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Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration
Pharmaceuticals 2011, 4(12), 1578-1590; doi:10.3390/ph4121578

Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich’s Ataxia: A New Synthetic Route

1 Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torreys Pines Road, La Jolla, CA 92037, USA 2 Repligen Corporation, 41 Seyon Street, Waltham, MA 02453, USA
* Author to whom correspondence should be addressed.
Received: 18 October 2011 / Revised: 30 November 2011 / Accepted: 30 November 2011 / Published: 14 December 2011
(This article belongs to the Special Issue HDAC Inhibitors)
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Friedreich’s ataxia (FRDA) is caused by transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin. Based on the hypothesis that the acetylation state of the histone proteins is responsible for gene silencing in FRDA, previous work in our lab identified a first generation of HDAC inhibitors (pimelic o-aminobenzamides), which increase FXN mRNA in lymphocytes from FRDA patients. Importantly, these compounds also function in a FRDA mouse model to increase FXN mRNA levels in the brain and heart. While the first generation of HDAC inhibitors hold promise as potential therapeutics for FRDA, they have two potential problems: less than optimal brain penetration and metabolic instability in acidic conditions. Extensive optimization focusing on modifying the left benzene ring, linker and the right benzene ring lead to a novel class of HDAC inhibitors that have optimized pharmacological properties (increased brain penetration and acid stability) compared to the previous HDAC inhibitors. This article will describe the chemical synthesis and pharmacological properties of these new HDAC inhibitors.
Keywords: HDAC inhibitor; Friedreich’s ataxia; click chemistry HDAC inhibitor; Friedreich’s ataxia; click chemistry
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Xu, C.; Soragni, E.; Jacques, V.; Rusche, J.R.; Gottesfeld, J.M. Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich’s Ataxia: A New Synthetic Route. Pharmaceuticals 2011, 4, 1578-1590.

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