The production of reactive oxygen species by mitochondria is implicated in the mitochondrial dysfunction associated with a range of diseases and ageing. In contrast, reactive oxygen species produced by mitochondria are involved in redox signalling pathways necessary for modulating a number of cell processes. Mitochondrially targeted antioxidants comprised of an antioxidant moiety linked to a lipophilic triphenylphosphonium cation have recently been used to decrease reactive oxygen species-mediated oxidative damage to mitochondria and to investigate the role of mitochondrial reactive oxygen species in redox signalling. These lipophilic cations are selectively accumulated by mitochondria within cells due to the mitochondrial membrane potential. This thesis presents the synthesis and characterization of mitochondrially targeted antioxidant superoxide dismutase and thiol peroxidase mimetics.
A mitochondrially targeted derivative of the Mn(II) macrocycle SOD mimetic M40403 (MitoSOD) was synthesized by Mn(II) template synthesis of a chiral tetraamine component and a triphenylphosphonium derivative of 2,6-pyridinedialdehyde. Racemic tetraamine was synthesized by mono-protection of racemic diamine followed by reductive amination of glyoxal and deprotection of di-protected tetraamine but overall this was found to be less efficient than a reported method based on trityl protection. The synthesis of the triphenylphosphonium derivative of 2,6-pyridinedialdehyde involved substitution of protected 4-bromo-2,6-pyridinedialdehyde by the thiolate of 3-mercaptoproanol followed by simultaneous deprotection and alkyl bromide formation, and triphenylphosphine substitution of the thioalkyl bromide substituent. MitoSOD was found to be more lipophilic than M40403 and was kinetically stable to dissociation to Mn(II) and macrocyclic ligand at physiological pH. Pulse radiolysis kinetic studies indicated both MitoSOD and M40403 catalyse the dismutation of superoxide. Fast conductivity and spectrophotometric measurements indicated the mechanism of catalysis involved reaction of the Mn(II) centre with superoxide to give a Mn(III)-peroxide intermediate which reacted with further superoxide to give the parent Mn(II) macrocycle. MitoSOD was significantly accumulated by mitochondria and this was dependent to some extent on the mitochondrial membrane potential. In addition, MitoSOD appeared to react with a product of mitochondrial succinate respiration.
A mitochondrially targeted derivative of the organoselenium thiol peroxidase mimetic ebselen (Mitoebselen) was synthesized by O-alkylation of a phenolic ebselen derivative with a triphenylphosphonium derivative of an alkyl iodide. Reaction of excess triphenylphosphine with an ebselen derivative containing an alkyl iodide substituent resulted in substitution of iodide and, unexpectedly, reduction of the isoselenazole moiety to the diselenide redox form. Mitoebselen and its diselenide were both readily reduced to a selenol by an excess of the physiological thiol glutathione. Reaction of the selenol with excess peroxide generated the diselenide, possibly via reaction of unreacted selenol with Mitoebselen formed from a selenenic acid intermediate or with selenenic acid directly. Mitoebselen and its diselenide were both oxidized by excess peroxide to a selenoxide but these reactions were much slower than those between selenol and peroxides, and those between Mitoebselen or its diselenide with glutathione. Together these studies suggested cyclic pathways other than a selenolisoselenazole-selenol cycle could be involved in Mitoebselen or ebselen-catalysed thiol peroxidation.
| Identifer | oai:union.ndltd.org:ADTP/217392 |
| Date | January 2005 |
| Creators | Kelso, Geoffrey F., 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 Geoffrey F. Kelso |
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