Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1-mediated nuclear export.

Chromosomal region maintenance 1 (CRM1 also known as Xpo1 and exportin-1) is the receptor for the nuclear export controlling the intracellular localization and function of many cellular and viral proteins that play a crucial role in viral infections and cancer. The inhibition of CRM1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses, for the treatment of cancer, and to overcome therapy resistance. Recently, selinexor has been approved as the first CRM1 inhibitor for the treatment of multiple myeloma, providing proof of concept for this therapeutic option with a new mode of action. However, selinexor is associated with dose-limiting toxicity and hence, the discovery of alternative small molecule leads that could be developed as less toxic anticancer and antiviral therapeutics will have a significant impact in the clinic. Here, we report a CRM1 inhibitor discovery platform. The development of this platform includes reporter cell lines that monitor CRM1 activity by using red fluorescent protein or green fluorescent protein-labeled HIV-1 Rev protein with a strong heterologous nuclear export signal. Simultaneously, the intracellular localization of other proteins, to be interrogated for their capacity to undergo CRM1-mediated export, can be followed by co-culturing stable cell lines expressing fluorescent fusion proteins. We used this platform to interrogate the mode of nuclear export of several proteins, including PDK1, p110α, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110α partially relies on CRM1-dependent nuclear export, TRIB2 is exported from the nucleus in a CRM1-independent manner. Compound screening revealed the striking activity of an organoselenium compound on the CRM1 nuclear export receptor.

(p-ClPhSe)2 modulation on carbohydrate and lipid metabolism requires the insulin-like signaling in Caenorhabditis elegans.

Organoselenium compounds modulate the metabolism by regulating carbohydrate and lipid syntheses and degradation in the liver, muscle, and adipose tissue. Notably, p-chloro-diphenyl diselenide (p-ClPhSe)2 can directly regulate the activities of enzymes involved in glucose metabolism, suggesting an insulin-like effect in rodents; however, there is still a lack of scientific evidence to confirm this hypothesis. The objective of this study was to investigate (p-ClPhSe)2 effects on glucose and lipid metabolism in Caenorhabditis elegans. The contribution of AGE-1/PI3K, AKT-1, AKT-2, PFK-1, DAF-16, and DAF-2 in the (p-ClPhSe)2 effects were also investigated. Our results demonstrate that (p-ClPhSe)2 acute exposure presented some toxicity to the worms, and therefore, lower concentrations were further used. (p-ClPhSe)2 reduced glucose and triglyceride levels to the baseline levels, after induction with glucose or fructose, in wild-type worms. This effect required proteins involved in the insulin/IGF-1 like signaling, such as the DAF-2, AGE-1, AKT-1 and AKT-2, PFK-1, but also DAF-16, which would be negatively regulated by DAF-2 activation. Moreover, the reduction in glucose and triglyceride levels, caused by (p-ClPhSe)2per se was lost in age-1/daf-16 worms, suggesting that insulin/IGF-1-like signaling in a DAF-2 and AGE-1/DAF-16 dependent-manner in C. elegans are necessary to effects of (p-ClPhSe)2. In conclusion, (p-ClPhSe)2 requires proteins involved in the IIS pathway to modulate carbohydrate and lipid metabolism.

Organoselenium transition metal complexes as promising candidates in medicine area.

The medicinal properties of transition metal complexes are greatly influenced by the nature and physico-chemical features of the ligand present in the complex structure. Due to the unique biological properties of the organoselenium compounds reflected in the variety of pharmacological activities (such as antioxidative, antiviral, antimicrobial and anticancer), the last years have brought increased interest for their use as a ligands compounds in the design and syntheses of range of transition metal-based coordination compounds that have been explored as antitumor and antimicrobial agents. Our aim in this review is to provide the overview of an recent development of the transition metal complexes bearing organoselenium ligands in the structure that could be promising choice for the treatment of various diseases, particularly cancer and infective diseases. For this purpose, the complexes of Co, Ni, Cu, Zn, Ru, Pd, Pt, Au and Sn as the most explored examples will be included and discussed.

Gold Meets Selenium: Dual Activation of Selenium-Containing Propargyl Alcohols Towards the Synthesis of 2H-Chromenes and Mechanistic Insights.

