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


Woolley, KL and Nadikudi, M and Koupaei, MN and Corban, M and McCartney, P and Bissember, AC and Lewis, TW and Gueven, N and Smith, JA, Amide linked redox-active naphthoquinones for the treatment of mitochondrial dysfunction, MedChemComm, 10, (3) pp. 399-412. ISSN 2040-2511 (2019) [Refereed Article]

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Copyright 2019 The Royal Society of Chemistry

DOI: doi:10.1039/c8md00582f


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.

Item Details

Item Type:Refereed Article
Keywords:redox-active naphthoquinones, mitochondrial dysfunction, idebenone, short chain quinones, mitochondria, drug discovery
Research Division:Chemical Sciences
Research Group:Organic chemistry
Research Field:Organic chemical synthesis
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Woolley, KL (Miss Krystel Woolley)
UTAS Author:Nadikudi, M (Ms Monila Nadikudi)
UTAS Author:Koupaei, MN (Ms Mitra Koupaei)
UTAS Author:Corban, M (Ms Monika Corban)
UTAS Author:Bissember, AC (Associate Professor Alex Bissember)
UTAS Author:Lewis, TW (Associate Professor Trevor Lewis)
UTAS Author:Gueven, N (Dr Nuri Guven)
UTAS Author:Smith, JA (Associate Professor Jason Smith)
ID Code:130605
Year Published:2019
Web of Science® Times Cited:8
Deposited By:Pharmacy
Deposited On:2019-02-06
Last Modified:2020-08-10
Downloads:2 View Download Statistics

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