Prediction of nucleoside-carcinogen reactivity. Alkylation of adenine, cytosine, guanine, and thymine and their deoxynucleosides by alkanediazonium ions

Abstract

MNDO semiempirical molecular orbital calculations for the SN2 alkylation of nucleic acid bases and deoxynucleosides by the methane-, ethane-, and propanediazonium ions are presented. An approximate correlation is demonstrated between the calculated relative activation enthalpies for attack at alternative base sites and the related experimental quantities for DNA modification by alkylnitrosoureas. The empirically observed shift from N- to O-alkylation with increasing complexity of the alkylating agent is reproduced by the calculations and rationalized by using an extension of a model worked out previously for the analogous reactions of simple nucleophiles. According to this model, the energetics of the related SN1 reactions, while not directly involved, have a profound influence on the SN2 transition-state geometries. For reactions in which the SN1 dissociation is unfavorable the forming bond to the incoming nucleophiles in the related SN2 transition state tends to be short and covalent interactions, which favor N-alkylation, play a significant role. When the SN1 reaction is more facile, the SN2 transition states are "looser" and the covalent interactions correspondingly smaller, leading to an overall shift away from N-alkylation. Consideration of the form of the electrostatic potential around the base, in conjunction with these ideas, provides a detailed explanation of the behavior of electrophiles toward the guanine N2-, 7-, and O6-positions. This model unifies much of the language already used in discussions of nucleic acid regiochemistry. At the same time it is consistent with the geometries and charge distributions in the transition states calculated for the gas-phase reaction processes.

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

“…For example, Ford and Scribner [26] have used MNDO calculations in studies of nucleobases' alkylation by alkylnitrosoureas. They have shown that optimal geometry of the transition state determines the preferences for either oxygen or nitrogen attack by these agents.…”

Model transition states for methane diazonium ion methylation of guanine runs in oligomeric DNA

“…2,5,9,10 However, for many alkylating agents, reaction at guanine O 6 represents less than 10% of the total alkylation in DNA and RNA. [4][5][6][7][8] The methane diazonium ion, CH 3 N 2 þ , is the reactive intermediate formed from MeNU, 3,[11][12][13][14][15] N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG), 16 methylnitrosocarbamates, 17 trimethyltriazenes, 18 and nitrosamines. 17 This intermediate undergoes sequence specific reactions with guanine N7 and guanine O 6 in DNA.…”