Herein, we report the synthesis of seleno-substituted chromenes from selenoalkynes and phenols. In this cascade reaction, the applied gold catalyst not only functions as a p-acid, but also as a Lewis acid, enabling the propargylic substitution in the first step to connect the oxygen carbon bond. Under the optimal reaction condition a total of 26 chromenes were accessible by this modular access. During scale up experiments, the hydrolysis of the vinylselenium substructure to the corresponding chromenones was observed. By revisiting the electron-rich starting materials, four chromenones were produced following a one-pot reaction using a single gold catalyst. To better understand the interaction of gold and selenium, a series of nuclear magnetic resonance studies and high-resolution mass spectrometry studies were performed, which led to the proposal of a mechanism for this transformation.

Divergent Electrochemical Synthesis of Indoles through pKa Regulation of Amides: Synthetic and Mechanistic Insights.

A divergent synthetic approach to access highly substituted indole scaffolds is illustrated. By virtue of a tunable electrochemical strategy, distinct control over the C-3 substitution pattern was achieved by employing two analogous 2-styrylaniline precursors. The chemoselectivity is governed by the fine-tuning of the acidity of the amide proton, relying on the appropriate selection of N-protecting groups, and assisted by the reactivity of the electrogenerated intermediates. Detailed mechanistic investigations based on cyclic voltametric experiments and computational studies revealed the crucial role of water additive, which assists the proton-coupled electron transfer event for highly acidic amide precursors, followed by an energetically favorable intramolecular C-N coupling, causing exclusive fabrication of the C-3 unsubstituted indoles. Alternatively, the implementation of an electrogenerated cationic olefin activator delivers the C-3 substituted indoles through the preferential nucleophilic nature of the N-acyl amides. This electrochemical approach of judicious selection of N-protecting groups to regulate pKa/E° provides an expansion in the domain of switchable generation of heterocyclic derivatives in a sustainable fashion, with high regio- and chemoselectivity.

Recent Progress in Synthesis and Application of Chiral Organoselenium Compounds.

Chiral organoselenium compounds have shown an important role as intermediates in many areas, such as drug discovery, organic catalysis, and nanomaterials. A lot of different methods have been developed to synthesize chiral compounds which contain selenium, because they have interesting properties and can be used in real life. Over the last few decades, a lot of progress has been made in synthesizing chiral organoselenium compounds. This work gives an overview of the progress made in creating new ways to synthesize chiral organoselenium compounds by categorizing them into groups based on the reactions they undergo. In addition, the use of chiral organoselenium compounds is also discussed.

Machine learning-based QSAR and LB-PaCS-MD guided design of SARS-CoV-2 main protease inhibitors.

The global outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 virus had led to profound respiratory health implications. This study focused on designing organoselenium-based inhibitors targeting the SARS-CoV-2 main protease (Mpro). The ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD) simulations was employed to elucidate plausible paths and conformations of ebselen, a synthetic organoselenium drug, within the Mpro catalytic site. Ebselen effectively engaged the active site, adopting proximity to H41 and interacting through the benzoisoselenazole ring in a π-π T-shaped arrangement, with an additional π-sulfur interaction with C145. In addition, the ligand-based drug design using the QSAR with GFA-MLR, RF, and ANN models were employed for biological activity prediction. The QSAR-ANN model showed robust statistical performance, with an r2training exceeding 0.98 and an RMSEtest of 0.21, indicating its suitability for predicting biological activities. Integration the ANN model with the LB-PaCS-MD insights enabled the rational design of novel compounds anchored in the ebselen core structure, identifying promising candidates with favorable predicted IC50 values. The designed compounds exhibited suitable drug-like characteristics and adopted an active conformation similar to ebselen, inhibiting Mpro function. These findings represent a synergistic approach merging ligand and structure-based drug design; with the potential to guide experimental synthesis and enzyme assay testing.

Synthesis, biological evaluation, and molecular docking studies of novel N-substituted piperazine-tethered thiophene-3-carboxamide selenides as potent antiproliferative agents with EGFR kinase inhibitory activity.

