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Tubastatin A HCl

HDAC6 inhibitor,potent and selective CAS# 1310693-92-5

Tubastatin A HCl

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Chemical structure

Tubastatin A HCl

3D structure

Chemical Properties of Tubastatin A HCl

Cas No. 1310693-92-5 SDF Download SDF
PubChem ID 57336514 Appearance Powder
Formula C20H22ClN3O2 M.Wt 371.86
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Tubastatin A HCl; TSA HCl
Solubility DMSO : 10.8 mg/mL (29.04 mM; Need ultrasonic and warming)
Chemical Name N-hydroxy-4-[(2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5-yl)methyl]benzamide;hydrochloride
SMILES CN1CCC2=C(C1)C3=CC=CC=C3N2CC4=CC=C(C=C4)C(=O)NO.Cl
Standard InChIKey LJTSJTWIMOGKRJ-UHFFFAOYSA-N
Standard InChI InChI=1S/C20H21N3O2.ClH/c1-22-11-10-19-17(13-22)16-4-2-3-5-18(16)23(19)12-14-6-8-15(9-7-14)20(24)21-25;/h2-9,25H,10-13H2,1H3,(H,21,24);1H
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Tubastatin A HCl

DescriptionTubastatin A HCl is a potent and selective inhibitor of HDAC6 with IC50 of 15 nM. It is selective (1000-fold more) against all other isozymes except HDAC8 (57-fold more).
TargetsHDAC6HDAC8    
IC5015 nM854 nM    

Protocol

Kinase Assay [1]
Enzyme inhibition assays are performed using the Reaction Biology HDAC Spectrum platform. The HDAC1, 2, 4, 5, 6, 7, 8, 9, 10, and 11 assays use isolated recombinant human protein; HDAC3/NcoR2 complex is used for the HDAC3 assay. Substrate for HDAC1, 2, 3, 6, 10, and 11 assays is a fluorogenic peptide from p53 residues 379-382 (RHKKAc); substrate for HDAC8 is fluorogenic diacyl peptide based on residues 379-382 of p53 (RHKAcKAc). Acetyl-Lys (trifluoroacetyl)-AMC substrate is used for HDAC4, 5, 7, and 9 assays. Tubastatin A is dissolved in DMSO and tested in 10-dose IC50 mode with 3-fold serial dilution starting at 30 μM. Control Compound Trichostatin A (TSA) is tested in a 10-dose IC50 with 3-fold serial dilution starting at 5 μM. IC50 values are extracted by curve-fitting the dose/response slopes.

Cell Assay [1]
Primary cortical neuron cultures are obtained from the cerebral cortex of fetal Sprague-Dawley rats (embryonic day 17). All experiments are initiated 24 hours after plating. Under these conditions, the cells are not susceptible to glutamate-mediated excitotoxicity. For cytotoxicity studies, cells are rinsed with warm PBS and then placed in minimum essential medium containing 5.5 g/L glucose, 10% fetal calf serum, 2 mM L-glutamine, and 100 μM cystine. Oxidative stress is induced by the addition of the glutamate analogue homocysteate (HCA; 5 mM) to the media. HCA is diluted from 100-fold concentrated solutions that are adjusted to pH 7.5. In combination with HCA, neurons are treated with Tubastatin A at the indicated concentrations. Viability is assessed after 24 hours by MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method.

Animal Administration [2]
The effects of HDAC6 targeting in dextran sodium sulfate (DSS) and adoptive transfer models of colitis are evaluated, using 10 mice per group. Freshly prepared 4% (wt/vol) DSS is added daily for 5 days to the pH-balanced tap water of WT B6 mice. Mice are treated daily for 7 days with tubacin or niltubacin (0.5 mg/kg of body weight/day, i.p.), and colitis is assessed by daily monitoring of body weight, stool consistency, and fecal blood. Stool consistency is scored as 0 (hard), 2 (soft), or 4 (diarrhea), and fecal blood (Hemoccult) is scored as 0 (absent), 2 (occult), or 4 (gross). To assess prevention of colitis in a T cell-dependent model, CD4+ CD45RBhi T cells (1×106) isolated from WT mice using magnetic beads (>95% cell purity, flow cytometry) are injected i.p. into B6/Rag1−/− mice plus CD4+ CD25+ Tregs (1.25×105) isolated using magnetic beads from HDAC6−/− or WT mice (>90% Treg purity, flow cytometry) and mice are monitored biweekly for clinical evidence of colitis. To assess therapy of established T cell-dependent colitis, B6/Rag1−/− mice are injected i.p. with CD4+ CD45RBhi cells (1×106). Once colitis has developed, mice also receive CD4+ CD25+ Tregs (5×105 cells) isolated as described above from HDAC6−/− or WT mice or treatment with HDAC6i (tubastatin A) or HSP90i (17-AAG). Mice are monitored for continued weight loss and stool consistency. At the cessation of the study, paraffin sections of colons stained with Alcian Blue or hematoxylin and eosin are graded histologically or evaluated by immunoperoxidase staining for Foxp3+ Treg infiltration.

