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Design and synthesis of N-phosphoryl peptide modified podophyllotoxin derivatives as potent anticancer agents.

A series of novel compounds with N-phosphoryl peptide modification at the C-4 position on podophyllotoxin were synthesized and evaluated for their cytotoxicity in vitro against K562 cell lines. Among these compounds 5c, 5f and 5k exhibited better cytotoxicity (IC(50) = 5.5 µM, 2.1 µM, and 3.1 µM, respectively) than podophyllotoxin and etoposide. Further study on compound 5f using flow cytometry analysis indicated that the anti-tumor effect might be due to the induction of apoptosis.