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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / chemical synthesis*
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Antibiotics, Antineoplastic / chemistry
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Antibiotics, Antineoplastic / metabolism
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Antibiotics, Antineoplastic / pharmacology
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology*
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Carcinoembryonic Antigen / genetics
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Carcinoembryonic Antigen / immunology
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Cell Division / drug effects
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Daunorubicin / chemistry*
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Daunorubicin / pharmacology
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Doxorubicin / analogs & derivatives*
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Doxorubicin / chemical synthesis
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Doxorubicin / chemistry*
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Doxorubicin / metabolism
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Doxorubicin / pharmacology
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Drug Screening Assays, Antitumor
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Drug Stability
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Escherichia coli / enzymology
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Glucuronates / chemical synthesis*
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Glucuronates / chemistry
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Glucuronates / metabolism
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Glucuronates / pharmacology
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Glucuronidase / genetics
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Glucuronidase / pharmacology
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Humans
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Hydrolysis
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Immunoglobulin Fab Fragments / genetics
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Immunoglobulin Fab Fragments / immunology
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Kinetics
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Leukemia L1210 / pathology
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Mice
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Prodrugs / chemical synthesis*
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Prodrugs / chemistry
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Prodrugs / metabolism
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Prodrugs / pharmacology
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Rats
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / pharmacology
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antibiotics, Antineoplastic
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Antibodies, Monoclonal
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Carcinoembryonic Antigen
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Glucuronates
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Immunoglobulin Fab Fragments
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N-(4-glucuronyl-3-nitrobenzyloxycarbonyl)doxorubicin
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Prodrugs
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Recombinant Fusion Proteins
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Doxorubicin
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Glucuronidase
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Daunorubicin