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 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.