2514-30-9

Basic information

• Product Name: 2 - (4 - Methylphenyl) - 1,2 - benzisothiazol - 3(2H)-one
• Synonyms: 2 - (4 - Methylphenyl) - 1,2 - benzisothiazol - 3(2H)-one;2-(4-Methylphenyl)-2,3-dihydrobenzisothiazol-3-one;2-p-Tolyl-1,2-benzisothiazolin-3-one;PBIT;PBIT, >=98%
• CAS NO: 2514-30-9
• Molecular Formula: C₁₄H₁₁NOS
• Molecular Weight: 241.31
• EINECS: -0
• Mol File: 2514-30-9.mol

Chemical Properties

• Melting Point: 136.7-137.1 °C(Solv: benzene (71-43-2); hexane (110-54-3))
• Boiling Point: 418.2±38.0 °C(Predicted)
• Appearance: white to beige/
• Density: 1.297±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C
• Solubility: DMSO: soluble10mg/mL, clear (warmed)
• PKA: -0.03±0.20(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.
• CAS DataBase Reference: 2 - (4 - Methylphenyl) - 1,2 - benzisothiazol - 3(2H)-one(CAS DataBase Reference)
• NIST Chemistry Reference: 2 - (4 - Methylphenyl) - 1,2 - benzisothiazol - 3(2H)-one(2514-30-9)
• EPA Substance Registry System: 2 - (4 - Methylphenyl) - 1,2 - benzisothiazol - 3(2H)-one(2514-30-9)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 2514-30-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
2 (4 Methylphenyl) 1,2 benzisothiazol 3(2H)-one is used as an inhibitor for JARID1 family demethylases for the purpose of increasing trimethylation of H3K4 in HeLa cells and blocking the proliferation of tumor cells expressing high levels of JARID1B.
Used in Cancer Research:
In cancer research, 2 (4 Methylphenyl) 1,2 benzisothiazol 3(2H)-one is used as a tool to study the role of JARID1 family demethylases in tumor cell proliferation and the potential therapeutic applications of targeting these enzymes in cancer treatment.
Used in Drug Development:
2 (4 Methylphenyl) 1,2 benzisothiazol 3(2H)-one is used as a lead compound in the development of new drugs targeting JARID1 family demethylases, with potential applications in the treatment of various types of cancer.

Biological Activity

PBIT is a specific Jumonji/AT-rich interaction domain 1 (JARID1) inhibitor. PBIT inhibits the JARID1B (KDM5B or PLU1) histone demethylase with an IC50 value of approximately 3 μM. PBIT also inhibits JARID1A and JARID1C with IC50 of 6 μM and 4.9 μM, respectively.

Biochem/physiol Actions

PBIT is a potent inhibitor of JARID1B (KDM5B) histone lysine demethylase that inhibits removal of H3K4me3 in UACC-812 cells. PBIT inhibits proliferation of cells overexpressing JARID1B. PBIT is selective for JARID1 enzymes and does not inhibit demethylases UTX or JMJD3.

in vitro

PBIT inhibits proliferation of cells expressing higher levels of JARID1B. PBIT (1-10 μM for UACC-812 cells, 2.5-10μM for MCF7 and MCF10A cells; 72 hours) inhibits cell proliferation in a JARID1B level-dependent manner.

Enzyme inhibitor

This JARID1 Histone Demethylase inhibitor (FW = 241.31 g/mol; CAS 2514-30-9; Soluble to 100 mM in DMSO), also named 2-(4-methylphenyl)- 1,2-benzisothiazol-3(2H)-one, targets the Jumonji AT-Rich Interactive Domain 1, with respective IC50 values of 3, 4.9 and 6 μM for JARID1B, JARID1A and JARID1C. The enzymes responsible for the demethylation of trimethylated lysine 4 in histone H3 (H3K4me3) are the Jumonji AT-rich interactive domain 1 (JARID1) or lysine demethylase-5 (KDM5) family of lysine demethylases. This family consists of JARID1A (also known as KDM5A or RBP2), JARID1B (also known as KDM5B or PLU1), JARID1C (also known as KDM5C or SMCX), and JARID1D (also known as KDM5D or SMCY) in mammals. Like other JmjC domain-containing demethylases, JARID1 enzymes catalyze histon demethylation in a Fe(II) and α-ketoglutarate (α-KG)-dependent reaction. Oxidative decarboxylation of α-KG results in an unstable hydroxylated methyl-lysine intermediate. Release of the hydroxyl and methyl groups as formaldehyde from this intermediate results in demethylation. JARID1 demethylases have been linked to human diseases such as cancer and X-linked mental retardation. Both JARID1A and JARID1B are potential oncoproteins, and both are overexpressed in a variety of cancers. Increased expression of JARID1A promotes a more stem-like phenotype and enhanced resistance to anticancer agents. PBIT was identified by high-throughput screening (using biotinylated H3K4me3 peptide substrate) of agents that are selective for JARID1 over UTX and JMJD3. PBIT increases levels of methylated H3K4 in JARIDB1-transfected HeLa cells and MCF7 cells. (JARID1A and JARID1B knock-out mice are viable, suggesting that inhibition of JARID1A or JARID1B has minimal effects on normal cells in vivo. ) PBIT also inhibits proliferation of breast cancer cell lines expressing high levels of JARIDB1.

