Design, Synthesis and Anti-proliferative Activity of 3-Aryl-Evodiamines

Abstract

Evodiamine and its analogues have received significant attention due to their antitumor activity. In this work, Pd catalyzed Suzuki-Miyaura coupling was employed as key reaction to diversify at C3 position of the natural product evodiamine. A library of new 3-aryl-evodiamine derivatives (6a – 6ae) were synthesized. The in vitro antitumor activity of the library of evodiamine derivatives were evaluated against various cancer cell lines (HCT116, 4T1, and HepG2). Most of them showed better cytotoxicity than that of evodiamine. The primary structure-activity relationship of 3-aryl-evodiamines was briefly discussed. In particular, the methylsulfonylbenzene derivative 6y had 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 evodiamine lead compounds development.