85405-01-2Relevant articles and documents
Identification of paraldol-deoxyguanosine adducts in DNA reacted with crotonaldehyde
Wang,McIntee,Cheng,Shi,Villalta,Hecht
, p. 1065 - 1074 (2000)
Crotonaldehyde (1) is a mutagen and carcinogen, but its reactions with DNA have been only partially characterized. In a previous study, we found that substantial amounts of 2-(2hydroxypropyl)-4-hydroxy-6-methyl-1,3-dioxane (paraldol, 7), the dimer of 3-hydroxybutanal (8), were released upon enzymatic or neutral thermal hydrolysis of DNA that had been allowed to react 0with crotonaldehyde. We have now characterized two paraldol-deoxyguanosine adducts in this DNA: N2-[2-(2-hydroxypropyl)-6-methyl-1,3-dioxan-4-yl]deoxyguanosine (N2-paraldoldG, 13) and N2-[2-(2-hydroxypropyl)-6-methyl-1,3-dioxan-4-yl]deoxyguanylyl-(5'-3')-thymi dine [N2-paraldol-dG-(5'-3')-thymidine, 14]. Four diastereomers of N2-paraldol-dG (13) were observed. Their overall structures were determined by 1H NMR, by MS, and by reaction of paraldol with deoxyguanosine and DNA. 1H NMR data showed that two diastereomers had all equatorial substituents in the dioxane ring, while two others had an axial 6-methyl group. Preparation of paraldol with the (R)- or (S)-configuration at the 6-position of the dioxane ring and the carbinol carbon of the 2-(2-hydroxypropyl) group allowed partial assignment of the absolute configurations of N2-paraldol-dG (13). Four diastereomers of N2-paraldol-dG-(5'-3')thymidine (14) were observed. Their overall structure was determined by 1H NMR, MS, and hydrolysis with snake venom or spleen phosphodiesterase. Reactions of nucleosides and nucleotides with paraldol demonstrated that adducts were formed only from deoxyguanosine and its monophosphates. Experiments with DNA that had been reacted with crotonaldehyde indicated that N2-paraldol-dG-containing adducts in DNA are relatively resistant to enzymatic hydrolysis. The results of this study demonstrate that the reaction of crotonaldehyde with DNA is more complex than previously recognized and that stable N2-paraldol-dG adducts are among those that should be considered in assessing mechanisms of crotonaldehyde mutagenicity and carcinogenicity.
Stereospecific synthesis of oligonucleotides containing crotonaldehyde adducts of deoxyguanosine
Nechev,Kozekov,Harris,Harris
, p. 1506 - 1512 (2007/10/03)
Crotonaldehyde reacts with DNA to form two diastereomeric 1,N2 cyclic adducts of deoxyguanosine. A synthesis of the two diastereomeric deoxynucleosides has been achieved by reaction of mixed diastereomers of 4-amino-1,2-pentanediol with 2-fluoro-O6-(trimethylsilylethyl)-deoxyinosine. The resulting N2-(1-methyl-3,4-dihydroxybutyl)-deoxyguanosine was treated with NaIO4, cleaving the vicinal diol to the aldehyde. Spontaneous cyclization gave the two diastereomers of the crotonaldehyde-adducted nucleoside that were readily separated by HPLC. The absolute configurations were assigned by an enantiospecific synthesis of one diastereomer from (S)-3-aminobutanoic acid. The synthetic strategy has been extended to preparation of a site-specifically adducted oligonucleotide by reaction of the mixed diastereomers of 4-amino-1,2-pentanediol with an 8-mer oligonucleotide containing 2-fluoro-O6-(trimethylsilylethyl)-deoxyinosine. The diastereomeric oligonucleotides were separated by HPLC and absolute configurations of the adducts were established by enzymatic digestion to the adducted nucleosides.
