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

Autor: Meka PN; Department of Chemistry and Biochemistry, 305 McCourtney Hall, The University of Notre Dame, Notre Dame, IN 46556, United States., Amatya E; Department of Chemistry and Biochemistry, 305 McCourtney Hall, The University of Notre Dame, Notre Dame, IN 46556, United States., Kaur S; Department of Pharmacology and Toxicology Department, The University of Kansas, Lawrence, KS 66045, United States., Banerjee M; Department of Chemistry and Biochemistry, 305 McCourtney Hall, The University of Notre Dame, Notre Dame, IN 46556, United States., Zuo A; Department of Chemistry and Biochemistry, 305 McCourtney Hall, The University of Notre Dame, Notre Dame, IN 46556, United States., Dobrowsky RT; Department of Pharmacology and Toxicology Department, The University of Kansas, Lawrence, KS 66045, United States. Electronic address: dobrowsky@ku.edu., Blagg BSJ; Department of Chemistry and Biochemistry, 305 McCourtney Hall, The University of Notre Dame, Notre Dame, IN 46556, United States. Electronic address: bblagg@nd.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2022 Sep 15; Vol. 70, pp. 116940. Date of Electronic Publication: 2022 Jul 16.
DOI: 10.1016/j.bmc.2022.116940
Abstrakt: 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.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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