3-(phenoxymethyl)phenyl)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: 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(3-(phenoxymethyl)phenyl)acetamide
• 英文别名: 2-(4,6-dimethylpyrimidin-2-yl)sulfanyl-N-[3-(phenoxymethyl)phenyl]ethanamide；2-(4,6-dimethylpyrimidin-2-yl)sulfanyl-N-[3-(phenoxymethyl)phenyl]acetamide
• 化学式: C₂₁H₂₁N₃O₂S
• 分子量: 379.483
• InChiKey: UTHZHWWWTOWRMG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  89.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  m-nitrobenzyl phenyl ether 在 potassium tert-butylate 、 铁粉 、 氯化铵 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 13.5h， 生成 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-(3-(phenoxymethyl)phenyl)acetamide
  参考文献：
  名称：

  Discovery of 2-((4,6-dimethylpyrimidin-2-yl)thio)- N -phenylacetamide derivatives as new potent and selective human sirtuin 2 inhibitors

  摘要：

  Human sirtuin 2 (SIRT2) plays pivotal roles in multiple biological processes such as cell cycle regulation, autophagy, immune and inflammatory responses. Dysregulation of SIRT2 was considered as a main aspect contributing to several human diseases, including cancer. Development of new potent and selective SIRT2 inhibitors is currently desirable, which may provide a new strategy for treatment of related diseases. Herein, a structure-based optimization approach led to new 2-((4,6-dimethylpyrimidin-2-yl) thio)-N-phenylacetamide derivatives as SIRT2 inhibitors. SAR analyses with new synthesized derivatives revealed a number of new potent SIRT2 inhibitors, among which 28e is the most potent inhibitor with an IC50 value of 42 nM. The selectivity analyses found that 28e has a very good selectivity to SIRT2 over SIRT1 and SIRT3. In cellular assays, 28e showed a potent ability to inhibit human breast cancer cell line MCF-7 and increase the acetylation of alpha-tubulin in a dose-dependent manner. This study will aid further efforts to develop highly potent and selective SIRT2 inhibitors for the treatment of cancer and other related diseases. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.04.010

文献信息

• [EN] NOVEL SIRT2 PROTEIN INHIBITOR AND PHARMACEUTICAL USE THEREOF<br/>[FR] NOUVEL INHIBITEUR DE PROTÉINE SIRT2 ET SON UTILISATION PHARMACEUTIQUE<br/>[ZH] 一类新型SIRT2蛋白抑制剂及其在制药中的用途
  申请人：UNIV XIHUA

  公开号：WO2018068357A1

  公开（公告）日：2018-04-19

  本发明公开了式Ⅰ所示的化合物或其药学上可接受的盐、晶型、溶剂合物：其中，Z选自（II）、（III）、（IV）或（V）；R1选自H或（VI）；R2选自（VII）或（VIII）；R3选自卤素、C1～C4烷基、C1～C4烷氧基或（IX）。本发明式Ⅰ所示的新化合物，不仅对SIRT2具有良好的抑制活性，而且对肿瘤具有很好的抑制作用，具有很好的药用潜力，为临床用药提供了一种新的潜在选择；同时，本发明新化合物的制备方法简便，反应条件温和，便于操作和控制，能耗小，产率高，成本低，可适合产业化生产。
• Discovery of 2-((4,6-dimethylpyrimidin-2-yl)thio)- N -phenylacetamide derivatives as new potent and selective human sirtuin 2 inhibitors
  作者：Lingling Yang、Xiaobo Ma、Chen Yuan、Yanying He、Ling Li、Sha Fang、Wei Xia、Tao He、Shan Qian、Zhihong Xu、Guobo Li、Zhouyu Wang

  DOI：10.1016/j.ejmech.2017.04.010

  日期：2017.7

  Human sirtuin 2 (SIRT2) plays pivotal roles in multiple biological processes such as cell cycle regulation, autophagy, immune and inflammatory responses. Dysregulation of SIRT2 was considered as a main aspect contributing to several human diseases, including cancer. Development of new potent and selective SIRT2 inhibitors is currently desirable, which may provide a new strategy for treatment of related diseases. Herein, a structure-based optimization approach led to new 2-((4,6-dimethylpyrimidin-2-yl) thio)-N-phenylacetamide derivatives as SIRT2 inhibitors. SAR analyses with new synthesized derivatives revealed a number of new potent SIRT2 inhibitors, among which 28e is the most potent inhibitor with an IC50 value of 42 nM. The selectivity analyses found that 28e has a very good selectivity to SIRT2 over SIRT1 and SIRT3. In cellular assays, 28e showed a potent ability to inhibit human breast cancer cell line MCF-7 and increase the acetylation of alpha-tubulin in a dose-dependent manner. This study will aid further efforts to develop highly potent and selective SIRT2 inhibitors for the treatment of cancer and other related diseases. (C) 2017 Elsevier Masson SAS. All rights reserved.