Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT)

J Med Chem. 1999 Sep 9;42(18):3623-8. doi: 10.1021/jm990124q.


Glucuronide prodrugs of 9-aminocamptothecin were synthesized. Prodrug 4, in which 9-aminocamptothecin was connected to glucuronic acid by an aromatic spacer via a carbamate linkage, was stable in both aqueous solution and human plasma. Prodrug 4 and its potassium salt 12 were 20-80-fold less toxic than 9-aminocamptothecin to human tumor cell lines. The simultaneous addition of beta-glucuronidase and 4 or 12 to tumor cells resulted in a cytotoxic effect equal to that of 9-aminocamptothecin alone. Prodrugs 4 and 12 were over 80 and 4000 times more soluble than 9-aminocamptothecin in aqueous solutions at pH 4.0, respectively. Compounds 4 and 12 may be useful for prodrug monotherapy of tumors that accumulate extracellular lysosomal beta-glucuronidase as well as for antibody-directed enzyme prodrug therapy (ADEPT) of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Camptothecin / analogs & derivatives*
  • Drug Design
  • Glucuronates / chemical synthesis*
  • Glucuronates / pharmacology
  • Glucuronidase / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Immunotherapy / methods
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacology
  • Solubility
  • Tumor Cells, Cultured


  • Antibodies
  • Antineoplastic Agents
  • Glucuronates
  • Prodrugs
  • Glucuronidase
  • Camptothecin