Antioxidants and antiinflammatory agents

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Ebselen

Reactive oxygen species (ROS) are involved in many biological processes including the inflammatory response. ' ' Ebselen (2-phenyl-1,2-benzisosele-nazol-3(2H)-one) (1) is an anti-oxidant and anti-inflammatory that has undergone Phase III clinical trials as a neuroprotective agent and is soon to become the first synthetic organoselenium therapeutic released on the market. Selenium is not liberated from Ebselen 1, and as such it is relatively non-toxic. The anti-inflammatory action of Ebselen 1 is attributed to its ability to interfere with a number of pathways to inflammation, either through its anti-oxidant capacity or through direct inhibition of enzymes.1,72,73

Ebselen 1 catalytically reduces peroxynitrite, a strong oxidant that is involved in inflammation.74 78 Peroxynitrite is formed from the reaction of nitric oxide with superoxide. Under physiological conditions peroxynitrite can lead to the formation of highly reactive 'NO2 and 'OH radical species. A recent study found that Ebselen 1 was a potent inhibitor of nitric oxide-induced apoptosis, possibly through generation of the Ebselen oxide after reaction with peroxynitrite.79 This study suggested that the Ebselen oxide can inactivate a key regulator of apop-tosis, the protein kinase JNK1, by oxidizing the sulfhydryl moiety.79

Figure 17.2 Ebselen - mechanism of GPx-like activity

Ebselen 1 acts as a GPx mimic by reducing hydroperoxides to water or the corresponding alcohol (Figure 17.2).72 There are a number of mechanisms proposed for this process. When the concentration of the thiol exceeds that of the hydroperoxide, Ebselen 1 first reacts with thiol to generate a selenol 2. This can then reduce hydroperoxides to yield seleninic acid 3, which, after loss of water, regenerates Ebselen 1.72,80 Evidence of the formation of selenol 2 was found by trapping with 1-chloro-2,4-dinitrobenzene and inhibition of activity by iodoacetate.81 83 An alternate mechanism appears to operate when hydroperoxide concentrations are higher, whereby Ebselen 1 is first oxidized by hydroperoxide to the oxide 4 before regeneration of Ebselen 1 by two equivalents of thiol.72,80 It is noteworthy that the sulfur analogue of Ebselen 1 is inactive and compounds such as 5, lacking direct Se—N bonds, are also inactive.80,84,85 Numerous compounds have been prepared as potential GPx mimics that contain Se—N bonds, and are discussed in an excellent review.1

Recent work by Zhao and Holmgren demonstrates that Ebselen 1 is also able to catalytically reduce hydroperoxides through reaction with the Trx system86 (Figure 17.3). Ebselen 1 is a substrate for TrxR and a rapid oxidant of reduced thioredoxin. Selenol 2 can be formed directly by TrxR/NADPH or from reaction with reduced Trx. Selenol 2 rapidly reduces hydroperoxides to form seleninic acid 3. Ebselen 1 is regenerated after spontaneous loss of water.86 Comparison of the interaction of Ebselen 1 with the Trx system and GSH showed that the rate of reduction of hydrogen peroxide was eight times higher with TrxR (50 nM) than GSH (1 mM). When the complete TrxR/Trx system was tested the hydrogen peroxide reductase activity of Ebselen 1 increased 13-fold.86 Given the ubiquitous nature of the Trx system this work suggests that much of the hydroperoxide-reducing ability of Ebselen 1 could result from the interaction between the two.

TrxR

NADPH

NADP+

Figure 17.3 Ebselen - interaction with TrxR/Trx system o

N-Ph

NHPh

Trx-S2

TrxR

NADPH

NADP+

Figure 17.3 Ebselen - interaction with TrxR/Trx system

The role of hydroperoxides in inflammation is well known. Hydroperoxides are essential for the activation of inflammatory enzymes known as the lipoxygenases (LOX) and cyclooxygenases (COX).17,87 Of the lipoxygenases, 5-LOX is considered to be critical to inflammation as it catalyses the biosynthesis of pro-inflammatory leukotrienes from arachidonic acid.88 LOX and COX are attractive targets for inhibition in the pursuit of novel anti-inflammatories.1 The capacity for Ebselen 1 to act as a LOX inhibitor is critical to its antiinflammatory activity. The inhibition of LOX by Ebselen 1 may be as a result of its anti-oxidant activity or through the direct interaction of Ebselen 1 and LOX.

Other anti-oxidants and anti-inflammatories

The efficacy of Ebselen 1 is somewhat limited by its poor solubility in water. In the pursuit of preparing GPx mimics with increased water solubility, Liu and co-workers prepared ^-cyclodextrins with an Ebselen 1 moiety tethered to the primary ring such as 6.89 These compounds had excellent aqueous solubility and cyclodextrin 6 displayed GPx activity on par with that of Ebselen 1.89

Engman and colleagues prepared the selenium analogue 7a of a known 5-LOX inhibitor, 2-benzyl-1-naphthol 7b.90 Phenylselenenyl-1-naphthol 7a showed no anti-oxidant activity in the presence of hydrogen peroxide and a thiol. In a lipid peroxidation model, anti-oxidant activity was poorer than the parent compound.

However, the selenium analogue 7a was a fivefold more potent inhibitor of leukotriene B4 synthesis than the parent and consequently a potentially efficient anti-inflammatory.90

Several research groups including those of Engman and Schiesser have prepared selenium-containing analogues of a number of biologically relevant anti-oxidants including tocopherols91,92 and carbohydrates93 in a bid to increase the solubility (and thus, efficacy). Recently Back and Moussa have prepared some interesting cyclic seleninate esters 8 that have GPx-like activity.94,95 The

Figure 17.4 Cyclic seleninate ester 8 - generation and mechanism of GPx-like activity

cyclic seleninate 8 was generated in situ from allyl-3-hydroxypropyl selenide 9 or (Figure 17.4). After oxidation of allyl selenide 9 with t-butylhydroperoxide the generated oxide 10 underwent a [2,3] sigmatropic rearrangement. Further oxidation and cyclization gave the cyclic seleninate ester 8.94,95 Seleninate ester 8 is believed to be the species acting as the GPx mimic. Reaction with two equivalents of thiol gives the seleninic acid 11 which is able to reduce the hydroperoxide to regenerate the cyclic seleninate ester.94,95 Using the t-butyl-hydroperoxide and benzyl thiol model, to test for GPx-like activity, cyclic seleninate ester 8 had substantially higher catalytic activity than Ebselen 1.94 Perhaps compounds containing a Se—O heterocycle merit the level of attention given to Se—N-containing compounds.

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