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Mol Biosyst. 2010 Feb;6(2):410-20. doi: 10.1039/b912336a. Epub 2009 Dec 1.

Novel 4 beta-anilino-podophyllotoxin derivatives: design synthesis and biological evaluation as potent DNA-topoisomerase II poisons and anti-MDR agents.

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ZJU-ENS joint laboratory of medicinal chemistry, School of Pharmaceutical Sciences, Zhejiang University, 388# Yuhangtang Rd., Hangzhou 310058, China.


A new series of 4 beta-anilino-podophyllotoxin analogs have been designed, synthesized and evaluated their bioactivities as novel DNA-topoisomerase II poisons as well as P-glycoprotein (P-gp)-dependent multidrug resistance (MDR) inhibitors. The new compounds show improved potency and efficacy with respect to the parent molecule etoposide (VP-16), one of the semisynthetic derivatives of podophyllotoxin. The treatment of 5k-n in KB/VCR cells caused G(2)/M phase arrest and finally induced apoptosis. Furthermore, molecular docking is applied to testify that 5k-n could not be the substrates of P-gp, which is consistent with the result of MDR1 and P-glycoprotein express tests. The most potent compound 5n is chosen for in vivo studies, the administration of 5n was effective in treatment of cancer with a lower dose than VP-16 in drug-sensitive xenograft model and drug-resistant xenograft model. Compound 5n is a potential drug candidate for anticancer chemotherapy.

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