Related Experiment Videos
Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes
F T Hatch1, M E Colvin, E T Seidl
1Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California, USA.
Abstract:
A set of 16 mutagenic aminoimidazo-azaarenes, including four that have been isolated from cooked foods and identified as bacterial mutagens and rodent carcinogens, was selected from a larger series previously published [Hatch et al. (1991): Environ Mol Mutagen 17:4-19] for an in-depth structure-activity study using computational methods. Structural features believed to affect mutagenic potency were tabulated. Molecular orbital energies and other electronic properties of these compounds were calculated using Huckel, semiempirical AM1, and ab initio quantum mechanical methods. Factor interrelationships were studied by multiple linear regression and canonical correlation analyses. Our goal was an improved understanding of the chemical basis of mutagenicity for this class of heterocyclic amines. The major findings were as follows: 1) mutagenic potency is related to the size of the aromatic ring system; 2) potency is enhanced by the presence and location of an N-methyl group; 3) potency is enhanced by addition of ring nitrogen atoms in pyridine, quinoline, and quinoxaline configurations; 4) potency is inversely related to the energy of the LUMO (lowest unoccupied molecular orbital) of the parent amines; 5) potency is directly, though weakly, related to the LUMO energy of the derived nitrenium ions; and 6) the calculated thermodynamic stability of the nitrenium ions (relative to the parent amine) is directly correlated with nitrenium LUMO energy and with the negative charge on the exocyclic nitrogen atom. Although this study raises several intriguing issues relating mutagenicity to chemical properties, further study will be required to determine the plausibility of the nitrenium ion as the ultimate mutagen for binding to DNA.
Insights
This study reveals that mutagenic potency in aminoimidazo-azaarenes is linked to aromatic ring size, N-methyl group presence, and ring nitrogen atoms. Lower lowest unoccupied molecular orbital (LUMO) energy in parent amines correlates with higher mutagenicity.
Area of Science:
- Environmental Chemistry
- Molecular Toxicology
- Computational Chemistry
Background:
- Aminoimidazo-azaarenes, found in cooked foods, are known bacterial mutagens and rodent carcinogens.
- Previous research identified a series of these compounds with varying mutagenic potencies.
Purpose of the Study:
- To conduct an in-depth structure-activity relationship (SAR) study of 16 mutagenic aminoimidazo-azaarenes using computational methods.
- To elucidate the chemical basis of mutagenicity for this class of heterocyclic amines.
Main Methods:
- Calculated molecular orbital energies and electronic properties using Huckel, semiempirical AM1, and ab initio quantum mechanical methods.
- Analyzed interrelationships between structural features and electronic properties using multiple linear regression and canonical correlation analyses.
Main Results:
- Mutagenic potency positively correlated with aromatic ring system size and the presence/location of N-methyl groups.
- Potency increased with additional ring nitrogen atoms (pyridine, quinoline, quinoxaline configurations).
- Potency was inversely related to the lowest unoccupied molecular orbital (LUMO) energy of parent amines and directly, though weakly, to the LUMO energy of derived nitrenium ions.
Conclusions:
- Chemical properties such as aromaticity, N-methylation, and electronic structure significantly influence mutagenic potency.
- The thermodynamic stability of nitrenium ions correlates with their LUMO energy and charge distribution.
- Further research is needed to confirm the role of nitrenium ions as ultimate mutagens that bind to DNA.