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 (IC50 = 0.09 μM) and RKO (IC50 = 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 (IC50 = 5.69 μM). Overall, compound 6b represents a promising dual topoisomerase 1/tubulin-targeting lead structure for the treatment of gastrointestinal tumor.