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 <i>in vitro</i> 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.