title: Theoretical studies of chemical reactivity of metabolically activated forms of aromatic amines toward DNA.
abstract: The metabolism of aromatic and heteroaromatic amines (ArNH₂) results in nitrenium ions (ArNH⁺) that modify nucleobases of DNA, primarily deoxyguanosine (dG), by forming dG-C8 adducts. The activated amine nitrogen in ArNH⁺ reacts with the C8 of dG, which gives rise to mutations in DNA. For the most mutagenic ArNH₂, including the majority of known genotoxic carcinogens, the stability of ArNH⁺ is of intermediate magnitude. To understand the origin of this observation as well as the specificity of reactions of ArNH⁺ with guanines in DNA, we investigated the chemical reactivity of the metabolically activated forms of ArNH₂, that is, ArNHOH and ArNHOAc, toward 9-methylguanine by DFT calculations. The chemical reactivity of these forms is determined by the rate constants of two consecutive reactions leading to cationic guanine intermediates. The formation of ArNH⁺ accelerates with resonance stabilization of ArNH⁺, whereas the formed ArNH⁺ reacts with guanine derivatives with the constant diffusion-limited rate until the reaction slows down when ArNH⁺ is about 20 kcal/mol more stable than PhNH⁺. At this point, ArNHOH and ArNHOAc show maximum reactivity. The lowest activation energy of the reaction of ArNH⁺ with 9-methylguanine corresponds to the charge-transfer π-stacked transition state (π-TS) that leads to the direct formation of the C8 intermediate. The predicted activation barriers of this reaction match the observed absolute rate constants for a number of ArNH⁺. We demonstrate that the mutagenic potency of ArNH₂ correlates with the rate of formation and the chemical reactivity of the metabolically activated forms toward the C8 atom of dG. On the basis of geometric consideration of the π-TS complex made of genotoxic compounds with long aromatic systems, we propose that precovalent intercalation in DNA is not an essential step in the genotoxicity pathway of ArNH₂. The mechanism-based reasoning suggests rational design strategies to avoid genotoxicity of ArNH₂ primarily by preventing N-hydroxylation of ArNH₂.
authors.affiliation: Department of Medicinal Chemistry, R&I iMed, AstraZeneca R&D , Pepparedsleden 1, S-431 83 Mölndal, Sweden. igor.shamovsky@astrazeneca.com
authors.forename: Igor
authors.initials: I
authors.lastname: Shamovsky
authors.forename: Lena
authors.initials: L
authors.lastname: Ripa
authors.forename: Niklas
authors.initials: N
authors.lastname: Blomberg
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
authors.forename: Peter
authors.initials: P
authors.lastname: Hansen
authors.forename: Christine
authors.initials: C
authors.lastname: Mee
authors.forename: Christian
authors.initials: C
authors.lastname: Tyrchan
authors.forename: Mike
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Peter
authors.initials: P
authors.lastname: Sjö
mesh_terms: D000588:Amines / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006841:Hydrocarbons, Aromatic / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D000588:Amines; D018736:DNA Adducts; D006841:Hydrocarbons, Aromatic; D009153:Mutagens; C116701:9-methylguanine; D006147:Guanine; D004247:DNA