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Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones

Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identifie...

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Detalles Bibliográficos
Autores principales: Feng, Zikai, Smith, Jason A., Gueven, Nuri, Quirino, Joselito P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169385/
https://www.ncbi.nlm.nih.gov/pubmed/32059451
http://dx.doi.org/10.3390/ph13020029
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author Feng, Zikai
Smith, Jason A.
Gueven, Nuri
Quirino, Joselito P.
author_facet Feng, Zikai
Smith, Jason A.
Gueven, Nuri
Quirino, Joselito P.
author_sort Feng, Zikai
collection PubMed
description Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts its therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives 1–16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy and polytherapy, respectively.
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spelling pubmed-71693852020-04-20 Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones Feng, Zikai Smith, Jason A. Gueven, Nuri Quirino, Joselito P. Pharmaceuticals (Basel) Article Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts its therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives 1–16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy and polytherapy, respectively. MDPI 2020-02-12 /pmc/articles/PMC7169385/ /pubmed/32059451 http://dx.doi.org/10.3390/ph13020029 Text en © 2020 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 (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Feng, Zikai
Smith, Jason A.
Gueven, Nuri
Quirino, Joselito P.
Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones
title Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones
title_full Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones
title_fullStr Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones
title_full_unstemmed Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones
title_short Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones
title_sort metabolic stability of new mito-protective short-chain naphthoquinones
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169385/
https://www.ncbi.nlm.nih.gov/pubmed/32059451
http://dx.doi.org/10.3390/ph13020029
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