N-hydroxy-4-({2-methyl-1H,2H,3H,4H,5H-pyrido[4,3-b]indol-5-yl}methyl)benzamide hydrochloride

• ChemBase编号: 73223
• 分子式: C20H22ClN3O2
• 平均质量: 371.86058
• 单一同位素质量: 371.14005464
• SMILES: c1c(ccc(c1)Cn1c2c(c3c1cccc3)CN(CC2)C)C(=O)NO.Cl
• Canonical SMILES: ONC(=O)c1ccc(cc1)Cn1c2ccccc2c2c1CCN(C2)C.Cl
• 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
• InChIKey: LJTSJTWIMOGKRJ-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: N-hydroxy-4-({2-methyl-1H,2H,3H,4H,5H-pyrido[4,3-b]indol-5-yl}methyl)benzamide hydrochloride
• IUPAC传统名: N-hydroxy-4-({2-methyl-1H,3H,4H-pyrido[4,3-b]indol-5-yl}methyl)benzamide hydrochloride
• 别名: Tubastatin A hydrochloride

登记号

• CAS号: 1310693-92-5
• PubChem SID: 162038143
• PubChem CID: 57336514

理论计算性质

• Acid pKa: 9.802132
• 质子受体: 3
• 质子供体: 2
• LogD (pH = 5.5): 0.58047235
• LogD (pH = 7.4): 2.2025433
• Log P: 2.5402005
• 摩尔折射率: 99.337 cm^3
• 极化性: 38.427925 Å^3
• 极化表面积: 57.5 Å^2
• 可自由旋转的化学键: 3
• 里宾斯基五规则: true

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: HDAC

产品相关信息

• 成盐信息: HCL

详细说明

Selleck Chemicals - S2627

Research Area

• Description: Cancer

Biological Activity

• Description: Tubastatin A is a potent HDAC6 inhibitor with IC50 of 15 nM.
• Targets: HDAC1; HDAC8
• IC50: 15 nM; 854 nM ^[1]
• In Vitro: Tubastatin A is substantially selective for all 11 HDAC isoforms and maintains over 1000-fold selectivity against all isoforms excluding HDAC8, where it has approximately 57-fold selectivity. In homocysteic acid (HCA) induced neurodegeneration assays, Tubastatin A displays dose-dependent protection against HCA-induced neuronal cell death starting at 5 μM with near complete protection at 10 μM. ^[1] At 100 ng/mL Tubastatin A increases Foxp3+ T-regulatory cells (Tregs) suppression of T cell proliferation in vitro. ^[2] Tubastatin A treatment in C2C12 cells would lead to myotube formation impairment when alpha-tubulin is hyperacetylated early in the myogenic process; however, myotube elongation occurs when alpha-tubulin is hyeperacetylated in myotubes. ^[3] A recent study indicates that Tubastatin A treatment increases cell elasticity as revealed by atomic force microscopy (AFM) tests without exerting drastic changes to the actin microfilament or microtubule networks in mouse ovarian cancer cell lines, MOSE-E and MOSE-L. ^[4]
• In Vivo: Daily treatment of Tubastatin A at 0.5mg/kg inhibits HDAC6 to promote Tregs suppressive activity in mouse models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully major histocompatibility complex (MHC)-incompatible cardiac allograft rejection. ^[2]

Protocol

• Protocol: Kinase Assay ^[1]
• Enzyme Inhibition Assays: Enzyme inhibition assays are performed by the Reaction Biology Corporation, Malvern, PA, using the Reaction Biology HDAC Spectrum platform. (www.reactionbiology.com) 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.
• Protocol: Cell Assay ^[1]
• Cell Lines: Primary cortical neuron of fetal Sprague-Dawley rats(embryonic day 17)
• Concentrations: 0-10 μM
• Incubation Time: 24 hours
• Methods: Primary cortical neuron cultures are obtained from the cerebral cortex of fetal Sprague-Dawley rats (embryonic day 17) as described previously. 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 (Invitrogen) containing 5.5 g/L glucose, 10% fetal calf serum, 2 mM L-glutamine, and 100 μM cystine. Oxidative stress was 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.
• Protocol: Animal Study ^[2]
• Animal Models: Na?ve CD45RBhi CD4+ CD25- cells (1 × 10^6) from WT or HDAC6-/- mice Are injected i.p. into B6/Rag1-/-mice.
• Formulation: Tubastatin A is dissolved in dimethyl sulfoxide (DMSO).
• Doses: 0.5 mg/kg
• Administration: Tubastatin A is injected i.p. daily.

References

• References: [1] Butler KV, et al, J Am Chem Soc, 2010, 132(31), 10842-10846.
• References: [2] de Zoeten EF, et al, Mol Cell Biol, 2011, 31(10), 2066-2078.
• References: [3] Di Fulvio S, et al, PloS One, 2011, 6(12):e28563.
• References: [4] Ketene AN, et al, Integr Biol (Camb), 2012, 4(5), 540-549.

参考文献

• Butler KV, et al, J Am Chem Soc, 2010, 132(31), 10842-10846.
• de Zoeten EF, et al, Mol Cell Biol, 2011, 31(10), 2066-2078.
• Di Fulvio S, et al, PloS One, 2011, 6(12):e28563.
• Ketene AN, et al, Integr Biol (Camb), 2012, 4(5), 540-549.