Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 162, Issue -, Pages 666-678Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.11.048
Keywords
Synthesis; Quinoline derivative; Antiproliferative; Structure-activity relationships; Mechanism of action
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Funding
- Natural Science Foundation of Guangdong Province [S2013010012138, 2016A030313349]
- Fundamental Research Funds for the Central Universities [413000099]
- Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund Project [cxpy2017005]
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A series of new quinoline derivatives was designed, synthesized and evaluated as potential antitumor agents. The results indicated that most compounds exhibited potent antiproliferative activity, and 7-(4-fluorobenzyloxy)- N-(2-(dimethylamino)-ethyl)quinolin-4-amine 10g was found to be the most potent antiproliferative agent against human tumor cell lines with an IC50 value of less than 1.0 mu M. Preliminary structure-activity relationships analysis suggested that (1) the large and bulky alkoxy substituent in position-7 might be a beneficial pharmacophoric group for antiproliferative activity; (2) the amino side chain substituents in position-4 facilitated the antiproliferative activity of this class of compounds; and (3) the length of the alkylamino side chain moiety affected the antiproliferative potency, with two CH2 units being the most favorable. Further investigation of the mechanism of action of this class of compounds demonstrated that the representative compound log triggered p53/Bax-dependent colorectal cancer cell apoptosis by activating p53 transcriptional activity. Moreover, the results showed that compound 10g effectively inhibited tumor growth in a colorectal cancer xenograft model in nude mice. Thus, these quinoline derivatives might serve as candidates for the development of new antitumor drugs. (C) 2018 Elsevier Masson SAS. All rights reserved.
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