Synthesis and biological evaluation of derivatives of 4-deoxypodophyllotoxin as antitumor agents

In an attempt to generate compounds with superior bioactivity and reduced toxicity, a series of derivatives of deoxypodophyllotoxin were synthesized by reacting 4′-demethyl-4-deoxypodophyllotoxin with substituted piperazines or their amino acid amides. The cytotoxic activity of these compounds against three human cancer cell lines was evaluated. We found that p-nitrophenylpiperazine substitution (Compound 8b) led to an increase in the potency of the compound. Compound 8b exhibited the most potent cytotoxicity against A-549, HeLa and SiHa cells (IC50 values were 0.102, 0.180 and 0.0195 μM, respectively). In addition, flow cytometric analysis showed that 8b induced cell cycle arrest in the G1 phase accompanied by apoptosis in A-549 cells.

Compound 8b exhibited the most potent cytotoxicity against A-549, HeLa and SiHa cells (IC50 values were 0.102, 0.180 and 0.0195 μM, respectively), and flow cytometric analysis showed that 8b induced cell cycle arrest in the G1 phase accompanied by apoptosis in A-549 cells.Figure optionsDownload as PowerPoint slideHighlights
► Nine novel piperazinyl derivatives of 4-deoxy-4′-demethylpophyllotoxin were synthesized.
► These compounds exhibited improved anticancer activity as compared with etoposide.
► Compound 8b induced cell cycle arrest in the G1 phase in A-549 cells.
► Compound 8b caused apoptosis in A-549 cells.