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Synthesis of new derivatives targeting mitochondrial dysfunction

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Woolley, KL 2018 , 'Synthesis of new derivatives targeting mitochondrial dysfunction', PhD thesis, University of Tasmania.

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Abstract

Mitochondrial dysfunction is implicated in many diverse diseases, including cancer, diabetes, neurodegeneration (i.e. Glaucoma, Alzheimer’s and Parkison’s disease) and autoimmune diseases. Although a lot of common diseases are associated with mitochondrial dysfunction, only a very limited number of approved therapeutics are currently available on the market that directly target and normalize mitochondrial function.
One of the most frequent inherited mitochondrial diseases is Leber’s Heriditary Optic Neuropahthy (LHON) that is characterized by acute vision loss. As first-in-class, the short chain benzoquinone idebenone was approved only recently by the European Medicine Agency (EMA) to treat LHON patients. Despite its clinical activity, this molecule has several drawbacks. First and foremost, idebenone displays a very short half-life in vivo, due to a rapid first-pass metabolism. Furthermore, idebenone depends on a single enzyme for its bioactivation called NQO1 (NAD(P)H:quinone oxidoreductase 1) that reduces the quinioid core by a two-electron mechanism. However, a large section of the general population carry a polymorphic form of the NQO1 gene (C609T) that inactivates the resulting protein. Failure to reduce idebenone to the benzoquinol form not only results in a loss of therapeutic activity but could also increase levels of reactive oxygen species (ROS) and may lead to toxicity and cell death.
Using idebenone as a lead compound, a suite of analogues were synthesized with the aim to establish a structure activity relationship (SAR). A large library of analogues containing a 3-methyl-naphthoquinone core was prepared. The functionality and physical properties of the side chain were investigated and optimisation based on polarity was employed to identify the highest level of cytoprotection against mitochondrial dysfunction. Under these conditions, the ability to restore adenosine triphosphate (ATP) levels and provide cytoprotection was achieved by attaching an amino alcohol or equivalent amine to the quinone core via a four-carbon linker that utilised amide coupling. Restoring ATP levels is essential, as insufficient ATP levels may result in cell death.
After significant optimisation of the side chain, core optimisation was undertaken. The importance of the methyl substituent at the C3-position of the naphthoquinone core was identified. Removal of this substituent resulted in a drop in cytoprotection and the ability to restore ATP levels. This effect is proposed to be due to conjugation with glutathione that prevents the analogues to shuttle in and out of the mitochondria. Also a comparative analysis of naphthoquinone, plastoquinone and benzoquinone cores was completed, when tested with a common side chain. The superiority of the naphthoquinone core over both plastoquinone and benzoquinone analogues was identified as these were unable to rescue ATP levels and provide cytoprotection under identical conditions. Using these optimised structural features, a redox active dye capable of sensing a reductive stimulus such as NQO1 was also developed.
Therefore, the identified analogues that are superior to idebenone require a naphthoquinone core with a methyl substituent in the C3 position, a sidechain containing a four-carbon linker and an amino alcohol or equivalent amine attached through an amide linkage. Biological analysis in vitro identified 34 analogues significantly superior to idebenone out of a total of 131 synthesised compounds. This is a significant result, as currently idebenone is the only therapeutic approved to treat LHON. Two of those analogues (70 and 80) have advanced to in vivo studies in two different disease models. Both new idebenone analogues were highly efficient and were shown to restore mitochondrial-dysfunction-induced vision loss in a mouse model of LHON and a rat model of diabetic retinopathy. Therefore, this research significantly advances the development of new therapeutics to treat mitochondrial dysfunction.
As a result of the research presented in this thesis, a provisional patent was filed in 2017.

Item Type: Thesis - PhD
Authors/Creators:Woolley, KL
Keywords: Mitochondria, idebenone, naphthoquinone, motochondrial dysfunction, neurodegeneration, fluroescent dye
Copyright Information:

Copyright 2017 the author

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