RESUMEN
2'-Deoxyadenosine was reacted with malonaldehyde in the presence of formaldehyde or acetaldehyde. The reactions were carried out at 37 degrees C in aqueous solution at acidic conditions. The reaction mixtures were analyzed by HPLC. In both reactions, two major products were formed. The reaction products were isolated and purified by C18 chromatography, and their structures were characterized by UV absorbance, fluorescence emission, (1)H and (13)C NMR spectroscopy, and mass spectrometry. The reaction products isolated from the mixture containing formaldehyde, malonaldehyde, and deoxyadenosine were identified as 3-(2'-deoxy-beta-D-ribofuranosyl)-7H-8-formyl[2,1-i]pyrimidopurine (M(1)FA-dA) and 9-(2'-deoxy-beta-D-ribofuranosyl)-6-(3,5-diformyl-1, 4-dihydro-1-pyridyl)purine (M(2)FA-dA). In the reaction mixture consisting of acetaldehyde, malonaldehyde, and deoxyadenosine, the identities of the products were determined to be 3-(2'-deoxy-beta-D-ribofuranosyl)-7-methyl-8-formyl[2, 1-i]pyrimidopurine (M(1)AA-dA) and 9-(2'-deoxy-beta-D-ribofuranosyl)-6-(3,5-diformyl-4-methyl-1, 4-dihydro-1-pyridyl)purine (M(2)AA-dA). The yields of the compounds were 1.8 and 0.7% for M(1)FA-dA and M(2)FA-dA, respectively, and 6.8 and 10% for M(1)AA-dA and M(2)AA-dA, respectively. All compounds exhibited marked fluorescent properties. These findings show that in addition to direct reaction of a specific aldehyde with 2'-deoxyadenosine, aldehyde conjugates also may react with the base. Although three of the adducts (M(1)FA-dA, M(2)FA-dA, and M(1)AA-dA) could not be detected in reactions carried out under neutral conditions, the possibility that trace amounts of the adducts may be formed under physiological conditions cannot be ruled out. Therefore, conjugate adducts must be considered in work that aims at clarifying the mechanism of aldehyde genotoxicity.
Asunto(s)
Acetaldehído/química , Aductos de ADN/química , Desoxiadenosinas/química , Formaldehído/química , Malondialdehído/química , FluorescenciaRESUMEN
The work reported here concerned the structural determination of adducts formed in reactions of nucleosides with chlorohydroxyfuranones and with conjugates of malonaldehyde and acetaldehyde. The chlorohydroxyfuranones are bacterial mutagens produced during chlorine disinfection of drinking-water, malonaldehyde is the major end-product of lipid peroxidation, and acetaldehyde is the major metabolite of ethanol. Exogenous sources of acetaldehyde are, for example, tobacco smoke and automobile emissions. The chlorohydroxyfuranones were found to form substituted and unsubstituted cyclic etheno adducts with adenosine, cytidine and guanosine and substituted cyclic propeno adducts with adenosine. The malonaldehyde-acetaldehyde conjugates reacted with adenosine to produce a strongly fluorescent dihydropyridine purine derivative and a substituted propenoformyl adenosine derivative. Most of the adducts identified in this study are new, and their mutagenic properties are as yet unknown.
Asunto(s)
Aductos de ADN/biosíntesis , Furanos/metabolismo , Adenosina/metabolismo , Carcinógenos/química , Carcinógenos/metabolismo , Citidina/metabolismo , Aductos de ADN/química , Furanos/química , Guanosina/metabolismo , Malondialdehído/metabolismo , Modelos Químicos , Mutágenos/química , Mutágenos/metabolismoRESUMEN
Malonaldehyde (malondialdehyde, MDA) was reacted with 2'-deoxyadenosine in buffered aqueous solution. HPLC analyses of the reaction mixtures showed that, besides the two previously characterized N6-propenal (M1dA) and N6-oxazocinyl (M3dA) adenine adducts, a third compound eluting at longer retention time was formed. The compound generated a strong peak in the chromatogram recorded by a fluorescence detector. The new compound was isolated by preparative C18 chromatography, and its structure was characterized by UV absorbance, fluorescence emission, 1H and 13C NMR spectroscopy, and mass spectrometry. The product was identified as 9-(2'-deoxyribosyl)-6-(3,5-diformyl-4-methyl-1, 4-dihydro-1-pyridyl)purine (M2AA-dA). The yield of the product was 0.8% following 7 days of reaction at 37 degreesC and pH 4.6. Lower yields were obtained at higher pH conditions. By the addition of acetaldehyde, the yield increased about 10-fold at all studied pH conditions. The adduct was most likely formed by an initial condensation of two molecules of malonaldehyde with one molecule of acetaldehyde followed by reaction of the condensation product with the exocyclic amino group of 2'-deoxyadenosine. The identification of this adduct shows that acetaldehyde may react with DNA bases also through an initially formed malonaldehyde-acetaldehyde condensation product.