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Many organic sulfur, selenium and tellurium compounds show considerable activity against microorganisms, including bacteria and fungi. This pronounced activity is often due to the specific, oxidizing redox behavior of the chalcogen-chalcogen bond present in such molecules. Interestingly, similar chalcogen-chalcogen motifs are also found in the elemental forms of these elements, and while those materials are insoluble in aqueous media, it has recently been possible to unlock their biological activities using naturally produced or homogenized suspensions of respective chalcogen nanoparticles. Those suspensions can be employed readily and often effectively against common pathogenic microorganisms, still their practical uses are limited as such suspensions are difficult to transport, store and apply. Using mannitol as stabilizer, it is now possible to lyophilize such suspensions to produce solid forms of the nanoparticles, which upon resuspension in water essentially retain their initial size and exhibit considerable biological activity. The sequence of Nanosizing, Lyophilization and Resuspension (NaLyRe) eventually provides access to a range of lyophilized materials which may be considered as easy-to-handle, ready-to-use and at the same time as bioavailable, active forms of otherwise insoluble or sparingly substances. In the case of elemental sulfur, selenium and tellurium, this approach promises wider practical applications, for instance in the medical or agricultural arena. [ABSTRACT FROM AUTHOR]

During the last decade, research into natural products has experienced a certain renaissance. The urgent need for more and more effective antibiotics in medicine, the demand for ecologically friendly plant protectants in agriculture, "natural" cosmetics and the issue of a sustainable and healthy nutrition in an ageing society have fuelled research into Nature's treasure chest of "green gold". Here, redox active secondary metabolites from plants, fungi, bacteria and other (micro-)organisms often have been at the forefront of the most interesting developments. These agents provide powerful means to interfere with many, probably most cellular signaling pathways in humans, animals and lower organisms, and therefore can be used to protect, i.e., in form of antioxidants, and to frighten off or even kill, i.e., in form of repellants, antibiotics, fungicides and selective, often catalytic "sensor/effector" anticancer agents. Interestingly, whilst natural product research dates back many decades, in some cases even centuries, and compounds such as allicin and various flavonoids have been investigated thoroughly in the past, it has only recently become possible to investigate their precise interactions and mode(s) of action inside living cells. Here, fluorescent staining and labelling on the one side, and appropriate detection, either qualitatively under the microscope or quantitatively in flow cytometers and plate readers, on the other, enable researchers to obtain the various pieces of information necessary to construct a fairly complete puzzle of how such compounds act and interact in living cells. Complemented by the more traditional activity assays and Western Blots, and increasingly joined by techniques such as proteomics, chemogenetic screening and mRNA profiling, these cell based bioanalytical techniques form a powerful platform for "intracellular diagnostics". In the case of redox active compounds, especially of Reactive Sulfur Species (RSS), such techniques have recently unraveled concepts such as the "cellular thiolstat", yet considerably more research is required in order to gain a full understanding of why and how such compounds act--often selectively--in different organisms. [ABSTRACT FROM AUTHOR]

Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-)chemical causes thereof, are often only poorly understood. A combination of the nematode- and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the "redox link" which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks. [ABSTRACT FROM AUTHOR]

Various secondary metabolites from plants, bacteria and fungi are redox active and able to modulate the intracellular redox equilibrium in living cells. Many of these compounds behave as antioxidants, yet some of them also cause oxidative modifications, which may ultimately result in cell death. Natural isothiocyanates and xanthohumol, for instance, appear to act specifically in and against cells with a disturbed redox balance, such as certain cancer cells. Similarly, polysulfane and pyocyanin derivatives employ the glutathione antioxidant defense system of cells to generate a lethal cocktail of reactive oxygen species. Together, these redox-modulating metabolites provide promising new leads to target selectively certain cancer cells. They may also be useful in the treatment of autoinflammatory diseases. [Copyright &y& Elsevier]

