Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy
| Autor: | Sofia Mitaku, Jean-Claude Jacquesy, Jean-Pierre Gesson, Xia Dong, Manfred Gerken, Klaus Bosslet, François Tillequin, Claude Monneret, Brigitte Renoux, Joerg Czech, Jean-Claude Florent, Sylvie Michel, Rainer Straub, Michel Koch, Martine Mondon, Solo Andrianomenjanahary, Gilbert Gaudel |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Daunorubicin
Recombinant Fusion Proteins Glucuronates Immunoglobulin Fab Fragments Mice Structure-Activity Relationship Drug Stability Drug Discovery medicine Escherichia coli Tumor Cells Cultured Structure–activity relationship Animals Humans Doxorubicin Prodrugs Cytotoxicity Leukemia L1210 Glucuronidase chemistry.chemical_classification Antibiotics Antineoplastic Hydrolysis Antibodies Monoclonal Adept Prodrug In vitro Carcinoembryonic Antigen Rats Kinetics Enzyme chemistry Biochemistry Molecular Medicine Drug Screening Assays Antitumor Cell Division medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 41(19) |
| ISSN: | 0022-2623 |
| Popis: | A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibody-directed enzyme prodrug therapy (ADEPT) is reported. These compounds (25a,b,c and 32a,b,c) have been designed to generate cytotoxic drugs after activation with beta-glucuronidase. As expected, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CEA-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L1210 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are better substrates for beta-glucuronidase than the corresponding para-substituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected the o-nitro prodrug 25c for clinical trials. |
| Databáze: | OpenAIRE |
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