期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 107, 期 -, 页码 12-25出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.10.045
关键词
4-Aminoquinazoline; Diaryl urea; Antiproliferative activity; c-Raf kinase; Structure-activity relationship
资金
- National Natural Science Foundation of China [21364002, 81260472]
- National Basic Research Program of China [2012CB723501]
- Guangxi Natural Science Foundation of China [2013GXNSFBA019200, 2013GXNSFGA019001, 2012GXNSFDA053007]
- State Key Laboratory Cultivation Base for Chemistry and Molecular Engineering of Medicinal Resources [CMEMR2012-A01, CMEMR2013-C03]
- Guangxi Education Department Common Project [2013YB025]
- Guangxi Pharmaceutical Industry Talent Small Highland Project [1313, 1105]
- Guangxi Graduate Education Innovation Projects [JGY2015023]
- Guangxi Normal University Key Project [2011ZD006]
- [IRT1225]
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 (7g, 7m, 7o, 8e, 8g, and 8m) showed stronger activity against a certain cell line compared with the positive reference drugs sorafenib and gefitinib. Among the six compounds, 8g exhibited the strongest activity. In particular, compound 8g 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 8g may be a potent antitumor agent, representing a promising lead for further optimization. (C) 2015 Elsevier Masson SAS. All rights reserved.
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