Arch Toxicol (1996) 70: 830—834  Springer-Verlag 1996 ORIGINAL INVESTIGATION Howard G. Shertzer · M. Wilson Tabor · I.T.D. Hogan Stephen J. Brown · Malcolm Sainsbury Molecular modeling parameters predict antioxidant efficacy of 3-indolyl compounds Received: 21 November 1995 / Accepted: 19 March 1996 Abstract Many dietary constituents, such as indole-3- carbinol, are chemoprotective in toxicity and carcino- genicity bioassays. Indole-3-carbinol and related congeners appear to protect partly via radical and electrophile scavenging. To develop better chemopro- tective indoles with lower intrinsic toxicity, we per- formed molecular graphic and quantum-mechanical analyses of model indolyl compounds to ascertain the determinant molecular features for antioxidant activ- ity. We examined eight structurally 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, bond lengths, dipole moments, electronic charge densities, and molecular size para- meters. 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 abstraction from the nitrogen. Antioxidant efficacy of 3-indolyl compounds was most strongly predicted by molecular size para- meters and by the energy of electron abstraction as calculated from the difference in heat of formation between the parent compound and its cation radical. A highly predictive multiple linear regression correla- tion model (r"0.97) was obtained using the para- meters of heat of formation, molecular weight, log P, and diplole moment. Key words Antioxidant · Indolyl compounds · Lipid peroxidation · Molecular modeling · Structure-activity relationships H.G. Shertzer ( ) · M. Wilson Tabor · S.J. Brown Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267—0056, USA I.T.D. Hogan · M. Sainsbury School of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK Introduction The dietary indoles, indole-3-carbinol, indole-3-aceto- nitrile and 3,3-diindolylmethane, occur naturally as glucosinolate conjugates in Brassica vegetables (Loub et al. 1975), and are released upon hydrolysis. They have been shown to protect against chemical carcino- genesis (Bailey et al. 1985; Wattenberg 1985, 1990) and chemically induced hepatotoxicity (Shertzer et al. 1987b, c, 1988, 1991). In the course of defining the mechanism by which indoles protect against chemically induced tissue damage, the compounds have been found to both inhibit (Shertzer 1980; Eisele et al. 1983; Shertzer et al. 1987c) and to induce (Shertzer 1982; Godlewski et al. 1985; Bradfield and Bjeldanes 1987; McDanell et al. 1987; Fong et al. 1990) the activities of several different enzymes. Although changes in the ac- tivities of enzymes, such as mixed-function oxidases and phase II enzymes, could alter the biological re- sponses of tissues exposed to carcinogens and toxi- cants, indole-3-carbinol and/or its metabolites have also been shown to be capable of scavenging biolo- gically reactive electrophiles (Shertzer et al. 1987a; Shertzer and Tabor 1988) and free radicals (Shertzer et al. 1988, 1991). Such scavenging provides an addi- tional and broader-based protection mechanism for certain indole compounds. To both elucidate the molecular and structural basis for radical quenching by 3-indolyl compounds, and identify and develop novel 3-indolyl compounds which exhibit enhanced antioxidant efficacy, we have exam- ined a number of such compounds for their antioxida- tion potential . In this paper we report the evaluation of a set of 3-indolyl congeners for the relationships be- tween antioxidation potential and electronic, polar, and steric parameters.