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Synthesis, Hydrolytic Activation and Cytotoxicity of Etoposide Prodrugs

Two 4′-propylcarbonoxy derivatives ( 2, 3) of etoposide ( 1), a topoisomerase II inhibitor, were synthesized and evaluated as potential prodrugs for anticancer therapy. Their activation via hydrolysis mechanisms was determined as a function of pH in buffer solutions, in human serum and in the presen...

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Published in:Bioorganic & medicinal chemistry letters 2002-02, Vol.12 (4), p.557-560
Main Authors: Wrasidlo, Wolf, Schröder, Ulrike, Bernt, Kathrin, Hübener, Nicole, Shabat, Doron, Gaedicke, Gerhard, Lode, Holger
Format: Article
Language:English
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Summary:Two 4′-propylcarbonoxy derivatives ( 2, 3) of etoposide ( 1), a topoisomerase II inhibitor, were synthesized and evaluated as potential prodrugs for anticancer therapy. Their activation via hydrolysis mechanisms was determined as a function of pH in buffer solutions, in human serum and in the presence of carboxyl ester hydrolase. Cytotoxicity was determined on various tumor cell lines and compared to the parent compound. On cell lines exhibiting resistance to etoposide we observed an enhanced cytotoxicity of the prodrugs of up to three orders of magnitude. Two prodrugs of the topoisomerase II inhibiting antitumor drug etoposide incorporating either hydrophilic or hydrophobic groups and differing in their substrate specificity for the activating enzyme carboxyl esterase were prepared. These new prodrugs show dramatically different activation kinetics and completely circumvent MDR-1 drug resistance.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(01)00801-0