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130605 - Amide linked redox-active naphthoquinones for the treatment of mitochondrial dysfunction (Auhot version).pdf (358.86 kB)

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

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posted on 2023-05-20, 00:30 authored by Krystel WoolleyKrystel Woolley, Nadikudi, M, Koupaei, MN, Monika CorbanMonika Corban, McCartney, P, Alexander BissemberAlexander Bissember, Trevor LewisTrevor Lewis, Nuri GuvenNuri Guven, Jason SmithJason Smith
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.

Funding

Royal Hobart Hospital Research Foundation

History

Publication title

MedChemComm

Volume

10

Pagination

399-412

ISSN

2040-2511

Department/School

School of Natural Sciences

Publisher

Royal Society of Chemistry

Place of publication

United Kingdom

Rights statement

Copyright 2019 The Royal Society of Chemistry

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified; Expanding knowledge in the chemical sciences; Expanding knowledge in the health sciences

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