Design, synthesis, biological evaluation of 6-(2-amino-1H-benzo[d] imidazole-6-yl)quinazolin-4(3H)-one derivatives as novel anticancer agents with Aurora kinase inhibition
Design, synthesis, biological evaluation of 6-(2-amino-1H-benzo[d] imidazole-6-yl)quinazolin-4(3H)-one derivatives as novel anticancer agents with Aurora kinase inhibition
复制标题
6-(2-氨基-1H-苯并[d]咪唑-6-基)喹唑啉-4(3H)-一衍生物的设计、合成和生物学评价作为具有极光激酶抑制作用的新型抗癌药物
DOI：
10.1016/j.ejmech.2020.112108
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发表时间：
2020-03-15
影响因子：
6.7
通讯作者：
Fan, Yanhua
中科院分区：
文献类型：
--
作者：
Fan, Chengcheng;Zhong, Ting;Fan, Yanhua
Aurora A kinase, a member of the Aurora kinase family, is frequently overexpressed in various human cancers. In addition, Overexpression of Aurora A kinase is associated with drug resistance and poor prognosis in many cancers including breast cancer. Therefore, Aurora A kinase has been considered as an attractive anticancer target for the treatment of human cancers. Herein, A series of 6-(2-amino-1H-benzo [d]imidazole-6-yl)quinazolin-4(3H)-one derivatives were designed, synthesized, and evaluated as Aurora A kinase inhibitors. The cell-based cytotoxicity assays showed that compound 16h was the most potent cytotoxic agent against all tested cancer cells and had a lower IC50 value than ENMD-2076 against MDA-MB-231 cells. Meanwhile, Aurora A kinase assay and Western blot analysis showed that 16h inhibited Aurora A kinase with an IC50 value of 21.94 nM and suppressed the phosphorylation of Histone H3 on Ser10 and Aurora A kinase on Thr288, which were consistent with the activation of Aurora A kinase. Accordingly, 16h caused aberrant mitotic phenotypes and obvious G2/M phase arrest in MDA-MB-231 cells and induced caspase-dependent apoptosis in MDA-MB-231 cells. These results demonstrated that 16h is a potential candidate for the development of anticancer agents targeting Aurora A kinase. (C) 2020 Elsevier Masson SAS. All rights reserved.
