Benzylamine antioxidants: Relationship between structure, peroxyl radical scavenging, lipid peroxidation inhibition, and cytoprotection
Yu, M.J.; McCowan, J.R.; Phebus, L.A.; Towner, R.D.; Ho, P.P.; Keith, P.T.; Luttman, C.A.; Saunders, R.D.; Ruterbories, K.J.; Lindstrom, T.D.
Journal of Medicinal Chemistry 36(9): 1262-1271
ISSN/ISBN: 0022-2623 PMID: 8487263 DOI: 10.1021/jm00061a018
Three homologous series of 3,5-dialkoxy-4-hydroxybenzylamines were prepared and tested (1) as peroxyl radical scavengers in homogeneous aqueous solution, (2) as inhibitors of iron-dependent peroxidation of rabbit brain vesicular membrane lipids, and (3) as cytoprotective agents using primary cultures of rat hippocampal neurons exposed to hydrogen peroxide. The structural requirements for efficient radical trapping in homogeneous solution differed from those for effective lipid peroxidation inhibition: In homogeneous solution a kinetic preference existed for smaller, less sterically encumbered substituents flanking the reactive phenolic hydroxyl group. Lipid peroxidation inhibition, on the other hand, required longer more lipophilic substituents. Consequently, a lipophilic alkoxyl substituent at C3 and a small substituent at C5 appeared optimal for efficient radical scavenging activity in both lipid and homogeneous solution. Maximal cytoprotection of rat hippocampal neurons exposed to hydrogen peroxide was also associated with more lipophilic derivatives although substituent length and substituent bulk may represent independent parameters for relating structure and efficacy in this system.