Sulphur metabolism in plants provides a wealth of natural products, including several chemically unusual substances, such as thiosulphinates, polysulphides and isothiocyanates. Many of these reactive sulphur species (RSS) exhibit a distinct redox behaviour in vitro, which translates into a rather interesting biological activity in vivo, such as antibiotic, fungicidal, pesticidal or anticancer activity. While the molecular basis for such activity has long remained obscure, research into sulphur-based redox systems during the past 5–10 years has achieved a better knowledge of the in vitro properties of RSS and has led to an improved understanding of their impact on intracellular redox signalling and control pathways in living cells. It has become apparent that the redox chameleon sulphur occurs in biological systems in about 10 different oxidation states, which give rise to an extensive and complicated network of sulphur-based redox events. Together, natural sulphur products from plants and their intracellular targets provide the basis for innovative design of novel antibiotics, fungicides, pesticides and anticancer agents. [ABSTRACT FROM AUTHOR]

Demonstrates the isolation of thioneine (T) from biological material. Transient generation of T in situ via removal of zinc from metallothionein underoxidoreductive conditions; Activation of group of enzymes in which zinc is bound at an inhibitory site.

Examines zinc-sulfur centers as possible targets of selenium redox biochemistry. Release of zinc from zinc/thiolate-coordination environments by selenium compounds; Oxidation of metallothionein by selenoenzyme glutathione peroxidase.

Selenium is an essential trace element. Although this chalcogen forms a wide variety of compounds, there are surprisingly few small-molecule organic selenium compounds (OSeCs) in biology. Besides its more prominent relative selenocysteine (SeCys), the amino acid selenomethionine (SeMet) is one example. SeMet is synthesized in plants and some fungi and, via nutrition, finds its way into mammalian cells. In contrast to its sulfur analog methionine (Met), SeMet is extraordinarily redox active under physiological conditions and via its catalytic selenide (RSeR')/selenoxide (RSe(O)R') couple provides protection against reactive oxygen species (ROS) and other possibly harmful oxidants. In contrast to SeCys, which is incorporated via an eloquent ribosomal mechanism, SeMet can enter such biomolecules by simply replacing proteinogenic Met. Interestingly, eukaryotes, such as yeast and mammals, also metabolize SeMet to a small family of reactive selenium species (RSeS). Together, SeMet, proteins containing SeMet and metabolites of SeMet form a powerful triad of redox-active metabolites with a plethora of biological implications. In any case, SeMet and its family of natural RSeS provide plenty of opportunities for studies in the fields of nutrition, aging, health and redox biology. [ABSTRACT FROM AUTHOR]

Multicomponent Passerini and Ugi reactions enable the fast and efficient synthesis of redox-active multifunctional selenium and tellurium compounds, of which some show considerable cytotoxicity against specific cancer cells. [ABSTRACT FROM AUTHOR]

Catalysts are employed in many areas of research and development where they combine high efficiency with often astonishing selectivity for their respective substrates. In biology, biocatalysts are omnipresent. Enzymes facilitate highly controlled, sophisticated cellular processes, such as metabolic conversions, sensing and signalling, and are prominent targets in drug development. In contrast, the therapeutic use of catalysts per se is still rather limited. Recent research has shown that small molecule catalytic agents able to modulate the redox state of the target cell bear considerable promise, particularly in the context of inflammatory and infectious diseases, stroke, ageing and even cancer. Rather than being “active” on their own in a more traditional sense, such agents develop their activity by initiating, promoting, enhancing or redirecting reactions between biomolecules already present in the cell, and their activity therefore depends critically on the predisposition of the target cell itself. Redox catalysts, for instance, preferably target cells with a distinct sensitivity towards changes in an already disturbed redox balance and/or increased levels of reactive oxygen species. Indeed, certain transition metal, chalcogen and quinone agents may activate an antioxidant response in normal cells whilst at the same time triggering apoptosis in cancer cells with a different pre-existing “biochemical redox signature” and closer to the internal redox threshold. In pharmacy, catalysts therefore stand out as promising lead structures, as sensor/effector agents which are highly effective, fairly selective, active in catalytic, i.e., often nanomolar concentrations and also very flexible in their structural design. [ABSTRACT FROM AUTHOR]

