title: Synthesis, hydrolytic activation and cytotoxicity of etoposide prodrugs.
abstract: 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.
authors.affiliation: Charité Children's Hospital, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany. wrasidlo@charite.de
authors.forename: Wolf
authors.initials: W
authors.lastname: Wrasidlo
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schröder
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bernt
authors.forename: Nicole
authors.initials: N
authors.lastname: Hübener
authors.forename: Doron
authors.initials: D
authors.lastname: Shabat
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gaedicke
authors.forename: Holger
authors.initials: H
authors.lastname: Lode
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004950:Esterases / Q000378:metabolism; D005047:Etoposide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D019384:Nucleic Acid Synthesis Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013552:Swine; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019384:Nucleic Acid Synthesis Inhibitors; D011355:Prodrugs; D005047:Etoposide; D004950:Esterases; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase