Late-stage functionalization of anticancer agent Daniquidone and the in vitro anticancer activities of the derivatives

Nitrogen heterocycles play an important role in drugs and natural products. C-H late-stage functionalization (LSF) of N-heterocycles might provide a direct route to construct diversified analogues with potential pharmaceutical activities. Here, we employed a Cu-catalyzed C–H LSF to modify an anticancer drug Daniquidone and successfully converted the N-α position C–H bond into C–O, C–C and C–S bonds. Anticancer activities of all modified compounds in vitro were measured against three cell lines. The results showed that compound 2i was the most active compound among all derivatives synthesized (IC 50 = 2.14 ± 1.23 μM against OVCAR-3, IC 50 = 4.07 ± 1.09 μM against A2780), 1b , 1g and 2j also exhibit increased activity compared to the parent drug Daniquidone. Besides, molecular docking simulations with 1b , 1g and 2j were conducted to further understand their binding modes. • Cu-catalyzed C–H late-stage functionalization in an anticancer drug Daniquidone . • Design and synthesis of a series of Daniquidone analogues. • Evaluation of anticancer activities of the analogues against three cell lines. • The most active compound was 2i , with over 10-fold potency than Daniquidone . • 1b , 1g and 2j exhibit increased activity compared to the parent drug Daniquidone.