malealdehyde and 2--deoxyadenosine

The computational analysis of multistep chemical interactions between 2'-deoxyadenosine and cis-2-butene-1,4-dial has been performed. The applied protocol includes generation of a multistep Gibbs free-energy reaction profile (PCM/M05-2X/6-311+G(d) level) for the transformations of the reagents to products, followed by evaluation of the rate constants, construction of the corresponding kinetic equations, and solving them. Such a procedure allows one to significantly extend the number of experimentally determined steps by addition of the ones computationally predicted. The primary products of the reaction are found to be four diastereomeric adducts characterized by virtually the same stability. The acid-catalyzed dehydration of these adducts leads to a more stable secondary product. Computational verification of UV and NMR spectra has also been performed. It has been revealed that simulated UV and NMR spectra of primary and secondary 2'-deoxyadenosine adducts of cis-2-butene-1,4-dial are in agreement with the experimental observations.

Topics: Aldehydes; Computer Simulation; Deoxyadenosines; Molecular Structure

Oxidation of deoxyribose in DNA produces a variety of electrophilic residues that are capable of reacting with nucleobases to form adducts such as M(1)dG, the pyrimidopurinone adduct of dG. We now report that deoxyribose oxidation in DNA leads to the formation of oxadiazabicyclo(3.3.0)octaimine adducts of dC and dA. We previously demonstrated that these adducts arise in reactions of nucleosides and DNA with trans-1,4-dioxo-2-butene, the beta-elimination product of the 2-phosphoryl-1,4-dioxobutane residue arising from 5'-oxidation of deoxyribose in DNA, and with cis-1,4-dioxo-2-butene, a metabolite of furan. Treatment of DNA with enediyne antibiotics capable of oxidizing the 5'-position of deoxyribose (calicheamicin and neocarzinostatin) led to a concentration-dependent formation of oxadiazabicyclo(3.3.0)octaimine adducts of dC and dA, while the antibiotic bleomycin, which is capable of performing only 4-oxidation of deoxyribose, did not give rise to the adducts. The nonspecific DNA oxidant, gamma-radiation, also produced the adducts that represented approximately 0.1% of the 2-phosphoryl-1,4-dioxobutane residues formed during the irradiation. These results suggest that the oxadiazabicyclo(3.3.0)octaimine adducts of dC and dA could represent endogenous DNA lesions arising from oxidative stresses that also give rise to other DNA adducts.

Topics: Aldehydes; Animals; Cattle; Chromatography, Liquid; Deoxyadenosines; Deoxycytidine; Deoxyribose; DNA; DNA Adducts; Mass Spectrometry; Molecular Structure; Oxidation-Reduction; Stereoisomerism

Furan is a hepatic toxicant and carcinogen in rodents. Its microsomal metabolite, cis-2-butene-1,4-dial, is mutagenic in the Ames assay. Consistent with this observation, cis-2-butene-1,4-dial reacts with 2'-deoxycytidine, 2'-deoxyguanosine, and 2'-deoxyadenosine to form diastereomeric adducts. HPLC analysis indicated that the rate of reaction with deoxyribonucleosides was dependent on pH. At pH 6.5, the relative reactivity was 2'-deoxycytidine > 2'-deoxyguanosine > 2'-deoxyadenosine whereas it was 2'-deoxyguanosine > 2'-deoxycytidine > 2'-deoxyadenosine at pH 8.0. Thymidine did not react with cis-2-butene-1,4-dial. The primary 2'-deoxyguanosine and 2'-deoxyadenosine reaction products were unstable and decomposed to secondary products. NMR and mass spectral analysis indicated that the initial 2'-deoxyadenosine and 2'-deoxyguanosine reaction products were hemiacetal forms of 3-(2'-deoxy-beta-D-erthyropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2''-al)-9H-imidazo[1,2-alpha]purine-9-one (structure 2) and 3-(2'-deoxy-beta-D-erythropentafuranosyl)-3,6,7,8-tetrahydro-7-(ethane-2''-al)-8-hydroxy-3H-imidazo[2,1-i]purine (structure 4), respectively. These adducts resulted from the addition of cis-2-butene-1,4-dial to the exo- and endocyclic nitrogens of 2'-deoxyadenosine and 2'-deoxyguanosine. The data provide support for the hypothesis that cis-2-butene-1,4-dial is an important genotoxic intermediate in furan-induced carcinogenesis.

Topics: Aldehydes; Animals; Carcinogens; Deoxyadenosines; Deoxyguanosine; DNA Adducts; Furans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mass Spectrometry; Microsomes, Liver; Molecular Structure; Nucleosides; Rats; Stereoisomerism