Discovery of novel 2-aminonicotinonitrile derivatives with new potential autophagy activity.

Background: To clarify the molecular mechanism of novel 2-aminonicotinonitrile autophagy enhancers, two series of novel 2-aminonicotinonitrile derivatives are synthesized and their structure-activity relationship and biological activity were analyzed. Results & methodology: Structure-activity relationship analysis revealed that substituents at C-4 and C-6 position of 7a contribute to enhance their autophagy-inducing activity, while C-5 position substituents have the opposite effect. The most promising compound 7g showed the strongest autophagy-inducing activity and better antiproliferative activity by inducing cell apoptosis and blocking cell cycle G1 arrest in SGC-7901 cells. Conclusion: The novel 2-aminonicotinonitrile autophagy enhancers were for the first time discovered and 7g might be a promising new autophagy enhancer with potential anticancer activity.