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

A series of 3-[α-(acylamino)acyl]-1-aryl-3-methyltriazenes 6a–l, 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 6a–l hydrolyse by cleavage of the triazene acyl group to afford the corresponding monomethyltriazenes. Studies in human plasma demonstrate that acylation of the α-amino group of the amino acid carrier is an effective means of reducing the chemical reactivity of the α-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.

Graphical abstractA series of novel prodrugs of antitumoral triazenes containing N-acylamino acid carriers (6) have been synthesised and their plasma and chemical stabilities were evaluated.Figure optionsDownload full-size imageDownload as PowerPoint slide