Design, synthesis and bioactivity evaluation of favorable evodiamine derivative scaffold for developing cancer therapy.

Natural product evodiamine is one of the most privileged scaffolds in drug discovery and is suitable for derivatization, which can be conducted quickly for structure optimization and structure-activity relationship research. In this work, a comprehensive SAR study on evodiamine scaffold with N14-3'-fluorophenyl substituted was completed, and compounds with high anti-tumor activity and good inhibitory effect on Top1 and Top2 were screened out. Tested evodiamine derivatives exhibited excellent broad-spectrum anti-tumor activity. Among them, compound 8b revealed 55.15% and 55.50% inhibition for Top1 and Top2 at 25 μM, as well as 0.16 and 0.13 μM IC50 value for MGC-803 and SGC-7901 cells, respectively; compound 9a revealed 70.50% and 71.81% inhibition for Top1 and Top2 at 25 μM, as well as 0.22 and 0.27 μM IC50 value for MGC-803 and SGC-7901 cells, respectively. The further biological evaluation showed that they could functionally induce apoptosis, significantly arrest the cell cycle at the G2/M phase, and markedly inhibit cell proliferation, migration and invasion. In addition, compound 9a performed a tumor inhibitory rate of 36.35% and showed no apparent toxicity in vivo. Overall, these optimized protocols will advance the progression of cancer chemotherapy and can be used to expand the options for screening therapeutic cancer drugs.