Quantitative structure-activity (QSAR) relationships of mutagenic aromatic and heterocyclic amines.
We extended our previous studies of mutagenic/carcinogenic heterocyclic aromatic amines formed during the cooking of foods to 66 aromatic and 99 heterocyclic amines for which mutagenic potency data are available. The amines require activation by enzymes to form metabolites reactive with DNA and exhibit an enormous range of potency as frameshift mutagens in the Ames/Salmonella assay. To ascertain factors that might influence potency, structural features and quantum mechanical parameters calculated by the Hückel method (and, for a subset of 20 amines, by semi-empirical AM1, and ab initio methods) were analyzed by multiple linear regression. The major findings were: (1) earlier findings on cooked food mutagens and their synthetic congeners can be extended to other amines; (2) mutagenic potency is directly related to the number of fused aromatic rings (size of the aromatic system), the number of ring nitrogen atoms (participation of lone electron pairs in the pi-cloud), and presence of a methyl substituent on a ring nitrogen; (3) potency is inversely related to the energy of the lowest unoccupied molecular orbital (LUMO) of the parent amine. Ford and Griffin (1992) and Sabbioni and Wild (1992) showed that the LUMO energy of the derived nitrenium ion is closely related to its stability (calculated with reference to aniline). Increased stability has been hypothesized to enhance the probability of adduct formation with DNA by avoiding detoxifying side reactions and increasing the lifetime of the ion. In the large heterogeneous series of amines in our present study the Hückel method energy of the highest occupied molecular orbital (HOMO), rather than the LUMO energy, of the nitrenium ion was marginally related to the potency of the parent amine. However, in the selected subset of 20 amines with ab initio calculation, the LUMO energy of the ion confirmed the previous reports. The contribution of quantum chemical factors to mechanistic insight on the mutagenicity and carcinogenicity of aromatic and heterocyclic amines is still under development.
Hatch
F T
FT
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA 94551, USA. fhatch@northstar.dartmouth.edu
Colvin
M E
ME
D000588:Amines / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006571:Heterocyclic Compounds / Q000737:chemistry*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry*; D012044:Regression Analysis; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D000588:Amines; D006571:Heterocyclic Compounds; D009153:Mutagens