[비가역적 GST 억제제/Irreversible GST Inhibitor] CNBSF [FDV-0031][CAS No. 3829-23-0]_Funakoshi - 코아사이언스

CNBSF

Irreversible GST Inhibitor

Cat.# FDV-0031 / Size: 10 mg

 

Background 

Glutathione S-Transferases (GSTs) are widely conserved in nature from bacteria to plants and animals. In human, over 20 members are identified and classified into three subfamilies cytosolic including seven classes alpha, mu, omega, pi, theta and zeta, mitochondrial and membrane bound microsomal members. GSTs play important roles in detoxification of endogenous toxic metabolism or xenobiotics through converting them to glutathione (GSH) conjugates.

Generally GSTs have two types of binding site, called G-site and H-site, for GSH and hydrophobic substrate, respectively. When GSTs bind to GSH, GSTs catalyze and stabilize thiolate anion of GSH. Once hydrophobic substrates binds to GSTs, GSTs transfer them to GSH to form GST conjugates. GST conjugates are quickly exported to extracellular space by multidrug resistance associated protein (MRP) transporters. Through the above processes, GSTs detoxify toxic compounds.
On the other hand, GSTs also neutralize pharmaceutical drugs via its detoxifying processes.

As many studies suggested expression level of GSTs are significantly increased in cancer cells, GSTs are considered as anticancer-resistant enzymes in cancer cells. Inhibition of GST activities is one of the promising strategy to improve drug efficiency in cancer cells. Some GST inhibitors have been developed so far, however, conventional inhibitors including ethacryic acid (EA), a representative GST inhibitor, were based on the competition with GSH. In general, competitive inhibitors are usually reversible and not sufficient in cells because of high concentration around mM order of GSH in cells. Although several irreversible inhibitors were also discovered and show potent inhibition in vitro, these compounds have low membrane-permeability and are not good at live cell experiments. To overcome conventional problems, highly membrane-permeable and irreversible inhibitors are desired. 

2-chloro-5-nitrobenzensulfonyl fluoride (CNBSF) is a novel type of irreversible GST inhibitor reported by Dr. Hiroshi Abe, Nagoya University, and co-workers (Ref.1). CNBSF is membrane-permeability and capable of entering into cytosol. Once CNBSF incorporated into cell, GSTs catch CNBSF in H-site as a hydrophobic xenobiotics. Subsequently GSTs convert CNBSF to GSH-conjugated CNBSF, called GS-5NBSF. In the case of GSTP1, a member of pi-type GST, Tyr108 residue in GSTP1 quickly reacts with sulfonyl fluoride group of GS-5NBSF, fluoride anion was leaved, and form covalent bound between GST and substrate. In the result of above scheme, GSTs covalently bound inhibitor-complex are inactivated.

 

Features 

・Membrane permeable
・Irreversible
・Long-term inhibition
・Higher inhibitory activity compared to conventional GST inhibitor; Ethacrynic Acid
・Considered to work for wide types of GST family
・Covalently binds to endogenous GST (GSTP1-1) (See Fig.4)

 

Specification 

Formulation C6H3ClFNO4S
CAS No. : 3829-23-0
Molecular weight : 239.6 g/mol
Solubility : Soluble in DMSO
Recommended concentration
For cell based experiments : 1 mM
For in vitro experiments : 0.1-1 mM
*The actual concentration should be optimized by yourself.

 

References 

1. Shishido, Y., et al., ChemBioChem. , 20 , 900 905 (2019)
"A covalent inhibitor for Glutathione S-Transferase Pi (GSTP1-1) in human cells."

 

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