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.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Binding Sites
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Cell Line, Transformed
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Glycosides / chemical synthesis
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Glycosides / chemistry
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Glycosides / pharmacology*
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HSP70 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / chemistry
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Hydrogen Bonding
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Lactams / chemical synthesis
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Lactams / chemistry
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Lactams / pharmacology*
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Mitochondria / metabolism
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Molecular Docking Simulation
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Oxidative Stress / drug effects
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Phenanthridines / chemical synthesis
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Phenanthridines / chemistry
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Phenanthridines / pharmacology*
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Phenethylamines / chemistry
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Rats
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Transcriptional Activation
Substances
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Glycosides
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HSP70 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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KU-596
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Lactams
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Neuroprotective Agents
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Phenanthridines
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Phenethylamines