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

Bioorg Med Chem. 2022 Sep 15:70:116940. doi: 10.1016/j.bmc.2022.116940. Epub 2022 Jul 16.

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.

Keywords: Heat shock protein 70; Heat shock protein 90; Mitochondrial bioenergetics; Molecular chaperones; Noviomimetics; Novologues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HSP90 Heat-Shock Proteins*
  • Mitochondria / metabolism
  • Novobiocin* / pharmacology
  • Respiration
  • Sugars

Substances

  • HSP90 Heat-Shock Proteins
  • Sugars
  • Novobiocin