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

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

  • Eur J Med Chem. 2019 Jan 15;162:666-678. doi: 10.1016/j.ejmech.2018.11.048.
Shangze Li 1 Lihua Hu 2 Jianru Li 3 Jiongchang Zhu 3 Feng Zeng 2 Qiuhua Huang 3 Liqin Qiu 3 Runlei Du 2 Rihui Cao 4
Affiliations

Affiliations

  • 1 Medical Science Research Center, Zhongnan Hospital of Wuhan University, Hubei, Wuhan, 430071, PR China.
  • 2 College of Life Sciences, Wuhan University, 299 Ba Yi Road, Wuchang, 430072, PR China.
  • 3 School of Chemistry, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou, 510275, PR China.
  • 4 School of Chemistry, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou, 510275, PR China. Electronic address: caorihui@mail.sysu.edu.cn.
Abstract

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.

Keywords

Antiproliferative; Mechanism of action; Quinoline derivative; Structure-activity relationships; Synthesis.

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