Abstract
Purpose. The synthesis of chemically stable triazene prodrugs capable of hydrolysing under physiological conditions to liberate cytotoxic monomethyltriazene alkylating agents.
Methods. A series of 3-aminoacyl-l-aryl-3-methyltriazenes was synthesised through reaction of l-aryl-3-methyltriazenes with N-BOC protected amino acids using the DCC method of activation, followed by deprotection of the amino function using HC1 in nitromethane. Half-lives for the hydrolysis of these compounds to the corresponding mono-methyltriazenes at 37°C in isotonic phosphate buffer and in 80% human plasma containing 20% phosphate buffer were determined by HPLC.
Results. The aminoacyltriazene prodrugs hydrolyse in isotonic phosphate buffer with t1/2 values ranging from 26 to 619 minutes. In human plasma, several decompose at the same rate as in phosphate buffer whereas those containing more lipophilic groups decompose more slowly. A β-alanyl derivative was found to be more stable in phosphate buffer (t1/2 = 180 minutes) than in plasma (t1/2 = 53 minutes). An N-acetylated α-alanyl derivative was found to be chemically stable in phosphate buffer (t1/2 = 10 hours) but liberated the cytotoxic drug in t1/2 = 41 minutes in plasma, demonstrating its ability to act as a substrate for plasma enzymes.
Conclusions. Aminoacyltriazenes are prodrugs of the antitumour monomethyltriazenes hydrolysing in human plasma with a range of reactivities. The acylation of the α-amino group seems to be an effective and simple means of reducing the chemical reactivity of the α-aminoacyl derivatives while retaining a rapid rate of enzymatic hydrolysis.
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Carvalho, E., Iley, J., Perry, M.d.J. et al. Triazene Drug Metabolites: Part 15. Synthesis and Plasma Hydrolysis of Anticancer Triazenes Containing Amino Acid Carriers. Pharm Res 15, 931–935 (1998). https://doi.org/10.1023/A:1011988918476
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DOI: https://doi.org/10.1023/A:1011988918476