Mutagenic potential of nitrenium ions of nitrobenzanthrones: correlation between theory and experiment.
The mutagenic activity of nine substituted nitrobenzanthrone (NBA) derivatives was recently established in the Ames assay and ranged from near inactivity to extremely high mutagenic activity (Takamura-Enya et al. 2006: Mutagenesis 21:399-404). Using thermochemical and molecular modeling techniques, the activation pathway of these NBA derivatives, namely 1-nitro-, 2-nitro-, 3-nitro-, 9-nitro-, 11-nitro-, 1,9-dinitro-, 3,9-dinitro-, 3,11-dinitro-, and 3,9,11-trinitrobenzanthrone, and the formation of the corresponding aryl-nitrenium ions, were investigated using density functional theory calculations. The calculated properties of the NBA derivatives were systematically compared with their bacterial mutagenic potency. Accommodation of the ligand substrates into the binding pocket of the bacterial nitroreductases was not sterically inhibited for the NBAs. Moreover, electron affinities, water elimination energies, esterification, and solvolysis energies did not reveal any possible links with the observed mutagenic potency of the NBAs. However, a strong negative linear correlation was found when the relative energies of the nitrenium ions of the mono and disubstituted NBAs were plotted against the logarithm of the mutagenic potency of the NBAs found in the different Salmonella typhimurium strains. Therefore, our data clearly indicate that the stability of the nitrenium ions is one critical determinant of the mutagenic potency of NBAs in Salmonella tester strains.
Reynisson
Jóhannes
J
School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom. johannes.reynisson@ntu.ac.uk
Stiborová
Marie
M
Martínek
Václav
V
Gamboa da Costa
Gonçalo
G
Phillips
David H
DH
Arlt
Volker M
VM
D001551:Benz(a)Anthracenes / Q000633:toxicity*; D004579:Electron Transport; D008958:Models, Molecular; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011789:Quantum Theory; D012486:Salmonella typhimurium / Q000235:genetics
D001551:Benz(a)Anthracenes; D009153:Mutagens; C117220:3-nitrobenzanthrone