Triazene drug metabolites. Part 16.¹ Kinetics and mechanism of the hydrolysis of aminoacyltriazenes

Abstract

Kinetic studies of the hydrolysis of 3-aminoacyl-1-aryl-3-methyltriazenes to the corresponding 1-aryl-3-methyltriazenes were carried out in pH 3–12 aqueous buffers at 25 °C. Pseudo-first-order rate constants were found to depend both on pH and buffer concentration. pH–Rate profiles for the compounds derived from α-amino acids, 3a–e, exhibit sigmoidal curves consistent with an HO^–-catalysed reaction proceeding via both protonated and unprotonated forms of the structure. For the β-amino acid derivative, 3f, the difference in reactivity between these two substrate forms is much less pronounced. For the N-acetylated derivative, 3g, only the unprotonated form is kinetically significant. Solvent deuterium isotope effects for the reaction of HO^– with the protonated substrate are ca. 0.8 and for the unprotonated substrate ca. 1.0, suggesting nucleophilic catalysis by HO^– for both forms. Both protonated and unprotonated forms of the substrate are subject to buffer catalysis. The Brönsted β value of 0.65 is consistent with general-base catalysis, as are the solvent deuterium isotope effect of ca. 1.3 for the imidazole-catalysed hydrolysis of the protonated substrate and the ratio of 1.1 for the piperidine- and 2,2,4,4-tetramethylpiperidine-catalysed hydrolyses of the unprotonated form.

References

1. Part 15: E. Carvalho, J. Iley, M. de J. Perry and E. Rosa, Pharm. Res., 1998, 15, 931.
2. V. S. Lucas and A. T. Huang, in Chemical Management of Melanoma, ed. H. F. Seigler, Martinns Nijhoff, The Hague, 1982.
3. T. A. Connors, P. M. Goddard, K. Merai, W. C. J. Ross and D. E. V. Wilman, Biochem. Pharmacol., 1976, 25, 241.
4. M. Julliard and G. Vernin, Ind. Eng. Chem. Prod. Res. Rev., 1981, 20, 287.
5. J. Iley, G. Ruecroft, E. Carvalho and E. Rosa, J. Chem. Res. (S), 1989, 162.
6. E. Carvalho, J. Iley and E. Rosa, J. Chem. Soc., Perkin Trans. 2, 1993, 865.
7. R. Wolfenden, Biochemistry, 1963, 2, 1090.
8. R. W. Hay, L. J. Porter and P. J. Morris, Aust. J. Chem., 1966, 19, 1197.
9. R. W. Hay and L. J. Porter, J. Chem Soc. (B), 1967, 1262.
10. I. M. Kovach, I. H. Pitman and T. Higuchi, J. Pharm. Sci., 1981, 70, 881.
11. M. J. Cho and L. C. Haynes, J. Pharm. Sci., 1985, 74, 883.
12. M. R. Wright, J. Chem Soc. (B), 1968, 548.
13. E. Jensen and H. Bundgaard, Int. J. Pharm., 1991, 71, 117.
14. W. P. Jencks and J. Regenstein, ‘Ionization Constants of Acids and Bases’, in Handbook of Chemistry and Molecular Biology, 3rd edn., vol. 1, ed. G. D. Fasman, CRC Press, Cleveland, OH, 1976, p. 305.
15. S. P. Datta and B. R. Rabin, Trans. Faraday Soc., 1956, 52, 1117.
16. J. T. Edsall and M. H. Blanchard, J. Am. Chem. Soc., 1933, 55, 2337.
17. B. Holmquist and T. Bruice, J. Am. Chem. Soc., 1969, 91, 2985.
18. N. S. Isaacs, Physical Organic Chemistry, Longman, Harlow, 1987.
19. R. G. Bates, Determination of pH, Wiley, New York, 1954.