Background: Cancer is one of the most serious clinical problems worldwide, and considerable efforts have been
devoted to discovering therapeutic agents with novel modes of action. Natural and synthetic coumarin derivatives have
attracted intense research interest due to their diverse structural features and remarkable array of biological properties.
Objective: In the present study, we synthesized a series of 4-MU derivatives containing urea-piperazine and thioureapiperazine
moieties and evaluated their antitumor activities to find efficacy antitumor drugs.
Method: Cell proliferation, apoptosis, cell cycle, the generation of reactive oxygen species and calcium were measured
using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was
determined by western blotting. The effect of 4l on apoptosis-related mRNA expression in NCI-H460 cells was
detected by RT-PCR.
Results: Most of the target compounds exhibited potential anticancer activities against tested cancer cells but had low
cytotoxicity to normal cells. Compound 4l inhibited the growth and proliferation of NCI-H460 cells and resulted in
apoptosis. Successive studies conducted with 4l in NCI-H460 cells demonstrated that this compound induced the
intracellular reactive oxygen species generation and calcium overload, suppressed nuclear factor-κB (NF-κB) activity
and regulated anti- and pro-apoptotic proteins. In addition, compound 4l effectively arrested NCI-H460 cells in G2
phase and altered the cell cycle regulatory proteins especially cyclin B1.
Conclusion: Compound 4l exerts significant anticancer effects on NCI-H460 cells in vitro through targeting of
mitochondria-dependent apoptotic pathway. These results indicate that the strategy for rational design of 4-MU
derivatives may identify potential anticancer agents.