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935881-37-1 molecular structure
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N-hydroxy-4-[(2S)-3-methyl-2-phenylbutanamido]benzamide

ChemBase ID: 72471
Molecular Formular: C18H20N2O3
Molecular Mass: 312.363
Monoisotopic Mass: 312.14739251
SMILES and InChIs

SMILES:
c1ccc(cc1)[C@@H](C(=O)Nc1ccc(cc1)C(=O)NO)C(C)C
Canonical SMILES:
ONC(=O)c1ccc(cc1)NC(=O)[C@H](c1ccccc1)C(C)C
InChI:
InChI=1S/C18H20N2O3/c1-12(2)16(13-6-4-3-5-7-13)18(22)19-15-10-8-14(9-11-15)17(21)20-23/h3-12,16,23H,1-2H3,(H,19,22)(H,20,21)/t16-/m0/s1
InChIKey:
LAMIXXKAWNLXOC-INIZCTEOSA-N

Cite this record

CBID:72471 http://www.chembase.cn/molecule-72471.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
N-hydroxy-4-[(2S)-3-methyl-2-phenylbutanamido]benzamide
IUPAC Traditional name
N-hydroxy-4-[(2S)-3-methyl-2-phenylbutanamido]benzamide
Synonyms
HDAC-42
(S)-HDAC 42
AR 42
OSU-HDAC 42
AR-42
CAS Number
935881-37-1
PubChem SID
162037396
PubChem CID
6918848

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S2244 external link Add to cart Please log in.
Data Source Data ID
PubChem 6918848 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 9.799228  H Acceptors
H Donor LogD (pH = 5.5) 3.167307 
LogD (pH = 7.4) 3.1656077  Log P 3.1673286 
Molar Refractivity 90.21 cm3 Polarizability 33.772896 Å3
Polar Surface Area 78.43 Å2 Rotatable Bonds
Lipinski's Rule of Five true 

PROPERTIES

PROPERTIES

Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Storage Condition
-20°C expand Show data source
Target
HDAC expand Show data source
Salt Data
Free Base expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S2244 external link
Research Area
Description Multiple myeloma, Lymphoma, Chronic lymphocytic leukaemia
Biological Activity
Description AR-42 (HDAC-42, OSU-HDAC42) is a pan-HDAC inhibitor with IC50 30 nM.
Targets HDAC
IC50 30 nM [1]
In Vitro AR-42 treatment induces histone hyperacetylation and p21WAF/CIP1 overexpression, and inhibits the growth of DU-145 cells with IC50 of 0.11 μM. [1] HDAC42 is potent in suppressing the proliferation of U87MG and PC-3 cells, in part, because of its ability to down-regulate Akt signaling. [2] AR-42 inhibits the growth of PC-3 and LNCaP cells with IC50 of 0.48 μM and 0.3 μM, respectively. Compared to SAHA, AR-42 exhibits distinctly superior apoptogenic potency, and causes markedly greater decreases in phospho-Akt, Bcl-xL, and survivin in PC-3 cells. [3] AR-42 treatment induces growth inhibition, cell- cycle arrest, apoptosis, and activation of caspases-3/7 in malignant mast cell lines. AR-42 treatment induces down-regulation of Kit via inhibition of Kit transcription, disassociation between Kit and heat shock protein 90 (HSP90), and up-regulation of HSP70. AR-42 treatment down-regulates the expression of p-Akt, total Akt, phosphorylated STAT3/5 (pSTAT3/5), and total STAT3/5. [6] AR-42 potently inhibits the growth of JeKo-1, Raji, and 697 cells with IC50 of <0.61 μm.="" ar-42="" also="" sensitizes="" cll="" cells="" to="" tnf-related="" apoptosis="" inducing="" ligand="" (trail),="" potentially="" through="" reduction="" of="" c-flip.="">[7] AR-42 treatment also induces autophagy through downregulation of Akt/mTOR signaling and inducing ER stress in hepatocellular carcinoma (HCC) cells. [8]
In Vivo The growth of PC-3 tumor xenografts is suppressed by 52% and 67% after treatment with AR-42 at 25 mg/kg and 50 mg/kg, respectively, whereas SAHA at 50 mg/kg suppresses growth by 31%. In contrast to mice treated with SAHA, intratumoral levels of phospho-Akt and Bcl-xL are markedly reduced in AR-42 treated mice. [3] In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, administration of AR-42 not only decreases the severity of prostatic intraepithelial neoplasia (PIN) and completely prevents its progression to poorly differentiated carcinoma, but also shifts tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively. [5] AR-42 significantly reduces leukocyte counts, and prolongs survival in three separate mouse models of B-cell malignancy without evidence of toxicity. [7]
Clinical Trials A Phase I study of AR-42 in treating patients with advanced or relapsed multiple myeloma, chronic lymphocytic leukemia, or lymphoma is currently ongoing.
Features More potent than SAHA.
Combination Therapy
Description Pretreatment of DU-145 cells with 0.25 μM AR-42 augments the effect of bleomycin, doxorubicin, and VP-16, but not 5-FU, on clonogenic inhibition, by targeting Ku70 acetylation. [4]
Protocol
Kinase Assay [1]
In vitro HDAC assay HDAC activity is analyzed by using a HDAC assay kit. This assay is based on the ability of DU-145 nuclear extract, which is rich in HDAC activity, to mediate the deacetylation of the biotinylated [3H]-acetyl histone H4 peptide that is bound to streptavidin agarose beads. The release of [3H]-acetate into the supernatant is measured to calculate the HDAC activity. Sodium butyrate (0.25-1 mM) is used as a positive control.
Cell Assay [1]
Cell Lines DU-145
Concentrations Dissolved in DMSO, final concentrations ~2.5 μM
Incubation Time 96 hours
Methods Cells are exposed to varous concentrations of AR-42 for 96 hours. The medium is removed and replaced by 150 μL of 0.5 mg/mL of MTT in RPMI 1640 medium, and the cells are incubated in the CO2 incubator at 37 °C for 2 hours. Supernatants are removed from the wells, and the reduced MTT dye is solubilized with 200 μL/well of DMSO. Absorbance is determined on a plate reader at 570 nm.
Animal Study [3]
Animal Models Intact male NCr athymic nude mice inoculated s.c. with PC-3 cells
Formulation Formulated in methylcellulose/Tween 80
Doses ~50 mg/kg/day
Administration Orally
References
[1] Lu Q, et al. J Med Chem, 2005, 48(17), 5530-5535.
[2] Chen CS, et al. J Biol Chem, 2005, 280(46), 38879-38887.
[3] Kulp SK, et al. Clin Cancer Res, 2006, 12(17), 5199-5206.
[4] Chen CS, et al. Cancer Res, 2007, 67(11), 5318-5327.
[5] Sargeant AM, et al. Cancer Res, 2008, 68(10), 3999-4009.
[6] Lin TY, et al. Blood, 2010, 115(21), 4217-4225.
[7] Lucas DM, et al. PLoS One, 2010, 5(6), e10941.

PATENTS

PATENTS

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