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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design, synthesis and biological evaluation of novel hydroxamates and 2-aminobenzamides as potent histone deacetylase inhibitors and antitumor agents
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Design, synthesis and biological evaluation of novel hydroxamates and 2-aminobenzamides as potent histone deacetylase inhibitors and antitumor agents

机译：新羟肟酸盐和2-氨基苯甲酰胺的设计，合成和生物学评价为有效的组蛋白脱乙酰酶抑制剂和抗肿瘤剂

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摘要

Many studies have indicated that histone deacetylase (HDAC) inhibitors are promising agents for the treatment of cancer. With the aim to search for novel potent HDAC inhibitors, we designed and synthesized two series of hydroxamates and 2-aminobenzamides compounds as HDAC inhibitors and antitumor agents. Those compounds were investigated for their HDAC enzymatic inhibitory activities and in vitro anti-proliferation activities against diverse cancer cell line (A549, HepG2, MGC80-3 and HCT116). Most of the synthesized compounds displayed potent HDAC inhibitory activity and anti proliferative activity. In particular, Compound 12a, N-(2-aminopheny1)-4-[(4-fluorophenoxy)methyl] benzamide, was shown to have the most HDAC inhibitory activity (70.6% inhibition at 5 mu M) and anti-tumor activity with IC50 value of as low as 3.84 mu M against HepG2 human liver hepatocellular carcinoma cell line, more than 4.8-fold lower than CS055 and 5.9-fold lower than CI994. HDAC isoform selectivity assay indicated 12a is a potent HDAC2 inhibitor. Docking study of 12a suggested that it bound tightly to the binding pocket of HDAC2. Further investigation showed that 12a could inhibit the migration and colony formation of A549 cancer cells. Furthermore, 12a remarkably induced apoptosis and G2/M phase cell cycle arrest in A549 cancer cells. Those results indicated that compound 12a could be a promising candidate for treatment of cancer. (C) 2017 Published by Elsevier Masson SAS.
机译：许多研究表明，组蛋白脱乙酰酶（HDAC）抑制剂是治疗癌症的有前途的药剂。旨在寻找新型有效的HDAC抑制剂，我们设计并合成了两系列的羟肟酸盐和2-氨基苯甲酰胺化合物，如HDAC抑制剂和抗肿瘤剂。研究了这些化合物，用于其HDAC酶促抑制活性和针对各种癌细胞系的体外抗增殖活动（A549，Hepg2，MgC8-3和HCT116）。大多数合成化合物显示出有效的HDAC抑制活性和抗增殖活性。特别地，显示化合物12a，n-（2-氨噬蛋白1）-4- [（4-氟苯氧基）甲基]苯甲酰胺，具有最高HDAC抑制活性（50.6％在5μmm m）和抗肿瘤活性IC50值低至3.84 mu m对针对Hepg2人肝肝细胞癌细胞系数，比CS055和5.9倍低的4.8倍低于CI994。 HDAC同种型选择性测定表明12A是有效的HDAC2抑制剂。对接12A的停靠研究表明它紧紧地绑在HDAC2的粘合口袋中。进一步的研究表明，12A可以抑制A549癌细胞的迁移和菌落形成。此外，在A549癌细胞中，12A显着诱导凋亡和G2 / M期细胞周期停滞。这些结果表明，化合物12a可以是治疗癌症的有希望的候选者。 （c）2017年由Elsevier Masson SA发布。

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    Xie Rui; Yao Yue; Tang Pingwah; Chen Guangyao; Liu Xia; Yun Fan; Cheng Chunhui; Wu Xinying; Yuan Qipeng;

  • 作者单位

    Beijing Univ Chem Technol Med Chem Res Div Beijing Lab Biomed Mat Coll Life Sci &

    Technol 15;

    Beijing Univ Chem Technol Med Chem Res Div Beijing Lab Biomed Mat Coll Life Sci &

    Technol 15;

    Beijing Univ Chem Technol Med Chem Res Div Beijing Lab Biomed Mat Coll Life Sci &

    Technol 15;

    Beijing Univ Chem Technol Med Chem Res Div Beijing Lab Biomed Mat Coll Life Sci &

    Technol 15;

    Beijing Univ Chem Technol Med Chem Res Div Beijing Lab Biomed Mat Coll Life Sci &

    Technol 15;

    Beijing Univ Chem Technol Med Chem Res Div Beijing Lab Biomed Mat Coll Life Sci &

    Technol 15;

    Beijing Univ Chem Technol Med Chem Res Div Beijing Lab Biomed Mat Coll Life Sci &

    Technol 15;

    Beijing Univ Chem Technol Med Chem Res Div Beijing Lab Biomed Mat Coll Life Sci &

    Technol 15;

    Beijing Univ Chem Technol Med Chem Res Div Beijing Lab Biomed Mat Coll Life Sci &

    Technol 15;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    Histone deacetylase inhibitor; Hydroxamates; 2-Aminobenzamides; Antiproliferation; Molecular docking;

    机译：组蛋白脱乙酰化酶抑制剂;羟肟酸盐;2-氨基苯甲酰胺;抗溶剂;分子对接;

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