Synthesis and evaluation of 3′- and 4′-substituted cyclohexyl noviomimetics that modulate mitochondrial respiration. (15th September 2022) - Meka, Penchala Narasimharao
Graphical abstract: Highlights: Potent Hsp90 C-terminal inhibitors based on KU-1202 were designed and synthesized. Most compounds had an impact at modulating mitochondrial bioenergetics studied using a Seahorse Analyzer. Compounds 78, 79 and 89 showed a significant shift in the ATP index toward OxPhos indicating its cytoprotective potential. Abstract: KU-32 (2 ) and KU-596 (3 ), are first and second generation cytoprotective novologues that are derivatives of novobiocin (1 ), a heat shock protein 90 (Hsp90) C-terminal inhibitor. Although 2 and 3 improve mitochondrial bioenergetics and have demonstrated considerable cytoprotective activity, they contain a synthetically demanding noviose sugar. This issue was initially addressed by creating noviomimetics, such as KU-1202 (4 ), which replaced the noviose sugar with ether-linked cyclohexyl derivatives that retained some cytoprotective potential due to their ability to increase mitochondrial bioenergetics. Based on structure–activity relationship (SAR) studies of KU-1202 (4 ), the current study investigated 3′- and 4′-substituted cyclohexyl scaffolds as noviomimetics and determined their efficacy at increasing mitochondrial bioenergetic as a marker for cytoprotective potential.