Chemistry:Trichostatin A
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| Other names | TSA |
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| Drug class | Histone deacetylase inhibitor |
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| Chemical and physical data | |
| Formula | C17H22N2O3 |
| Molar mass | 302.374 g·mol−1 |
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Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs (i.e., sirtuins).[1] However, there are recent reports of the interactions of this molecule with sirtuin 6 as well.[2]
Pharmacology
Pharmacodynamics
| Enzyme | IC50 (nM) |
|---|---|
| HDAC1 | 4.99 |
| HDAC2 | 2.7 |
| HDAC3 | 5.21 |
| HDAC4 | 27.6 |
| HDAC5 | 776 |
| HDAC6 | 16.4 |
| HDAC7 | 482 |
| HDAC8 | 486 |
| HDAC9 | >1,000 |
| HDAC10 | 24.3 |
| HDAC11 | >1,000 |
TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. TSA can be used to alter gene expression by interfering with the removal of acetyl groups from histones (histone deacetylases, HDAC) and therefore altering the ability of DNA transcription factors to access the DNA molecules inside chromatin. It is a member of a larger class of histone deacetylase inhibitors (HDIs or HDACIs) that have a broad spectrum of epigenetic activities. TSA inhibits HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, and HDAC10 with low-nanomolar IC50 values ranging from 2.7 to 27.6 nM.[3][4][5]
As an HDAC inhibitor, TSA has some potential as an anti-cancer drug.[6] One suggested mechanism is that TSA promotes the expression of apoptosis-related genes, leading to cancerous cells surviving at lower rates, thus slowing the progression of cancer.[7] Other mechanisms may include the activity of HDIs to induce cell differentiation, thus acting to "mature" some of the de-differentiated cells found in tumors. HDIs have multiple effects on non-histone effector molecules, so the anti-cancer mechanisms are truly not understood at this time.[8][9]
Injection of TSA directly into the hippocampus has been found to enhance fear extinction in rodents.[10][11] TSA represses IL (interleukin)-1β/LPS (lipopolysaccharide)/IFNγ (interferon γ)-induced nitric oxide synthase 2 (NOS2) expression in murine macrophage-like cells but increases LPS-stimulated NOS2 expression in murine N9 and primary rat microglial cells.[12]
Chemistry
Analogues
Vorinostat (SAHA) is structurally related to TSA and used to treat cutaneous T cell lymphoma.[13]
See also
References
- ↑ "Trichostatin A-like hydroxamate histone deacetylase inhibitors as therapeutic agents: toxicological point of view". Current Medicinal Chemistry 11 (12): 1629–1643. June 2004. doi:10.2174/0929867043365099. PMID 15180568.
- ↑ "Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development". Journal of Medicinal Chemistry 61 (23): 10922–10928. December 2018. doi:10.1021/acs.jmedchem.8b01455. PMID 30395713.
- ↑ Cite error: Invalid
<ref>tag; no text was provided for refs namedTatamiyaSaitoSugawara2004 - ↑ Cite error: Invalid
<ref>tag; no text was provided for refs namedNottFassHaggarty2013 - ↑ Maier T, Beckers T, Hummel RP, Feth M, Muller M, Bar T, Volz J, "Novel Sulphonylpyrroles as Inhibitors of Hdac S Novel Sulphonylpyrroles", US patent 8232297, published 2012-07-31, issued 31 July 2012, assigned to 4sc AG
- ↑ "Clinical development of histone deacetylase inhibitors as anticancer agents". Annual Review of Pharmacology and Toxicology 45: 495–528. 2005. doi:10.1146/annurev.pharmtox.45.120403.095825. PMID 15822187.
- ↑ "Histone Deacetylase Inhibitors: Mechanisms and Clinical Significance in Cancer: HDAC Inhibitor-Induced Apoptosis". Programmed Cell Death in Cancer Progression and Therapy. Advances in Experimental Medicine and Biology. 615. 2008. pp. 261–298. doi:10.1007/978-1-4020-6554-5_13. ISBN 978-1-4020-6553-8.
- ↑ "Histone deacetylase inhibition and the regulation of cell growth with particular reference to liver pathobiology". Journal of Cellular and Molecular Medicine 13 (9B): 2990–3005. September 2009. doi:10.1111/j.1582-4934.2009.00831.x. PMID 19583816.
- ↑ "Chapter 4 - Histone Deacetylase Inhibitors in Cancer Prevention and Therapy". Epigenetics of Cancer Prevention. Translational Epigenetics. 8. Academic Press. January 2019. pp. 75–105. doi:10.1016/b978-0-12-812494-9.00004-4. ISBN 978-0-12-812494-9.
- ↑ "HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?". Biochemical Society Transactions 42 (2): 569–581. April 2014. doi:10.1042/BST20130233. PMID 24646280.
- ↑ "Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction". Behavioral Neuroscience 121 (5): 1125–1131. October 2007. doi:10.1037/0735-7044.121.5.1125. PMID 17907845.
- ↑ "HDAC inhibitors as anti-inflammatory agents". British Journal of Pharmacology 150 (7): 829–831. April 2007. doi:10.1038/sj.bjp.0707166. PMID 17325655.
- ↑ "Vorinostat-An Overview". Indian Journal of Dermatology 60 (4): 419. 2015. doi:10.4103/0019-5154.160511. PMID 26288427.
Further reading
- "Use of epigenetic modification to induce FOXP3 expression in naïve T cells". Transplantation Proceedings 41 (5): 1848–1854. June 2009. doi:10.1016/j.transproceed.2009.02.101. PMID 19545742.
External links
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