Living cells maintain a delicate balance between oxidizing and reducing species, and many disorders such as rheumatoid arthritis and Alzheimer''s disease have been associated with a disturbed intracellular ‘redox equilibrium’. The past few years have witnessed accelerated research into how natural redox responses and antioxidant defence systems are activated and how they restore a healthy redox balance. To function properly, many of these processes rely on a powerful sulfur redox chemistry, which is best exemplified by the complex, newly emerging cysteine-based redox regulation of the glutathione and thioredoxin pathways. Other redox systems based on oxidatively activated amino acid side chains in proteins are also becoming increasingly important, but are still barely understood or explored. [Copyright &y& Elsevier]

In biology, sulfur frequently occurs in the form of cysteine, an amino acid that fulfills a wide range of different functions in proteins including disulfide formation, metal-binding, electron donation, hydrolysis, and redox-catalysis. The ‘redox-chameleon’ sulfur appears in several oxidation states in vitro, each of them exhibiting specific reactivity, redox-activity, and metal-binding properties. While cysteine-peptidases rely on reduced cysteine to catalyze hydrolytic reactions, many redox-enzymes use distinctively different cysteine redox-couples for exchange, electron, atom, and radical transfer reactions. Although cysteine and cystine can still be considered as the most abundant forms of cysteine in vivo, other modifications such as cysteine acids and sulfur-centered radicals are becoming increasingly important in biochemical research. As such, the biochemistry of sulfur remains a source of continuous investigation and excitement. [Copyright &y& Elsevier]

Selenium sulfide, in analogy with selenium dioxide, is often considered as SeS 2. At closer inspection, however, selenium sulfide represents a large family of rather complicated molecules which differ depending on the mode of preparation. Together, these compounds share extraordinarily low solubility in virtually any solvent with a biological activity rather impressive for such simple molecules. The surface reactivity of such microscopic and nanoscopic materials, prepared chemically or by fermentation, may provide an answer to this riddle and explain activities by a combination of physical, redox, metal binding, covalent, and non-covalent interactions with biomolecules and cells. • Selenium sulfide is not simply SeS 2 , it is the name for an extended family of interchalogen compounds, often of the general formula Se n S 8-n. • Although Se n S 8-n species are notoriously insoluble, they show considerable biological activity, best known in shampoos against dandruff. • Nanoscopic Se n S 8-n particles may react on their surface with reducing agents and metal ions, in part explaining bioavailability and activity. • Anionic Se x S y 2− species may be formed upon successive reduction and act as redox modulators and 'corkscrews' toward membranes, metals, and proteins. • Due to their ease of preparation and high reactivity, selenium sulfides may be used more widely in medicine and agriculture. [ABSTRACT FROM AUTHOR]

Highlights: [•] Synthesis of seleninic acid based redox modulators with amphiphilic properties. [•] Surface tension measurements to show aggregation in the low millimolar range. [•] Pronounced activity of these novel molecules on cell membranes. [•] Regulation of Ca2+ influx at lower and lysis of membranes at higher concentrations. [•] Activity of these compounds against the representative fungus S. cerevisiae. [Copyright &y& Elsevier]

Abstract: Various selenium- and tellurium-containing molecules are able to modulate the intracellular redox state of cells, an effect which may be used for the (selective) targeting of cancer cells, which are naturally under oxidative stress (OS). As macrophages also generate an environment rich in Reactive Oxygen Species (ROS) and nitric oxide ( NO), they may represent an additional, prime target for such redox-modulating agents. A range of selenium and tellurium-containing quinones have therefore been synthesized and subsequently tested in macrophage culture. The tellurium agents were generally cytotoxic at very low concentrations, and their mode of action seemed to involve the upregulation of intracellular ROS levels. This redox-modulating effect was confirmed by simple yeast-based chemogenetic analysis in conjunction with in vitro redox assays and electrochemistry. Together, these studies point towards an intracellular build-up of superoxide radicals as the most likely cause of toxicity. In contrast, some of the selenium derivatives were less toxic and exerted a pronounced inhibitory effect on the formation of lipopolysaccharide-induced NO production. Whilst the Te-analogues therefore may enable the resolute, effective and fairly selective targeting of macrophages, the selenium agents could act less severely, but equally effectively by interfering with inflammatory signalling molecules. [Copyright &y& Elsevier]

