title: Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents.
abstract: 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.
authors.affiliation: 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: cjn288@sina.com.
authors.forename: Jia-Nian
authors.initials: JN
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Xian-Fu
authors.initials: XF
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: 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.
authors.forename: De-Wen
authors.initials: DW
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Guang-Ji
authors.initials: GJ
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xing-Can
authors.initials: XC
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Heng-Shan
authors.initials: HS
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D062105:Molecular Docking Simulation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D014508:Urea; D019908:Proto-Oncogene Proteins c-raf
keywords: 4-Aminoquinazoline; Antiproliferative activity; Diaryl urea; Structure–activity relationship; c-Raf kinase