Synthetic and oxidative studies on 8-(arylamino)-2'-deoxyguanosine and -guanosine derivatives.

Abstract

Facile aerial oxidation is a general feature of guanine ribo-and 2'-deoxyribonucleosides that are substituted at the 8-position by an aminoaryl group. In previous work, it had been suggested that two of the major oxidation products are a pair of diastereomers having a spiro structure. These were presumed to be related by a chiral difference at the spiro carbon atom. The pattern of the oxidative process involves a contraction of the pyrimidine ring. It was thought to be analogous to that suggested by other investigators for the oxidation of uric acid, but for which no really definitive evidence had been presented. We have been able now to isolate in a crystalline state one of the diastereomers produced by the aerial oxidation of 8-phenylaminoguanosine under alkaline conditions. Analysis by X-ray diffraction has now confirmed the type of spiro structure promulgated previously. These findings also imply that spiro compounds are likely to be produced during the aerial oxidation of any 8-arylaminoguanine nucleoside or 2'-deoxynucleoside. In addition, this work adds considerable weight to the results of Poje and Sokolic-Maravic who proposed that a spiro intermediate is produced during the aerial oxidation of uric acid (12,13). However, they found this compound to be unstable to base, in contrast to the arylaminoguanine oxidation products. In the course of the above work we showed that the 8-arylamino derivatives of guanosine can be converted by the Barton deoxygenation method to the corresponding 2'-deoxyribonucleosides. This makes available a number of the latter compounds, which are not easily prepared by other methods.

Site-specific incorporation of N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-AAF) into oligonucleotides using modified 'ultra-mild' DNA synthesis

“…β-Mercaptoethanol was added to avoid aerial oxidation of dG-AAF arising during long incubation at higher temperatures (43,44). Although preliminary stability tests at the nucleoside level with iPrPac-dG-AAF (6) revealed some cleavage of the N 8 acetyl group of dG-AAF under these conditions, no decomposition was observed at the oligonucleotide level.…”

“…The reaction mixture was then incubated for 15 min at 37°C with 0.5 μl (5 U) of calf intestine phosphatase and directly injected into the HPLC using the gradient described above. For the digestion of oligonucleotide containing the dG-AF adduct, the addition of 1 mM of DTT to the digestion buffer was necessary to avoid complete oxidation and degradation of the dG-AF nucleoside ( 5 ) (32,43,44). The resulting peaks were identified by co-injection with the corresponding standards and eluted at the following time periods: dC (3.4 min), dG (5.5 min), T (6.3 min), dA (8.2 min), dG-AAF (24.2 min), dG-AF (24.8 min) and iPrPac-dG-AAF (30.8 min).…”

Singlet Molecular Oxygen Reactions with Nucleic Acids, Lipids, and Proteins

“…It was concluded that the oxidized guanine nucleosides were the 4 R * and 4 S * diastereomers of N -(β- d - erythro -pentofuranosyl)­spiroiminodihydantoin. , This also rules out another earlier suggestion implicating unstable 5-hydroxy-8-oxo-4,8-dihydroguanosine (5-OH-8-oxoGuo) that is, in fact, the precursor of dSp. The reassignment was mostly made by considering similar rearrangement reactions of 5-hydroxyurate and an oxidation product of C8-arylamine of guanine that give rise respectively to related spiroiminodihydantoin compounds. The presence of a spirocyclic connectivity in dSp diastereomers was further established on the basis of unambiguous SELINQUATE 13 C NMR measurements .…”

Structure and potential mutagenicity of new hydantoin products from guanosine and 8-oxo-7,8-dihydroguanine oxidation by transition metals.

“…The best clues came from two related purine pathways: a) uric acid oxidation, whose uncatalyzed mechanism has been studied by Poje and co-workers (30) [the related enzymecatalyzed oxidation to form allantoin was studied in depth by Tipton's laboratory (31)]; and b) the aerobic oxidation of carcinogenic aryl amine adducts at C8 of G studied by Johnson and co-workers (32). These electron-rich purines share with OG the propensity to form products derived from opening of the sixmembered ring.…”