Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: Synthesis and stability of N-acylamino acid derivatives of triazenes

Perry, Maria de Jesus; Carvalho, Emília; Rosa, Eduarda and Iley, Jim (2009). Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: Synthesis and stability of N-acylamino acid derivatives of triazenes. European Journal of Medicinal Chemistry, 44(3) pp. 1049–1056.

DOI: https://doi.org/10.1016/j.ejmech.2008.06.022

Abstract

A series of 3-[a-(acylamino)acyl]-1-aryl-3-methyltriazenes 6ael, potential cytotoxic triazene prodrugs, were synthesised by coupling 1-aryl- 3-methyltriazenes to N-acylamino acids. Their hydrolysis was studied in isotonic pH 7.4 phosphate buffer and in human plasma, while hydrolysis of the derivative 6a was studied in more depth across a range of pH values. Prodrugs 6ael hydrolyse by cleavage of the triazene acyl group to afford the corresponding monomethyltriazenes. Studies in human plasma demonstrate that acylation of the a-amino group of the amino acid carrier is an effective means of reducing the chemical reactivity of the a-aminoacyl derivatives while retaining a rapid rate of enzymatic hydrolysis. These derivatives displayed log P values that suggest they should be well absorbed through biological membranes.