Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents
- Eur J Med Chem. 2016 Jan 1:107:12-25. doi: 10.1016/j.ejmech.2015.10.045.
- 1. State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy, Guangxi Normal University, Yucai Road 15, Guilin 541004, Guangxi, PR China. Electronic address: [email protected].
- 2. State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy, Guangxi Normal University, Yucai Road 15, Guilin 541004, Guangxi, PR China.
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.