•Flavonoid or metal flavonoid-modified APTES-FTO electrodes for OH sensing.•(M-)Fls-APTES-FTO can serve as sensitive and selective electrochemical sensors.•Electrochemical monitoring of OH radical in physiological samples at pH 7.4.•Detection of OH concentration as low as 2–10 nM.•Quercetin-APTES-FTO proved as the most sensitive and promising electrode.In the present work, three flavonoids (Fls) namely, quercetin (quer), morin (mor), and primuletin (prim) as well as their metal; (Cu(II) and Fe(III)) complexes (M-Fls) were deposited on APTES-FTO ((3-aminopropyl)triethoxysilane-fluorine doped tin oxide) electrodes. The formation of the (M-)Fls-APTES-FTO surface was verified and characterized through AT-FTIR. These surfaces were found to detect the OH radical at a concentration as low as 2 nM using cyclic and square wave voltammetry and the decrease in the anodic peak currents of (M-)Fls-APTES-FTO working electrodes could be taken as a measure of the OH radical concentration in the sample. Furthermore, a comparison of the decrease in the peak currents of (M-)Fls-APTES-FTO caused by OH to the decrease noted in the presence of 100-fold higher concentrations of other reactive oxygen species (ROS including superoxide anion, alkylperoxide anion, singlet oxygen, chlorine monoxide, and hydrogen peroxide), confirmed a high selectivity and rather insignificant interference by other ROS of no more than 4%. Thus, this method provides significant selectivity in the electrochemical detection of the OH radical. Among the (M-)Fls tested for hydroxyl radical detection, the most sensitive ones were Fe-quer, Cu-quer and Fe-mor deposited on APTES-FTO.

•Sulfur-rich waters from two mineral wells exhibit activity against Steinernema feltiae and Candida albicans.•Sulfur particles, produced by milling, are active against HCT-116 colon cancer cells.•Similar tellurium particles are active against HCT-116 cells.•Sulfide-rich waters provide a sustainable source of sulfur species applicable in agriculture and possibly also in medicine.Sulfur and its various compounds play a major role in agriculture and medicine. Natural waters rich in hydrogen sulfide may therefore be seen as a sustainable resource for biologically active sulfur species. By sampling such waters from two readily accessible mineral wells in Germany, we are able to show that such waters exhibit interesting nematicidal and antimicrobial activity which may be used in an agricultural context. Whilst applications in the field of agriculture could, in theory, result in an amalgamation of irrigation, soil enrichment and phyto-protection, therapeutic uses are more complex and complicated by the many physiological effects associated with hydrogen sulfide and its oxidized derivatives. The latter may include polysulfides (Sx2-) as well as small sulfur particles. Indeed, we have recently noted significant cytotoxic properties of clean, mechanically produced sulfur nanoparticles against HCT-116 colon cancer cells. Since sulfur-rich natural waters are known to deposit elemental sulfur upon oxidation, they may therefore be used as a natural (re)source of sulfur particles, possibly obtained by direct oxidation on air, mild oxidation with sulfur dioxide or enzymatic oxidation employing Thiobacillus. A similar biotechnological approach involving Staphylococcus carnosus and selenite (SeO32−) produces biologically active selenium nanoparticles of excellent quality and with a pronounced biological activity. Eventually, natural spa waters rich in sulfide seem to open up various interesting opportunities in medicine and eco-friendly agriculture.Download high-res image (267KB)Download full-size image

•Synthesis of 1,2-bis(pyridinyl)methyldiselanes by reductive selenation is reported.•Base-catalyzed reductive selenation was carried out using sodium hydrogen selenide.•Current protocol affords high yields under mild conditions, avoiding toxic H2Se.•Anti-proliferative activity of diselanes against cancer and pathogenic cells studied.•Structure elucidation of 1,2-bis(pyridine-3-yl)methyldiselane by X-ray crystallography.An efficient synthetic protocol affording symmetrical 1,2-bis(pyridine-2/3/4-yl)methyldiselanes from pyridine-2/3/4-carbaldehyde in high yields at room temperature, without using highly toxic hydrogen selenide, has been developed. The synthesis involves the reductive selenation of pyridine-2/3/4-carbaldehyde with sodium hydrogen selenide, NaHSe in the presence of piperidine hydrochloride followed by NaBH4 reduction under mild conditions. Primary screening of the anti-proliferative activity of the newly synthesized compounds against several mammalian cell lines and pathogenic strains has been carried out. The crystal structure of 1,2-bis(pyridine-3-yl)methyldiselane has been established by X-ray diffraction analysis.Crystal structure of 1,2-bis(pyridine-3-yl)methyldiselane.

Several amphiphilic, chalcogen-based redox modulators have been synthesized which exhibit a widespread, yet in some instances also selective, biological activity which is most likely based on their ability to modulate the intracellular redox balance and to interact with cellular membranes and specific proteins.

