Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/20943
Título: Triazene drug metabolites. Part 17
Synthesis and plasma hydrolysis of acyloxymethyl carbamate derivatives of antitumour triazenes
Autor: Carvalho, E
Francisco, AP
Iley, J
Rosa, E
Palavras-chave: Biochemistry & Molecular Biology
Chemistry, Medicinal
Chemistry, Organic
Data: 2000
Citação: BIOORGANIC & MEDICINAL CHEMISTRY. - Vol. 8, n. 7 (JUL 2000), p. 1719-1725
Resumo: A series of 3-acyloxymethyloxycarbonyl-1-aryl-3-methyltriazenes 5 was synthesised by the sequential reaction of 1-aryl-3-methyltriazenes with (i) chloromethyl chloroformate, (ii) NaI in dry acetone, and (iii) either the silver carboxylate or the carboxylic acids in the presence of silver carbonate. The hydrolysis of these compounds was studied in pH 7.7 isotonic phosphate buffer and in human plasma. Triazene acyloxycarbamates demonstrated their ability to act as substrates for plasma enzymes. For compound 5f, a pH-rate profile was obtained which showed the hydrolysis to involve acid-base catalysis. The reaction is also buffer catalysed. Thus, at pH 7.7, pH-independent, base-catalysed and buffer-catalysed processes all contribute to the hydrolysis reaction. The sensitivity of the hydrolysis reaction to various structural parameters in the substrates indicates that hydrolysis occurs at the ester rather than the carbamate functionality. In plasma, the rates of hydrolysis correlate with partition coefficients, the most lipophilic compounds being the most stable. An aspirin derivative suffers two consecutive enzymatic reactions, the scission of the aspirin acetyl group being followed by the scission of the acyloxy ester group. These results indicate that triazene acyloxymethyl carbamates are prodrugs of the antitumour monomethyltriazenes. They combine chemical stability with a rapid enzymatic hydrolysis, and are consequently good candidates for further prodrug development. Moreover, this type of derivative allowed the synthesis of mutual prodrugs, associating the antitumour monomethyltriazenes with anti-inflammatory NSAIDs as well as with the anticancer agent butyric acid. (C) 2000 Elsevier Science Ltd. All rights reserved.
URI: http://hdl.handle.net/10451/20943
ISSN: 0968-0896
Aparece nas colecções:FF - Produção Científica 2000-2009

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