Reaction Pattern and Mechanistic Aspects of Iodine and Iodine-Based Reagents in Selenylation of Aliphatic, Aromatic, and (Hetero)Cyclic Systems.

Organoselenium compounds have been the subject of extensive research since the discovery of the biologically active compound ebselen. Ebselen has recently been found to show activity against the main protease of the virus responsible for COVID-19. Other organoselenium compounds are also well-known for their diverse biological activities, with such compounds exhibiting interesting physical properties relevant to the fields of electronics, materials, and polymer chemistry. In addition, the incorporation of selenium into various organic molecules has garnered significant attention due to the potential of selenium to enhance the biological activity of these molecules, particularly in conjunction with bioactive heterocycles. Iodine and iodine-based reagents play a prominent role in the synthesis of organoselenium compounds, being valued for their cost-effectiveness, non-toxicity, and ease of handling. These reagents efficiently selenylate a broad range of organic substrates, encompassing alkenes, alkynes, and cyclic, aromatic, and heterocyclic molecules. They serve as catalysts, additives, inducers, and oxidizing agents, facilitating the introduction of different functional groups at alternate positions in the molecules, thereby allowing for regioselective and stereoselective approaches. Specific iodine reagents and their combinations can be tailored to follow the desired reaction pathways. Here, we present a comprehensive review of the progress in the selenylation of organic molecules using iodine reagents over the past decade, with a focus on reaction patterns, solvent effects, heating, microwave, and ultrasonic conditions. Detailed discussions on mechanistic aspects, such as electrophilic, nucleophilic, radical, electrochemical, and ring expansion reactions via selenylation, multiselenylation, and difunctionalization, are included. The review also highlights the formation of various cyclic, heterocyclic, and heteroarenes resulting from the in situ generation of selenium intermediates, encompassing cyclic ketones, cyclic ethers, cyclic lactones, selenophenes, chromones, pyrazolines, pyrrolidines, piperidines, indolines, oxazolines, isooxazolines, lactones, dihydrofurans, and isoxazolidines. To enhance the reader's interest, the review is structured into different sections covering the selenylation of aliphatic sp2/sp carbon and cyclic sp2 carbon, and then is further subdivided into various heterocyclic molecules.

Bis(1-methylimidazol-2-yl) diselenide and its evaluation as a chemical radio-protector: role of kinetic rate constants for ROS scavenging and glutathione peroxidase like activity.

Bis(1-methylimidazol-2-yl) diselenide (MeImSe), a derivative of selenoneine, has been examined for bimolecular rate constants for scavenging of various radiolytically and non-radiolytically generated reactive oxygen species (ROS). Further, its potential to show glutathione peroxidase (GPx)-like activity and to protect in vitro models of DNA and lipid against radiation induced strand breakage and lipid peroxidation, respectively were studied. The results confirmed that MeImSe scavenged all major short-lived (hydroxyl radical) and long-lived (peroxyl radical, carbonate radical, nitrogen dioxide radical, hypochlorite and hydrogen peroxide) oxidants involved in the radiation toxicity either directly or through GPx-like catalytic mechanism. The rate constants of MeImSe for these oxidants were found to be comparable to analogous sulfur and selenium-based compounds. The enzyme kinetics study established that MeImSe took part in the GPx cycle through the reductive pathway. Further, MeImSe inhibited the radiation induced DNA strand cleavage and lipid peroxidation with half maximal inhibitory concentration (IC50) of ∼ 60 µM and ∼100 µM, respectively. Interestingly, MeImSe treatment in the above concentration range (>100 µM) did not show any significant toxicity in normal human lung fibroblast (WI26) cells. The balance between efficacy and toxicity of MeImSe as a chemical radioprotector was attributed to the formation of less reactive intermediates during its oxidation/reduction reactions as evidenced from NMR studies.HighlightsMeImSe, a derivative of selenoneine protects DNA and lipid from radiation damageMeImSe scavenges all major short- and long-lived oxidants involved in radiation toxicityRate constants of MeImSe for ROS scavenging determined by pulse radiolysis techniqueFirst organoselenium compound reported to scavenge nitrogen dioxide radicalMeImSe exhibits GPx-like activity through reductive pathway.

