Synthesis of novel 4,7-disubstituted quinoline derivatives as autophagy inducing agents via targeting stabilization of ATG5.

A series of new 4,7-disubstituted quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 10c, 10g, 10i, 10j and 10k displayed potent antiproliferative activity with IC value of lower than 5.0 μM against human tumor cell lines, and N-(3-nitrophenyl)-7-((3,4,5-trimethoxybenzyl)oxy)quinoline - 4-amine 10k was found to be the most potent antiproliferative agent against HCT-116, HepG2, BCG-823, A549 and A2780 cell lines with IC values of 0.35, 1.98, 0.60, 0.39 and 0.67 μM, respectively. The antitumor efficacy of the representative compound 10k in mice was also evaluated, and the results showed that compound 10k effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 10k could inhibit colorectal cancer growth through inducing autophagy via excessively targeting stabilization of ATG5. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.