References:
[1]. Kyle V. Butler et al. Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A J. Am. Chem. Soc., 2010, 132 (31), pp 10842-10846 [2]. de Zoeten EF, et al. Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells. Mol Cell Biol. 2011 May;31(10):2066-78. [3]. Di Fulvio S, et al. Dysferlin interacts with histone deacetylase 6 and increases alpha-tubulin acetylation. PLoS One. 2011;6(12):e28563. [4]. Ketene AN, et al. Actin filaments play a primary role for structural integrity and viscoelastic response in cells. Integr Biol (Camb). 2012 May;4(5):540-9. [5]. Brijmohan AS, et al. HDAC6 Inhibition Promotes Transcription Factor EB Activation and Is Protective in Experimental Kidney Disease. Front Pharmacol. 2018 Feb 1;9:34.

Tubastatin A HCl Dilution Calculator

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Tubastatin A HCl Molarity Calculator

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Preparing Stock Solutions of Tubastatin A HCl

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.6892 mL 13.4459 mL 26.8918 mL 53.7837 mL 67.2296 mL
5 mM 0.5378 mL 2.6892 mL 5.3784 mL 10.7567 mL 13.4459 mL
10 mM 0.2689 mL 1.3446 mL 2.6892 mL 5.3784 mL 6.723 mL
50 mM 0.0538 mL 0.2689 mL 0.5378 mL 1.0757 mL 1.3446 mL
100 mM 0.0269 mL 0.1345 mL 0.2689 mL 0.5378 mL 0.6723 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Tubastatin A HCl

Tubastatin A HCl is a selective inhibitor of HDAC6 with IC50 value of 15 nM [1].

HDAC6 (histone deacetylase 6) is an enzyme and plays an important role in a variety of processes, including transcriptional regulation, cell cycle preogression and developmental events. Abnormal expression of HDAC6 is correlated with many kinds of diseases, including Alzheimer's disease and cancers [1].

Tubastatin A HCl is a potent HDAC6 inhibitor and has the most selective compared with other HDAC isoforms. When tested with primary cortical neuron cells, Tubastatin A HCl treatment protected HCA-induced neuronal cell death in a dose range from 5 μM to 10 μM [1]. In HaCaT cells, administration of Tubastatin A HCl prevented sodium arsenite from inducing association of Nrf2 mRNA with ribosomes and elevation of Nrf2 protein by selectively inhibitng HDAC6 activity and had no effect on other HDACs [2]. Using atomic force microscopy study, Ketene AN et al. revealed that Tubastatin A HCl increased cell elasticity by inhibiting HDAC6 [3].

References:
[1].  Kyle V. Butler, Jay Kalin, Camille Brochier, et al. Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A [J]. J. Am. Chem. Soc., 2010, 132 (31), pp 10842–10846.
[2].  Kappeler KV, Zhang J, Dinh TN, et al. Histone deacetylase 6 associates with ribosomes and regulates de novo protein translation during arsenite stress [J]. Toxicol Sci. 2012 May;127(1):246-255.
[3].  Ketene AN, Roberts PC, Shea AA, et al. Actin filaments play a primary role for structural integrity and viscoelastic response in cells [J]. Integr Biol (Camb). 2012 May;4(5):540-549.

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References on Tubastatin A HCl

Therapeutic effects of histone deacetylase inhibitors in a murine asthma model.[Pubmed:27565183]

Inflamm Res. 2016 Dec;65(12):995-1008.

