Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones
1
Australian Centre for Research on Separation Sciences (ACROSS), School of Natural Sciences-Chemistry, College of Science and Engineering, University of Tasmania, Hobart, TAS 7005, Australia
2
School of Natural Sciences-Chemistry, College of Science and Engineering, University of Tasmania, Hobart, TAS 7005, Australia
3
Division of Pharmacy, School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, TAS 7005, Australia
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(2), 29; https://doi.org/10.3390/ph13020029
Received: 4 December 2019 / Revised: 30 December 2019 / Accepted: 8 February 2020 / Published: 12 February 2020
(This article belongs to the Section Pharmacology)
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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Keywords:
mitochondrial dysfunction; idebenone; short-chain quinone; metabolic stability; HepG2 cell culture; reverse-phase liquid chromatography
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MDPI and ACS Style
Feng, Z.; Smith, J.A.; Gueven, N.; Quirino, J.P. Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones. Pharmaceuticals 2020, 13, 29.
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