Description
Ebselen is one of the selenium-containing anti-inflammatory drugs.In 2003, Rocha and co-workers identified diselenides as a new class of antiinflammatory agents.In 2014, Nogueira and co-workers reported the synthesis and anti-inflammatory activity of salicyclic-based diselenides and selenocynates.Recently, Wilhelm and co-workers identified 4-phenylselenyl-7-chloroquinoline 270 as a potent antiinflammatory compound.
Chemical Properties
yellow to beige crystalline powder
Uses
antioxidant, lipoxygenase inhibitor, inhibits oxidation of LDL
Uses
Ebselen is a lipid-soluble organoselenium compound. Numerous in vivo experiments have demonstrated that ebselen is able to inhibit both vasospasm and tissue damage in cerebral stroke/ischemia animal models (i.e. rat, mice, guinea pig and dog).For example, ebselen has been shown to provide significant protection against ischemic damage in both gray and white matter, and in the ventral posterior nucleus of rodent brains.Additionally, administration of ebselen in gerbils significantly reduces neuronal death induced by ischemia and reperfusion in the hippocampal CA1 region.It has been reported that ebselen inhibits inositol monophosphatase and acts as a safe treatment for bipolar disorder.
The optimal GPx-like activity of ebselen was observed at neutral or nearphysiological pH (7.4), and the activity of ebselen was barely detected in acidic medium.During ischemia, brain pH falls rapidly within the first 5 min from 7.0 to 6.2, which is not optimal for ebselen's GPx-like activity.Meanwhile, since ebselen has shown promising activity in the treatment of stroke, it seems that GPx-like activity of ebselen in the brain may not occur.Thus, the enzymatic reduction of ebselen by TrxR might be the main contribution to its antioxidant property during ischemia. Unlike inorganic and aliphatic selenium compounds, ebselen does not liberate the selenium moiety, which remains within the ring structure. Subsequent metabolism involves methylation, glucuronidation and hydroxylation. Additionally, ebselen could also inhibit enzymes such as lipoxygenases, nitric oxide synthases, nitrogen oxides, protein kinase C and H1/K1-ATPase.
Besides the relationship with redox systems, another neuroprotective mechanism of ebselen is involved in controlling the expression of gaminobutyric acid shunt enzymes to supply the tricarboxylic acid cycle, and significantly inhibiting acetylcholinesterase activity,demonstrating its engagement in the metabolic system.
Uses
2-Phenyl-1,2-benzoselenazol-3-one acts as an antiinfammatory compounds,, in addition to that it acts as a modulator of KVβ subunits.
Definition
ChEBI: A benzoselenazole that is 1,2-benzoselenazol-3-one carrying an additional phenyl substituent at position 2. Acts as a mimic of glutathione peroxidase.
Reactions
Ebselen is a substrate for mammalian TrxR and can be converted to ebselen selenol by consuming NADPH.The reduction reaction acts with an apparent KM value of 2.5 mM and a kcat of 588 min-1. Oxidants such as H2O2 react with ebselen selenol to produce ebselen selenenic acid (EbSeOH), and spontaneously produce H2O and ebselen to form a redox cycling mechanism for ebselen.
Upon the addition of Trx to TrxR, NADPH and ebselen, the reaction rate increases several-fold. This may be achieved by a very fast oxidation of reduced Trx by ebselen at a reaction rate constant42107 M1 s1.This rate is orders of magnitude faster than the reaction of reduced Trx with a substrate such as insulin disulfides. Thus, ebselen can compete with disulfide substrates for the reduction by Trx. These results indicate that ebselen can serve as a mediator in the redox environment via the Trx system.
General Description
Ebselen is a sympathomimetic amine.
Biochem/physiol Actions
Ebselen, a glutathione-peroxidase-mimic, elicits anti-inflammatory activity. It also has anti-atherosclerotic functionality. Ebselen displays antibacterial action on) multidrug-resistant Staphylococcus aureus (MRSA) infections and could be a potential therapeutic target for treating MRSA based skin infection. It is regarded as neuroprotective agent and elicits chemopreventive functionality in inflammation-associated carcinogenesis.
Clinical Use
Ebselen and its analogs have also been shown to be inhibitors of Bacillus anthracis TrxR. The ebselen analogs displayed antibacterial activity on Bacillus subtilis, S. aureus, Bacillus cereus and M. tuberculosis. There existed a high resistance barrier for the bacteria to develop ebselen-resistant strains and isolating resistant mutants was found to be difficult and, ultimately, unsuccessful.28 The reason for the difficulty of developing ebselen-resistant bacteria may be because ebselen has exerted a multiple drug-target mechanism, although the exact mechanism is not yet known. In addition to the thioredoxin and GSH systems, ebselen has been reported to have some other potential targets in bacteria, which may help it to overcome the bacterial drug resistance. Ebselen was identified as an inhibitor of diguanylate cyclases by a high-throughput screening in another study by covalent binding to Cys residues.29 This may block the cyclic-di-GMP signaling pathway, regulating biofilm formation, flagella-mediated motility in Pseudomonas aeruginosa, and thus its pathogenesis. Ebselen was identified as an inhibitor of the cysteine protease domain (CPD) in the Clostridium difficile major virulence factor toxin B (TcdB) by another high-throughput screening study.
A CPD can bind with one or two ebselen molecules with a covalent modification probably occurring at the active site Cys. The treatment of ebselen blocked the toxic effects of TcdB and the pathology of C. difficile infection in mice.30 Another study also indicated that ebselen is a potent inhibitor of the M. tuberculosis Ag85 complex by binding covalently to a Cys residue (C209) located near the Ag85C active site, which is central to the synthesis of major components of the inner and outer leaflets of the mycobacterial outer membrane.
Synthesis
There are three main methods for the synthesis of Ebselen:.
A. N-phenylbenzamide was used as the starting material, and the C-Li bond was generated by lithiation of its neighbors through n-BuLi, then Se atoms were allowed to insert into the C-Li bond to form a double anionic compound, and finally ebselenium was obtained by oxidizing the ring closure with a suitable oxidizing agent. The ring-closing yield was lower than 20% when Br2 or I2 was used as the oxidizing agent, which was increased to 42% when FeCl3 was used, and further increased to 63% when CuBr2 was used.
B. Using 2,2-diselenobisbenzoic acid as the starting material, a multi-step reaction was carried out to obtain substituted 2-methylselenylbenzamide, which was then subjected to ring-closing and hydrolysis by PCl5 to obtain ebselenium.
C. Lesser and Kamigata et al. used 2,2-diselenobisbenzoic acid as the starting material, and the diselenide bond was cleaved by SOCl2 to form intermediate 3, and then reacted with aniline to obtain ebselen by ring-closing.
References
[1] Molecular actions of ebselen – an anti-inflammatory antioxidant
[2] M PARNHAM H S. Ebselen: prospective therapy for cerebral ischaemia.[J]. Expert opinion on investigational drugs, 2000, 9 3: 607-619. DOI:
10.1517/13543784.9.3.607[3] HIROSHI MASUMOTO . Kinetic study of the reaction of ebselen with peroxynitrite[J]. FEBS Letters, 1996, 398 2: Pages 179-182. DOI:
10.1016/s0014-5793(96)01237-9[4] Ebselen, a glutathione peroxidase mimetic seleno-organic compound, as a multifunctional antioxidant. Implication for inflammation-associated carcinogenesis
