Design, Synthesis, and Anticancer Activity Evaluation of Novel Betulin Derivatives

A series of novel betulin-28-isatin hydrazone derivatives was prepared, which were evaluated for their anticancer activity. Among them, 3β-hydroxy-lup-20(29)-ene-28-[(5-bromo-1H-indole-2,3-dione)-3-yl]hydrazone exhibited the most potent anticancer activity against A549 cells, with an IC₅₀ value of 6.95 µM, being 3.85-fold more potent than its parental compound betulin. Meanwhile, it also exhibited a negligible anti-proliferative activity against the human normal GES-1 cells, indicating its significant selectivity in inhibiting the proliferation of cancer cells than normal cells. The further virtual screening and mechanism studies suggested that this compound exerts its anticancer activity through the inhibition of PI3K-Akt signaling pathway. In summary, 3β-hydroxy-lup-20(29)-ene-28-[(5-bromo-1H-indole-2,3-dione)-3-yl]hydrazone can be used as a valuable skeleton for developing novel anticancer agents.