• J. Med. Chem. · Sep 1999

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

    • Y L Leu, S R Roffler, and J W Chern.
    • Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
    • J. Med. Chem. 1999 Sep 9; 42 (18): 3623-8.

    AbstractGlucuronide 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.

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