Organoselenium compounds, an overview on the biological activities beyond antioxidant properties

For a long period, Selenium was considered mainly a toxic element and has been the object of disputes for its controversial balance between beneficial and toxic effects. Nowadays, many evidences demonstrated its role as essential microelement in mammalian diet, having an essential role in redox homeostasis of all the living systems. Around 25 proteins were discovered to contain a selenocysteine in place of the more common sulfureted amino acid and, in this protein, selenium has the main role in the catalytic center playing a key role in several major metabolic pathways such as thyroid hormone metabolism, antioxidant defense systems, and immune functions. Many studies report that selenium has a protective effect against some forms of cancer, cardiovascular disease mortality, regulates the inflammatory mediators in asthma, maintains bone homeostasis and protects against bone loss. Antioxidant activities of organoselenium compounds has been widely studied and discussed in a number of recent review articles. In this communication, taking inspiration from a number of recent publications, we want to highlight that other biological activities can be envisioned for organoselenium compounds deriving from the peculiar reactivity of this element. Introduction In the past, selenium has been the focus of disputes for its beneficial and toxic effects. Nonetheless, many evidences have shown that selenium is an essential element in the mammalian diet. More recently, environmental and dietary studies of both inorganic and organic compounds containing selenium, are back interest considering also the long-term effects of selenium in the human diet (Nogueira and Rocha, 2011). There are approximately 25 selenoproteins containing a selenocysteine at their active center. So, Se plays a key role in several major metabolic pathways such as thyroid hormone metabolism, antioxidant defense systems, and immune functions. Many studies report that selenium has a protective effect against some forms of cancer, cardiovascular disease mortality, regulates the inflammatory mediators in asthma, maintains bone homeostasis and protects against bone loss (Chua Tan et al., 2016). Selenium is essential for humans and animals for his role as antioxidant. This aspect has been widely studied and discussed. In literature are reported extensive evidences of the antioxidant selenium activity, this is the reason why the focus of this overview is centered in other health-effects of this element. Selenium biology and human health Selenium was discovered in 1817 by Bezellius. In 1957, Schwarz and Foltz discovered that selenium is an essential trace element, which prevents hepatic necrosis in the rats and in 1973 it was discovered that it is present in biological systems as selenocysteine, as part of glutathione peroxidase (GPx). These findings have influenced the opinion of the scientific community and many research groups developed efficient methodologies for the preparation of selenium-containing compounds (Ferandez-Lodeiro et al., 2014). In Nature, inorganic selenium can be found dissolved in water or soil as selenides, selenite and selenate whereas organic selenium containing compounds are generally present in the air, soil and plants as volatile derivatives: methylselenides, trimethylselenonium ions and different selenoamino acid (Pyrzynska, 2002). The 20th International Electronic Conference on Synthetic Organic Chemistry 1–30 November 2016 Selenium enters in the food chain through plants, that are the primary source of this exential microelement for mammalian. High level of Se concentration were reported in cereals and nuts and some of their not fully purified derivatives (Pophaly et al., 2014 , Achibat et al., 2015).The intake of Se varies hugely worldwide, ranging from deficient to toxic concentrations. The reason of the intake variability is related to the Se content of the soil and others factors that determine its availability in the food chain. These factors are: Se speciation, soil pH, organic matter content and the presence of ions that can make complexes with Se (Rayman, 2012). Selenium deficiency has been associated and proposed as cause for several human diseases such as Keshan disease and Kashin-Beck disease. Keshan disease is associated with low levels of selenium in soil and food in endemic area and has been demonstrated that the incidence of Keshan disease decreases significantly after selenium supplementation (Yakubov et al., 2014). The assimilation of selenium can be increased by some diet rich in low molecular weight proteins and some vitamins (especially vitamins B, C and D). The recommended intake of selenium varies depending on geographical regions. In consideration of the low selenium daily intake for some populations there is a supplementation of fertilizers with inorganic selenate. Selenium is characterized by a narrow safety range between deficiency and toxic doses and, for this reason, a deep investigation on the biological activity of the element and its organic derivatives is particularly challenging (Kieliszek and Blazejak, 2013). There are biochemical systems in which selenium replaces the sulfur, as in the case of amino acids cysteine and methionine, giving rise to the corresponding selenomethionine and selenocysteine (Achibat et al., 2015). In addition, Selenium is involved in metabolism of lipid hydroperoxides