4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide

• ChemBase ID: 72672
• Molecular Formular: C11H14ClNO3
• Molecular Mass: 243.68676
• Monoisotopic Mass: 243.06622099
• SMILES: c1c(cc(c(c1)OCCCC(=O)NO)C)Cl
• Canonical SMILES: ONC(=O)CCCOc1ccc(cc1C)Cl
• InChI: InChI=1S/C11H14ClNO3/c1-8-7-9(12)4-5-10(8)16-6-2-3-11(14)13-15/h4-5,7,15H,2-3,6H2,1H3,(H,13,14)
• InChIKey: JHSXDAWGLCZYSM-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide
• IUPAC Traditional name: 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide
• Synonyms: 4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide; Droxinostat; Droxinostat

Database IDs

• CAS Number: 99873-43-5
• MDL Number: MFCD01326592
• PubChem SID: 162037593
• PubChem CID: 568416

CALCULATED PROPERTIES

• Acid pKa: 8.906647
• H Acceptors: 3
• H Donor: 2
• LogD (pH = 5.5): 2.126404
• LogD (pH = 7.4): 2.1133182
• Log P: 2.1265736
• Molar Refractivity: 61.493 cm^3
• Polarizability: 23.88337 Å^3
• Polar Surface Area: 58.56 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO; DMSO: ≥20 mg/mL
• Apperance: white to off-white powder

Safety Information

• Storage Condition: -20°C
• European Hazard Symbols: Harmful (Xn)
• German water hazard class: 3
• Risk Statements: 22-37/38-41
• Safety Statements: 26-39
• GHS Pictograms: GHS05; GHS07
• GHS Signal Word: Danger
• GHS Hazard statements: H302-H315-H318-H335
• GHS Precautionary statements: P261-P280-P305 + P351 + P338
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: HDAC

Product Information

• Purity: ≥98% (HPLC)
• Salt Data: Free Base
• Empirical Formula (Hill Notation): C11H14ClNO3

DETAILS

Selleck Chemicals - S1422

Research Area

• Description: Cancer

Biological Activity

• Description: Droxinostat (CMH, 5809354) is a selective inhibitor of HDAC3, HDAC6 and HDAC8 with IC50 of 16.9 μM, 2.47μM and 1.46 μM, respectively.
• Targets: HDAC3; HDAC6; HDAC8
• IC50: 16.9 μM; 2.47 μM; 1.46 μM ^[3]
• In Vitro: Droxinostat is originally identified as a sensitizer of PPC-1 cells to FAS and TRAIL by downregulating the expression of c-Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein (c-FLIP). ^[1]In PPC-1 cells cultured in suspension but not adherent conditions, Droxinostat (20 μM–60 μM) sensitizes cells to anoikis by initially activating caspase 8 with subsequent activation of the mitochondrial pathway. Similarly, Droxinostat also sensitizes other cancer cell lines including PC-3, DU-145, T47D, and OVCAR-3, but not LNCaP or MB-MDA-468, to anoikis or CH-11-induced apoptosis. ^[2]However, the direct targets of Droxinostat remains enigma until recently. It is revealed that in histone deacetylases (HDAC) isoform 1-10, Droxinostat selective inhibits HDAC3, 6, and 8, with IC50 values of 16.9 μM, 2.47 μM, and 1.46 μM, respectively, without inhibiting other HDAC members (IC50 > 20 μM). ^[3]In MCF-7 breast cancer cells, Droxinostat (10 μM–100 μM) sensitizes cells to apoptosis by decreasing c-FLIP_L and c-FLIP_S expression, reducing cell survival, and inducing apoptosis. ^[4]
• In Vivo: In SCID mice models, Droxinostat (30 μM)-treated PPC-1 cells results in decreased distant tumor formation than untreated cells. ^[2]
• Features: Droxinostat is a selective inhibitor of HDAC3, 6, and 8 and acts as a sensitizer to death receptor stimuli.

Protocol

• Protocol: Kinase Assay ^[3]
• HDAC Inhibition Assay: HDAC inhibition is assessed using the CycLex HDACs fluorometric assay according to the manufacturer's protocol and using crude nuclear extract from HeLa cells (principally HDAC1 and HDAC2). The relative activity is expressed as (fluorescence intensity of treated samples/fluorescence intensity of controls) × 100%.
• Protocol: Cell Assay ^[1]
• Cell Lines: PPC-1 cells
• Concentrations: 0–100 μM, dissolved in DMSO (final concentration of DMSO is 0.5%)
• Incubation Time: 24 hours
• Methods: PPC-1 cells (1 × 10^4) are seeded overnight into 96-well flat-bottomed plates in 100 μL of medium containing 2.5% FCS. The next day, Droxinostat is added. CH-11 antibody (100 ng/mL) is then added and the cells are incubated for 24 hours before assessing cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye reduction assay.
• Protocol: Animal Study ^[2]
• Animal Models: Male severe combined immunodeficient (SCID) mice models treated with PPC-1 cells
• Formulation: dsRed-PPC-1 cells that treated with Droxinostat (30 μM) or PBS buffer control are either injected via the tail vein or subcutaneously into the hind limbs

References

• References: [1] Schimmer AD, et al. Cancer Res, 2006, 66(4), 2367-2375.
• References: [2] Mawji IA, et al. J Natl Cancer Inst, 2007, 99(10), 811-822.
• References: [3] Wood TE, et al. Mol Cancer Ther, 2010, 9(1), 246-256.
• References: [4] Bijangi-Vishehsaraei K, et al. Mol Cell Biochem, 2010, 342(1-2), 133-142.

Sigma Aldrich - D6321

Biochem/physiol Actions
Droxinostat is a selective inhibitor of HDAC3, HDAC6, and HDAC8.

REFERENCES

• Schimmer AD, et al. Cancer Res, 2006, 66(4), 2367-2375.
• Mawji IA, et al. J Natl Cancer Inst, 2007, 99(10), 811-822.
• Wood TE, et al. Mol Cancer Ther, 2010, 9(1), 246-256.
• Bijangi-Vishehsaraei K, et al. Mol Cell Biochem, 2010, 342(1-2), 133-142.