Interactions of N7-guanyl methyl- and thioether-substituted d(CATGCCT) derivatives with d(AGGNATG)

Enzymatic reaction of the carcinogen ethylene dibromide with GSH yields the half-mustard S-(2-bromoethyl)GSH, which reacts with DNA to form S-[2-(N7-guanyl)ethyl]GSH as the major adduct. Varying ratios of mutations to N7-guanyl DNA adduct levels had been observed when bacteria were treated with various half-mustards [Humphreys, W. G., Kim, D.-H., Cmarik, J. L., Shimada, T., and Guengerich, F.P. (1990) Biochemistry 29, 10342-10350]. Derivatives of the model oligonucleotide d(CATGCCT) were prepared with the single Gua substituted with N7-methylGua,N-acetyl-S-[2-(N6-guanyl)ethyl]Cys methyl ester, S-[2-(N7-guanyl)ethyl]GSH, or S-[2-(N7-guanyl)ethyl]GSH dimethyl ester. The hybridization of these oligonucleotides with the complement d(AGGCATG) was examined using UV melting profiles. The melting temperature (Tm) was reduced in the order N7-methylGua (least change) << N-acetyl-S-[2-(N7-guanyl)ethyl]Cys methyl ester < S-[2-(N7-guanyl)ethyl]GSH methyl ester < S-[2-(N7-guanyl)ethyl]GSH. These results indicate interaction of the adduct side chain with the rest of the oligonucleotide that was not observed in previous NMR studies [Oida, T., Humphreys, W. G., and Guengerich, F. P. (1991) Biochemistry 30, 10513-10522]. UV mixing plots indicated that d(CATGCCT) oligonucleotides containing the Gua adducts still pair with d(AGGNATG) containing Cyt but not the other three bases (at "N"). CD spectroscopic studies showed considerably reduced molar ellipticity for all oligonucleotide pairs containing the N7-guanyl adducts, even under conditions where duplex formation was extensive as judged by the UV melting and mixing studies.(ABSTRACT TRUNCATED AT 250 WORDS)