Cephalosporin derivatives of doxorubicin as prodrugs for activation by monoclonal antibody-beta-lactamase conjugates

J Med Chem. 1995 Apr 14;38(8):1380-5. doi: 10.1021/jm00008a016.

Abstract

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-beta-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 delta-carboxybutanamido derivative 4 and the alpha-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 beta-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 delta-carboxybutanamido prodrug 4 were both activated in an immunospecific manner by L6-E. cloacae beta-lactamase, a monoclonal antibody conjugate that binds to receptors on H2981 lung adenocarcinoma cells.

MeSH terms

  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Carbohydrate Sequence
  • Cell Line
  • Cephalosporins / chemical synthesis*
  • Cephalosporins / pharmacokinetics
  • Cephalosporins / pharmacology
  • Doxorubicin / chemistry*
  • Drug Screening Assays, Antitumor
  • Molecular Sequence Data
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • beta-Lactamases / chemistry
  • beta-Lactamases / pharmacology*

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Cephalosporins
  • Prodrugs
  • Doxorubicin
  • beta-Lactamases