Design and Synthesis of Water-Soluble Glucuronide Derivatives of Camptothecin for Cancer Prodrug Monotherapy and Antibody-Directed Enzyme Prodrug Therapy (ADEPT)

• Published in: Journal of medicinal chemistry 1999-09, Vol.42 (18), p.3623-3628
• Main Authors: Leu, Yu-Ling, Roffler, Steve R, Chern, Ji-Wang
• Format: Article
• Language: English
• Subjects: 9-aminocamptothecin; Antibodies - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; camptothecin; Camptothecin - analogs & derivatives; Drug Design; General aspects; Glucuronates - chemical synthesis; Glucuronates - pharmacology; Glucuronidase - metabolism; glucuronides; Humans; Hydrogen-Ion Concentration; Immunotherapy - methods; Medical sciences; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Solubility; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• 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 β-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 β-glucuronidase as well as for antibody-directed enzyme prodrug therapy (ADEPT) of cancer.