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 β-oxidation pathway could be exploited to deliver and biotransform the prodrugs ω-(phenoxy)alkanoic acids, 3-(phenoxy)acrylic acids, and ω-(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 ω-(2,6-dimethylphenoxy)alkanoic acids. 3-and 5-(1-Methyl-1H-imidazol-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 β-oxidation is a potentially useful delivery system for targeting antioxidants to mitochondria.

The syntheses of 3-(1-methyl-1H-imidazol-2-ylthio)acrylic acid and 3-(1-methyl-1H-imidazol-2-ylthio)propanoic acid, mitochondria-targeted prodrugs of the antioxidant methimazole, are described. The method of Fan et al. (Fan et al., Synthesis 2006, 2286) for the reaction of phenols with propiolic acid and propiolate esters was modified to synthesize (E)-3-(1-methyl-1H-imidazol-2-ylthio)acrylic acid. The intermediate tert-butyl (E)-3-(1-methyl-1H-imidazol-2-ylthio)acrylate was prepared by the reaction of tert-butyl propiolate with methimazole; the use of tert-butyl propiolate rather than methyl propiolate gave tert-butyl (E)-3-(1-methyl-1H-imidazol-2-ylthio)acrylate as the predominant isomer. Acid hydrolysis of the intermediate ester afforded the target compound. 3-(1-Methyl-1H-imidazol-2-ylthio)propanoic acid was synthesized from 3-bromopropanoic acid and methimazole under conditions that gave preferential substitution on sulfur and minimized substitution on nitrogen.

Synthesis of 3-(1-Methyl-1H-imidazol-2-ylthio)propanoic Acid and (E)-3-(1-Methyl-1H-imidazol-2-ylthio)acrylicAcid. -The E/Z ratio of the reaction products of (I) with methyl or tert-butyl propiolate (II) or (V) is studied (only some yields are given). -(HATTAN, C. M.; SHOJAIE, J.; LAU*, S. S.; ANDERS, M. W.; Synth. Commun. 43 (2013) 1, 1-8, http://dx.