STRUCTURAL AND QUANTUM-CHEMICAL FACTORS AFFECTING MUTAGENIC POTENCY OF AMINOIMIDAZO-AZAARENES

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 p ublished [Hatch et al. (1991): Environ Mol Mutagen 17:4-19] for on in- depth structure-activity study using computational methods. Structural features believed to affect mutagenic potency were tabulated. Molecul ar orbital energies and other electronic properties of these compounds were calculated using Huckel, semiempirical AM1, and ab initio quantu m mechanical methods. Factor interrelationships were studied by multip le linear regression and canonical correlation analyses. Our goal was on improved understanding of the chemical basis of mutagenicity for th is 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 on N-methyl g roup; 3) potency is enhanced by addition of ring nitrogen atoms in pyr idine, quinoline, and quinoxaline configurations; 4) potency is invers ely related to the energy of the LUMO (lowest unoccupied molecular orb ital) of the parent amines; 5) potency is directly, though weakly, rel ated to he LUMO energy of the derived nitrenium ions; and 6) the calcu lated thermodynamic stability of the nitrenium ions (relative to the p arent amine) is directly correlated with nitrenium LUMO energy and wit h the negative charge on the exocyclic nitrogen atom. Although this st udy raises several intriguing issues relating mutagenicity to chemical properties, further study will be required to determine the plausibil ity of the nitrenium ion as the ultimate mutagen for binding to DNA. ( C) 1996 Wiley-Liss, Inc.