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Synthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicity
dc.contributor.author | Kusuma, Bhaskar Reddy | |
dc.contributor.author | Zhang, Liang | |
dc.contributor.author | Sundstrom, Teather | |
dc.contributor.author | Peterson, Laura B. | |
dc.contributor.author | Dobrowsky, Rick T. | |
dc.contributor.author | Blagg, Brian S. J. | |
dc.date.accessioned | 2017-04-12T15:46:06Z | |
dc.date.available | 2017-04-12T15:46:06Z | |
dc.date.issued | 2012-06-28 | |
dc.identifier.citation | Kusuma, 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/jm300544c | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/23630 | |
dc.description.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 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.publisher | American Chemical Society | en_US |
dc.rights | This 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.title | Synthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicity | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Kusuma, Bhaskar Reddy | |
kusw.kuauthor | Zhang, Liang | |
kusw.kuauthor | Sundstrom, Teather | |
kusw.kuauthor | Peterson, Laura B. | |
kusw.kuauthor | Dobrowsky, Rick T. | |
kusw.kuauthor | Blagg, Brian S. J. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1021/jm300544c | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |