Histone deacetylase inhibitor trichostatin

Herold C, Ganshnayer M, Ocker M, Hermann M, Geerts A, Hahn EG Schuppan D. (2002) The histone-deacetylase inhibitor trichostatin A blocks proliferation and triggers apoptotic programs in hepatoma cells. J Hepatol 36 233-240. 

T. Niki, K. Rombouts, P. J. De Bleser, K. de Smet, V. Rogiers, D. Schuppan, M. Yoshida, G. Gabbiani, and A. Geerts, A histone deacetylase inhibitor, trichostatin A, suppresses myofibroblastic differentation of rat hepatic stellate cells in primary culture. Hepatology 29 858-867 (1999). 

Sternson SM, Wong JC, Grozinger CM, Schreiber SL, Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin, Org. Lett., 3 4239-4242, 2001. 

Camelo S et al (2005) Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 164(1-2) 10-21... 

An aldehyde-aldehyde coupling was also the key transformation in the synthesis of the histone deacetylase inhibitor trichostatin A (74), developed by Duan and Wang 79). Reaction of p-nitrobenzaldehyde (75) and propionaldehyde (60) catalyzed by (5)-12 gave the rather unstable enantiopure 76, which was used directly for the subsequent steps towards trichostatin A (74). Notably, the chiral secondary alcohol group is oxidized later on in the sequence. Similar to some of the examples already depicted above, the organocatalytic introduction of the targeted stereogenic center is carried out very early in the multi-step sequence (Scheme 18) (79). 

In vivo administration of the histone deacetylase inhibitor trichostatin A corrected the site-specific hypoacetylation states on H3 and H4 and improved the phenotype of the disease, hi this study, novel histone modifications such as H3K18 methylation, H4K31 methylation, and H4K31 acetylation were also discovered and foimd to be differentially expressed in the disease... 

Furumai R, Komatsu Y, Nishino N, Khochbin S, Yoshida M, Horinouchi S (2001) Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proc Natl Acad Sci U S A 98(l) 87-92... 

The past few years witnessed some important developments that established a molecular link between CpG methylation and the status of histone acetylation. It was shown that the methyl-binding protein MeCp2 contains a transcriptional repressor domain that interacts directly with the multiprotein corepressor complex mSin3A [84,86]. Antibodies against MeCP2 coprecipitated mSin3A, HDACl and HDAC2, and the deacetylase inhibitor trichostatin A (TSA) relieved the repression. 

Jung, M., Hoffmann, K., Brosch, G. and Loidl, P. (1997) Analogues of trichostatin A and trapoxin B as histone deacetylase inhibitors. Bioorganic Medicinal Chemistry Letters, 7, 1655-1658. 

Histone deacetylase inhibitors, depsipeptide (FR901228), trichostatin A (TSA), and valproic acid, increase NIS expression in thyroid cancer cell lines (Kitazono et al., 2001 Kogai et al., 2006). Depsipeptide significantly induces NIS mRNA and iodide uptake in follicular thyroid cancer cell lines (FTC 133 and FTC 236) and two anaplastic cancer cell lines (SW-1736 and KAT-4) at a low concentration (Ing/ml) in vitro (Kitazono et al., 2001). Pharmacokinetics of depsipeptide in patients have indicated that levels of more than 500ng/ml are... 

Fortson WS, Kayarthodi S, Fujimura Y, Xu H, Matthews R, Grizzle WE, Rao VN, Bhat GK, Reddy ES. Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive nostate cancca ceUs. Int J Oncol. 2011 39 111-9. 

SCHEME 6.9 Synthesis of histone deacetylase inhibitors based on the structure of trichostatin A. 

Histone Acetylation. Figure 1 Histone acetylation is a posttranslational modification of lysine residues of histones. This modification is catalyzed by histone actyl transferases (HATs), which transfer an acetyl group (yellow) from acetyl-Coenzyme A onto the E-amino group of the lysine residue. Histone deacetylation is catalyzed by histone deacetylases (HDACs), which hydrolyze the lysine bound acetyl group. HDAC inhibitors like Trichostatin A (TSA) are known to inhibit the deacetylation reaction in vivo and in vitro. 

Crystal structures of a histone deacetylase-like protein (HDLP) and HDAC8 have confirmed a general pharmacophore model for HDAC inhibitors, comprising a cap joined by a hydrophobic linker to a zinc-binding group (ZBG). This model is exemplified by SAHA and the natural product HDACi Trichostatin A (TSA) 2. 

Trichostatin A (38a) is a ( , )-A -hydroxy-7-oxo-2,4-heptadienamide isolated from some strains of Streptomyces hydroscopicus and is an antifungal antibiotic [65] as well as a potent inhibitor of mammalian histone deacetylase used in cancer chemoprevention. Two other metabolites with similar biological activity have also been isolated trichostatin B (38b), which is the corresponding ferric chelate [65] and trichostatin C (38c), a glucopyranosyl derivative [66]. 

The natural product trichostatin A is known to be a potent inhibitor of histone deacetylase (HDAc). There is increasing evidence that the acetylation and deacetylation of proteins is an important regulatory modification in many cellular processes, and an imbalance of histone acetylation has been associated with malignant disease. HDAc inhibitors lead to a reversal of transcriptional repression and associated upregu-lation of tumor sequences. They have also been observed to result in the inhibition of angiogenesis. ... 

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