(2E,4E,6R)-7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide

• ChemBase ID: 3905
• Molecular Formular: C17H22N2O3
• Molecular Mass: 302.36818
• Monoisotopic Mass: 302.16304257
• SMILES: ONC(=O)/C=C/C(=C/[C@H](C(=O)c1ccc(N(C)C)cc1)C)/C
• Canonical SMILES: ONC(=O)/C=C/C(=C/[C@H](C(=O)c1ccc(cc1)N(C)C)C)/C
• InChI: InChI=1S/C17H22N2O3/c1-12(5-10-16(20)18-22)11-13(2)17(21)14-6-8-15(9-7-14)19(3)4/h5-11,13,22H,1-4H3,(H,18,20)/b10-5+,12-11+/t13-/m1/s1
• InChIKey: RTKIYFITIVXBLE-QEQCGCAPSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (2E,4E,6R)-7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide
• IUPAC Traditional name: trichostatin a; TSA
• Synonyms: TSA; Trichostatin A; 7-[4-(Dimethylamino)Phenyl]-N-Hydroxy-4,6-Dimethyl-7-Oxo-2,4-Heptadienamide; [R-(E,E)]-7-[4-(Dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide; Trichostatin A

Database IDs

• CAS Number: 58880-19-6
• MDL Number: MFCD03848392
• PubChem SID: 24900542; 160967340; 46506659
• PubChem CID: 444732
• CHEBI ID: 46024
• CHEMBL: 99
• Chemspider ID: 392575
• DrugBank ID: DB04297
• Wikipedia Title: Trichostatin_A

CALCULATED PROPERTIES

JChem

• Acid pKa: 9.567311
• H Acceptors: 4
• H Donor: 2
• LogD (pH = 5.5): 2.406459
• LogD (pH = 7.4): 2.4066641
• Log P: 2.409631
• Molar Refractivity: 90.2389 cm^3
• Polarizability: 33.119965 Å^3
• Polar Surface Area: 69.64 Å^2
• Rotatable Bonds: 6
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 2.36
• LOG S: -3.85
• Solubility (Water): 4.25e-02 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; ethanol: soluble2 mg/mL

Safety Information

• Storage Condition: -20°C
• RTECS: MI5215000
• European Hazard Symbols: Harmful (Xn)
• German water hazard class: 3
• Risk Statements: 20/21/22-36/37/38-43
• Safety Statements: 26-36
• GHS Pictograms: GHS07
• GHS Signal Word: Warning
• GHS Hazard statements: H302-H312-H315-H317-H319-H332-H335
• GHS Precautionary statements: P261-P280-P305 + P351 + P338
• Personal Protective Equipment: dust mask type N95 (US), Eyeshields, Faceshields, Gloves
• Storage Temperature: -20°C

Pharmacology Properties

• Target: HDAC
• Pregnancy Category: D—teratogenic
• Gene Information: human ... HDAC1(3065), HDAC4(9759), HDAC6(10013), HDAC8(55869)mouse ... ENSMUSG00000061062(15181)rat ... Hdac7a(84582)

Product Information

• Purity: ≥98% (HPLC)
• Salt Data: Free Base
• Biological Source: from Streptomyces sp.
• Quality Level: PREMIUM

DETAILS

DrugBank - DB04297

Drug information: experimental

Selleck Chemicals - S1045

Research Area

• Description: Cancer

Biological Activity

• Description: Trichostatin A (TSA) is an HDAC inhibitor with IC50 of ~1.8 nM.
• Targets:

  HDAC

• IC50:

  ~1.8 nM ^[1]

• In Vitro: Trichostatin A inhibits the proliferation of eight breast carcinoma cell lines including MCF-7, T-47D, ZR-75-1, BT-474, MDA-MB-231, MDA-MB-453, CAL 51, and SK-BR-3 with mean IC50 of 124.4 nM (range, 26.4-308.1 nM), with more potency against cell lines that express ERα than the ERα-negative cell lines. Trichostatin A inhibits HDAC activity similarly in all the breast cancer cell lines with mean IC50 of 2.4 nM (range, 0.6-2.6 nM), and results in pronounced histone H4 hyperacetylation. ^[1] Unlike trapoxin (TPX) and Chlamydocin which potently inhibit HDAC1 or HDAC4 but not HDAC6, Trichostatin A inhibits these HDACs to a similar extent with IC50 of 6 nM, 38 nM, and 8.6 nM, respectively. ^[2] Trichostatin A (100 ng/mL) treatment induces the expression of transforming growth factor β type II receptor (TβRII) in MIA PaCa-2 cells through the recruitment of p300 and PCAF into a Sp1-NF-Y HDAC complex that binds the DNA element of TβRII promoter, which is associated with a concomitant acetylation of Sp1 and an overall decrease in the amount of HDAC associated with the complex. ^[4]
• In Vivo: Administration of Trichostatin A at 0.5 mg/kg for 4 weeks displays potent antitumor activity in the N-methyl-N-nitrosourea carcinogen-induced rat mammary carcinoma model, without any measurable toxicity at doses up to 5 mg/kg. ^[1] Single intraperitoneal doses of 10 mg/kg Trichostatin A in nontransgenic and spinal muscular atrophy (SMA) model mice results in increased levels of acetylated H3 and H4 histones and modest increases in survival motor neuron (SMN) gene expression. Administration of Trichostatin A at 10 mg/kg/day improves survival, attenuates weight loss, and enhances motor behavior in the SMA model mice. ^[5]

