期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 182, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.111670
关键词
Tubulin polymerization inhibitors; Benzodiazepine derivatives; Antiproliferative activity; Cell cycle arrest; Apoptosis; In vivo antitumor activity
资金
- Natural Science Foundation of Guangdong Province [2018A030313539]
- youth innovation project of Guangdong university [E1-KFD015181K35]
- Science Foundation of Guangdong Provincial Hospital of Chinese Medicine [2017KT1525]
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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