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Synthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicity
Kusuma, Bhaskar Reddy Zhang, Liang Sundstrom, Teather Peterson, Laura B. Dobrowsky, Rick T. Blagg, Brian S. J.
Kusuma, Bhaskar Reddy
Zhang, Liang
Sundstrom, Teather
Peterson, Laura B.
Dobrowsky, Rick T.
Blagg, Brian S. J.
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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.
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2012-06-28
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American Chemical Society
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Kusuma_2012.pdf
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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