Combination Therapy

• Description:

  Loosening-up the chromatin structure induced by pretreatment with Trichostatin A (10 ng/mL) increases the anti-tumor efficiency of VP-16, ellipticine,Doxorubicin, and Cisplatin, with significant sensitization by >10-fold for VP-16 in topoisomerase II inhibitor-resistant D54 cells. Trichostatin A enhances VP-16-induced apoptosis in a p53-dependent and -independent manner. ^[3]

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro HDAC activity: Total cellular extracts are prepared from each breast cancer cell line (MCF-7, T-47D, ZR-75-1, BT-474, MDA-MB-231, MDA-MB-453, CAL 51, or SK-BR-3). A 20 μL crude cell extract (~2.5 ×10^5 cells), in the presence of varying concentrations of Trichostatin A in 0.1% (v/v) ethanol or 0.1% (v/v) ethanol as vehicle control, are incubated for 60 minutes at 25 °C with 1 μL (~1.5 × 10^6 cpm) of [^3H]acetyl-labeled histone H4 peptide substrate (NH2-terminal residues 2-20) that has been acetylated with [^3H]acetic acid, sodium salt (3.7 GBq/mmol) by an in vitro incorporation method. Each 200 μL reaction is quenched with 50 μL of 1 M HCl/0.16 M acetic acid and extracted with 600 μL of ethyl acetate, and released [^3H]acetate is quantified by scintillation counting. IC50 values are determined graphically using nonlinear regression to fit inhibition data to the appropriate dose-response curve.
• Protocol: Cell Assay ^[1]
• Cell Lines: MCF-7, T-47D, ZR-75-1, BT-474, MDA-MB-231, MDA-MB-453, CAL 51, and SK-BR-3
• Concentrations: Dissolved in absolute ethanol, final concentrations ~10 μM
• Incubation Time: 96 hours
• Methods:

  Cells are exposed to various concentrations of Trichostatin A for 96 hours. After treatment, cell proliferation is estimated using the sulforhodamine B colorimetric assay. Cell viability is determined by trypan blue exclusion.

• Protocol: Animal Study ^[1]
• Animal Models: Inbred virgin female (Ludwig/Wistar/Olac) rats bearing tumors induced with NMU
• Formulation: Dissolved in DMSO
• Doses: ~5 mg/kg/day
• Administration: Injection s.c.

References

• References: [1] Vigushin DM, et al. Clin Cancer Res, 2001, 7(4), 971-976.
• References: [2] Furumai R, et al. Proc Natl Acad Sci U S A, 2001, 98(1), 87-92.
• References: [3] Kim MS, et al. Cancer Res, 2003, 63(21), 7291-7300.
• References: [4] Huang W, et al. J Biol Chem, 2005, 280(11), 10047-10054.
• References: [5] Avila AM, et al. J Clin Invest, 2007, 117(3), 659-671.

Sigma Aldrich - T8552

Frequently Asked Questions
Live Chat and Frequently Asked Questions are available for this Product.
Biochem/physiol Actions
Inhibits histone deacetylase at nanomolar concentrations; resultant histone hyperacetylation leads to chromatin relaxation and modulation of gene expression. May be involved in cell cycle progression of several cell types, inducing cell growth arrest at both G and G/M phases; may induce apoptosis. Enhances the efficacy of anticancer agents that target DNA.

REFERENCES

• Kim MS, et al. Cancer Res, 2003, 63(21), 7291-7300.
• Huang W, et al. J Biol Chem, 2005, 280(11), 10047-10054.
• Vigushin DM, et al. Clin Cancer Res, 2001, 7(4), 971-976.
• Furumai R, et al. Proc Natl Acad Sci U S A, 2001, 98(1), 87-92.
• Avila AM, et al. J Clin Invest, 2007, 117(3), 659-671.