• R Lougerstay-Madec, J C Florent, C Monneret, F Nemati, and M F Poupon.
• Unité Mixte de Recherche 176, CNRS/Institut Curie, Paris, France.
• Anticancer Drug Des. 1998 Dec 1; 13 (8): 995-1007.

AbstractThe design and synthesis of the mustard pro-prodrugs which can be used in ADEPT is reported. Prodrugs 1 and 2 include a glucuronide group which is connected to the drug via an aromatic and/or aliphatic bis-carbamate spacer. The design of these new prodrugs takes advantage of a spontaneous 1,6-elimination and/or an intramolecular cyclization reaction after enzymatic cleavage. Thus, enzymatic-catalyzed hydrolysis of the glucuronyl moiety of 1 by Escherichia coli beta-glucuronidase results in the liberation of the parent mustard drug 20 with formation of CO2, 2-nitro-4-hydroxymethylphenol 19 and dimethylimidazolidinone 21. Surprisingly, prodrug 2 was not cleaved under the same conditions. According to in vitro experiments, prodrugs 1 and 2 were approximately 50- and 80-fold less cytotoxic than the parent drug and, when treated with beta-glucuronidase, the level of cytotoxic activity of 1 became comparable to that of the drug. Stability of 1 in phosphate buffer was satisfactory. These results demonstrate that 1 is a prodrug that can be specifically activated to release the cytotoxic agent.

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