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Design, synthesis, and antitumor evaluation of quinoline‐imidazole derivatives
Author(s) -
Xiao Zhen,
Lei Fei,
Chen Xiuying,
Wang Xiaolei,
Cao Lujie,
Ye Kejun,
Zhu Wufu,
Xu Shan
Publication year - 2018
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201700407
Subject(s) - quinoline , chemistry , imidazole , pi3k/akt/mtor pathway , stereochemistry , in vitro , a549 cell , cell culture , protein kinase b , mtt assay , signal transduction , biochemistry , biology , organic chemistry , genetics
A series of compounds bearing quinoline‐imidazole ( 8a–e , 9a–e , 10a–e , 11a–e , and 12a–e ) not reported previously were designed and synthesized. The target compounds were evaluated for antitumor activity against A549, PC‐3, HepG2, and MCF‐7 cells by the MTT method, with NVP‐BEZ235 being the positive control. Most compounds showed moderate activity and compound 12a showed the best activity against HepG2, A549, and PC‐3 cells, with half‐maximal inhibitory concentration (IC 50 ) values of 2.42 ± 1.02 µM, 6.29 ± 0.99 µM, and 5.11 ± 1.00 µM, respectively, which was equal to NVP‐BEZ235 (0.54 ± 0.13 µM, 0.36 ± 0.06 µM, 0.20 ± 0.01 µM). Besides, the IC 50 value of 12a against the cell line WI‐38 (human fetal lung fibroblasts) was 32.8 ± 1.23 µM, indicating that the target compounds were selective for cancer cells. So, 11a and 12a were evaluated against PI3Kα and mTOR to find out if the compounds acted through the PI3K‐Akt‐mTOR signal transduction pathway. The inhibition ratios to PI3Kα and mTOR were slightly lower than that of NVP‐BEZ235, suggesting there may be some other mechanisms of action. The structure–activity relationships and docking study of 11a and 12a revealed that the latter was superior. Moreover, the target compounds showed better in vitro anticancer activity when the C‐6 of the quinoline ring was replaced by a bromine atom.