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.Graphical abstractThe synthesized agents induced cell death when incubated with cancer cells. On the other hand, some of these compounds exhibited quite low toxicity when incubated with normal cells.Highlights► Passerini multicomponent reaction is used for the synthesis of multifunctional redox agents. ► Agents combining two, three or even four redox centers were synthesized in a good yield. ► These agents inhibited cell proliferation and induced cell death when incubated with cancer cells. ► Oxidative stress and decrease in reduced glutathione are the reasons for the agent's toxicities.

Cysteine residues in proteins and enzymes often fulfill rather important roles, particularly in the context of cellular signaling, protein–protein interactions, substrate and metal binding, and catalysis. At the same time, some of the most active cysteine residues are also quite sensitive toward (oxidative) modification. S-Thiolation, S-nitrosation, and disulfide bond and sulfenic acid formation are processes which occur frequently inside the cell and regulate the function and activity of many proteins and enzymes. During oxidative stress, such modifications trigger, among others, antioxidant responses and cell death. The unique combination of nonredox function on the one hand and participation in redox signaling and control on the other has placed many cysteine proteins at the center of drug design and pesticide development. Research during the past decade has identified a range of chemically rather interesting, biologically very active substances that are able to modify cysteine residues in such proteins with huge efficiency, yet also considerable selectivity. These agents are often based on natural products and range from simple disulfides to complex polysulfanes, tetrahydrothienopyridines, α,β -unsaturated disulfides, thiuramdisulfides, and 1,2-dithiole-3-thiones. At the same time, inhibition of enzymes responsible for posttranslational cysteine modifications (and their removal) has become an important area of innovative drug research. Such investigations into the control of the cellular thiolstat by thiol-selective agents cross many disciplines and are often far from trivial.

Traditionally, the activity of most polysulfanes has been associated with the redox behaviour of the sulfur-sulfur bond. Here we show that polysulfanes, such as diallyltri- and tetrasulfide, also interact with cellular membranes and certain metalloproteins. Together, multiple interactions with various biological targets may explain best the biological activity of such compounds.

Many tumor cells exhibit a disturbed intracellular redox state resulting in higher levels of reactive oxygen species (ROS). As these contribute to tumor initiation and sustenance, catalytic redox agents combining significant activity with substrate specificity promise high activity and selectivity against oxidatively stressed malignant cells. We describe here the design and synthesis of novel organochalcogen based redox sensor/effector catalysts. Their selective anticancer activity at submicromolar and low micromolar concentrations was established here in a range of tumor entities in various biological systems including cell lines, primary tumor cell cultures, and animal models. In the B-cell derived chronic lymphocytic leukemia (CLL), for instance, such compounds preferentially induce apoptosis in the cancer cells while peripheral blood mononuclear cells (PBMC) from healthy donors and the subset of normal B-cells remain largely unaffected. In support of the concept of sensor/effector based ROS amplification, we are able to demonstrate that underlying this selective activity against CLL cells are pre-existing elevated ROS levels in the leukemic cells compared to their nonmalignant counterparts. Furthermore, the catalysts act in concert with certain chemotherapeutic drugs in several carcinoma cell lines to decrease cell proliferation while showing no such interactions in normal cells. Overall, the high efficacy and selectivity of (redox) catalytic sensor/effector compounds warrant further, extensive testing toward transfer into the clinical arena.

Tellurium has long appeared as a nearly ‘forgotten’ element in Biology, with most studies focusing on tellurite, tellurate and a handful of organic tellurides. During the last decade, several discoveries have fuelled a renewed interest in this element. Bioincorporation of telluromethionine provides a new approach to add heavy atoms to selected sites in proteins. Cadmium telluride (CdTe) nanoparticles are fluorescent and may be used as quantum dots in imaging and diagnosis. The antibiotic properties of tellurite, long known yet almost forgotten, have attracted renewed interest, especially since the biochemical mechanisms of tellurium cytotoxicity are beginning to emerge. The close chemical relationship between tellurium and sulfur also transcends into in vitro and in vivo situations and provides new impetus for the development of enzyme inhibitors and redox modulators, some of which may be of interest in the field of antibiotics and anticancer drug design.

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.

The diverse proteins and enzymes involved in metal trafficking between and inside human cells form numerous transport networks which are highly specific for each essential metal ion and apoprotein. Individual players include voltage-gated ion channels, import and export proteins, intracellular metal-ion sensors, storage proteins and chaperones. In the case of calcium, iron and copper, some of the most apparent trafficking avenues are now well established in eukaryotes, while others are just emerging (e.g. for zinc, manganese and molybdenum). Chemistry provides an important contribution to many issues surrounding these transport pathways, from metal binding-constants and ion specificity to metal-ion exchange kinetics. Ultimately, a better understanding of these processes opens up opportunities for metal-ion-related therapy, which goes beyond traditional chelate-based metal ion detoxification.

