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

• Published in: European journal of medicinal chemistry 2020-11, Vol.205, p.112661-112661, Article 112661
• Main Authors: Chen, Jia-Nian, Li, Ting, Cheng, Li, Qin, Tai-Sheng, Sun, Ye-Xiang, Chen, Chu-Ting, He, Yue-Zhen, Liu, Guang, Yao, Di, Wei, Ying, Li, Qiu-Yin, Zhang, Guang-Ji
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Autophagy; Cell Line, Tumor; Chemistry Techniques, Synthetic; Ferroptosis; Glutathione Peroxidase - chemistry; Glutathione Peroxidase - metabolism; Humans; Intracellular Space - drug effects; Intracellular Space - metabolism; Molecular Docking Simulation; Protein Conformation; Quinazolines - chemistry; Quinazolinyl-arylurea; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Urea - chemical synthesis; Urea - chemistry; Urea - metabolism; Urea - pharmacology; Urinary Bladder Neoplasms - pathology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112661

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 IC50 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. A series of quinazolinyl-arylurea derivatives were synthesized. Compound 7j exhibited the best profile with lower IC50 value against T24 cells and favorable selectivity. Compound 7j could induce three different death forms including apoptosis, ferroptosis, and autophagy. [Display omitted] •A series of quinazolinyl-arylurea derivatives were synthesized.•T24 cell line was sensitive to most compounds.•Compound 7j possessed low IC50 value and favorable selectivity.•Compound 7j induced three death forms: apoptosis, ferroptosis, and autophagy.