Synthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicity
Year: 2012
Type: article
Abstract: Compound 2 (KU-32) is a first-generation novologue (a novobiocin-based, C-terminal, heat shock protein 90 (Hsp90) inhibitor) that decreases glucose-induced death of primary sensory neurons and reverses numerous clinical indices of diabetic peripheral neuropathy in mice. The current study sought to exploit the C-terminal binding site of Hsp90 to determine whether the optimization of hydrogen bonding and hydrophobic interactions of second-generation novologues could enhance neuroprotective activity. Using a series of substituted phenylboronic acids to replace the coumarin lactone of 2, we identified that electronegative atoms placed at the meta-position of the B-ring exhibit improved cytoprotective activity, which is believed to result from favorable interactions with Lys539 in the Hsp90 C-terminal binding pocket. Consistent with these results, a meta-3-fluorophenyl substituted novologue (13b) exhibited a 14-fold lower ED(50) for protection against glucose-induced toxicity of primary sensory neurons compared to 2.
Source: Journal of Medicinal Chemistry
DOI: 10.1021/jm300544c
Institution: University of Kansas
Language: English
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G3047413037, G3958390639, Chaperone therapeutics for the treatment of DPN, G5538855039, G6142126022, Caveolin-1 and Altered Neuregulinism in Diabetic Neuropathy, G7050361831, Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors, HSP90 Inhibitors, Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors, Oxidative Stress and the Mitochondrial Proteome in Diabetic Neuropathy
OpenAlex ID: W2087177161