US EPA

7435574 

Journal Article 

Synthesis of self-immolative glucuronide-based prodrugs of a phenol mustard 

Lougerstay-Madec, R; Florent, JC; Monneret, C; Nemati, F; Poupon, MF 

1998 

Yes 

Anti-Cancer Drug Design
ISSN: 0266-9536 

13 

8 

995-1007 

English 

10335272 

WOS:000080343200010 

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. 

ADEPT; Glucuronide; Phenol mustards; Prodrug; 2 nitro 4 hydroxymethylphenol; beta glucuronidase; buffer; carbon dioxide; dimethylimidazolidinone; glucuronide; mustard gas derivative; phenol derivative; phosphate; prodrug; unclassified drug; article; controlled study; cyclization; cytotoxicity; drug design; drug elimination; drug hydrolysis; drug stability; drug synthesis; escherichia coli; human; human cell; priority journal; Antineoplastic Agents; Chromatography, High Pressure Liquid; Drug Design; Drug Screening Assays, Antitumor; Drug Stability; Glucuronates; Glucuronidase; Humans; Hydrolysis; Mustard Compounds; Phenols; Prodrugs; Tumor Cells, Cultured