Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Aniline Compounds / chemical synthesis
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Animals
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Apoptosis / drug effects
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Cell Cycle / drug effects
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Etoposide / pharmacology
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Humans
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Mice
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Neoplasms / drug therapy
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Podophyllotoxin / analogs & derivatives*
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Podophyllotoxin / chemical synthesis
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Podophyllotoxin / chemistry
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Podophyllotoxin / pharmacology
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Topoisomerase II Inhibitors*
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Xenograft Model Antitumor Assays
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Aniline Compounds
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Enzyme Inhibitors
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Topoisomerase II Inhibitors
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Etoposide
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Podophyllotoxin