The production of reactive oxygen species by mitochondria results in mitochondrial dysfunction through oxidative stress. Because mitochondria play such a crucial role in cell function through the production of energy and the regulation of apoptosis this mitochondrial damage can lead to cellular dysfunction and ultimately to the pathophysiology of many diseases.
A series of mitochondria-targeted derivatives of vitamin E (MitoE) have been synthesised. The synthesis begins from readily available starting materials and can be systematically varied to create a MitoE analogue of desired lipophilicity. The syntheses of MitoE₂, MitoE₄, MitoE₆, MitoE₁₀ and MitoE₁₁ have been completed and are reported herein. MitoE₂ and MitoE₁₀ have been assessed for antioxidant efficacy and they are significantly more potent than untargeted vitamin E analogues.
Modification of the phenolic functionality of vitamin E causes significant perturbation to its biological activity. Substitution at this position with a succinoyl ester results in potent pro-apoptotic activity and selective toxicity to malignant cells. A mitochondria-targeted analogue of vitamin E succinate (MitoE succinate) has been synthesised by reaction of MitoE₁₁ with succinic anhydride. This compound is a particularly potent inducer of apoptosis in malignant cells and is non-toxic to non-malignant cells.
MitoQ₁₀ is well established as a potent mitochondria-targeted antioxidant in vitro, however in vivo results are limited. In this study MitoQ₁₀ was examined in an ex vivo cardiac model of ischemia-reperfusion injury. It was found to be significantly more effective than untargeted antioxidants at reducing cardiac and mitochondrial dysfunction, as well as tissue damage induced by ischemia and reperfusion.
Because mitochondria play a key role in a wide range of pathologies, imaging mitochondrial function in vivo would have great diagnostic value. A series of fluorine containing phosphonium salts have been synthesised these compounds have potential applications in �⁹F MRI imaging.
Identifer | oai:union.ndltd.org:ADTP/217859 |
Date | January 2008 |
Creators | Adlam, Victoria Jean, n/a |
Publisher | University of Otago. Department of Chemistry |
Source Sets | Australiasian Digital Theses Program |
Language | English |
Detected Language | English |
Rights | http://policy01.otago.ac.nz/policies/FMPro?-db=policies.fm&-format=viewpolicy.html&-lay=viewpolicy&-sortfield=Title&Type=Academic&-recid=33025&-find), Copyright Victoria Jean Adlam |
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