Design, synthesis, structure-activity relationships and mechanism of action of new quinoline derivatives as potential antitumor agents

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 poten...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2019-01, Vol.162, p.666-678
Main Authors: Li, Shangze, Hu, Lihua, Li, Jianru, Zhu, Jiongchang, Zeng, Feng, Huang, Qiuhua, Qiu, Liqin, Du, Runlei, Cao, Rihui
Format: Article
Language:English
Subjects:
Antiproliferative
Mechanism of action
Quinoline derivative
Structure-activity relationships
Synthesis
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Summary: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 μM. 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 10g 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. A series of new quinoline derivatives was designed, synthesized and evaluated as promising antitumor agents. The representative compound 10g could trigger p53/Bax-dependent colorectal cancer cell apoptosis by activating p53 transcriptional activity. [Display omitted] •A series of new quinolines derivatives was synthesized and evaluated as antitumor agent.•Compound 10g was found to be the most potent antiproliferative agent.•Compound 10g triggered p53/Bax-dependent colorectal cancer cell apoptosis by activating p53 transcriptional activity.•Compound 10g effectively inhibited tumor growth in a colorectal cancer xenograft model in nude mice.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2018.11.048