Various human illnesses, including several types of cancer and infectious diseases, are related to changes in the cellular redox homeostasis. During the last decade, several approaches have been explored which employ such disturbed redox balances for the benefit of therapy. Compounds able to modulate the intracellular redox state of cells have been developed, which effectively, yet also selectively, appear to kill cancer cells and a range of pathogenic microorganisms. Among the various agents employed, certain redox catalysts have shown considerable promise since they are non-toxic on their own yet develop an effective, often selective cytotoxicity in the presence of the ‘correct’ intracellular redox partners. Aminoalkylation, amide coupling and multicomponent reactions are suitable synthetic methods to generate a vast number of such multifunctional catalysts, which are chemically diverse and, depending on their structure, exhibit various interesting biological activities.

Garlic has long been considered as a natural remedy against a range of human illnesses, including various bacterial, viral and fungal infections. This kind of antibiotic activity of garlic has mostly been associated with the thiosulfinate allicin. Even so, recent studies have pointed towards a significant biological activity of trisulfides and tetrasulfides found in various Allium species, including a wide range of antibiotic properties and the ability of polysulfides to cause the death of certain cancer cells. The chemistry underlying the biological activity of these polysulfides is currently emerging. It seems to include a combination of several distinct transformations, such as oxidation reactions, superoxide radical and peroxide generation, decomposition with release of highly electrophilic Sx species, inhibition of metalloenzymes, disturbance of metal homeostasis and membrane integrity and interference with different cellular signalling pathways. Further research in this area is required to provide a better understanding of polysulfide reactions within a biochemical context. This knowledge may ultimately form the basis for the development of ‘green’ antibiotics, fungicides and possibly anticancer agents with dramatically reduced side effects in humans.

Certain cancer cells proliferate under conditions of oxidative stress (OS) and might therefore be selectively targeted by redox catalysts. Among these catalysts, compounds containing a chalcogen and a quinone redox centre are particularly well suited to respond to the presence of OS. These catalysts combine the specific electrochemical features of quinones and chalcogens. They exhibit high selectivity and efficiency against oxidatively stressed rat PC12, human Jurkat and human Daudi cells in cell culture, where their mode of action most likely involves the catalytic activation of existent and the generation of new reactive oxygen species. The high efficiency and selectivity shown by these catalysts makes them interesting for the development of anti-cancer drugs.

Various human illnesses, including several types of cancer and infectious diseases, are related to changes in the cellular redox homeostasis. During the last decade, several approaches have been explored which employ such disturbed redox balances for the benefit of therapy. Compounds able to modulate the intracellular redox state of cells have been developed, which effectively, yet also selectively, appear to kill cancer cells and a range of pathogenic microorganisms. Among the various agents employed, certain redox catalysts have shown considerable promise since they are non-toxic on their own yet develop an effective, often selective cytotoxicity in the presence of the ‘correct’ intracellular redox partners. Aminoalkylation, amide coupling and multicomponent reactions are suitable synthetic methods to generate a vast number of such multifunctional catalysts, which are chemically diverse and, depending on their structure, exhibit various interesting biological activities.

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.

Garlic has long been considered as a natural remedy against a range of human illnesses, including various bacterial, viral and fungal infections. This kind of antibiotic activity of garlic has mostly been associated with the thiosulfinate allicin. Even so, recent studies have pointed towards a significant biological activity of trisulfides and tetrasulfides found in various Allium species, including a wide range of antibiotic properties and the ability of polysulfides to cause the death of certain cancer cells. The chemistry underlying the biological activity of these polysulfides is currently emerging. It seems to include a combination of several distinct transformations, such as oxidation reactions, superoxide radical and peroxide generation, decomposition with release of highly electrophilic Sx species, inhibition of metalloenzymes, disturbance of metal homeostasis and membrane integrity and interference with different cellular signalling pathways. Further research in this area is required to provide a better understanding of polysulfide reactions within a biochemical context. This knowledge may ultimately form the basis for the development of ‘green’ antibiotics, fungicides and possibly anticancer agents with dramatically reduced side effects in humans.

Tellurium has long appeared as a nearly ‘forgotten’ element in Biology, with most studies focusing on tellurite, tellurate and a handful of organic tellurides. During the last decade, several discoveries have fuelled a renewed interest in this element. Bioincorporation of telluromethionine provides a new approach to add heavy atoms to selected sites in proteins. Cadmium telluride (CdTe) nanoparticles are fluorescent and may be used as quantum dots in imaging and diagnosis. The antibiotic properties of tellurite, long known yet almost forgotten, have attracted renewed interest, especially since the biochemical mechanisms of tellurium cytotoxicity are beginning to emerge. The close chemical relationship between tellurium and sulfur also transcends into in vitro and in vivo situations and provides new impetus for the development of enzyme inhibitors and redox modulators, some of which may be of interest in the field of antibiotics and anticancer drug design.