Synthesis and biological evaluation of quinoline derivatives inducing cell apoptosis mediated by PI3K/AKT/mTOR pathway

Colorectal cancer (CRC) is one of the most common and deadly cancers worldwide and drug resistance of chemotherapy pose a great challenge to the treatment for CRC. In the prior report, the novel quinoline derivatives with acylhydrazide as a promising pharmacophore demonstrated excellent antifungal activity, but the anticancer activity of these novel quinoline derivatives has not been evaluated. In this study, six quinoline derivatives were synthesized and their cytotoxicity was evaluated against colorectal cancer HCT116 and Caco-2 cells. The IC 50 values of compound 3a were 1.56 and 0.83 μM against HCT116 and Caco-2 cells respectively for 48 h. The IC 50 values of compound 3d were 4.36 and 4.04 μM against HCT116 and Caco-2 cells respectively for 48 h. Compound 3a and 3d significantly inhibited the proliferation and migration of HCT116 and Caco-2 cells. Mechanistic studies showed that compound 3a and 3d induced cell apoptosis of colorectal cancer cells by disrupting mitochondrial membrane potential and increasing the production of reactive oxygen species. Further analysis revealed that compound 3a and 3d could inhibit the growth of colorectal cancer cells by regulating PI3K/AKT/mTOR signaling pathway. Moreover, compound 3a exhibited low acute toxicity and good anti-tumor activity in vivo . After treatment with compound 3a of 10 mg/kg, the tumor weight of mice decreased by 80.46% compared with 5-Fu (31.86%). These results suggest that compound 3a and 3d were promising leading compounds for the development of anti-colorectal cancer drugs.