Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT).
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.
Leu
Y L
YL
Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Roffler
S R
SR
Chern
J W
JW
D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives*; D015195:Drug Design; D005965:Glucuronates / Q000138:chemical synthesis* / Q000494:pharmacology; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007167:Immunotherapy / Q000379:methods; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000970:Antineoplastic Agents; D005965:Glucuronates; D011355:Prodrugs; D005966:Glucuronidase; D002166:Camptothecin