title: Connecting the chemical and biological reactivity of epoxides.
abstract: 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 S(N)2 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 S(N)2 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 O(6)-/N7-guanine adduct ratio are directly related to their mutagenicity in vitro.
authors.affiliation: Departamento de Química física, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, E-37008, Salamanca, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: González-Pérez
authors.forename: Rafael
authors.initials: R
authors.lastname: Gómez-Bombarelli
authors.forename: Jorge
authors.initials: J
authors.lastname: Arenas-Valgañón
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pérez-Prior
authors.forename: M Pilar
authors.initials: MP
authors.lastname: García-Santos
authors.forename: Emilio
authors.initials: E
authors.lastname: Calle
authors.forename: Julio
authors.initials: J
authors.lastname: Casado
mesh_terms: D000477:Alkylating Agents; D018736:DNA Adducts; D004852:Epoxy Compounds / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D018736:DNA Adducts; D004852:Epoxy Compounds; D011725:Pyridines; C008633:4-(4-nitrobenzyl)pyridine