Design, synthesis and anti-proliferative activity of 3-aryl-evodiamine derivatives

Evodiamine and its analogues have received significant attention owing to their antitumor activity. In this work, Pd-catalyzed Suzuki-Miyaura coupling was employed as a key reaction to diversify the natural product evodiamine at the C3 position. A library of new 3-aryl-evodiamine derivatives (6a-6ae) was synthesized. The in vitro antitumor activity of these compounds were evaluated against various cancer cell lines (HCT116, 4T1, and HepG2). Most of them showed better cytotoxicity than evodiamine. Herein, the primary structure-activity relationship of 3-aryl-evodiamine derivatives was briefly discussed. In particular, the methylsulfonylbenzene derivative 6y exhibited excellent anti-proliferative activity against HCT116 (IC₅₀ = 0.58 ± 0.04 μM) and 4T1 cells (IC₅₀ = 0.99 ± 0.07 μM), providing a promising evodiamine analogue for antitumor drug development. This work would offer new insights for the development of evodiamine-based compounds.