Synthesis and cytotoxic activity of novel derivatives of 4′-demethylepipodophyllotoxin

Nine novel 4β-N-substituted-5-FU-4′-demethylepipodophyllotoxin derivatives were synthesized and evaluated as potential antitumor agents. All of the target compounds showed more significant cytotoxic activity against HL-60 and A-549 in vitro than VP-16 and 5-FU. Among them, 4β-N-substituted-phenylalanine 5-Fu pentyl ester-4′-demethylepipodophyllotoxin (9g) was found to exhibit most potent cytotoxic activity against HL-60 and A-549 cell (IC50 is 0.04 and <0.01 μM, respectively).