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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7169385 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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