Journal Article
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
Fan, C; Zhong, T; Yang, H; Yang, Y; Wang, D; Yang, X; Xu, Y; Fan, Y
European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254
Elsevier Masson SAS
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. © 2020 Elsevier Masson SAS
6-(1H-benzo[d]imidazole-6-yl)quinazolin-4(3H)-one derivatives; Aurora A kinase; Cell apoptosis; Cell cycle arrest; 1,1 diethyl 3 [6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]urea; 1,1 dimethyl 3 [6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]urea; 4(3h) quinazolinone derivative; antineoplastic agent; aurora kinase inhibitor; caspase 3; caspase 9; enmd 2076; histone H3; methyl[6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]carbamate; n [6 (3 butyl 4 oxo 3,4 dihydroquinazolin 6 yl) 1h benzo[d]imidazole 2 yl]propionamide; n [6 (3 methyl 4 oxo 3,4 dihydroquinazolin 6 yl) 1h benzo[d]imidazole 2 yl]ethylsulfonamide; n [6 (3 methyl 4 oxo 3,4 dihydroquinazolin 6 yl) 1h benzo[d]imidazole 2 yl]propionamide; n [6 [3 (2 morpholino 2 oxoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]ethylsulfonamide; n [6 [3 (2 morpholino 2 oxoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]propionamide; n [6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]benzamide; n [6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]cyclohexanecarboxamide; n [6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]cyclopropanecarboxamide; n [6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]ethylsulfonamide; n [6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]morpholine 4 carboxamide; n [6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]pentanamide; n [6 [3 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]propionamide; n [6 [3 (3 morpholinopropyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]propionamide; n [6 [3 methyl 2 (2 morpholinoethyl) 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]propionamide; n [6 [3 methyl 4 oxo 2 [(4 propionylpiperzin 1 yl)methyl] 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]propionamide; n [6 [3 [2 (1h indol 3 yl)ethyl] 4 oxo 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]propionamide; n [6 [4 oxo 3 [2 (piperidin 1 yl)ethyl] 3,4 dihydroquinazolin 6 yl] 1h benzo[d]imidazole 2 yl]propionamide; staurosporine; unclassified drug; antineoplastic agent; AURKA protein, human; aurora A kinase; benzimidazole derivative; protein binding; protein kinase inhibitor; quinazolinone derivative; antineoplastic activity; antiproliferative activity; apoptosis; Article; controlled study; cytotoxicity assay; drug design; drug potency; drug screening; drug synthesis; enzyme inhibition; female; G2 phase cell cycle checkpoint; hinge region; histone phosphorylation; human; human cell; hydrogen bond; IC50; M phase cell cycle checkpoint; male; MDA-MB-231 cell line; molecular docking; MTT assay; Western blotting; cell proliferation; drug design; drug effect; drug screening; enzyme active site; metabolism; synthesis; tumor cell line; Antineoplastic Agents; Apoptosis; Aurora Kinase A; Benzimidazoles; Catalytic Domain; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; Humans; Molecular Docking Simulation; Protein Binding; Protein Kinase Inhibitors; Quinazolinones