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Título
Connecting the Chemical and Biological Reactivity of Epoxides
Autor(es)
Materia
Mutagenic Epoxides
Alkylation reaction
Alkylation Mechanism
Kinetics
Clasificación UNESCO
2210 Química Física
2210.03 Cinética Química
Fecha de publicación
2012-11-21
Editor
American Chemical Society
Citación
González-Pérez, M., Gómez-Bombarelli, R., Arenas-Valgañón, J., Pérez-Prior, M.T., García-Santos, M.P., Calle, E., Casado, J. (2012). Connecting the Chemical and Biological Reactivity of Epoxides. Chem. Res. Toxicol., 25, 12, 2755–2762.
Resumen
[EN] The chemical reactivity of the mutagenic epoxides (EP) propylene oxide (PO), 1,2-epoxybutane (1,2-EB), and cis- and trans-2,3-epoxybutane (cis- and trans-2,3-EB) with 4-(p-nitrobenzyl)pyridine (NBP), a bionucleophile model for SN2 alkylating agents with high affinity for the guanine-N7 position, was investigated kinetically. It was found that three reactions are involved simultaneously: the alkylation reaction of NBP by EP, which yields the corresponding NBP-EP adducts through an SN2 mechanism, and EP and NBP-EP hydrolysis reactions. PO and 1,2-EB were seen to exhibit a higher alkylating potential than cis- and trans-2,3-EB. From a study of the correlations between the chemical reactivity (kinetic parameters) and the biological effectiveness of oxiranes, the following conclusions can be drawn: (i) the hydrolysis reactions of epoxides must be taken into account to understand their bioactivity. (ii) The fraction (f) of the alkylating oxirane that forms the adduct and the adduct life (AL) permit the potential of epoxides as bioactive molecules to be rationalized even semiquantitatively; and (iii) alkylation of DNA by epoxides and the O6-/N7-guanine adduct ratio are directly related to their mutagenicity in vitro.
URI
ISSN
0893-228X
DOI
10.1021/TX300389Z
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