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dc.contributor.authorKusuma, Bhaskar Reddy
dc.contributor.authorZhang, Liang
dc.contributor.authorSundstrom, Teather
dc.contributor.authorPeterson, Laura B.
dc.contributor.authorDobrowsky, Rick T.
dc.contributor.authorBlagg, Brian S. J.
dc.date.accessioned2017-04-12T15:46:06Z
dc.date.available2017-04-12T15:46:06Z
dc.date.issued2012-06-28
dc.identifier.citationKusuma, B. R., Zhang, L., Sundstrom, T., Peterson, L. B., Dobrowsky, R. T., & Blagg, B. S. J. (2012). Synthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicity. Journal of Medicinal Chemistry, 55(12), 5797–5812. http://doi.org/10.1021/jm300544cen_US
dc.identifier.urihttp://hdl.handle.net/1808/23630
dc.description.abstractCompound 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 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 ED50 compared to 2 for protection against glucose-induced toxicity of primary sensory neurons.en_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm300544c.en_US
dc.titleSynthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicityen_US
dc.typeArticleen_US
kusw.kuauthorKusuma, Bhaskar Reddy
kusw.kuauthorZhang, Liang
kusw.kuauthorSundstrom, Teather
kusw.kuauthorPeterson, Laura B.
kusw.kuauthorDobrowsky, Rick T.
kusw.kuauthorBlagg, Brian S. J.
kusw.kudepartmentMedicinal Chemistryen_US
dc.identifier.doi10.1021/jm300544cen_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccess


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