Recent Advances in the Synthesis and Antioxidant Activity of Low Molecular Mass Organoselenium Molecules.

Selenium is an essential trace element in living organisms, and is present in selenoenzymes with antioxidant activity, like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). The search for small selenium-containing molecules that mimic selenoenzymes is a strong field of research in organic and medicinal chemistry. In this review, we review the synthesis and bioassays of new and known organoselenium compounds with antioxidant activity, covering the last five years. A detailed description of the synthetic procedures and the performed in vitro and in vivo bioassays is presented, highlighting the most active compounds in each series.

Synthesis and glutathione peroxidase (GPx)-like activity of selenocystine (SeC) bioconjugates of biotin and lipoic acid.

The conjugation of active biomolecules provides insight into their bioreactivity, leading to many applications in biotechnology and materials science. Herein, we report L-selenocystine (SeC) bioconjugates of lipoic acid (universal antioxidant) and biotin (Vitamin-H). The SeC-bioconjugates, SeC-Biotin (1) and SeC-Lipoic acid (2) were synthesized using solid phase peptide synthesis (SPPS) method and were characterized by multinuclear 1D (1H, 13C, 77Se) and 2D (1H-1H COSY and 1H-13C TOCSY) NMR spectroscopy, ESI-MS spectrometry, and RP-HPLC. The GPx-like enzyme mimicking activity of the SeC-bioconjugates 1 and 2 has been investigated through the coupled reductase assay method for the catalytic reductions of hydrogen peroxide into water. A significant enhancement in GPx-like enzymatic activity was observed for both novel bioconjugates SeC-Biotin (1) and SeC-Lipoic acid (2) as compared to diphenyl diselenide (Ph2Se2), L-selenocystine (SeC), biotin, lipoic acid, and ebselen.

Distribution and Effects of Selenoneine by Ingestion of Extract from Mackerel Processing Residue in Mice.

Selenoneine is an organic selenium compound contained in blood and dark muscle of fish. It has a strong antioxidative capacity and is considered useful as a new functional food material. However, the distribution and effects of selenoneine in the mammalian body have not been thoroughly examined. In this study, a selenoneine-rich mackerel extract was developed and fed to mice at 0.07% in standard rodent chow (ME diet) for 32 days to examine its distribution in the body. Selenoneine was distributed in the liver, kidney, and spleen in mice fed with mackerel extract, but it was not distributed in the plasma or erythrocytes. Moreover, concentrations of the major selenium-containing protein were not affected by the mackerel extract. The results of this study suggest that selenoneine is absorbed in the body following ingestion of low doses in crude material and preferentially accumulates in organs and later distributes in erythrocytes. Biochemical analyses of plasma in male mice showed that the glucose level was significantly increased and LDL-cholesterol level was significantly decreased by ME diet feeding. The results indicate that male mice are sensitive to ME diet.

Structural and biochemical analysis of human inositol monophosphatase-1 inhibition by ebselen.

