Mitochondrial biotransformation of ω-(phenoxy) alkanoic acids, 3-(phenoxy) acrylic acids, and ω-(1-methyl-1H-imidazol-2-ylthio)alkanoic acids: A prodrug strategy for targeting cytoprotective antioxidants to mitochondria

Mitochondrial reactive oxygen species (ROS) generation and the attendant mitochondrial dysfunction are implicated in a range of disease states. The objective of the present studies was to test the hypothesis that the mitochondrial beta-oxidation pathway could be exploited to deliver and biotransform the prodrugs omega-(phenoxy) alkanoic acids, 3-(phenoxy) acrylic acids, and omega-(1-methyl-1H-imidazol-2-ylthio) alkanoic acids to the corresponding phenolic antioxidants or methimazole. 3-and 5-(Phenoxy) alkanoic acids and methyl-substituted analogs were biotransformed to phenols; rates of biotransformation decreased markedly with methyl-group substitution on the phenoxy moiety. 2,6-Dimethylphenol formation from the analogs 3-([2,6-dimethylphenoxy] methylthio) propanoic acid and 3-(2,6-dimethylphenoxy) acrylic acid was greater than that observed with omega-(2,6-dimethylphenoxy) alkanoic acids. 3-and 5-(1-Methyl-1Himidazol-2- ylthio) alkanoic acids were rapidly biotransformed to the antioxidant methimazole and conferred significant cytoprotection against hypoxia-reoxygenation injury in isolated cardiomyocytes. Both 3-(2,6-dimethylphenoxy) propanoic acid and 3-(2,6-dimethylphenoxy) acrylic acid also afforded cytoprotection against hypoxia-reoxygenation injury in isolated cardiomyocytes. These results demonstrate that mitochondrial beta-oxidation is a potentially useful delivery system for targeting antioxidants to mitochondria. (C) 2010 Elsevier Ltd. All rights reserved.