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Issue 3, 2019
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Amide linked redox-active naphthoquinones for the treatment of mitochondrial dysfunction

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Abstract

Naphthoquinones have been investigated as potential therapeutic molecules for neurodegenerative disorders, which is largely based on their anti-oxidative potential. However, a theoretical framework for the pleiotropic protective effects of naphthoquinone derivatives is largely missing. We synthesized a library of novel short chain 2,3-disubstituted naphthoquinone derivatives and measured their redox characteristics to identify a potential connection with their biological activity. Using two cell lines with different reducing potential, the compounds were tested for their inherent toxicity, acute rescue of ATP levels and cytoprotective activity. For the first time, a structure–activity-relationship for naphthoquinones has been established. Our results clearly demonstrate that it is the group on the alkyl side chain and not solely the redox characteristics of the naphthoquinone unit or lipophilicity that determines the extent of cytoprotection by individual compounds. From this, we developed a number of amide containing naphthoquinones with superior activity in ATP rescue and cell viability models compared to the clinically used benzoquinone idebenone.

Graphical abstract: Amide linked redox-active naphthoquinones for the treatment of mitochondrial dysfunction

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Publication details

The article was received on 26 Nov 2018, accepted on 20 Dec 2018 and first published on 16 Jan 2019


Article type: Research Article
DOI: 10.1039/C8MD00582F
Citation: Med. Chem. Commun., 2019,10, 399-412

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    Amide linked redox-active naphthoquinones for the treatment of mitochondrial dysfunction

    K. L. Woolley, M. Nadikudi, M. N. Koupaei, M. Corban, P. McCartney, A. C. Bissember, T. W. Lewis, N. Gueven and J. A. Smith, Med. Chem. Commun., 2019, 10, 399
    DOI: 10.1039/C8MD00582F

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