Design, synthesis, and in vitro evaluation of cyclic nitrones as free radical traps for the treatment of stroke

Journal of Medicinal Chemistry
T L FevigC E Thomas

Abstract

Analogs of the cyclic nitrone free radical trap 1 (3,3-dimethyl-3,4-dihydroisoquinoline N-oxide, a cyclic analog of phenyl-tert-butylnitrone (PBN)) were prepared in which (1) the fused phenyl ring was replaced with a naphthalene ring, an electron rich heterocycle, or a dimethylphenol, (2) the nitrone-containing ring comprised five, six, or seven atoms, and (3) the gem-dimethyl group was replaced with spirocyclic groups. The most active antioxidant, which bears a dimethylphenol fused to a 7-membered ring nitrone (compound 6h), inhibited lipid peroxidation in vitro with an IC50 of 22 microM, a 75-fold improvement over that of 1. The previously observed correlation between lipophilicity and activity vs lipid peroxidation in vitro has been further substantiated and refined by this study. Moreover, certain classes of compounds (namely, dimethylphenols 6g,h and furan 6j) have now been found which are considerably more active in vitro than expected on the basis of their log k'(w) values.

References

Mar 1, 1992·Lipids·G Minotti, S D Aust
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Citations

Mar 10, 2001·Antioxidants & Redox Signaling·Y Kotake
Jan 1, 2008·Acta Crystallographica. Section E, Structure Reports Online·Jin-Long WuShan-Lin Liu
May 1, 2001·Free Radical Research·K R MaplesY K Zhang
Feb 16, 2008·Biochemical Pharmacology·Ramón Soto-OteroCosimo Altomare
Dec 21, 2016·The Journal of Organic Chemistry·Grégory DurandBéatrice Tuccio
May 12, 2010·Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine·Yan HuangUNKNOWN Project Group for Demonstration Study of Syndrome Differentiation Protocol and Effect Evaluation of Acute Ischemic Stroke
Dec 9, 2014·Acta Crystallographica. Section E, Structure Reports Online·Lucimara Julio MartinsFernando Coelho
Jan 16, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mary E Trudeau-LameMichael LaFontaine
Jun 18, 2010·Journal of the American Chemical Society·Daniel M D'SouzaSongwei Zhang
Jun 8, 2000·Journal of Medicinal Chemistry·A DhainautS Goldstein

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