Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity

  • Bioorg Med Chem Lett. 2018 Sep 1;28(16):2701-2704. doi: 10.1016/j.bmcl.2018.03.071.
Zheng Zhang  1 ,  Zhenyuan You  2 ,  Rick T Dobrowsky  2 ,  Brian S J Blagg  3
Affiliations
  • 1. Department of Chemistry and Biochemistry, The University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, United States.
  • 2. Department of Pharmacology and Toxicology Department, The University of Kansas, Lawrence, KS 66045, United States.
  • 3. Department of Chemistry and Biochemistry, The University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, United States. Electronic address: [email protected].
PMID: 29759728 DOI: 10.1016/j.bmcl.2018.03.071
Abstract

KU-596 is a second-generation C-terminal heat shock protein 90 KDa (HSP90) modulator based on the natural product, novobiocin. KU-596 has been shown to induce HSP70 levels and manifest neuroprotective activity through induction of the heat shock response. A ring-constrained analog of KU-596 was designed and synthesized to probe its binding orientation and ability to induce HSP70 levels. Compound 2 was found to exhibit comparable or increased activity compared to KU-596, which is under clinical investigation for the treatment of neuropathy.

Keywords
Hsp90 C-terminal inhibitor; Neuroprotective; Novologue; Ring-constrained.
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