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

Abstract

The DNA reaction pattern of the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, was examined at N7 and O(6) sites in guanine runs occurring in oligonucleotides and model oligonucleotides. Density functional B3LYP/6-31G*, and SCF 3-21G and STO-3G energies of model transition states were calculated in the gas phase and in the CPCM reaction field. For nucleotides containing two, three, and four stacked guanines with counterions in the gas phase, O(6) reactivity is greater than N7 reactivity. In the reaction field, N7 reactivity is 9.0 to 9.8 times greater than O(6) reactivity. For a double-stranded oligonucleotide containing two stacked guanines with counterions in the reaction field, the N7 and O(6) reactivities of the 3'-guanine are 3.9 times greater than the corresponding sites in the 5'-guanine. For double-stranded oligonucleotides with three or four stacked guanines and counterions, the reactivities of the interior guanines are higher than corresponding reactivities of guanines at the ends. These reaction patterns agree with most of the available experimental data. Activation energy decomposition analysis for gas-phase reactions in a double-stranded dinucleotide containing two stacked guanines with counterions indicates that selectivity at O(6) is almost entirely due to electrostatic forces. Selectivity at N7 also has a large electrostatic interaction. However, the orbital interaction also contributes significantly to the gas-phase selectivity, accounting for 32% of the total interaction energy difference between the 3'- and 5'-guanine reactions. In aqueous solution, the relative orbital contribution to N7 selectivity is likely to be larger.

A density functional theory investigation on the formation mechanisms of DNA interstrand crosslinks induced by chloroethylnitrosoureas

“…By IRC computations, this complex has been found and its relative energy is −7.02 kcal/mol. This result is consistent with the previous theoretical results about the mechanism of DNA alkylation by the methanediazonium ion,33–35 which suggested the existence of an ion‐molecular complex of diazonium and guanine. The energy barrier from the 1 ‐Gua complex to 2 (6.11 kcal/mol) is similar to the reported energy barrier of O 6 ‐guanine alkylation by the methanediazonium ion (4.2 kcal/mol34).…”

Comparative theoretical investigation of the formation of DNA interstrand crosslinks induced by two kinds of N‐nitroso compounds: nitrosoureas and nitrosamines

“…By IRC calculations, a complex of 4 ‐guanine was found as a potential minimum existing between the reactants and the transition states. This ion–molecule complex was also obtained in previous theoretical researches on the mechanism of DNA alkylation by methanediazonium ion . The energy barrier from the ion–molecule complex to 5 is 5.6 kcal/mol, which is similar with the reported energy barrier of O 6 ‐guanine alkylation by methanediazonium ion (4.2 kcal/mol).…”

Effect of Lonidamine on Systemic Therapy of DB-1 Human Melanoma Xenografts with Temozolomide

“…Inhibition of both the MPC and Complex II explain the effect of LND on tumor respiration that produces the selective effect of this drug on tumor energy status. Selective tumor acidification enhances the activities of nitrogen mustard alkylating agents by a complex mechanism that has been described extensively (40)(41)(42)(43)(44)(45)(46) that involves stabilizing the alkylating intermediate aziridinium cation, which is degraded by OH -ions; inhibition of glutathione transferase activity also neutralizes aziridinium cation intermediates and acid inhibition of O 6 -alkyltransferase also called O 6 -methylguanine transferase (MGMT), a key enzyme involved in repair N-mustard alkylation of DNA at the N 7 and O 6 positions of guanine, also contributes to acid potentiation of N-mustard antineoplastic activity. Potentiation of doxorubicin activity appears to occur by a cation-trapping mechanism; the neutral weakly basic form of doxorubicin crosses the plasma membrane and is trapped in the tumor cell as a result of protonation in the acidified cytosol.…”