2514-30-9 Usage
Description
2 (4 Methylphenyl) 1,2 benzisothiazol 3(2H)-one, also known as PBIT, is a reversible, cell-permeable inhibitor of JARID1 family demethylases. It is effective in removing methyl groups from trimethylated lysine 4 on histone 3 (H3K4me3) and does not significantly affect the activity of UTX and JMJD3 demethylases. PBIT increases trimethylation of H3K4 in HeLa cells and blocks the proliferation of tumor cells expressing high levels of JARID1B.
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
Check Digit Verification of cas no
The CAS Registry Mumber 2514-30-9 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 2,5,1 and 4 respectively; the second part has 2 digits, 3 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 2514-30:
(6*2)+(5*5)+(4*1)+(3*4)+(2*3)+(1*0)=59
59 % 10 = 9
So 2514-30-9 is a valid CAS Registry Number.
2514-30-9Relevant articles and documents
Potassium bromide catalyzed N[sbnd]S bond formation via oxidative dehydrogenation
Yu, Tian-Qun,Hou, Yong-Sheng,Jiang, Yi,Xu, Wen-Xuan,Shi, Tao,Wu, Xia,Zhang, Jin-Chao,He, Dian,Wang, Zhen
, p. 2084 - 2087 (2017)
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.
Domino Reactions Initiated by Copper-Catalyzed Aryl-I Bond Thiolation For the Switchable Synthesis of 2,3-Dihydrobenzothiazinones and Benzoisothiazolones
Xiong, Jin,Zhong, Guofeng,Liu, Yunyun
supporting information, p. 550 - 555 (2018/12/14)
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.).
Ebsulfur as a potent scaffold for inhibition and labelling of New Delhi metallo-β-lactamase-1 in vitro and in vivo
Su, Jianpeng,Liu, Jiayun,Chen, Cheng,Zhang, Yuejuan,Yang, Kewu
supporting information, p. 192 - 201 (2018/12/02)
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.