OBJECTIVE AND DESIGN: To investigate the therapeutic effects of various HDAC inhibitors on the development of chronic allergic airway disease in mice with airway inflammation, airway remodeling, and airway hyperresponsiveness. SUBJECTS: Wild-type BALB/C mice (N = 72). TREATMENT: Tubastatin A HCl [TSA, a selective histone deacetylase 6 (HDAC6) inhibitor], PCI-34051 (a selective HDAC8 inhibitor), and givinostat (a broad-spectrum HDAC inhibitor that inhibits class I and class II HDACs and several pro-inflammatory cytokines). METHODS: Mice were divided into six groups: control, asthma, dexamethasone (positive control), TSA, PCI-34051, and givinostat (n = 12 per group). Twenty-four hours after OVA nebulization, airway hyperresponsiveness, inflammation, and remodeling were assessed. RESULTS: The chronic asthma mouse model produced typical airway inflammation, airway remodeling, and airway hyperresponsiveness. Administration of PCI-34051 and dexamethasone reduced the eosinophilic inflammation and airway hyperresponsiveness in asthma to reduce the airway remodeling. Treatment with Tubastatin A HCl reduced airway inflammation and was associated with decreased IL-4, IL-5 and total inflammatory cell count, as well as goblet cell metaplasia and subepithelial fibrosis; however, this outcome was not as effective as that with dexamethasone. TGF-beta1 expression in the cytoplasm of airway epithelium of mice in the Tubastatin A HCl group was reduced and expression of alpha-SMA in the airway smooth muscle was also decreased. CONCLUSIONS: The results suggested that treatment with HDAC inhibitors can reduce airway inflammation, airway remodeling, and airway hyperresponsiveness in chronic allergic airway disease in mice.

[Therapeutic effects of Tubastatin A Hcl on airway inflammation in acute mice asthma model].[Pubmed:28648015]

Zhonghua Yi Xue Za Zhi. 2017 Jun 27;97(24):1888-1892.

Objective: To investigated the therapeutic effects of Tubastatin A HCl, a selective HDAC6 inhibitor, on airway inflammation in acute mice bronchial asthma (asthma) model. Methods: A total of 48 BALB/C mice were randomly divided into control group, asthma group, dexamethasone group and Tubastatin A HCl group with 12 mice in each group. Then the airway hyperresponsiveness was assessed in each group; total cell number, different cell number, levels of Interleukin (IL)-4, IL-5 and Interferon-gamma (IFN-gamma) in the bronchoalveolar lavage fluid (BALF) were detected; the lung tissues of each group were stained with HE to observe the inflammatory cells infiltration. AB-PAS was used to observe the goblet cell metaplasia in tracheal epithelium. Masson staining was used to observe the collagen deposition in lung tissue. Results: The airway reactivity in Tubastatin A HCl group was significantly lower than that in asthma group [(4.18+/-0.94) vs (6.02+/-0.47), P<0.05]; in the Tubastatin A HCl group, the total inflammatory cells [(57.0+/-5.7)x10(4)/ml vs (87.0+/-5.6)x10(4)/ml], eosinophil cells [(6.8+/-1.7)x10(4)/ml vs (12.3+/-3.5)x10(4)/ml] and levels of IL-4 [(19.3+/-2.7) vs (26.2+/-3.2)ng/ml] in BALF were obviously lower than those of asthma group (all P<0.05); IL-5 in Tubastatin A HCl group was lower and IFN-gamma was higher than that of asthma group, while there were no significant differences (both P>0.05). The degree of inflammatory cells infiltrations around the airway and vascular, number of inflammatory cells [(9.80+/-2.42) vs (20.67+/-7.53)], score of inflammation [(2.20+/-0.70) vs (3.60+/-0.68) points, ], and percentage of goblet cell metaplasia [(50.46+/-5.03)% vs (71.06+/-5.38)%] in the lung tissue of Tubastatin A HCl group were lower than that of asthma group (all P<0.05). Although collagen deposition in the lung tissue of Tubastatin A HCl group was lower than asthma group, there were no significant differences (P>0.05). However, all of the above results in the dexamethasone group were slightly better than Tubastatin A HCl group, which had no significant differences (P>0.05). Conclusion: Tubastatin A HCl can effectively alleviate the level of airway inflammation in acute asthma, but its anti-inflammatory effect is limited, which is not as significant as dexamethasone.

Description

Tubastatin A (Hydrochloride) is a potent and selective HDAC6 inhibitor with IC50 of 15 nM in a cell-free assay, and is selective (1000-fold more) against all other isozymes except HDAC8 (57-fold more).

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