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Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones

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Feng, Z, Smith, JA, Gueven, N ORCID: 0000-0003-3782-767X and Quirino, JP ORCID: 0000-0002-8275-9672 2020 , 'Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones' , Pharmaceuticals, vol. 13, no. 2 , pp. 1-12 , doi: 10.3390/ph13020029.

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Abstract

Short-chain quinones (SCQs) have been identified as potential drug candidates againstmitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of theactive quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives andidentified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinoneidebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, whichsignificantly restricts its therapeutic activity. Therefore, this study assessed the metabolic stability ofthe 16 identified naphthoquinone derivatives 1–16 using hepatocarcinoma cells in combination withan optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showedsignificantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chainof SCQs, increased stability for some compounds was observed. Metabolic conversion from thederivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. Theseresults highlight the therapeutic potential of naphthoquinone-based SCQs and provide essentialinsights for future drug design, prodrug therapy and polytherapy, respectively.

Item Type: Article
Authors/Creators:Feng, Z and Smith, JA and Gueven, N and Quirino, JP
Keywords: mitochondrial dysfunction, idebenone, short-chain quinone, metabolic stability, HepG2 cell culture, reverse-phase liquid chromatography
Journal or Publication Title: Pharmaceuticals
Publisher: MDPI
ISSN: 1424-8247
DOI / ID Number: 10.3390/ph13020029
Copyright Information:

Copyright 2020 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

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