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

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 identi...

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Autores principales: Xu, Chunping, Soragni, Elisabetta, Jacques, Vincent, Rusche, James R., Gottesfeld, Joel M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060102/
https://www.ncbi.nlm.nih.gov/pubmed/27721337
http://dx.doi.org/10.3390/ph4121578
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author Xu, Chunping
Soragni, Elisabetta
Jacques, Vincent
Rusche, James R.
Gottesfeld, Joel M.
author_facet Xu, Chunping
Soragni, Elisabetta
Jacques, Vincent
Rusche, James R.
Gottesfeld, Joel M.
author_sort Xu, Chunping
collection PubMed
description 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.
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spelling pubmed-40601022014-06-17 Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich's Ataxia: A New Synthetic Route Xu, Chunping Soragni, Elisabetta Jacques, Vincent Rusche, James R. Gottesfeld, Joel M. Pharmaceuticals (Basel) Article 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. MDPI 2011-12-14 /pmc/articles/PMC4060102/ /pubmed/27721337 http://dx.doi.org/10.3390/ph4121578 Text en © 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/)
spellingShingle Article
Xu, Chunping
Soragni, Elisabetta
Jacques, Vincent
Rusche, James R.
Gottesfeld, Joel M.
Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich's Ataxia: A New Synthetic Route
title Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich's Ataxia: A New Synthetic Route
title_full Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich's Ataxia: A New Synthetic Route
title_fullStr Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich's Ataxia: A New Synthetic Route
title_full_unstemmed Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich's Ataxia: A New Synthetic Route
title_short Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich's Ataxia: A New Synthetic Route
title_sort improved histone deacetylase inhibitors as therapeutics for the neurodegenerative disease friedreich's ataxia: a new synthetic route
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060102/
https://www.ncbi.nlm.nih.gov/pubmed/27721337
http://dx.doi.org/10.3390/ph4121578
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