Synthesis, structure-activity relationships and preliminary mechanism of action of novel water-soluble 4-quinolone-3-carboxamides as antiproliferative agents.

A series of novel water-soluble 4-quinolone-3-carboxamides was prepared and evaluated as antiproliferative agents. Preliminary results indicated that most compounds tested in this study showed potent antiproliferative potencies against human tumor cell lines, and compound 8k was found to be the most potent antiproliferative agents with IC50 value of lower than 10 μM against nine human tumor cell lines. These results suggested that (1) the alkylamino side chain substituent was the advisable pharmacophoric group for the enhanced antiproliferative activities; (2) the length of the alkylamino side chain moiety also affected their antiproliferative potencies, and three methylene units were more favorable; (3) introducing arylated alkyl substituent into N1-position of quinolone facilitated antiproliferative activities of this class of compounds. Further investigations on mechanism of action of this class of compound demonstrated that the representative compound 8k could trigger p53/Bax-independent colorectal cancer cell apoptosis via inducing ROS accumulation.