Abstract
Eight 4'-ester epipodophyllotoxin derivatives (9-16) were designed and synthesized with the aim to overcome drug-resistance and improve water-solubility simultaneously. These compounds were superior to etoposide (1) in causing cellular protein-linked DNA breaks and inhibiting KB and 1-resistant KB-7d cell replication. Compounds 9 and 10 showed significant inhibitory activity against DNA topoisomerase II in vitro. Compound 10 also exhibited an in vitro DNA cleavage pattern similar to that of GL-331 (5). A hypothetical model on the action mode of 1-analogues is proposed based on the results.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Binding Sites
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Cell Division / drug effects
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Cell Line, Tumor
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DNA Topoisomerases, Type II / metabolism
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Etoposide / analogs & derivatives*
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Etoposide / chemical synthesis
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Etoposide / chemistry
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Etoposide / pharmacology*
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Humans
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Molecular Structure
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Topoisomerase II Inhibitors*
Substances
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4'-ester etoposide
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Antineoplastic Agents
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Topoisomerase II Inhibitors
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Etoposide
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DNA Topoisomerases, Type II