The reaction of 3, 4-epoxy-1-butene with deoxyguanosine and DNA in vitro: synthesis and characterization of the main adducts

Abstract

The reaction of guanosine with 3, 4-epoxy-1-butene in acetic acid gives two main products of N-7 alkylation. After acidic hydrolysis the two aglycones have been isolated by h.p.l.c. and shown to be the regioisomeric 7-(2-hydroxy-3-buten-1-yl) guanine(I) and 7-(1-hydroxy-3-buten-2-yl) guanine(II), arising through nudeophilic attack by N-7 of the purine at the two oxirane carbons of 3, 4-epoxy-1-butene. Spectral characteristics of both compounds are presented, including u.v., ¹H n.m.r. and mass spectra. Deoxyguanosine reacts with 3, 4-epoxy-1-butene in 50% methanol-water at 37°C to give the N-7 akylated deoxynucleosides corresponding to I and II in a 59:41 ratio. The reaction rate depends on the nudeoside concentration, with second order rate constants at 37°C of 1.6 × 10⁻² and 1.1 ×10⁻² h⁻¹ M⁻¹ for the formation of the two deoxynucleoside adduct corresponding to I and II, respectively. The same two compounds I and II in a similar (54:46) ratio have been identified after acidic or thermal hydrolysis of DNA which had been reacted with 3, 4-epoxy-1-butene under similar conditions. The half life for the spontaneous depurination of I and II in the adducted DNA under physiological conditions (37°C, pH 7.2) is 50 h.