N(14)-substituted evodiamine derivatives as dual topoisomerase 1/tubulin-Inhibiting anti-gastrointestinal tumor agents

Gastrointestinal tumor is an important factor threatening human health. Natural product-based drug discovery is a popular paradigm for expanding the chemical space and identifying new molecular entities that ameliorate human disease. Evodiamine-inspired medicinal chemistry presents therapeutic potential for treating tumors in different tissues via multi-target inhibition. Here, by focusing on the discovery of anti-gastrointestinal tumor drugs, a series of N (14) alkyl-substituted evodiamine derivatives were designed and synthesized. The structure–activity relationship studies culminated in the identification of the N (14)-propyl-substituted evodiamine analog 6b , which showed low nanomolar inhibitory activity against MGC-803 (IC 50  = 0.09 μM) and RKO (IC 50  = 0.2 μM) cell lines. Moreover, compound 6b was effective in inducing apoptosis , arresting the cell cycle in the G2/M phase, and inhibiting migration and invasion of MGC-803 and RKO cell lines in a dose-dependent manner in vitro. Further antitumor mechanism studies revealed that compound 6b significantly inhibited topoisomerase 1 (inhibition rate of 58.3% at 50 μM) and tubulin polymerization (IC 50  = 5.69 μM). Overall, compound 6b represents a promising dual topoisomerase 1/tubulin-targeting lead structure for the treatment of gastrointestinal tumor.