Triazene drug metabolites. Part 17: Synthesis and plasma hydrolysis of acyloxymethyl carbamate derivatives of antitumour triazenes

A series of 3-acyloxymethyloxycarbonyl-1-aryl-3-methyltriazenes 5 was synth esised by the sequential reaction of 1-aryl-3-methyltriazenes with (i) chlo romethyl chloroformate, (ii) NaI in dry acetone, and (iii) either the silve r 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 a bility to act as substrates for plasma enzymes. For compound 5f, a pH-rate profile was obtained which showed the hydrolysis to involve acid-base catal ysis. The reaction is also buffer catalysed. Thus, at pH 7.7, pH-independen t, base-catalysed and buffer-catalysed processes all contribute to the hydr olysis reaction. The sensitivity of the hydrolysis reaction to various stru ctural parameters in the substrates indicates that hydrolysis occurs at the ester rather than the carbamate functionality. In plasma, the rates of hyd rolysis correlate with partition coefficients, the most lipophilic compound s being the most stable. An aspirin derivative suffers two consecutive enzy matic reactions, the scission of the aspirin acetyl group being followed by the scission of the acyloxy ester group. These results indicate that triaz ene acyloxymethyl carbamates are prodrugs of the antitumour monomethyltriaz enes. They combine chemical stability with a rapid enzymatic hydrolysis, an d are consequently good candidates for further prodrug development. Moreove r, this type of derivative allowed the synthesis of mutual prodrugs, associ ating the antitumour monomethyltriazenes with anti-inflammatory NSAIDs as w ell as with the anticancer agent butyric acid. (C) 2000 Elsevier Science Lt d. All rights reserved.