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Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy
J C Florent1, X Dong, G Gaudel
1UMR 176 CNRS/Institut Curie, Section Recherche, 26 rue d'Ulm, F-75248 Paris Cedex 05, France.
Abstract:
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.
Insights
New prodrugs for antibody-directed enzyme prodrug therapy (ADEPT) were developed. These compounds release cytotoxic drugs upon beta-glucuronidase activation, showing promise for cancer treatment.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Antibody-directed enzyme prodrug therapy (ADEPT) offers targeted cancer treatment.
- Development of novel prodrugs is crucial for enhancing ADEPT efficacy.
- Daunorubicin and doxorubicin are potent cytotoxic agents requiring targeted delivery.
Purpose of the Study:
- To synthesize and evaluate novel daunorubicin and doxorubicin prodrugs for ADEPT.
- To design prodrugs activated by beta-glucuronidase for targeted drug release.
- To assess the stability, cytotoxicity, and enzymatic activation of new prodrug candidates.
Main Methods:
- Synthesis of six novel prodrugs (25a,b,c and 32a,b,c) of daunorubicin and doxorubicin.
- Enzymatic cleavage assays using Escherichia coli beta-glucuronidase and a fusion protein.
- Cytotoxicity assays against murine L1210 cell lines.
- Stability studies in plasma and kinetic analysis of enzymatic cleavage.
Main Results:
- The synthesized prodrugs were stable and significantly less cytotoxic than doxorubicin.
- Enzymatic cleavage by beta-glucuronidase successfully released the active cytotoxic drugs.
- Ortho-substituted phenyl carbamates (25a,b,c) demonstrated superior substrate activity for beta-glucuronidase.
- The o-nitro prodrug 25c was selected for clinical trials based on stability and cleavage kinetics.
Conclusions:
- Novel daunorubicin and doxorubicin prodrugs are effective candidates for ADEPT.
- The designed prodrugs exhibit favorable stability and targeted activation profiles.
- The o-nitro prodrug 25c shows significant potential for clinical application in cancer therapy.