Mechanism-Based Insights into Removing the Mutagenicity of Aromatic Amines by Small Structural Alterations

Aromatic and heteroaromatic amines
(ArNH2) are activated
by cytochrome P450 monooxygenases, primarily CYP1A2, into reactive N-arylhydroxylamines that can lead to covalent adducts with
DNA nucleobases. Hereby, we give hands-on mechanism-based guidelines
to design mutagenicity-free ArNH2. The mechanism of N-hydroxylation
of ArNH2 by CYP1A2 is investigated by density functional
theory (DFT) calculations. Two putative pathways are considered, the
radicaloid route that goes via the classical ferryl-oxo oxidant and
an alternative anionic pathway through Fenton-like oxidation by ferriheme-bound
H2O2. Results suggest that bioactivation of
ArNH2 follows the anionic pathway. We demonstrate that
H-bonding and/or geometric fit of ArNH2 to CYP1A2 as well
as feasibility of both proton abstraction by the ferriheme-peroxo
base and heterolytic cleavage of arylhydroxylamines render molecules
mutagenic. Mutagenicity of ArNH2 can be removed by structural
alterations that disrupt geometric and/or electrostatic fit to CYP1A2,
decrease the acidity of the NH2 group, destabilize arylnitrenium
ions, or disrupt their pre-covalent transition states with guanine.