Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: synthesis and stability of N-acylamino acid derivatives of triazenes.
A series of 3-[alpha-(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 alpha-amino group of the amino acid carrier is an effective means of reducing the chemical reactivity of the alpha-aminoacyl derivatives while retaining a rapid rate of enzymatic hydrolysis. These derivatives displayed logP values that suggest they should be well absorbed through biological membranes.
Perry
Maria de Jesus
Mde J
iMed.UL, CECF, Faculty of Pharmacy, University of Lisbon, Avenida Professor Gama Pinto, 1649-019 Lisbon, Portugal. mjprocha@ff.ul.pt
Carvalho
Emília
E
Rosa
Eduarda
E
Iley
Jim
J
D000477:Alkylating Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D021241:Spectrometry, Mass, Electrospray Ionization; D014226:Triazenes / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
D000477:Alkylating Agents; D011355:Prodrugs; D014226:Triazenes