Cephalosporin Derivatives of Doxorubicin as Prodrugs for Activation by Monoclonal Antibody-β-Lactamase Conjugates

Article abstract of DOI:10.1021/jm00008a016

The synthesis of a series of cephalosporin doxorubicin derivatives that differ with respect to the substituent at position 7 of the cephem nucleus is described.These compounds are designed as prodrugs of doxorubicin for activation by monoclonal antibody-β-lactamase conjugates.The key step in the synthesis of this series of compounds involves the use of the phenylacetamido group as an enzymatically removable protecting group for the 7-amino group on the cephem.In vitro cytotoxicity assays with H2981 lung adenocarcinoma cells revealed that cephalosporin doxorubicin derivatives were all less toxic than the released drug.Prodrugs containing negatively charged groups in the side chain, such as the δ-carboxybutanamido derivative 4 and the α-sulfophenylacetyl derivative 5, displayed the least cytotoxic activity and were 46- and 26-fold less toxic than doxorubicin, respectively.The efficiency of activation of all the prodrugs was evaluated in cytotoxicity assays on H2981 cells with the β-lactamases from Enterobacter cloacae P99, Escherichia coli TEM-1, and Bacillus cereus (type II).In general, the E. cloacae enzyme was found to most rapidly activate the majority of these prodrugs.Phenylacetamido prodrug 2 and δ-carboxybutanamido prodrug 4 were both activated in an immunospecific manner by L6-E. cloacae β-lactamase, a monoclonal antibody conjugate that binds to receptore on H2981 lung adenocarcinoma cells.

Full text of DOI:10.1021/jm00008a016

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.