Bipolar disorder is a major psychiatric disorder associated with cognitive impairment and a high suicide rate. Frontline therapy for this condition includes lithium (Li+)-containing treatments that can exert severe side effects. One target of Li+ is inositol monophosphatase-1 (IMPase1); inhibition of IMPase1 through small-molecule compounds may provide an alternative treatment for bipolar disorder. One such compound is the anti-inflammatory drug ebselen, which is well tolerated and safe; however, ebselen's exact mechanism of action in IMPase1 inhibition is not fully understood, preventing rational design of IMPase1 inhibitors. To fill this gap, we performed crystallographic and biochemical studies to investigate how ebselen inhibits IMPase1. We obtained a structure of IMPase1 in space group P21 after treatment with ebselen that revealed three key active-site loops (residues 33-44, 70-79, and 161-165) that are either disordered or in multiple conformations, supporting a hypothesis whereby dynamic conformational changes may be important for catalysis and ebselen inhibition. Using the thermal shift assay, we confirmed that ebselen significantly destabilizes the enzyme. Molecular docking suggests that ebselen could bind in the vicinity of His217. Investigation of the role of IMPase1 residues His217 and Cys218 suggests that inhibition of IMPase1 by ebselen may not be mediated via covalent modification of the active-site cysteine (Cys218) and is not affected by the covalent modification of other cysteine residues in the structure. Our results suggest that effects previously ascribed to ebselen-dependent inhibition likely result from disruption of essential active-site architecture, preventing activation of the IMPase1-Mg2+ complex.Communicated by Ramaswamy H. Sarma.

Synthesis, Reactions, and Antioxidant Properties of Bis(3-amino-1-hydroxybenzyl)diselenide.

Bis(3-amino-1-hydroxybenzyl)diselenide containing two ortho groups was synthesized from 7-nitro-3H-2,1-benzoxaselenole and in situ generated sodium benzene tellurolate (PhTeNa). One-pot synthesis of 1,3-benzoselenazoles was achieved from bis(3-amino-1-hydroxybenzyl)diselenide and aryl aldehydes using acetic acid as a catalyst. The X-ray crystal structure of chloro-substituted benzoselenazole revealed a planar structure with T-shaped geometry around the Se atom. Both natural bond orbital and atoms in molecules calculations confirmed the presence of secondary Se···H interactions in bis(3-amino-1-hydroxybenzyl)diselenide and Se···O interactions in benzoselenazoles, respectively. The glutathione peroxidase (GPx)-like antioxidant activities of all compounds were evaluated using a thiophenol assay. Bis(3-amino-1-hydroxybenzyl)diselenide and benzoselenazoles showed better GPx-like activity compared to that of the diphenyl diselenide and ebselen, used as references, respectively. Based on 77Se{1H} NMR spectroscopy, a catalytic cycle for bis(3-amino-1-hydroxybenzyl)diselenide using thiophenol and hydrogen peroxide was proposed involving selenol, selenosulfide, and selenenic acid as intermediates. The potency of all GPx mimics was confirmed by their in vitro antibacterial properties against the biofilm formation of Bacillus subtilis and Pseudomonas aeruginosa. Additionally, molecular docking studies were used to evaluate the in silico interactions between the active sites of the TsaA and LasR-based proteins found in Bacillus subtilis and Pseudomonas aeruginosa.

Antibacterial Activity of Ebselen.

Ebselen is a low-molecular-weight organoselenium compound that has been broadly studied for its antioxidant, anti-inflammatory, and cytoprotective properties. These advantageous properties were initially associated with mimicking the activity of selenoprotein glutathione peroxidase, but the biomedical impact of this compound appear to be far more complex. Ebselen serves as a substrate or inhibitor with multiple protein/enzyme targets, whereas inhibition typically originates from the covalent modification of cysteine residues by opening the benzisoselenazolone ring and S-Se bond formation. The inhibition of enzymes of various classes and origins has been associated with substantial antimicrobial potential among other activities. In this contribution, we summarize the current state of the art regarding the antibacterial activity of ebselen. This activity, alone and in combination with commercial pharmaceuticals, against pathogens, including those resistant to drugs, is presented, together with the molecular mechanism behind the reactivity. The specific inactivation of thioredoxin reductase, bacterial toxins, and other resistance factors is considered to have certain therapeutic implications. Synergistic action and sensitization to common antibiotics assisted with the use of ebselen appear to be promising directions in the treatment of persistent infections.

Neuropharmacology of Organoselenium Compounds in Mental Disorders and Degenerative Diseases.

