Synthesis and biological evaluation of conjugates of deoxypodophyllotoxin and 5-FU as inducer of caspase-3 and -7

In order to generate compounds with superior antitumor activity and reduced toxicity, a series of conjugates of deoxypodophyllotoxin and 5-FU were synthesized by coupling 4′-demethyl-4-dexoypodophyllotoxin with N-(5-fluorouracil-N1-ly acetic)- amino acids (or 5-fluorouracil-N1-ly acetic acid). The cytotoxic activity of these compounds against four human cancer cell lines (HL-60, A-549, HeLa and SiHa) were evaluated, and results indicated that these compounds were more potent in terms of cytotoxicity than either parent compound DPT or anticancer drug VP-16 and 5-FU. In addition, we found that 14d induced cell cycle arrest in the G2/M phase accompanied by apoptosis in A-549 cells, and 14d activated caspase-3 and -7. These results suggested that caspase-mediated pathways are involved in 14d induced apoptosis.

The target conjugates exhibited more potent cytotoxicities than VP-16. Compound 14d induced cells cycle arrested in G2/M phase and apoptosis by activation to caspase-3 and -7.Figure optionsDownload as PowerPoint slideHighlights
► Seven conjugates of deoxypophyllotoxin and 5-FU were synthesized.
► These compounds exhibited improved cytotoxic activity as compared with VP-16.
► Compound 14d induced cell cycle arrest in the G2/M phase in A-549 cells.
► Compound 14d caused apoptosis by induction of caspase-3 and -7.