No abstract

The advance in the area of synthesis and reactivity of organoselenium, as well as the discovery that selenium was the cause of severe intoxication episodes of livestock in the 1930s and the subsequent determination that selenium was an essential trace element in the diet for mammals, has motivated intense studies of the biological properties of both organic and inorganic selenium compounds. In this review, we shall cover a wide range of toxicological and pharmacological effects, in which organoselenium compounds are involved but the effects of inorganic compounds were not discussed in detail here. The molecular toxicity of inorganic selenium was described in relation to its interaction with endogenous -SH groups to allow a comparison with that of synthetic organoselenium compounds. Furthermore, in view of the recent points of epidemiological evidence that overexposure to selenium can facilitate the appearance of chronic degenerative diseases, we also briefly revised the history of selenium toxicity and physiology and how environmental selenium can reach inside the mammalian cells. The biological narrative of the element selenium, in the last century, has been marked by a contrast between its toxic and its beneficial effects. Thus, the potential therapeutic use of simple organoselenium compounds has not yet been sufficiently explored and, consequently, we cannot discard this class of compounds as promising pharmaceutical agents. In effect, the future of the organochalcogens as pharmacological agents will depend on more detailed toxicological studies in the oncoming years.

The aim of this study was to investigate the effect of Krebs cycle intermediates on basal and quinolinic acid (QA)- or iron-induced TBARS production in brain membranes. Oxaloacetate, citrate, succinate and malate reduced significantly the basal and QA-induced TBARS production. The potency for basal TBARS inhibition was in the order (IC50 is given in parenthesis as mM) citrate (0.37) > oxaloacetate (1.33) = succinate (1.91) > > malate (12.74). alpha-Ketoglutarate caused an increase in TBARS production without modifying the QA-induced TBARS production. Cyanide (CN-) did not modify the basal or QA-induced TBARS production; however, CN- abolished the antioxidant effects of succinate. QA-induced TBARS production was enhanced by iron ions, and abolished by desferrioxamine (DFO). The intermediates used in this study, except for alpha-ketoglutarate, prevented iron-induced TBARS production. Oxaloacetate, citrate, alpha-ketoglutarate and malate, but no succinate and QA, exhibited significantly iron-chelating properties. Only alpha-ketoglutarate and oxaloacetate protected against hydrogen peroxide-induced deoxyribose degradation, while succinate and malate showed a modest effect against Fe2+/H2O2-induced deoxyribose degradation. Using heat-treated preparations citrate, malate and oxaloacetate protected against basal or QA-induced TBARS production, whereas alpha-ketoglutarate induced TBARS production. Succinate did not offer protection against basal or QA-induced TBARS production. These results suggest that oxaloacetate, malate, succinate, and citrate are effective antioxidants against basal and iron or QA-induced TBARS production, while alpha-ketoglutarate stimulates TBARS production. The mechanism through which Krebs cycle intermediates offer protection against TBARS production is distinct depending on the intermediate used. Thus, under pathological conditions such as ischemia, where citrate concentrations vary it can assume an important role as a modulator of oxidative stress associated with such situations.

Here, we addressed the pharmacology and toxicology of synthetic organoselenium compounds and some naturally occurring organoselenium amino acids. The use of selenium as a tool in organic synthesis and as a pharmacological agent goes back to the middle of the nineteenth and the beginning of the twentieth centuries. The rediscovery of ebselen and its investigation in clinical trials have motivated the search for new organoselenium molecules with pharmacological properties. Although ebselen and diselenides have some overlapping pharmacological properties, their molecular targets are not identical. However, they have similar anti-inflammatory and antioxidant activities, possibly, via activation of transcription factors, regulating the expression of antioxidant genes. In short, our knowledge about the pharmacological properties of simple organoselenium compounds is still elusive. However, contrary to our early expectations that they could imitate selenoproteins, organoselenium compounds seem to have non-specific modulatory activation of antioxidant pathways and specific inhibitory effects in some thiol-containing proteins. The thiol-oxidizing properties of organoselenium compounds are considered the molecular basis of their chronic toxicity; however, the acute use of organoselenium compounds as inhibitors of specific thiol-containing enzymes can be of therapeutic significance. In summary, the outcomes of the clinical trials of ebselen as a mimetic of lithium or as an inhibitor of SARS-CoV-2 proteases will be important to the field of organoselenium synthesis. The development of computational techniques that could predict rational modifications in the structure of organoselenium compounds to increase their specificity is required to construct a library of thiol-modifying agents with selectivity toward specific target proteins.

Este artigo de revisão aborda uma reflexão sobre o potencial terapêutico ou tóxico de compostos orgânicos de selênio, dando particular ênfase ao disseleneto de difenila e alguns dos seus análogos estruturais. Algumas características moleculares relacionadas com a toxicidade e farmacologia do disseleneto de difenila in vitro e in vivo são abordadas. Os artigos revisados, que abordam experimentos in vivo, indicam que a interação do disseleneto de difenila com tióis pode determinar seu potencial farmacológico ou toxicológico. Além disso, uma limitada ativação da rota de toxicidade, isto é, a oxidação controlada de moléculas de alto peso molecular, que contém grupos tióis, poderia contribuir para os efeitos farmacológicos do disseleneto de difenila. Concluise que a síntese de compostos orgânicos de selênio deve ser direcionada para o desenvolvimento de novos disselenetos de diorganoila que possam interagir com alvos moleculares específicos.In this review, we summarized the potential role of synthetic organoseleno compounds as therapeutic or toxic agents, giving emphasis almost exclusively to diphenyl diselenide, the simplest of the diaryl diselenides, and some of its analogs. We presented the main molecular aspects related to the in vitro toxicity and pharmacology of diphenyl diselenide and also provided in vivo data indicating that the interaction of diphenyl diselenide with thiols can dictate either its toxicological or pharmacological property. The papers covered in this review indicate that a limited activation of the "toxic pathway", i.e., a controlled oxidation of specific high molecular weight thiol-containing molecules could contribute to the pharmacological effects of diphenyl diselenide. In conclusion, this review reinforces the necessity of developing new diorganoyl diselenides that could interact with specific molecular targets.