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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design, synthesis and biological evaluation of novel 4-anilinoquinazoline derivatives as hypoxia-selective EGFR and VEGFR-2 dual inhibitors
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Design, synthesis and biological evaluation of novel 4-anilinoquinazoline derivatives as hypoxia-selective EGFR and VEGFR-2 dual inhibitors

机译：新型4- anilinoquinazoline衍生物的设计，合成和生物学评价为缺氧选择性EGFR和VEGFR-2双抑制剂

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摘要

Tyrosine kinase inhibitors (TKIs) have achieved substantial clinical effects for cancer treatment while causing a number of adverse effects. Since hypoxia is an intrinsic difference between solid tumor and healthy tissues, one strategy to overcome the adverse effects of 'Ms is to enhance the specificity of anti-tumor activity by selectively targeting hypoxic region of tumors. Herein, we designed and synthesized a series of novel 4-anilinoquinazoline derivatives by introducing 3-nitro-1,2,4-triazole group to the side chain of vandetanib with modification of aniline moiety. Lead compounds, 10a and 10g, exhibited potent inhibitory activity against EGFR and VEGFR-2 kinase. Moreover, these two compounds were shown to enhance anti-proliferative activities on A549 and H446 cells under hypoxic conditions compared to vandetanib and dramatically down-regulate VEGF gene expression. In vivo studies confirmed that 10a and lOg not only inhibited tumor growth in A549 xenografts of BALB/c-nu mice but also significantly reduce toxicity associated with weight loss compared to vandetanib. These results suggest that EGFR/VEGFR-2 dual inhibitors, 10a and 10g, emerged as potential hypoxia-selective anti-tumor drugs with less toxicity for inhibiting in vitro and in vivo models of non-small cell lung cancer cells. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：酪氨酸激酶抑制剂（TKIS）对癌症治疗的临床疗效进行了大量的临床效果，同时导致一些不利影响。由于缺氧是固体肿瘤和健康组织之间的内在差异，因此通过选择性地靶向肿瘤的缺氧区域来提高抗肿瘤活性的不良反应的一种策略。在此，我们通过将3-硝基-1,2,4-三唑基团引入Vandetanib的侧链与苯胺部分的改性来设计和合成一系列新的4-嗜酸性喹唑啉衍生物。铅化合物，10A和10G，对EGFR和VEGFR-2激酶发表了有效的抑制活性。此外，与Vandetanib相比，这些两种化合物在缺氧条件下，在缺氧条件下增强了A549和H446细胞的抗增殖活性，并显着降低了VEGF基因表达。在体内研究证实，10A和Log不仅抑制Balb / C-Nu小鼠的A549异种移植物中的肿瘤生长，而且与Vandetanib相比，与减肥相关的毒性显着降低。这些结果表明，EGFR / VEGFR-2双抑制剂，10A和10G，作为潜在的缺氧选择性的抗肿瘤药物，具有较少抑制体外和非小细胞肺癌细胞体内模型的毒性较小的毒性。 （c）2019年Elsevier Masson SAS。版权所有。

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    Wei Huiqiang; Duan Yuqing; Gou Wenfeng; Cui Jie; Ning Hongxin; Li Deguan; Qin Yong; Liu Qiang; Li Yiliang;

  • 作者单位

    Peking Union Med Coll Inst Radiat Med Tianjin Key Lab Radiat Med &

    Mol Nucl Med Tianjin 300192;

    Peking Union Med Coll Inst Radiat Med Tianjin Key Lab Radiat Med &

    Mol Nucl Med Tianjin 300192;

    Peking Union Med Coll Inst Radiat Med Tianjin Key Lab Radiat Med &

    Mol Nucl Med Tianjin 300192;

    Tianjin Univ Tradit Chinese Med Tianjin 300193 Peoples R China;

    Peking Union Med Coll Inst Radiat Med Tianjin Key Lab Radiat Med &

    Mol Nucl Med Tianjin 300192;

    Peking Union Med Coll Inst Radiat Med Tianjin Key Lab Radiat Med &

    Mol Nucl Med Tianjin 300192;

    Univ Texas MD Anderson Canc Ctr Dept Melanoma Med Oncol Houston TX 77030 USA;

    Peking Union Med Coll Inst Radiat Med Tianjin Key Lab Radiat Med &

    Mol Nucl Med Tianjin 300192;

    Peking Union Med Coll Inst Radiat Med Tianjin Key Lab Radiat Med &

    Mol Nucl Med Tianjin 300192;

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

    Tyrosine kinase inhibitor; 3-Nitro-1; 2; 4-triazole; Hypoxia; EGFR; VEGFR-2; Vandetanib;

    机译：酪氨酸激酶抑制剂;3-硝基-1;2;4-三唑;缺氧;EGFR;VEGFR-2;Vandetanib;

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