IC 50

6, 3, 4.9, and 28 μm for jarid1a, jarid1b, jarid1c, and jarid1d, respectively

References

1) Sayegh?et al.?(2013),?Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen; J. Biol. Chem.,?288?9408

Upstream product

• 19602-82-5 2,2'-dithiodibenzoic acid dichloride 
• 106-49-0 p-toluidine 
• 444993-97-9 ethyl 2-[N-(p-methylphenyl)sulfenamoyl]benzoate 
• 318975-04-1 N-[2-(ethoxycarbonyl)benzenesulfenyl]-1,2-benzisothiazolin-3-one 
• 623-10-9 N-(4-methylphenyl)hydroxylamine 
• 2634-33-5 1,2-benzisothiazolin-3-one 
• 624-31-7 4-tolyl iodide 
• 62303-05-3 2-iodo-N-(p-tolyl)benzamide 
• 4892-02-8 Methyl thiosalicylate 
• 136926-09-5 2-bromo-N-(4-methylphenyl)benzamide 
• 119-80-2 2,2'-dithiobenzoic acid 
• 1236311-86-6 2-ethylbenzo[d]-1,3-oxathiin-4-one 1-oxide 
• 38057-98-6 2-ethylbenzo[d]-1,3-oxathiin-4-one 
• 79054-73-2 N-(p-methylphenyl)-2-(methylthio)benzamide 

Downstream Products

• 88112-09-8 7-methyldibenzo<1,4>thiazepin-11(10H)-one 

Relevant articles and documents

Potassium bromide catalyzed N[sbnd]S bond formation via oxidative dehydrogenation

N-Substituted benzo[d]isothiazol-3(2H)-ones are a family of compounds with extremely important application. Recently, we have developed a new green pathway to synthesize these compounds via potassium bromide-catalyzed intramolecular oxidative dehydrogenative cyclization. This reaction has high functional group tolerance and affords excellent yield even in gram scale.

Electrochemical synthesis for benzisothiazol-3(2H)-ones by dehydrogenative N[sbnd]S bond formation

Herein, we report an electrochemical method for the synthesis of benzisothiazol-3(2H)-ones from 2-mercaptobenzamides. The electrochemical reaction proceeds through intramolecular N[sbnd]H/S[sbnd]H coupling cyclization reaction by generating H2 as the nonhazardous side product. Moreover, the developed procedure is highly advantageous due to its short reaction time, mild conditions and wide substrate scope without the employment of metal catalyst and exogenous-oxidant.2009 Elsevier Ltd. All rights reserved.

Ebsulfur as a potent scaffold for inhibition and labelling of New Delhi metallo-β-lactamase-1 in vitro and in vivo

The superbug infection caused by New Delhi metallo-β-lactamase (NDM-1) has grown into an emerging threat, labelling and inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. Here, we report a potent covalent scaffold, ebsulfur, for targeting the protein in vitro and in vivo. Enzymatic kinetic study indicated that eighteen ebsulfurs gained except 1a–b and 1f inhibited NDM-1, exhibiting an IC50 value ranging of 0.16–9 μM, and 1g was found to be the best, dose- and time-dependent inhibitor with an IC50 of 0.16 μM. Also, these ebsulfurs effectively restored the antibacterial activity of cefazolin against E. coli expressing NDM-1, and the best effect was observed to be from 1g, 1i and 1n, resulting in an 256-fold reduction in MIC of the antibiotic at a dose of 16 μg/mL. The equilibrium dialysis study implied that the ebsulfur disrupted the coordination of one Zn(II) ion at active site of NDM-1. Labelling of NDM-1 using a constructed fluorescent ebsulfur Ebs-R suggested that the inhibitor covalently bound to the target through SDS-PAGE analysis in vitro. Also, labelling NDM-1 in living E. coli cells with Ebs-R by confocal microscopic imaging showed the real-time distribution change process of intracellular recombinant protein NDM-1. Moreover, the cytotoxicity of these ebsulfurs against L929 mouse fibroblastic cells was tested, and their capability to restore antibacterial activity of antibiotic against clinical strains E. coli EC08 producing NDM-1 was determined. The ebsulfur scaffold proposed here is valuable for development of the covalent irreversible inhibitors of NDM-1, and also for labelling the target in vitro and in vivo.

