Modification of deoxyguanosine by chloroethylene oxide

Reaction of deoxyguanosine in glacial acetic acid with chloroethylene oxide, a proposed reactive metabolite of vinyl chloride, led to a single, strongly fluorescent product in nearly quantitative yield. The u.v. spectra indicated alkylation of N-7 of guanine, which was confirmed following reduction of the reaction product by sodium borohydride to 7-(2-hydroxyethyl)guanine, and the synthesis of the same modified guanine via a stereoselective 7-N hydroxy alkylation using 2,3-epoxy-1-propanol. In agreement with the expected structure 7-(2-oxoethyl)guanine reacted with the carbonyl specific reagent 2,4-dinitrophenylhydrazine (2,4-DNPH). However, its i.r. and proton n.m.r. spectra did not support the existence of a simple aldehyde group. Moreover, the 2,4-dinitrophenylhydrazone was labile, 7-(2-oxoethyl)guanine being produced when excess 2,4-DNPH was removed. This instability was interpreted as being due to the reversible formation of a hemiacetal ring between O6 of the guanine residue and the aldehyde carbon of the 2-oxoalkyl group resulting in O6,7-(1'-hydroxyethano)guanine. This conformation was supported by the occurrence in field desorption mass spectra of the ions of m/e = 175 and 292 which are interpreted as O6,7-ethenoguanine and O6,7-ethenodeoxyguanosine resulting from the elimination of H2O of the hydroxyethano residue. O6,7-(1'-hydroxyethano)guanine might be expected to cause faulty base pairing during replication of DNA, which may be the molecular basis of the carcinogenicity of vinyl chloride.