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Bioactivity profiles of cytoprotective short-chain quinones

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journal contribution
posted on 2023-05-20, 22:49 authored by Feng, ZK, Nadikudi, M, Krystel WoolleyKrystel Woolley, Hemasa, AL, Sueanne Chear, Jason SmithJason Smith, Nuri GuvenNuri Guven
Short-chain quinones (SCQs) have been investigated as potential therapeutic candidates against mitochondrial dysfunction, which was largely thought to be associated with the reversible redox characteristics of their active quinone core. We recently reported a library of SCQs, some of which showed potent cytoprotective activity against the mitochondrial complex I inhibitor rotenone in the human hepatocarcinoma cell line HepG2. To better characterize the cytoprotection of SCQs at a molecular level, a bioactivity profile for 103 SCQs with different compound chemistries was generated that included metabolism related markers, redox activity, expression of cytoprotective proteins and oxidative damage. Of all the tested endpoints, a positive correlation with cytoprotection by SCQs in the presence of rotenone was only observed for the NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent reduction of SCQs, which also correlated with an acute rescue of ATP levels. The results of this study suggest an unexpected mode of action for SCQs that appears to involve a modification of NQO1-dependent signaling rather than a protective effect by the reduced quinone itself. This finding presents a new selection strategy to identify and develop the most promising compounds towards their clinical use.

Funding

National Foundation for Medical Research and Innovation

History

Publication title

Molecules

Volume

26

Issue

5

Article number

1382

Number

1382

Pagination

1-24

ISSN

1420-3049

Department/School

School of Pharmacy and Pharmacology

Publisher

Molecular Diversity Preservation International

Place of publication

Matthaeusstrasse 11, Basel, Switzerland, Ch-4057

Rights statement

Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/).

Repository Status

  • Open

Socio-economic Objectives

Expanding knowledge in the biological sciences; Expanding knowledge in the chemical sciences

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