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Design, synthesis, and biological evaluation of novel benzodiazepine derivatives as anticancer agents through inhibition of tubulin polymerization in vitro and in vivo

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收录情况： ◇ SCIE

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机构： [a]Department of Phase I Clinical Research Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China [b]Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China [c]School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

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关键词： Tubulin polymerization inhibitors Benzodiazepine derivatives Antiproliferative activity Cell cycle arrest Apoptosis In vivo antitumor activity

摘要：

A series of novel structurally-related tubulin polymerization inhibitors based on benzodiazepine were designed, synthesized, and evaluated for anticancer activity. Extensive structure modifications were performed to investigate the detailed structure and activity relationships (SARs). Most compounds exhibited potent antiproliferative activity against a panel of cancer cell lines. Among these compounds, the optimal compound, 9a, possessed the most superior activity, including cytotoxicity against five cancer cell lines (IC50 = 6-15 nM) and inhibition of tubulin polymerization (IC50= 1.65 +/- 0.11 mu M). Mechanistic studies revealed that 9a could disrupt intracellular microtubule organization, arrest cell cycle at the G(2)/M phase and eventually induce cell apoptosis. Compound 9a exhibited good metabolic stability with a t(1/2) of 161.2 min, which was much better than the reference compound CA-4. Moreover, the disodium salt of 9a, 9a-P, exhibited excellent in vivo antitumor activity in xenograft mice model with inhibitory rate of 893%, which was better than the reference compounds CA-4P (inhibitory rate: 52.8%) and Y-01P (inhibitory rate: 77.7%). Altogether, 9a could serve as a promising lead compound for the development of highly efficient anticancer agents. (C) 2019 Elsevier Masson SAS. All rights reserved.

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出版当年[2018]版：

大类 | 2 区

医学

小类 | 1 区药物化学

最新[2025]版：

大类 | 2 区医学

小类 | 1 区药物化学

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出版当年[2017]版：

Q1 CHEMISTRY, MEDICINAL

最新[2023]版：

Q1 CHEMISTRY, MEDICINAL

影响因子： 6 最新[2023版] 6.1 最新五年平均 4.816 出版当年[2017版] 4.527 出版当年五年平均 4.519 出版前一年[2016版] 4.833 出版后一年[2018版]

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第一作者机构： [a]Department of Phase I Clinical Research Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

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