Abstract: Many types of cancer cells are associated with a disturbed intracellular redox balance and oxidative stress (OS). Among the various agents employed to modulate the intracellular redox state of cells, certain redox catalysts containing quinone and chalcogen moieties have shown considerable promise. Passerini multicomponent reaction has been developed for the synthesis of agents combining two, three or even four redox centers in one molecule in a good yield. When incubated with cancer cells these agents inhibited cell proliferation and induced apoptotic cell death. Interestingly, some of these redox active compounds exhibited quite low toxicity with normal cells. The cause was obviously OS, which was reflected by significant decrease in reduced glutathione, subsequently cell cycle arrest and induction of apoptosis. [Copyright &y& Elsevier]

Abstract: The volatile substance allicin gives crushed garlic (Allium sativum) its characteristic odor and is a pro-oxidant that undergoes thiol–disulfide exchange reactions with –SH groups in proteins and glutathione. The antimicrobial activity of allicin is suspected to be due to the oxidative inactivation of essential thiol-containing enzymes. We investigated the hypothesis that at threshold inhibitory levels allicin can shunt yeast cells into apoptosis by altering their overall redox status. Yeast cells were treated either with chemically synthesized, pure allicin or with allicin in garlic juice. Allicin-dependent cell oxidation was demonstrated with a redox-sensitive GFP construct and the shift in cellular electrochemical potential (E hc) from less than −215 to −181mV was calculated using the Nernst equation after the glutathione/glutathione disulfide couple (2GSH/GSSG) in the cell was quantified. Caspase activation occurred after allicin treatment, and yeast expressing a human antiapoptotic Bcl-XL construct was rendered more resistant to allicin. Also, a yeast apoptosis-inducing factor deletion mutant was more resistant to allicin than wild-type cells. We conclude that allicin in garlic juice can activate apoptosis in yeast cells through its oxidizing properties and that this presents an alternative cell-killing mechanism to the previously proposed specific oxidative inactivation of essential enzymes. [ABSTRACT FROM AUTHOR]

Tumor cells proliferate under conditions of oxidative stress. A novel therapeutic approach would be to enhance the cellular effects of the reactive oxygen species formed under these conditions by supplementation with a redox catalyst. This provides a means to target and specifically destroy cancer cells via oxidation of redox-sensitive proteins, such as transcription factors, while leaving cells with a normal redox balance largely unaffected. We have previously reported a preliminary observation on the effects of pro-oxidant catalysts that enhance cancer cell death. This paper presents a detailed in vitro investigation into the mechanism of action of synthetic glutathione peroxidase mimics on a model Sp1 transcription factor peptide. The structure and redox potential of these mimics correlate with their ability to catalyze the oxidation of this zinc-binding motif by H2O2 and these compounds promise therapeutic potential by promoting H2O2-induced PC12 cell death. [Copyright &y& Elsevier]

In biological systems, the amino acid cysteine combines catalytic activity with an extensive redox chemistry and unique metal binding properties. The interdependency of these three aspects of the thiol group permits the redox regulation of proteins and metal binding, metal control of redox activity, and ligand control of metal-based enzyme catalysis. Cysteine proteins are therefore able to act as “redox switches,” to sense concentrations of oxidative stressors and unbound zinc ions in the cytosol, to provide a “storage facility” for excess metal ions, to control the activity of metalloproteins, and to take part in important regulatory and signaling pathways. The diversity of cysteine''s multiple roles in vivo is equally as fascinating as it is promising for future biochemical and pharmacological research. [Copyright &y& Elsevier]