MOLECULAR MODELING PARAMETERS PREDICT ANTIOXIDANT EFFICACY OF 3-INDOLYL COMPOUNDS

Many dietary constituents, such as indole-3-carbinol, are chemoprotect ive in toxicity and carcinogenicity: bioassays, Indole-Li-carbinol and related congeners appear to prefect partly via radical and electrophi le scavenging. To develop better chemoprotective indoles with lower in trinsic toxicity, we performed molecular graphic and quantum-mechanica l analyses of model indolyl compounds to ascertain the determinant mol ecular features for antioxidant activity. We examined eight structural ly related 3-indolyl compounds for relationships between antioxidation potential (using in vitro lipid peroxidation assays) and electronic, polar, and steric parameters, including bond dissociation energies, bo nd lengths, dipole moments, electronic charge densities, and molecular size parameters. Electronic features of the 3-methylene carbon and 1- nitrogen were not predictive of antioxidative potency due to extensive charge delocalization of the cation radical following electron abstra ction from the nitrogen, Antioxidant efficacy of 3-indolyl compounds w as most strongly predicted by molecular size parameters and by the ene rgy of electron abstraction as calculated from the difference in heat of formation between the parent compound and its cation radical, A hig hly predictive multiple linear regression correlation model (r(2) = 0. 97) was obtained using the parameters of heal of formation, molecular weight, log P, and diplole moment.