Synthesis of hybrid 4-deoxypodophyllotoxin–5-fluorouracil compounds that inhibit cellular migration and induce cell cycle arrest

A series of deoxypodophyllotoxin–5-fluorouracil hybrid compounds were synthesized, and their cytotoxic activity was evaluated using four human cancer cell lines (HeLa, A549, HCT-8, and HepG2) and the human normal cell line WI-38. The synthesized compounds exhibited greater cytotoxic activity in tumor cells and reduced toxicity in the normal cell line compared with the anticancer drug VP-16 and 5-FU. Additionally, the most potent of these compounds—4′-O-demethyl-4-deoxypodophyllotoxin-4′-yl 4-((6-(2-(5-fluorouracil-yl) acetamido) hexyl) amino)-4-oxobutanoate (compound 22)—induced cell-cycle arrest in the G2/M phase by regulating levels of cdc2, cyclinB1, and p-cdc2 in A549 cells. Furthermore, compound 22 may inhibited the migration of A549 cells via down-regulation of MMP-9 and up-regulation of TIMP-1.

Graphical abstractCompound 22 inhibits the migration of A549 cells regulating MMP-9 and TIMP-1, and induces cell cycle arrest in the G2/M phase involving cdc2, cyclinB1 and p-cdc2.Figure optionsDownload full-size imageDownload as PowerPoint slide