In this paper, a series of novel 5-fluorouracil-dithiocarbamate conjugates were designed, synthesized and evaluated in vitro . The results of cytotoxicity assays illuminated that these conjugates had anti-tumor activity against B16, Hela and U87MG, and compound P3 exhibited excellent growth inhibition against U87MG cells. Interestingly, the cytotoxicity of these conjugates was significantly increased when combined with copper ions. Meanwhile, colony-formation assays, transwell migration assays, cell apoptosis assays and cell cycle distribution assays were performed to explore the anti-tumor mechanism of conjugates. Compound P3 and P4 exhibited good biological activity in above four experiments when combined with copper ions. Especially, P3 displayed better bioactivity compared to the other three compounds. These results indicated that conjugates might be metabolized in the cells to produce dithiocarbamates, then metabolites formed complexes with copper ions, generating anti-tumor effects. Furthermore, conjugates and their metabolized dithiocarbamate derivatives were investigated by molecular docking, the results exhibited that P3 had the strongest interaction with the proteins 6CCY and 5T92, which was consistent with the obtained results of cell experiments. Compound P3 might be a potential lead-compound for the treatment of breast cancer and glioma. Further research in vivo about these compounds would be performed in our following work.
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