Quantum-chemical studies on mutagenicity of aromatic and heteroaromatic amines

Abstract

Arylamines are well-known as widespread industrial and environmental mutagens and carcinogens. Their bioactivity stems from enzymatic metabolic activation to reactive and highly electrophilic intermediates. In this work, computational investigations related to the biological activity of these compounds have been reviewed, especially focusing on studies reporting results from quantum-mechanical calculations. Correlations between relative mutagenicities and structural and electronic features of the parent amines and of their derived nitrenium ion intermediates were examined, with the aim of achieving a clearer comprehension of the main factors determining the genotoxic potential of this type of compounds.

Theoretical Studies of the Mechanism of N-Hydroxylation of Primary Aromatic Amines by Cytochrome P450 1A2: Radicaloid or Anionic?

“…For example, published results suggest protective effects of bulky groups regardless of their impact on the stability of ArNH + , 10,18,19 and inductive functional groups show reverse effects on the stability of ArNH + and the mutagenic potency of ArNH 2 . 6,10,19−24 Thus, electron-withdrawing functions like CF 3 , CHF 2 , CN, NO 2 , F, Cl, or C(O)NH 2 , 6,20−24 and alpha pyridine-like nitrogens (α-N) 6,16,17 that decrease the stability of ArNH + frequently amplify the mutagenic potency of ArNH 2 . Studies of aniline (PhNH 2 ) and a number of aniline derivatives with electron-donating groups, such as OH, Me, OMe, NH 2 , or NMe 2 , which stabilize ArNH + , showed that these compounds do not follow the classical ArNH + -mediated mechanism of mutagenicity.…”

“…The nitrenium stabilization concept is found to be very useful in discriminating mutagenic and nonmutagenic ArNH 2 in large data sets since the stability of ArNH + represents the most important descriptor of mutagenicity of ArNH 2 . , However, the stability of ArNH + clearly correlates with the mutagenic potency of ArNH 2 only within structural subclasses. ,,− There are distinct motifs in the SMR that cannot be linked to the stability of ArNH + . For example, published results suggest protective effects of bulky groups regardless of their impact on the stability of ArNH + , ,, and inductive functional groups show reverse effects on the stability of ArNH + and the mutagenic potency of ArNH 2 . ,,− Thus, electron-withdrawing functions like CF 3 , CHF 2 , CN, NO 2 , F, Cl, or C­(O)­NH 2 , ,− and alpha pyridine-like nitrogens (α-N) ,, that decrease the stability of ArNH + frequently amplify the mutagenic potency of ArNH 2 . Studies of aniline (PhNH 2 ) and a number of aniline derivatives with electron-donating groups, such as OH, Me, OMe, NH 2 , or NMe 2 , which stabilize ArNH + , showed that these compounds do not follow the classical ArNH + -mediated mechanism of mutagenicity.…”

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi

“…Although there is evidence to suggest heteroaromatic amines have a reduced risk of being mutagenic 52 and that increases in polarity can also reduce hERG inhibition, 53 it was unfortunate that pyridine or pyrimidine analogues of 20 had lower activity (i.e., 51 , 52 , and 53 ) and were not considered as suitable leads.…”

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

“…Prediction of mutagenicity of reagent-sized ArNH 2 fragments is vital for the success of drug discovery programs, and special attention has been devoted to this issue in the literature. Currently, the mutagenicity of ArNH 2 can be predicted by three types of computational methods, which are based on either statistics, structural alerts, or mechanistic considerations. − ,− Despite the abundance of experimental data and the availability of computational approaches and relevant databases, the prediction of mutagenicity of ArNH 2 still represents a significant challenge to computational and theoretical chemistry. ,,,,, Quantitative structure–mutagenicity relationships usually suggest a variety of factors that increase mutagenic potency of ArNH 2 : increase of lipophilicity, high energy of the highest occupied molecular orbital (HOMO), low energy of the lowest unoccupied molecular orbital (LUMO), low “chemical hardness” (LUMO–HOMO), high “chemical softness”, stability of ArNH + (reactive electrophilic metabolites of ArNH 2 ), negative charge density at the exocyclic nitrogen of ArNH + , presence of a pyridine-like nitrogen (i.e., aromatic nitrogen with sp 2 lone pair) in the α-position to the NH 2 group, and size of the aromatic system. ,,,− ,,,,− Although these descriptors reflect an array of steps in the mutagenic activation of ArNH 2 and are important for mutagenic activity, ,,,, their ability to discriminate between mutagenic and nonmutagenic compounds , or to describe mutagenic potency in diverse sets of active mutagens ,,,,,, is limited. Thus, high lipophilicity, high energy of HOMO, and even stability of ArNH + turn out to be unimportant to define high mutagenic potency or to discriminate a propensit...…”