Catalytic application of selenium and tellurium compounds as glutathione peroxidase enzyme mimetics

Review J. Braz. Chem. Soc., Vol. 21, No. 11, 2032-2041, 2010. Printed in Brazil - ©2010 Sociedade Brasileira de Química 0103 - 5053 $6.00+0.00 Catalytic Application of Selenium and Tellurium Compounds as Glutathione Peroxidase Enzyme Mimetics Eduardo E. Alberto,*,a Vanessa do Nascimentob and Antonio L. Braga*,b a Department of Chemistry, Federal University of Santa Maria, Santa Maria-RS, Brazil Department of Chemistry, Federal University of Santa Catarina, Florianópolis-SC, Brazil b A glutationa peroxidase (GPx) é uma importante enzima que faz parte do sistema de defesa do organismo frente a substâncias nocivas formadas durante o metabolismo do oxigênio, como peróxidos e seus derivados. Diversas estratégias para desenvolver novos miméticos, assim como para aumentar a atividade mimética da GPx em compostos como disselenetos, selenetos e teluretos, vêm sendo propostas nos últimos anos. Nesta revisão é apresentado um balanço, dos últimos dez anos, referente ao desenvolvimento e à avaliação de catalisadores organoselênio ou organotelúrio capazes de mimetizar a atividade da GPx. Diferentes mecanismos de ação destes compostos também são apresentados, de acordo com os novos avanços desta relevante área de pesquisa. This review covers the past decade of intensive research on the design, synthesis and screening of organoselenides and tellurides as catalyst able to mimic the activity of the selenoenzyme glutathione peroxidase (GPx). This important enzyme forms part of the detoxification system in humans which deals with harmful peroxides and their byproducts formed during oxygen metabolism. Several strategies to enhance the GPx-like activity of compounds such as diselenides, selenides and tellurides have been proposed in recent years. Different mechanisms of action of these compounds are also presented in this review highlighting new advances in this exciting research field. Keywords: glutathione peroxidase (GPx), selenoenzyme, mimetic, selenium, tellurium, selenides 1. Introduction Interest in organochalcogen compounds has been growing since the 1970s, when many reports described the identification of various selenoproteins, which are involved in a widely number of mammals’ biochemistry mechanisms.1 Synthetic developments and the design of new organoselenium compounds have been attracting considerable attention, particularly due to their ability to mimic natural compounds with important biological properties (e.g., antioxidant, antitumor, anti-inflammatory and anti-infective activity).2 Selenoenzymes constitute important mammalian antioxidant enzymes which protect biomembranes and other cellular components from oxidative stress. The oxidative stress is associated to the activity of peroxides and byproducts derived from them, which are produced *e-mail: during the metabolism of oxygen in aerobic cells.3 These substances are known as reactive oxygen species (ROS) and are harmful substances, which destroy key biological components and cause damage to cell membranes. Several diseases, including neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease and other physiological and inflammatory processes are linked to the activity of ROS.4 As part of a complex and sophisticated detoxification system, the enzyme glutathione peroxidase (GPx) plays a pivotal role catalyzing the reduction of hazardous peroxides and their byproducts to water or alcohols.5 The most important amino acid in the active site of the enzyme is L-selenocysteine 1 which is responsible for reducing hydroperoxides at the expense of the tripeptide glutathione GSH 2.6 The ability that the enzyme has to promote the reduction of peroxides lies in the redox properties of the selenol moiety of L-selenocysteine, the catalytic cycle of GPx is Vol. 21, No. 11, 2010 O HSe 2033 Alberto et al. O OH O HO NH2 N H NH2 1 SH H N O OH O 2 Figure 1. L-selenocysteine 1 and glutathione 2. shown in Scheme 1. Initially, the selenol functionality in the enzyme E–SeH 3 reacts with a peroxide molecule to generate the corresponding alcohol or water and selenenic acid E–SeOH 4. The latter then reacts with one equivalent of glutathione to produce water and the corresponding selenenyl sulfide E–Se–SG 5. The last step is the reaction of glutathione with selenenyl sulfide producing the oxidized glutathione (GSSG) and regenerating the reduced enzyme 3 to resume the catalytic cycle.7 E SeH GSSG ROOH 3 GSH ROH to their well-known ability to undergo two-electron redox cycle between chalcogen (II) and (IV) species.8 Although a wide range of structurally diverse organoselenides and tellurides have been investigated by several groups over the past forty years,9 the aim of this manuscript is to cover the latest contributions in the field of new organoselenium and organotellurium compounds designed for pronounced glutathione peroxidase like catalytic activity. 2. Catalytic Application of Chalcogen Compounds as Glutathione Peroxidase Enzyme Mimetics 2.1. Organoselenium compounds The first synthetic molecule found to be able to mimic the GPx activity was the compound known as ebselen 6, Figure 2. This heterocyclic compound exhibits anti-inflammatory, anti-atherosclerotic and cytoprotective properties with relatively low toxicity.10 Because of these properties, ebselen is used as a standard for comparison with selenium compounds in terms of GPx like activity. O E SeOH E Se SG 5 N Se 4 6 H2O N R Se O GSH O NHR 7a: R = Me 7b: R = i-Pr 7c: R = Ph O R Se N 8a: R = Me 8b: R = CO2Et 8c: R = Ph Scheme 1. Redox cycle of GPx. Figure 2. Ebselen 6 and its derivatives 7a-c and 8a-c. The total process consists of the reduction of one equivalent of a reactive oxygen species at the expense of two equivalents of glutathione, producing two equivalents of water (when R = H) and oxidized glutathione (GSSG) Scheme 2. However, the exact mechanism of its activity has not been elucidated, and this topic is subject of continuous research. Furthermore, its poor solubility in water remains a problem for optimal therapeutic development. In order to enhance its solubility and to increase its activity, research has been focused on the modification of the structure of ebselen. Several structural modifications, including substituent effects and isosteric replacement, have been proposed over the years.11 Recently, Singh et al.12 have proposed the synthesis and evaluation of ebselen derivatives 7a-c, Figure 2. With exception of compound 7a, these compounds possessing an ortho-coordinating amide group are more active as a GPx mimic than the parent ebselen.12 The enhanced activity of these derivatives is attributed to the intramolecular nonbonding interactions between the oxygen of the amide moiety and selenium. These findings are supported by the elucidation of the crystal X-ray structure of the tested ROOH 2 GSH ROH GSSG H2O GPx (cat) R = H or alkyl Scheme 2. Global reaction of GPx like. Since the discovery that seleniu (...truncated)