and hydrogen peroxide. It is an integral part of some enzymes, including iodothyronine deiodinases (ID), thioredoxin reductase (TRxR) and GPx (Kieliszek and Błażejak, 2013). GPx has a crucial role in protecting the organism against oxidative damage, in particular catalyzing the reduction of hydroperoxides using glutathione and other thiol cofactors regenerated by specific NADPH dependents reductase. After the synthesis of ebselen as lead compound endowed with GPx-like activity, numerous studies aimed to the development of small-organoselenium molecules having similar mimic action of GPx were reported. The compounds obtained for this purpose can be classified into some main categories like cyclic selenyl amides, diselenides, linear or cyclic selenides, vinyl selenides and so on. These compounds owe their activity to the reactivity of selenium-centers that is exploited in the oxidation of thiol mediated by peroxides (Bhabak and Mugesh, 2010). Mugesh and coworkers deeply investigated the GPx-like mechanism reporting a complex reaction mechanism involving ebselen and its analogues in the reduction of peroxides. Based on the evidence of some spectroscopy-based assays several different compounds were synthetized and proposed as GPx-like candidate. As an example, recently some of us synthesized new diselenides having antioxidant properties, superior to that displayed by ebselen thus suggesting their possible application as therapeutic drugs for the treatment of oxidative stress-related diseases (Nascimento et al., 2014). In the last years, the interest on Se supplementation in diet is increasing, consequently many food products enriched with selenium were developed. The developed functional foods are obtained by increasing the selenium concentration in soil (e.g. for for the biofortification), or using selenium as an additive. With these strategies, several selenium-enriched foods were proposed like potatoes, mushroom, onion, garlic and fermented food product. All these products respond mainly to a market request not fully supported by scientific evidences, especially in those areas, in which selenium is naturally present in the soil. Among these products probably the most interesting are those deriving from fermentation because this The 20th International Electronic Conference on Synthetic Organic Chemistry 1–30 November 2016 process (e.g. operated by lactobacteria) offers the possibility to transform inorganic selenium to some organic forms (Pophaly et al., 2014). The main effect of selenium on human health is the antioxidant activity. This property is reflected in the broader perspective considering that the pro-oxidant factors may favor the development of several diseases. In addition, oxidative stress may be involved in diseases such as Parkinson, Alzheimer, diabetes and atherosclerosis. In this regard organoselenium compounds could represent a new interesting instrument to reduce, control or prevent the damage produced by the reactive species of oxygen (Nogueira and Rocha 2011). Role of Selenium in Immune functions Many studies shown that poor Se intake weakens immune system, as example, there are studies on relationships between dietary Selenium and viral infections. In most cases, the selenium deficiency, results in genetic mutations that increase the virulence of the virus (Huang et al., 2013). Increased level in dietary Se in mice showed to boost signaling during T cell receptor (TCR) induced activation (Hoffmann et al., 2010). So, TCR signaling in CD4+ T-cells was enhanced with Se intake. Selenium supplementation has pronounced immune stimulant effects, including an enhancement of proliferation of activated T cells, increased lymphocyte-mediated tumor cytotoxicity, and natural killer cell activity. Furthermore Se promote differentiation of CD4+ T cells into T-helper-1 (Th1) rather than Thelper-2 (Th2) effector cells. This effect may reduce the Th2type immune responses that drive asthma while boosting Th1 response which is, in turn, required for antiviral and anticancer immunity (Rayman 2012, Huang et al., 2013). Many evidences suggest an important role of selenium in inflammatory response. Recent studies hypothesized that the supplementation may regulate inflammatory gene expression at the epigenetic level, such as the decreased acetilation of NFkB in primary and immortalized macrophages (Narayan et al., 2014). Previous studies have demonstrated that selenoproteins in macrophages down-regulate the inducible NO synthase, a pro-inflammatory gene, while other studies demonstrated that selenium supplementation polarizes macrophages towards anti-inflammatory phenotypes (Nelson et al., 2011). Antimicrobial activity of some organoselenium compounds: During the last ten years a large variety of selenium derivatives were designed and tested as antimicrobial agents and their activity was confirmed with in vivo and in vitro assay against a broad range of microorganisms, included bacteria and fungi (Braga et al., 2010; Alberto et al., 2011; Vargas et al., 2012) The bacterial resistance to antibiotics and the strong needs of new strategies and new drugs to contrast this world problem pushed the research to test know drugs or known biologically active compounds on new targets. An example is the idea of the repositioning of ebselen (compound 1, Fig 1) and its derivative ebselen oxide (compound 2, Fig.1) that demonstrated to inhibit the biofilm formation and motility in Pseudomonas aeruginosa ( Lieberman et al.,