Abstract

Bis- β -carboline alkaloids are widely distributed in natural products and represent a promising drug-like scaffold for discovering drugs and bioactive molecules. In this study, we utilized the structural simplification strategy to construct a novel bis- β -carboline scaffold via “one-pot” condensation-Mannich reaction. The simplified bis- β -carboline derivatives were obtained in good yield. Antitumor evaluation revealed most compounds, especially 3m , displayed potent antitumor activity (IC 50 values for 3m : 0.96 μM ∼ 1.52 μM). More importantly, 3m displayed valuable antitumor properties including anti-migration and anti-invasion activity against cancer cells, antiangiogenic and vascular-disrupting properties. Mechanistic studies revealed 3m potently inhibited both Top1 and Top2 activity, thus interfering with DNA synthesis in cancer cells. Taken together, this study developed a new synthetic methodology to construct a novel bis- β -carboline scaffold, which represents a promising lead structure for antitumor drug discovery.