title: Synthesis of self-immolative glucuronide-based prodrugs of a phenol mustard.
abstract: The 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.
authors.affiliation: Unité Mixte de Recherche 176, CNRS/Institut Curie, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Lougerstay-Madec
authors.forename: J C
authors.initials: JC
authors.lastname: Florent
authors.forename: C
authors.initials: C
authors.lastname: Monneret
authors.forename: F
authors.initials: F
authors.lastname: Nemati
authors.forename: M F
authors.initials: MF
authors.lastname: Poupon
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005965:Glucuronates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D009150:Mustard Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010636:Phenols / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D005965:Glucuronates; D009150:Mustard Compounds; D010636:Phenols; D011355:Prodrugs; D005966:Glucuronidase