Neurodegenerative and mental disorders are a public health burden with pharmacological treatments of limited efficacy. Organoselenium compounds are receiving great attention in medicinal chemistry mainly because of their antioxidant and immunomodulatory activities, with a multi-target profile that can favor the treatment of multifactorial diseases. Therefore, the purpose of this review is to discuss recent preclinical studies about organoselenium compounds as therapeutic agents for the management of mental (e.g., depression, anxiety, bipolar disorder, and schizophrenia) and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis). We have summarized around 70 peer-reviewed articles from 2016 to the present that used in silico, in vitro, and/or in vivo approaches to assess the neuropharmacology of selenium- containing compounds. Among the diversity of organoselenium molecules investigated in the last five years, diaryl diselenides, Ebselen-derivatives, and Se-containing heterocycles are the most representative. Ultimately, this review is expected to provide disease-oriented information regarding the neuropharmacology of organoselenium compounds that can be useful for the design, synthesis, and pharmacological characterization of novel bioactive molecules that can potentially be clinically viable candidates.

Click Chemistry of Selenium Dihalides: Novel Bicyclic Organoselenium Compounds Based on Selenenylation/Bis-Functionalization Reactions and Evaluation of Glutathione Peroxidase-like Activity.

A number of highly efficient methods for the preparation of novel derivatives of 9-selenabicyclo[3.3.1]nonane in high yields based on selenium dibromide and cis,cis-1,5-cyclooctadiene are reported. The one-pot syntheses of 2,6-diorganyloxy-9-selenabicyclo[3.3.1]nonanes using various O-nucleophiles including alkanols, phenols, benzyl, allyl, and propargyl alcohols were developed. New 2,6-bis(1,2,3-triazol-1-yl)-9-selenabicyclo[3.3.1]nonanes were obtained by the copper-catalyzed 1,3-dipolar cycloaddition of 2,6-diazido-9-selenabicyclo[3.3.1]nonane with unsubstituted gaseous acetylene and propargyl alcohol. The synthesis of 2,6-bis(vinylsulfanyl)-9-selenabicyclo[3.3.1]nonane, based on the generation of corresponding dithiolate anion from bis[amino(iminio)methylsulfanyl]-9-selenabicyclo[3.3.1]nonane dibromide, followed by the nucleophilic addition of the dithiolate anion to unsubstituted acetylene, was developed. The glutathione peroxidase-like activity of the obtained water-soluble products was estimated and compounds with high activity were found. Overall, 2,6-Diazido-9-selenabicyclo[3.3.1]nonane exhibits the highest activity among the obtained compounds.

Unexpected Formation and Potent Antioxidant Activity of Macrocyclic Dimers Containing Disulfide and Selenide Groups.

During attempts to prepare spirodithiaselenuranes as GPx mimetics, a series of unexpected dimeric macrocycles was obtained, each containing two selenide and two disulfide moieties in rings ranging from 18- to 26-membered. The products showed potent GPx-like activity in an NMR assay based on their ability to catalyze the reduction of hydrogen peroxide with benzyl thiol. The high catalytic activity was attributed to transannular effects during selenide to selenoxide oxidation. This redox process was also characterized by an induction period that indicated autocatalysis in the formation of an intermediate selenoxide from the oxidation of the corresponding selenide.

Nano-based formulations as an approach for providing a novel identity for organoselenium compounds.

