Synthesis of self-immolative glucuronide-based prodrugs of a phenol mustard.
Anticancer Drug Des
; 13(8): 995-1007, 1998 Dec.
Article
en En
| MEDLINE
| ID: mdl-10335272
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenoles
/
Compuestos de Mostaza
/
Profármacos
/
Glucuronatos
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Anticancer Drug Des
Asunto de la revista:
ANTINEOPLASICOS
/
FARMACOLOGIA
Año:
1998
Tipo del documento:
Article
País de afiliación:
Francia