Abstract
Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which largely depends on the reversible redox characteristics of the active quinone core. We recently identified 11 naphthoquinone derivatives, 1–11, from a library of SCQs that demonstrated enhanced cytoprotection and improved metabolic stability compared to the clinically used benzoquinone idebenone. Since the toxicity properties of our promising SCQs were unknown, this study developed multiplex methods and generated detailed toxicity profiles from 11 endpoint measurements using the human hepatocarcinoma cell line HepG2. Overall, the toxicity profiles were largely comparable across different assays, with simple standard assays showing increased sensitivity compared to commercial toxicity assays. Within the 11 naphthoquinones tested, the L-phenylalanine derivative 4 consistently demonstrated the lowest toxicity across all assays. The results of this study not only provide useful information about the toxicity features of SCQs but will also enable the progression of the most promising drug candidates towards their clinical use.
Highlights
Mitochondrial dysfunction causes a large number of diverse mitochondrial diseases, such as Friedreich’s ataxia (FA) [1], Leigh syndrome (LS) [2], mitochondrial encephalopathy, lactic acidosis, stroke-like episodes syndrome (MELAS) [3], maternally inherited diabetes and deafness (MIDD) [4], Leber’s hereditary optic neuropathy (LHON) [5], and dominant optic atrophy (DOA) [6]
Potential drug candidates that protect against mitochondrial dysfunction include short-chain quinones (SCQs), which possess reversible redox characteristics due to their quinone core [11,12,13]
The multiplex detection of compatible assays described in this study provides a convenient, cost-effective, and rapid approach to increase throughput
Summary
Mitochondrial dysfunction causes a large number of diverse mitochondrial diseases, such as Friedreich’s ataxia (FA) [1], Leigh syndrome (LS) [2], mitochondrial encephalopathy, lactic acidosis, stroke-like episodes syndrome (MELAS) [3], maternally inherited diabetes and deafness (MIDD) [4], Leber’s hereditary optic neuropathy (LHON) [5], and dominant optic atrophy (DOA) [6]. Despite the high incidence of disorders with a mitochondrial pathology, there is a scarcity of approved drugs that aim to directly protect against mitochondrial dysfunction. This significant unmet medical need requires new drug candidates that could be of benefit to a multitude of indications. Potential drug candidates that protect against mitochondrial dysfunction include short-chain quinones (SCQs), which possess reversible redox characteristics due to their quinone core [11,12,13]. Several SCQs are currently in clinical development. The vitamin E derivative vatiquinone (EPI-743/PTC-743), an antioxidant that targets NAD(P)H:quinone oxidoreductase 1 (NQO1), was initially developed for FA (Phase II, NCT01962363, 3 × 400 mg for 18 months, with reported improved neurological functions) [14] and LS
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
