Current Organic Chemistry - Volume 20, Issue 2, 2016

Electrophilic Selenium, Sulfur and Tellurium reagents are widely applied in a number of chemo, regio and stereospecific transformations for the installation of new functional groups in organic electron rich substrates as well as the synthesis of heterocyclic scaffolds. The most recent review articles are here currently updated demonstrating the continuously growing interest in this kind of reagents.

The review describes reactions of selenium and tellurium halides with alkenes and alkynes leading to useful organochalcogen compounds with main focus on the literature of last decade. The reactions of selenium dichloride and dibromide - new electrophilic reagents, which have been recently introduced in organic synthesis, along with the reactions of "classic" electrophilic reagents selenium and tellurium tetrahalides are discussed. The application of selenium dihalides in the last decade allows carrying out a series of previously unknown efficient reactions, which provide a variety of useful products including novel heterocyclic compounds. As a rule, reactions of selenium dihalides with alkynes proceed as anti-addition to give anti-Markovnikov products, whereas reactions of tellurium tetrahalides with alkynes occur in most cases as syn-addition to give Markovnikov products. However, there are exceptions to the rules, which are discussed in the review. For example, reactions of tellurium tetrahalides with acetylene proceed as anti-addition. Addition of selenium dihalides to alkenes gives Markovnikov products or a mixture of Markovnikov and anti-Markovnikov products. The formation of Markovnikov thermodynamic products in this case is the result of rearrangement of initial formed anti-Markovnikov kinetic products. The trends of reactions of selenium dihalides with alkenes and alkynes can be rationalized by assuming the formation of seleniranium and selenirenium intermediates. Stereoselective syn-addition of tellurium tetrachloride to alkynes apparently proceeds via a mechanism involving the 4-membered transition state.

This review presents synthetic procedures applied to the preparation of chiral (mainly optically active) hypervalent chalcogenuranes. The stereoisomerization mechanisms of hypervalent derivatives of sulfur, selenium and tellurium and their selected interconversions are also presented.

A tetrahydroselenophene (selenolane) skeleton, which is a five-membered heterocycle containing a selenium atom, has attracted increasing interest due to the significant stability and the high redox activity. Several water- soluble tetrahydroselenophene derivatives having one or two hydrophilic functional groups (e.g., OH and NH2) have been synthesized and applied to biological phenomena relevant to the redox homeostasis. In the first part of this mini review, the structure and redox properties of such water-soluble cyclic selenides and their oxidized forms (i.e., selenoxides) are reviewed. Then, three applications of tetrahydroselenophene derivatives to biologically important issues, i.e., our attempts (1) to design selenide-based mimics of well-known selenoenzyme glutathione peroxidase (GPx), which catalyzes reduction of harmful hydroperoxides (ROOH), (2) to elucidate oxidative folding pathways of proteins that couple with thiol-disulfide redox reactions of cysteine residues existing in the polypeptide chain, and (3) to model molecular chaperone- like functions of protein disulfide isomerase (PDI), which helps a nascent protein chain fold into the native structure in endoplasmic reticulum, are summarized. Finally, it is concluded that tetrahydroselenophenes will be useful structural motifs for molecular design of functional selenium compounds with versatile utilities, such as selenoenzyme mimics and selenium antioxidant drugs for prevention or treatment of diseases caused by aberration of redox homeostasis in cells.

Organoselenium compounds are molecules with important potential therapeutic applications. Seleniumcontaining 5-membered heterocycles have emerged as an important class of biological compounds. In the past five years, several articles related to the design, synthesis and biological evaluation of these compounds have been published. These heterocycles have been applied as antioxidants, cytotoxic agents, apoptosis inducers and chemopreventors, and they possess antidepressant activity, among others. This review describes the methodologies involved in the synthesis of biologically significant selenium-containing 5-membered heterocycles from 2010 to the present.

