Selectivity in nucleoside alkylation and aralkylation in relation to chemical carcinogenesis

Abstract

The sites of benzylation of adenosine and guanosine by different benzylating agents in various solvent mixtures were investigated in order to determine those properties of chemical reactivity which lead to reaction on the exocyclic amino and oxo groups. Modification of these sites, as opposed to ring nitrogen sites, can be associated with carcinogenic potential, and was found to be favored by changes in reaction medium or leaving group which would advance carbon leaving group bond breakage. The extents of reaction on the exocyclic amino group of guanosine were greater than for the exocyclic O1 23456 site but the ratio of reaction at 06 8/N2 increased with increasing leaving group hardness, suggesting that the charge localization or hardness of the reaction center determines the distribution of products over these two sites.

Nucleoside–Metallacarborane Conjugates for Base‐Specific Metal Labeling of DNA

“…A strong dependence of the specificity of alkylation on the nature of the alkylating species has been repeatedly found in early works on alkylation of nucleobases by carcinogens. [29][30][31][32] Agents that are not particularly ionic in nature mainly alkylate sites with a high relative nucleophilicity through a bimolecular displacement (S N 2) mechanism, whereas electrophiles with more ionic character prefer to react at the less nucleophilic sites. Owing to the presence of a positive charge on the oxygen atom of the dioxane moiety linked to B-8 of the metallacarborane complex, the electron density at C-1 of dioxane is strongly decreased.…”

“…An additional aspect which should be taken into consideration is the increase of the hardness of the electrophilic carbon center in dioxane due to the proximity of the oxonium oxygen atom and therefore preferential reaction with the harder oxygen ionic center of the thymine or guanine base than with the softer nitrogen one. [30][31][32][33] The site for base alkylation in the final products 8 a-c derived from 3 a-c was determined by comparing the UV spectra of 8 a-c ( Table 2) with those of other alkylation products described in the literature, [29] and was subsequently confirmed by NMR spectroscopy using the HMBC technique to analyze the fully protected precursors 3 a-c. First, the signals of the methylene groups of the 3-oxapentoxy linker were assigned in the 1 H and 13 C NMR spectra using 1 H-1 H COSY and DEPT techniques for designating signals in the 13 C NMR spectrum. The DEPT procedure was applied to distinguish between CH (DEPT 90) and CH 2 (DEPT 135) groups.…”

Nucleophilic properties of purine bases: inherent reactivity versus reaction conditions

“…The other sources are connected with various specific interactions between the reagents and/or the environment. These include the following: solvent effects [16,17], solvent-assisted reaction mechanisms [18,19], the influence of pH on ionic equilibriums [20][21][22][23][24] or specific interactions between reagents, in particular HBs and steric interactions [19,25].…”

Degradation of nucleic acids and nucleotides in several conditions with perspectives of retrieval: A review

“…as is expected, access to some sites is limited in doublestranded DNA relative to single-stranded DNA [7,8], but, reactions are not completely precluded even at locations on Watson-Crick hydrogen bonding surfaces of the bases that reside near the helical axis of the duplex. The factors that determine the atom site selectivity for a given DNAalkylating agent are complex [7][8][9][10][11]. A recent detailed study of alkylation by diazonium ions led to the conclusion that atom site selectivities seen in duplex dna do not reflect intrinsic nucleophilicities of the heteroatoms in the nucleobases.…”