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Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones

Citation

Feng, Z and Smith, JA and Gueven, N and Quirino, JP, Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones, Pharmaceuticals, 13, (2) pp. 1-12. ISSN 1424-8247 (2020) [Refereed Article]


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Copyright Statement

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

DOI: doi:10.3390/ph13020029

Abstract

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 116 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.

Item Details

Item Type:Refereed Article
Keywords:mitochondrial dysfunction, idebenone, short-chain quinone, metabolic stability, HepG2 cell culture, reverse-phase liquid chromatography
Research Division:Medical and Health Sciences
Research Group:Pharmacology and Pharmaceutical Sciences
Research Field:Pharmaceutical Sciences
Objective Division:Manufacturing
Objective Group:Human Pharmaceutical Products
Objective Field:Human Pharmaceutical Treatments (e.g. Antibiotics)
UTAS Author:Feng, Z (Mr Zikai Feng)
UTAS Author:Smith, JA (Dr Jeremy Smith)
UTAS Author:Gueven, N (Dr Nuri Guven)
UTAS Author:Quirino, JP (Associate Professor Lito Quirino)
ID Code:137761
Year Published:2020
Deposited By:Pharmacy
Deposited On:2020-03-03
Last Modified:2020-04-09
Downloads:0

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