Cu-catalyzed late-stage diversification and anti-proliferative activity evaluation of evodiamine

A series of N-13-arylated evodiamine derivatives (3a-3v) were designed and synthesized via a Cu-catalyzed late-stage diversification of the bioactive natural product evodiamine. The antitumor activities of these synthesized derivatives against HCT-116, 4T1, and SU-DHL-6 cells were evaluated in vitro, demonstrating that direct introduction of aryl groups at the N-13 position through C-N coupling led to unsatisfactory cytotoxicity. Based on previous studies, the preliminary structure-activity relationship analysis indicated that inserting a suitable pharmacophore fragment between the N-13 position and the introduced aryl group can enhance the anti-tumor activity of N-13 evodiamine derivatives containing aromatic functional groups. This study provides helpful insights for the further development of antitumor evodiamine analogues.