Design, synthesis, antitumor activities and biological studies of novel diaryl substituted fused heterocycles as dual ligands targeting tubulin and katanin
Design, synthesis, antitumor activities and biological studies of novel diaryl substituted fused heterocycles as dual ligands targeting tubulin and katanin
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新型二芳基取代稠合杂环作为微管蛋白和剑蛋白双配体的设计、合成、抗肿瘤活性和生物学研究
DOI：
10.1016/j.ejmech.2019.05.072
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发表时间：
2019-09-15
影响因子：
6.7
通讯作者：
Wang, Yang
中科院分区：
文献类型：
--
作者：
Gao, Feng;Liang, Yuru;Wang, Yang
微管是肿瘤治疗的重要靶点之一。将β -内酰胺类化合物和嘌呤类化合物微管蛋白聚合抑制剂和角朊蛋白活性上调调节剂的结构结合，设计了一类新的二芳基取代咪唑[4,5-c]吡啶-2-酮类化合物和咪唑[4,5-c]吡啶类化合物。通过体外抗肿瘤活性评价和机制研究，鉴定出1,6-二芳基- 1h -咪唑[4,5-c]吡啶-2(3H)- 1 20b为首个同时靶向微管蛋白和角蛋白的双功能药物。体内实验证实，化合物20b能显著抑制异种移植肿瘤生长，具有良好的药动学特征，具有独特的双靶向微管机制，具有进一步开发抗肿瘤候选药物的潜力。(C) 2019 Elsevier Masson SAS。版权所有。
Microtubule is one of the important targets for cancer treatment. A novel class of diaryl substituted imidazo[4,5-c]pyridin-2-ones and imidazo[4,5-c]pyridines were designed based on combination principles by merging the structures of beta-lactams and purine-type compounds known as tubulin polymerization inhibitor and katanin activity up-regulator, respectively. Their antitumor activities were evaluated in vitro and the mechanism was elucidated, leading to the identification of 1,6-diaryl-1H-imidazo[4,5-c]pyridin-2(3H)-one 20b as the first bifunctional agent that can target both tubulin and katanin simultaneously. The in vivo assays verified that compound 20b significantly inhibited xenograft tumor growth with good pharmacokinetic characteristics, demonstrating a promising potential for further development into anti-tumor drug candidates with a unique mechanism of dual-targeting microtubule. (C) 2019 Elsevier Masson SAS. All rights reserved.