The organoselenium compounds belong to a class of synthetic molecules that displays a remarkable spectrum of promising pharmacological properties. Despite the huge amount of preclinical data that supports a bright outlook for organoselenium compounds, some toxicity issues and physicochemical limitations delay the development of more advanced studies. Currently, several scientific reports demonstrated that the association of nanotechnology has emerged as an alternative to improve solubility and safety issues of these molecules as well as enhance pharmacological properties. Therefore, our main objective was to address studies that reported the development and biological evaluations of nano-based formulations to synthetic organoselenium compounds incorporation by constructing an integrative literature review. The data survey was performed using the Science Direct, PubMed, Web of Science, and SCOPUS online databases, covering studies that were published from January 2011 up to October 2021. In the last decade, there has been an exponential growth in research regarding the incorporation of synthetic organoselenium compounds into distinct nanocarrier systems such as nanocapsules, nanoemulsions, micelles, and others, reinforcing that the association of such molecules and nanotechnology is a promising alliance. The reports investigated many nanosystems containing selenium organic molecules intending oral, intravenous, and cutaneous applications. Besides that, these systems were evaluated in a variety of in vitro techniques and in vivo models, concerning their pharmacological potential, biodistribution profile, and safety. In summary, the findings indicate that the production of nano-based formulations containing organoselenium compounds either improved physicochemical and biological properties or minimize toxicological issues of compounds.

Synthesis of 1,2-diselenides via potassium persulfate-mediated diselenation of allenamides with diselenides.

An efficient potassium persulfate-mediated radical addition of allenamides with diselenides was developed to create a workable route to 1,2-diselenide products. The reaction tolerates a wide spectrum of functional groups to deliver the products in good to excellent yields. Mechanistic investigations including a calculation study indicated that the radical cascade proceeds through a vinyl radical intermediate, which is formed via a selenium radical added to the terminal CC double bond of allenamides.

An analysis of the content changes in free and combinative forms of organic selenium in radish sprouts cultivated with solutions of selenoamino acids.

Selenium (Se) is critical for human health, but human intake of Se is often inadequate. Organic forms of dietary Se are considered safe and more bioavailable than inorganic forms. Along with a generally high nutritional value, sprouts are sensitive to Se treatment. This study used selenomethionine and methylselenocysteine solutions to cultivate Se-enriched sprouts under an optimized hydroponic condition. Content change and transformations of the selenoamino acids were analyzed by a developed HPLC-ESI-MS/MS method. Uptake of both selenomethionine and methylselenocysteine was dose-dependent and involved active transport and passive diffusion, as demonstrated by the respiratory and aquaporin inhibition assays. Passive diffusion played a dominant role. Free methylselenocysteine was the predominant form in samples. Selenomethionine and methylselenocysteine were capable of mutual transformation. Moreover, the selenoprotein generation was associated with the increasing Se concentration of the culture solutions. The results provided scientific references for the efficient utilization of organic Se in sprouts.

Selenium as an emerging versatile player in heterocycles and natural products modification.

The diverse pharmacological activities of organoselenium compounds are closely correlated to their ability to scavenge and induce reactive oxygen species (ROS), their intrinsic oxidative properties, and their Se(0) release property. The incorporation of selenium into small molecules, and particularly into heterocycles and natural products, has shown great potential in altering the potency and selectivity of these molecules. Therefore, selenium will play an important role in drug discovery in the near future. We summarize how different organoselenium species affect cellular oxidative stress levels, and try to correlate the structural properties of selenium-containing heterocycles and natural product derivatives to their biological activities and therapeutic applications. We also provide some information to guide the rational design of selenium-containing drugs.

Selenocystine-Derived Label-Free Fluorescent Schiff Base Nanocomplex for siRNA Delivery Synergistically Kills Cancer Cells.

Chemo and siRNA synergic treatments for tumors is a promising new therapeutic trend. Selenocystine, a selenium analog of cysteine, has been considered a potential antitumor agent due to its redox perturbing role. In this study, we developed a nanocarrier for siRNA based on a selenocystine analog engineered polyetherimide and achieved traceable siRNA delivery and the synergic killing of tumor cells. Notably, we applied the label-free Schiff base fluorescence mechanism, which enabled us to trace the siRNA delivery and to monitor the selenocystine analogs' local performance. A novel selenocystine-derived fluorescent Schiff base linker was used to crosslink the polyetherimide, thereby generating a traceable siRNA delivery vehicle with green fluorescence. Moreover, we found that this compound induced tumor cells to undergo senescence. Together with the delivery of a siRNA targeting the anti-apoptotic BCL-xl/w genes in senescent cells, it achieved a synergistic inhibition function by inducing both senescence and apoptosis of tumor cells. Therefore, this study provides insights into the development of label-free probes, prodrugs, and materials towards the synergic strategies for cancer therapy.

