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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors
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Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors

机译：异吡啶吡啶的设计，合成和抗癌特性作为有效的血氯胺结合位点抑制剂

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摘要

A series of novel isocombretapyridines were designed and synthesized based on a lead compound isocombretastatin A-4 (isoCA-4) by replacing 3,4,5-trimethoxylphenyl with substituent pyridine nucleus. The MTT assay results showed that compound 20a possessed the most potent activities against all tested cell lines with IC50 values at nanomolar concentration ranges. Moreover, 20a inhibited tubulin polymerization at a micromolar level and also displayed potent anti-vascular activity in vitro. Further mechanistic studies were conducted to demonstrate that compound 20a could bind to the colchicine site of tubulin,and disrupte the cell microtubule networks, induce G2/M phase arrest, promote apoptosis and depolarize mitochondria of K562 cells in a dose-dependent manner. Notably, 20a exhibited more potent tumor growth inhibition activity with 68.7% tumor growth inhibition than that of isoCA-4 in H22 allograft mouse model without apparent toxicity. The present results suggested that compound 20a may serve as a promising potent microtubule-destabilizing agent candidate for the development of therapeutics to treat cancer. Crown Copyright (C) 2020 Published by Elsevier Masson SAS. All rights reserved.
机译：一系列新颖isocombretapyridines的是通过置换设计并基于铅化合物isocombretastatin A-4（isoCA-4）合成3,4,5- trimethoxylphenyl与取代吡啶核。 MTT测定结果表明，化合物20A具有抵抗在纳摩尔浓度范围内所有测试细胞系的IC 50个值的最有效的活动。此外，图20A抑制微管蛋白聚合在微摩尔水平，并且还显示在体外有效的抗血管活性。进一步的机制研究进行了证明化合物20a可以结合到微管蛋白的秋水仙碱站点，disrupte细胞微管网络，诱导G2 / M期阻滞，促进细胞凋亡和K562细胞以剂量依赖的方式去极化线粒体。值得注意的是，图20A与68.7％的肿瘤生长抑制比isoCA-4在H22，没有明显的毒性同种异体移植小鼠模型的表现出更有效的肿瘤生长抑制活性。目前的结果表明，化合物20a可以作为一个有前途的有效的微管去稳定剂的候选治疗剂的开发以治疗癌症。皇冠版权所有（C）2020发布时间由Elsevier马森SAS。版权所有。

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  • 作者

    Shuai Wen; Li Xinnan; Li Wenlong; Xu Feijie; Lu Lixue; Yao Hong; Yang Limei; Zhu Huajian; Xu Shengtao; Zhu Zheying; Xu Jinyi;

  • 作者单位

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

    Univ Nottingham Sch Pharm Div Mol Therapeut &

    Formulat Univ Pk Campus Nottingham NG7 2RD;

    China Pharmaceut Univ State Key Lab Nat Med 24 Tong Jia Xiang Nanjing 210009 Peoples R China;

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

    Isocombretapyridines; Tubulin inhibitors; Colchicine binding site; Anti-vascular; Antitumor;

    机译：异黄素丙啶;小蛋白抑制剂;血氯化氨酸结合位点;抗血管;抗肿瘤;

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