Design, Synthesis, Biological Evaluation and Molecular Docking Studies of 5-fluorouracil-dithiocarbamate Conjugates

Background Novel anti-tumor bioactivity compounds were designed by the strategy of modular hybridization with the bioactivity advantages of 5-fluorouracil and dithiocarbamate derivatives.Methods A series of novel 5-fluorouracil-dithiocarbamate conjugates were synthesized, characterized and evaluated for their cytotoxic activities in vitro against B16, Hela and U87MG by MTT assay. Colony-formation, transwell migration, cell apoptosis and cell cycle distribution assays were performed to explore the anti-tumor activities and mechanism of conjugates for compounds P3 and P4. Conjugates, dithiocarbamate derivatives combined with copper ions and 5-fluorouracil were investigated by molecular docking.Results The results of cytotoxicity assays illuminated that these conjugates had anti-tumor activity against B16, Hela and U87MG. Interestingly, the cytotoxicity of these conjugates was significantly increased when combined with copper ions, and compound P3 displayed better bioactivity compared to the other compounds. Conjugates might be metabolized in the cells to produce dithiocarbamates, and then metabolites formed complexes with copper ions, generating better anti-tumor effects. Molecular docking studies exhibited that compound P3 appeared the strongest interaction with the receptors 6CCY and 5T92.Conclusion Compound P3 exhibited better anti-tumor bioactivity and might be emerged as the lead compound for the treatment of glioma. Further research in vivo will be performed in our following work.