Organoselenium compounds can reduce H2O2 and organic hydroperoxides mimicking the antioxidant activity of glutathione peroxidase (GPx). This catalytic process reduces the peroxides, which play a key role in oxidative stress, thus inhibiting their harmful action. Thus, it is not surprising that a lot of effort has been devoted toward the synthesis and design of numerous GPx mimics, which, nevertheless, show minor efficiency when compared to the native enzyme. In this context, quantum chemistry tools are an important support to rational drug design, because they allow to investigate in detail the structural and electronic properties of the organochalcogen compound with the aim of establishing links with its potential catalytic activity. In this review, we have collected the information from the available quantum chemistry studies about the reactivity of organic selenides with peroxides and thiols, delineating the analysis on monoselenides and ebselen, which will be critically discussed and gathered for a more complete overview of their GPx-like activity; few novel results will be presented to interpret very recent experimental mechanistic findings.

Mitochondria are key organelles involved, among others, in the ATP synthesis. Mitochondrial physiology is strictly dependent on its integrity. Since ATP synthesis is necessary to many of the physiological processes in cells, changes in mitochondrial physiology and/or integrity are of particular importance to cell activity. Mitochondrial dysfunction could lead to apoptotic cell death, which is often associated with the release of “mitochondrial factors”, under these situations. Therefore, drugs targeting this organelle are of interest in the pharmacological and/or toxicological research field. In this sense, organochalcogens (especially organoselenium and organotellurium compounds) are known to have a variety of pharmacological and/or toxicological properties. However, data concerning its effects on mitochondrial activity are still limited. Indeed, the basic molecular mechanism(s) involved in their mitochondrial effect is a critical point that deserves further attention. In this mini-review we sought to discuss the current scenario about the effect of some organoselenium and organotellurium compounds on mitochondrial function/activity, to better understand/ correlate the pharmacological/toxicological activity associated with these molecules.

The last decade has witnessed a growing interest in natural and synthetic polysulfanes and their potential uses in Medicine and Agriculture. Whilst the chemistry and biochemistry of these organic sulfur compounds is slowly emerging and biological applications are being put into practice, their inorganic equivalents, the hydrogen polysulfides, have attracted little attention so far. Recently, studies conducted in the field of hydrogen sulfide (H2S) signaling have revealed a potential role of such simple sulfur molecules in the redox control of cysteine proteins and associated, extensive cellular signaling. It is therefore worthwhile to consider more closely the chemistry of inorganic polysulfides, their possible formation and occurrence in Biology and likely interactions with biologically relevant functional groups and molecules. Here, a specific focus seems to be on thiol and disulfide groups in proteins and enzymes of the cellular thiolstat.

Selenium plays its physiological chemistry in mammalian living cells as the selenol group of a selenocysteinyl residue found in few numbers of selenoproteins. These proteins have antioxidant properties and catalyze redox reactions, for instance, the selenol-mediated decomposition of peroxides (glutathione peroxidase catalyzed reactions) or the selenol-thiol-mediated reduction of disulfide bonds (the thioredoxin reductase catalyzed reactions). Organochalcogens can mimic the glutathione peroxidase activity (GPx-like activity) by diverse mechanisms. Ebselen and diphenyl diselenide are two types of organoselenium compounds that have been extensively studied in the literature because they posses interesting biochemical and pharmacological properties. They can interact with reactive species (peroxynitrite, peroxides) and have anti-inflammatory properties. Ebselen was used with borderline efficacy in human trials associated with brain ischemia/reperfusion. Experimental models confirmed the neuroprotective effects of ebselen and diselenides in a variety of in vitro and in vivo models of neurotoxicity, including those associated with brain ischemia and acidosis. Ebselen is registered as a safe drug, but it has not yet been approved for the treatment of brain pathologies. In fact, the major problem with organoselenium compounds is that they have no specific target, but modulate general physiological/pathological processes (e.g., inflammatory response/oxidative stress). Thus, the future of organoselenium compounds as potential therapeutic agent will require the synthesis of target-directed molecules.