Domino Reactions Initiated by Copper-Catalyzed Aryl-I Bond Thiolation For the Switchable Synthesis of 2,3-Dihydrobenzothiazinones and Benzoisothiazolones

The three-component reactions of o-iodobenzamides, elemental sulfur and dichloromethane (DCM) providing 2,3-dihydro-4H-benzo[e][1,3]thiazin-4-ones (2,3-dihydrobenzothiazinones) are accomplished via copper-catalyzed aryl C?I thiolation and subsequent N-, S-hetero ring formation. In addition, the in situ aryl C?I bond thiolation is also employed for the switchable synthesis of benzo[d]isothiazol-3(2H)-ones (benzoisothiazolones) by subjecting o-iodobenzamides, elemental sulfur to the copper-catalyzed condition with microwave irradiation. (Figure presented.).

Co-Catalyzed Intramolecular S-N Bond Formation in Water for 1,2-Benzisothiazol-3(2H)-ones and 1,2,4-Thiadiazoles Synthesis

An efficient and versatile Co-catalyzed intramolecular S-N bond formation in water to synthesize 1,2-benzisothiazol-3(2H)-one and 1,2,4-thiadiazoles derivatives in good to excellent yields was developed. The transformation showed great tolerance with a broad range of substituents. The mother liquor was able to be recycled 6 times with minor loss in product yield.

Broad spectrum anti-infective properties of benzisothiazolones and the parallels in their anti-bacterial and anti-fungal effects

Various mono- and bis-benzisothiazolone derivatives were synthesized and screened against different strains of bacteria and fungi in order to understand the effect of multiple electrophilic sulfur atoms and substitution pattern in the immediate vicinity of reactive sulfur. Staphyllococcus aureus-ATCC 7000699, MRSA and S. aureus-ATCC 29213 (Quality Control strain) were more susceptible to this class of compounds, and the most potent derivative 1.15 had MIC50 of 0.4?μg/mL (cf. Gentamicin?=?0.78?μg/mL). CLogP value, optimally in the range of 2.5–3.5, appeared to contribute more to the activity than the steric and electronic effects of groups attached at nitrogen. By and large, their anti-fungal activities also followed a similar trend with respect to the structure and CLogP values. The best potency of IC50?=?0.1?μg/mL was shown by N-benzyl derivative (1.7) against Aspergillus fumigatus; it was also potent against Candida albicans, Cryptococcus neoformans, Sporothrix schenckii, and Candida parapsilosis with IC50 values ranging from 0.4 to 1.3?μg/mL. Preliminary studies also showed that this class of compounds have the ability to target malaria parasite with IC50 values in low micromolar range, and improvement of selectivity is possible through structure optimization.

Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1

We report the discovery and characterization of a series of benzoisothiazolone inhibitors of PHOSPHO1, a newly identified soluble phosphatase implicated in skeletal mineralization and soft tissue ossification abnormalities. High-throughput screening (HTS)

Copper-catalyzed intramolecular N-S bond formation by oxidative dehydrogenative cyclization

Copper-catalyzed synthesis of benzo[d]isothiazol-3(2H)-ones and N-acyl-benzothiazetidine by intramolecular dehydrogenative cyclization is described. In this reaction, a new nitrogen-sulfur (N-S) bond is formed by N-H/S-H coupling. The present reaction has

Preparation of benzisothiazolones from 2-bromobenzamides and sulfur under copper catalysis conditions

A convenient two-stage method has been developed for preparing benz[d]isothiazol-3(2H)-ones from 2-bromobenzamides and sulfur in a one-pot process under copper catalysis conditions. The method is suitable for the synthesis of N-aryl-, benzyl-, and alkyl-substituted benzisothiazolones. The yields of the benzisothiazolones depend on the nature of the starting amide and can reach 91%.

Benzisothiazolones arrest the cell cycle at the G2/M phase and induce apoptosis in HeLa cells

Anticancer activities of a series of benzisothiazolones having alkyl, aryl and aralkyl substituents on the nitrogen atom and the mechanistic basis of cytotoxicity are presented. Cellular responses like DNA laddering, disruption of mitochondrial membrane potential and caspase-3 activation on incubation of HeLa cells with representative compounds from this group suggested the induction of apoptosis through an intrinsic pathway. Their ability to arrest the cell cycle at the G2/M phase was confirmed by flow cytometric analysis.