Molecular modeling parameters predict antioxidant efficacy of 3-indolyl compounds.
Many dietary constituents, such as indole-3-carbinol, are chemoprotective in toxicity and carcinogenicity bioassays. Indole-3-carbinol and related congeners appear to protect partly via radical and electrophile scavenging. To develop better chemoprotective indoles with lower intrinsic toxicity, we performed molecular graphic and quantum-mechanical analyses of model indolyl compounds to ascertain the determinant molecular features for antioxidant activity. 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 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 abstraction from the nitrogen. Antioxidant efficacy of 3-indolyl compounds was most strongly predicted by molecular size parameters 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 correlation model (r2 = 0.97) was obtained using the parameters of heat of formation, molecular weight, log P, and diplole moment.
Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0056, USA.
H G
HG
Shertzer
M W
MW
Tabor
I T
IT
Hogan
S J
SJ
Brown
M
M
Sainsbury
D000975:Antioxidants / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D016014:Linear Models; D015227:Lipid Peroxidation / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D010743:Phospholipids / Q000378:metabolism; D013025:Glycine max; D013329:Structure-Activity Relationship
C103841:3-(2,4,6-trimethylbenzyl)indole; C103840:3-(4-hydroxybenzyl)indole; D000975:Antioxidants; D007211:Indoles; D010743:Phospholipids