Activation barriers for DNA alkylation by carcinogenic methane diazonium ions.
Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The SN2 transition states of the methylation reactions at N7, N3, and O6 of guanine; N7, N3, and N1 of adenine; N3 and O2 of cytosine; and O2 and O4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor-like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine N1 are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 A shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base-water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine.
Ekanayake
Kaushalya S
KS
Department of Chemistry, The University of Illinois at Chicago, 845 W. Taylor Street, Chicago, Illinois 60607-7061, USA.
Lebreton
Pierre R
PR
D000478:Alkylation; D002273:Carcinogens / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D003979:Diazonium Compounds / Q000737:chemistry*; D008697:Methane / Q000737:chemistry*; D013816:Thermodynamics
D002273:Carcinogens; D003979:Diazonium Compounds; D004247:DNA; D008697:Methane