**2. Mimics and models of glutathione peroxidase**

### **2.1 Ebselen analogues as GPx mimics/models**

Synthetic selenium compounds with significant GPx activity have potential therapeutic applications (**Figure 3**). The first synthetic compound that has been shown to mimic the GPx activity was ebselen ([2-phenyl-1,2-benzisoselenazole-3)-(2*H*)-one] (**1**) [40–43]. Furthermore, the synthesis of such compounds may help in understanding the chemistry at the active site of GPx. The initial success of ebselen was mainly due to its very low toxicity and high stability of the selenazole moiety does

**Figure 3.** *Some representative examples of Ebselen analogues as GPx mimics.*

not allow the elimination of selenium during the biotransformations. Therefore, the selenium metabolism of this compound does not interfere with the organism and as a result ebselen used in clinical trials for the treatment of patients suffering from active ischemia stroke.

In literature there were a several animal model studies have demonstrated that ebselen reduces oxidative stress in ischemia-reperfusion in heart and that it exhibits promising neuroprotective effect in brain. In addition to this, ebselen can be toxic to cells suggested in recent evidences. It has been shown that ebselen inhibits certain cell growth and induces apoptosis. However, the mechanism underlying the toxicity of ebselen is not known, the cellular glutathione (GSH) level appears to be depleted by ebselen. The GSH depletion increases the susceptibility of cells to oxidant injury as the reduced GSH is important for cell survival.

After the discovery that ebselen exhibits significant antioxidant activity by mimicking the active site of GPx, much attention has been devoted to the design and synthesis of novel analogues of ebselen. The ebselen homolog **2**, tetrahedral carbon is incorporated into the heterocycle, retains the Se-N bond essential for the GPx activity. The selenazole model system **3** has been used extensively to understand the antioxidant redox chemistry of selenocysteine at the active site of GPx and several such compounds has been synthesized and evaluated for its GPx activity (**Figure 4**) [44].

According to this mechanism the corresponding selenenyl sulfide is mainly the reaction of ebselen **1** with a thiol (RSH). The obtained intermediate compound is found to be unstable in the assay system, and therefore, undergoes a disproportionation reaction to generate the stable diselenide. Subsequent reaction of with peroxide produces the selenenic acid and seleninic acid. During this mechanism when RSH is depleted in the reaction mixture, the seleninic acid and interestingly, the selenenic acid having a free N-H moiety undergoes cyclization to regenerate ebselen1 [45].

Back and co-workers [46], reported the catalytic cycle of di(3-hydroxy-propyl) selenide **9** and acts an efficient catalyst for the reduction of t-BuOOH in the presence of BnSH. The compound **9** involves the formation of an unusual spirodioxyselenurane

**Figure 4.** *Proposed catalytic cycle of ebselen and related compounds [45, 46].*

*Functional Mimics of Glutathione Peroxidase: Spirochalcogenuranes, Mechanism and Its… DOI: http://dx.doi.org/10.5772/intechopen.102430*

**10**. The oxidation of compound **9** with t-BuOOH produces the transient selenoxide **10**, which undergoes a spontaneous cyclization to produce the dioxyselenurane **11** isolated compound structure was confirmed by spectroscopic methods and single X-ray crystallography.

The reaction of **11** with BnSH produces an intermediate **12**, which upon reaction with second equivalent of BnSH regenerates the selenide **9** with elimination of BnSSBn (**Figure 5**). When t-BuOOH is present in the reaction mixture, compound **10** is recyclized to compound **11**. Although the reactivity of compound **9** was only about 15times higher than that of ebselen under indentical condition, the catalytic mechansium involves the formation of an unusual spiro compound [47].
