A novel 20 (R) dammarane panaxadiol-indole-2 ',3' -dione derivative was found to inhibit the growth and migration of colorectal cancer cells by inhibiting EGFR-mediated RalA/EMT pathway.

Panaxadiol (PD) is a secondary metabolite of ginsenosides and has excellent anti-tumor activity. In this study, by coupling PD with the anti-tumor active fragment 1H-indole-2, 3-dione, 24 novel PD derivatives were designed and synthesized to enhance their anti-tumor efficacy and tumor selectivity. Among them, the proliferation inhibition rate of compound 4e on colorectal cancer cells (IC50 = 4.46 ± 0.70 μM) was 16.92 times lower than that of HEK293, showing a relatively high therapeutic window. Mechanologically, compound 4e inhibits CDKs activity, induces G0/G1 cycle arrest, reduces mitochondrial membrane potential and ROS activity, induces apoptosis, and inhibits migration and invasion. It is worth noting that for the first time, we discovered that compound 4e regulates the RalA/EMT pathway by inhibiting EGFR rather than RalB, disrupts the formation of filamentate feet and cytoskeletal remodeling, and interferes with the migration and growth of colorectal cancer cells. In vivo experiments further confirmed that compound 4e has higher anti-tumor activity and safety than 5-fluorouracil. Overall, we reported 4e as a promising candidate for the treatment of colorectal cancer.