Chemoselective Preparation of New Families of Phenolic-Organoselenium Hybrids-A Biological Assessment.

Being aware of the enormous biological potential of organoselenium and polyphenolic compounds, we have accomplished the preparation of novel hybrids, combining both pharmacophores in order to obtain new antioxidant and antiproliferative agents. Three different families have been accessed in a straightforward and chemoselective fashion: carbohydrate-containing N-acylisoselenoureas, N-arylisoselenocarbamates and N-arylselenocarbamates. The nature of the organoselenium framework, number and position of phenolic hydroxyl groups and substituents on the aromatic scaffolds afforded valuable structure-activity relationships for the biological assays accomplished: antioxidant properties (antiradical activity, DNA-protective effects, Glutathione peroxidase (GPx) mimicry) and antiproliferative activity. Regarding the antioxidant activity, selenocarbamates 24-27 behaved as excellent mimetics of GPx in the substoichiometric elimination of H2O2 as a Reactive Oxygen Species (ROS) model. Isoselenocarbamates and particularly their selenocarbamate isomers exhibited potent antiproliferative activity against non-small lung cell lines (A549, SW1573) in the low micromolar range, with similar potency to that shown by the chemotherapeutic agent cisplatin (cis-diaminodichloroplatin, CDDP) and occasionally with more potency than etoposide (VP-16).

Selenium Dihalides Click Chemistry: Highly Efficient Stereoselective Addition to Alkynes and Evaluation of Glutathione Peroxidase-Like Activity of Bis(E-2-halovinyl) Selenides.

Highly efficient stereoselective syntheses of novel bis(E-2-chlorovinyl) selenides and bis(E-2-bromovinyl) selenides in quantitative yields by reactions of selenium dichloride and dibromide with alkynes were developed. The reactions proceeded at room temperature as anti-addition giving products exclusively with (E)-stereochemistry. The glutathione peroxidase-like activity of the obtained products was estimated and compounds with high activity were found. The influence of substituents in the products on their glutathione peroxidase-like activity was discussed.

Structure-Activity Studies Reveal Scope for Optimisation of Ebselen-Type Inhibition of SARS-CoV-2 Main Protease.

The reactive organoselenium compound ebselen is being investigated for treatment of coronavirus disease 2019 (COVID-19) and other diseases. We report structure-activity studies on sulfur analogues of ebselen with the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro ), employing turnover and protein-observed mass spectrometry-based assays. The results reveal scope for optimisation of ebselen/ebselen derivative- mediated inhibition of Mpro , particularly with respect to improved selectivity.

Diselenides and Selenocyanates as Versatile Precursors for the Synthesis of Pharmaceutically Relevant Compounds.

Organoselenium chemistry has undergone extensive development during the past decades, mostly due to the unique chemical properties of organoselenium compounds that have been widely explored in a number of synthetic transformations, as well as due to the interesting biological properties of these compounds. Diselenides and selenocyanates constitute the promising classes of organoselenium compounds that possess interesting biological effects, and that can be used in the preparation of other selenium compounds. The combination of diselenide and selenocyanate moieties with other biologically relevant molecules (such as heterocycles, steroids, etc.) is a way for the development of compounds with promising pharmaceutical potential. Therefore, the aim of this review is to highlight the recent achievements in the use of diselenides or selenocyanates as precursors for the synthesis of pharmaceutically relevant compounds, preferentially compounds with antitumor and antimicrobial activities.