Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives.

Autor: Chen JN; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: cjn288@sina.com., Li T; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: litingfendou@163.com., Cheng L; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: missliesel@163.com., Qin TS; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: qintaisheng@sina.com., Sun YX; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: wks72018@sina.com., Chen CT; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: cctichen@sina.com., He YZ; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: yzhe226@sina.com., Liu G; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: liuguang_007@126.com., Yao D; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: petto19@163.com., Wei Y; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: weiying423@sina.com., Li QY; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: lqy061828@sina.com., Zhang GJ; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Yucai Road 15, Guilin, 541004, Guangxi, PR China. Electronic address: zhanggj914@126.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2020 Nov 01; Vol. 205, pp. 112661. Date of Electronic Publication: 2020 Jul 24.
DOI: 10.1016/j.ejmech.2020.112661
Abstrakt: Based on the structural modification of molecular-targeted agent sorafenib, a series of quinazolinyl-arylurea derivatives were synthesized and evaluated for their anti-proliferative activities against six human cancer cell lines. Compared with other cell lines tested, T24 was more sensitive to most compounds. Compound 7j exhibited the best profile with lower IC 50 value and favorable selectivity. In this study, we focused on 7j-induced death forms of T24 cells and tried to elucidate the reason for its potent proliferative inhibitory activity. Compound 7j treatment could trigger three different cell death forms including apoptosis, ferroptosis, and autophagy; which form would occur depended on the concentrations and incubation time of 7j: (1) Lower concentrations within the initial 8 h of 7j treatment led to apoptosis-dependent death. (2) Ferroptosis and autophagy occurred in the case of higher concentrations combining with extended incubation time through effectively regulating the Sxc - /GPx4/ROS and PI3K/Akt/mTOR/ULK1 pathways, respectively. (3) The above death forms were closely associated with intracellular ROS generation and decreased mitochondrial membrane potential induced by 7j. In molecular docking and structure-activity relationship analyses, 7j could bind well to the active site of the corresponding receptor glutathione peroxidase 4 (GPx4). Compound 7j could be a promising lead for molecular-targeted anti-bladder cancer agents' discovery.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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