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 identified...
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| Format: | Article |
| Language: | English |
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MDPI AG
2011-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | http://www.mdpi.com/1424-8247/4/12/1578/ |
| _version_ | 1811206482120671232 |
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| author | Joel M. Gottesfeld James R. Rusche Elisabetta Soragni Vincent Jacques Chunping Xu |
| author_facet | Joel M. Gottesfeld James R. Rusche Elisabetta Soragni Vincent Jacques Chunping Xu |
| author_sort | Joel M. Gottesfeld |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T03:48:17Z |
| format | Article |
| id | doaj.art-14df0754ad924544837a78138dbd98b9 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-04-12T03:48:17Z |
| publishDate | 2011-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-14df0754ad924544837a78138dbd98b92022-12-22T03:49:03ZengMDPI AGPharmaceuticals1424-82472011-12-014121578159010.3390/ph4121578Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich’s Ataxia: A New Synthetic RouteJoel M. GottesfeldJames R. RuscheElisabetta SoragniVincent JacquesChunping XuFriedreich’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.http://www.mdpi.com/1424-8247/4/12/1578/HDAC inhibitorFriedreich’s ataxiaclick chemistry |
| spellingShingle | Joel M. Gottesfeld James R. Rusche Elisabetta Soragni Vincent Jacques Chunping Xu Improved Histone Deacetylase Inhibitors as Therapeutics for the Neurodegenerative Disease Friedreich’s Ataxia: A New Synthetic Route Pharmaceuticals HDAC inhibitor Friedreich’s ataxia click chemistry |
| 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 | HDAC inhibitor Friedreich’s ataxia click chemistry |
| url | http://www.mdpi.com/1424-8247/4/12/1578/ |
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