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 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.
Highlights
Mitochondrial dysfunction has been linked to a vast number of disorders ranging from primary mitochondrial disorders such as Leber’s Hereditary Optical Neuropathy (LHON) to common diseases associated with mitochondrial dysfunction such as diabetes [1,2,3]
Potential drugs to protect against mitochondrial dysfunction include short chain quinones (SCQs), which possess reversible redox characteristics due to the quinone core [4,5,6]
Idebenone showed a significant reduction from t = 2 h onwards (p < 0.001) with ~27.3% remaining at t = 6 h, which was consistent with its short half-life in vivo [15,18]
Summary
Mitochondrial dysfunction has been linked to a vast number of disorders ranging from primary mitochondrial disorders such as Leber’s Hereditary Optical Neuropathy (LHON) to common diseases associated with mitochondrial dysfunction such as diabetes [1,2,3]. We recently reported the design and synthesis of a library of > 148 short-chain naphthoquinone derivatives [11] that intended to overcome the known limitations of idebenone such as limited bioactivation and rapid metabolic inactivation From this panel, 16 SCQs (1-16, Table 1) showed significantly improved cytoprotective activity in vitro compared to idebenone (p < 0.033) under conditions of mitochondrial dysfunction [11]. A simple and efficient analytical methodology was developed based on gradient-elution reverse-phase liquid chromatography (RP-LC) in conjunction with sample preparation by acetonitrile (ACN) precipitation This methodology allowed for the required quantitation of SCQs at appropriate μM concentrations in the highly complex cell culture media used in in vitro metabolic stability studies.
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