Bioactivity Profiles of Cytoprotective Short-Chain Quinones

Short-chain quinones (SCQs) have been investigated as potential therapeutic candidates against mitochondrial dysfunction, which was largely thought to be associated with the reversible redox characteristics of their active quinone core. We recently reported a library SCQs, some showed potent cytoprotective activity complex I inhibitor rotenone in human hepatocarcinoma cell line HepG2. To better characterize cytoprotection SCQs at molecular level, bioactivity profile for 103 different compound chemistries generated that included metabolism related markers, activity, expression proteins and oxidative damage. Of all tested endpoints, positive correlation by presence only observed NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent reduction also correlated an acute rescue ATP levels. The results this study suggest unexpected mode action appears involve modification NQO1-dependent signaling rather than protective effect reduced itself. This finding presents new selection strategy identify develop most promising compounds towards clinical use.