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.