Synthesis and evaluation of 3′- and 4′-substituted cyclohexyl noviomimetics that modulate mitochondrial respiration

Development of Hsp90 C-terminal inhibitors with noviomimetics that manifest anti-proliferative activities

“…Research Article neurodegenerative diseases. 20 However, the functional groups selected in this study sought to explore electrostatic interactions and investigate whether large, bulky substituents could be tolerated at the 4-position of cyclohexyl ring while incorporating the aryl amide side chain that exhibits antiproliferative activity. Surprisingly, none of the novologues exhibited anti-proliferative activity against these cancer cell lines (Table 1).…”

“…19 Based on 4, 3′-and 4′-substituted cyclohexyl scaffolds were identified as good noviomimetics that increased mitochondrial bioenergetics as needed for cytoprotective activity. 20 However, the noviomimetics that contain a cyclohexyl scaffold have not been tested for their anti-proliferative activities when coupled to an aryl amide side chain.…”

Enniatin A Analogues as Novel Hsp90 Inhibitors that Modulate Triple-Negative Breast Cancer

“…Unfortunately, most of these molecules failed due to cardiac and ocular toxicities, as well as dose-escalating toxicities, associated with pan -inhibition of all four Hsp90 isoforms that results in induction of the pro-survival heat shock response (HSR), which includes the overexpression of Hsp90. , Therefore, a need exists for inhibitors that can provide an alternative mechanism of action. Several approaches are currently being explored to minimize the deleterious consequences that result from pan -Hsp90 inhibition and include C-terminal inhibition, − disruption of Hsp90 C-terminal dimerization, isoform-selective inhibition, − and disruption of Hsp90 protein–protein interactions (PPIs) between client substrates and/or cochaperones …”