Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents.
Through a structure-based molecular hybridization approach, a series of novel quinazolinyl-diaryl urea derivatives were designed, synthesized, and screened for their in vitro antiproliferative activities against three cancer cell lines (HepG2, MGC-803, and A549). Six compounds (7 g, 7 m, 7 o, 8 e, 8 g, and 8 m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8 g exhibited the strongest activity. In particular, compound 8 g induced A549 apoptosis, arrested cell cycle at the G0/G1 phase, elevated intracellular reactive oxygen species level, and decreased mitochondrial membrane potential. This compound can also effectively regulate the expression of apoptosis- and cell cycle-related proteins, and influence the Raf/MEK/ERK pathway. Molecular docking and structure-activity relationship analyses revealed that it can bind well to the active site of the receptor c-Raf, which was consistent with the biological data. Therefore, compound 8 g may be a potent antitumor agent, representing a promising lead for further optimization.
['Chen|Jia-Nian|JN|', 'Wang|Xian-Fu|XF|', 'Li|Ting|T|', 'Wu|De-Wen|DW|', 'Fu|Xiao-Bo|XB|', 'Zhang|Guang-Ji|GJ|', 'Shen|Xing-Can|XC|', 'Wang|Heng-Shan|HS|']
D000970:Antineoplastic Agents D017209:Apoptosis D020134:Catalytic Domain D002453:Cell Cycle D045744:Cell Line, Tumor D060326:Chemistry Techniques, Synthetic D015195:Drug Design D004354:Drug Screening Assays, Antitumor D056945:Hep G2 Cells D006801:Humans D053078:Membrane Potential, Mitochondrial D062105:Molecular Docking Simulation D019908:Proto-Oncogene Proteins c-raf D017382:Reactive Oxygen Species D013329:Structure-Activity Relationship D014508:Urea
Antiproliferative activity 4-Aminoquinazoline Diaryl urea Structure–activity relationship c-Raf kinase