Synthesis, SAR study, and bioactivity evaluation of a series of Quinoline-Indole-Schiff base derivatives: Compound 10E as a new Nur77 exporter and autophagic death inducer

Compound 10E is a new Nur77 exporter and autophagic death inducer which showed potent antiproliferative activity at micromolar concentrations against three different liver cancer cells. [Display omitted] •New Quinoline-Indole-Schiff base derivatives with naphthalene are potent anti-HCC agents.•10E greatly inhibits cell migration and promotes cell apoptosis in liver cancer cells.•Molecular docking and MD simulation studies suggest 10E as a valuable small ligand of Nur77.•10E has a good affinity to Nur77 with KD values of 2.25–4.10 μM.•10E induces the sub-cellular localization of Nur77 and results in autophagic death. We previously reported 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole- 2-carbohydrazide derivatives as new Nur77 modulators. In this study, we explored whether the 8-methoxy-2-methylquinoline moiety and bicyclic aromatic rings at the N’-methylene position were critical for their antitumor activity against hepatocellular carcinoma (HCC). For this purpose, a small library of 5-substituted 1H-indole-2-carbohydrazide derivatives was designed and synthesized. We found that the 8-methoxy-2-methylquinoline moiety was a fundamental structure for its biological function, while the introduction of the bicyclic aromatic ring into the N’-methylene greatly improved its anti-tumor effect. We found that the representative compound 10E had a high affinity to Nur77. The KD values were in the low micromolar (2.25–4.10 μM), which were coincident with its IC50 values against the tumor cell lines (IC50