In the context of structural investigation and optimization of various potential EGFR inhibitors, a novel series of asymmetrical piperazine-tethered trisubstituted thiophene-3-carboxamide selenide derivatives were synthesized and evaluated for their antiproliferative potential against selected human cancer cell lines. These derivatives, built based on a previously identified hit molecule, were synthesized via multiple-step reactions, including optimization of the C-Se cross-coupling reaction. Two compounds, 17i and 18i, displayed significant cytotoxicity (IC50 value: 4.82 ± 0.80 µM and 1.43 ± 0.08 µM) against HCT116 and A549 cancer cell lines, respectively. Quantitative analysis of apoptotic stages using Annexin V-FITC/PI double staining validated their apoptotic potential. Further, compound 18i demonstrated a remarkable inhibition of EGFR kinase, with an IC50 concentration of 42.3 nM. The lead compound 18i, with remarkable in vitro cytotoxicity, apoptosis induction capability, and EGFR inhibition, emerges as a promising candidate for anticancer therapy.

Short Communication: Novel Di- and Triselenoesters as Effective Therapeutic Agents Inhibiting Multidrug Resistance Proteins in Breast Cancer Cells.

Breast cancer has the highest incidence rate among all malignancies worldwide. Its high mortality is mainly related to the occurrence of multidrug resistance, which significantly limits therapeutic options. In this regard, there is an urgent need to develop compounds that would overcome this phenomenon. There are few reports in the literature that selenium compounds can modulate the activity of P-glycoprotein (MDR1). Therefore, we performed in silico studies and evaluated the effects of the novel selenoesters EDAG-1 and EDAG-8 on BCRP, MDR1, and MRP1 resistance proteins in MCF-7 and MDA-MB-231 breast cancer cells. The cytometric analysis showed that the tested compounds (especially EDAG-8) are inhibitors of BCRP, MDR1, and MRP1 efflux pumps (more potent than the reference compounds-novobiocin, verapamil, and MK-571). An in silico study correlates with these results, suggesting that the compound with the lowest binding energy to these transporters (EDAG-8) has a more favorable spatial structure affecting its anticancer activity, making it a promising candidate in the development of a novel anticancer agent for future breast cancer therapy.

Di- and Triselenoesters-Promising Drug Candidates for the Future Therapy of Triple-Negative Breast Cancer.

Breast cancer is a major malignancy among women, characterized by a high mortality rate. The available literature evidence indicates that selenium, as a trace element, has chemopreventive properties against many types of cancer; as such, compounds containing it in their structure may potentially exhibit anticancer activity. Accordingly, we have undertaken a study to evaluate the effects of novel selenoesters (EDAG-1, -7, -8, -10) on MCF-7 and MDA-MB-231 breast cancer cells. Our analysis included investigations of cell proliferation and viability as well as cytometric determinations of apoptosis/autophagy induction, changes in mitochondrial membrane polarity (ΔΨm), caspase 3/7, 8, and 9 activities, and Bax, Bcl-2, p53, Akt, AMPK, and LC3A/B proteins. The obtained data revealed that the tested derivatives are highly cytotoxic and inhibit cell proliferation even at nanomolar doses (0.41-0.79 µM). Importantly, their strong proapoptotic properties (↑ caspase 3/7) are attributable to the effects on both the extrinsic (↑ caspase 8) and intrinsic (↓ ΔΨm and Bcl-2, ↑ Bax, p53, and caspase 9) pathways of apoptosis. Moreover, the tested compounds are autophagy activators (↓ Akt, ↑ autophagosomes and autolysosomes, AMPK, LC3A/B). In summary, the potent anticancer activity suggests that the tested compounds may be promising drug candidates for future breast cancer therapy.

Asymmetric Synthesis and Applications of Chiral Organoselenium Compounds: A Review.

The synthesis and application of organoselenium compounds have developed rapidly, and chiral organoselenium compounds have become an important intermediate in the field of medicine, materials, organic synthesis. The strategy of developing a green economy is still a challenge in the synthesis of chiral organoselenium compounds with enantioselective properties. This review covers in detail the synthesis of chiral organoselenium compounds from 1979 to 2024 and their application in the fields of asymmetric synthesis and catalysis.

Dynamics of Changes in the cAMP/cGMP Concentration Ratio in the Thymus and Spleen of Laboratory Mice during Vaccination against Plague and Tularemia against the Background of Immunomodulation.

Vaccine strains Yersinia pestis EV NIIEG at a dose of 103 CFU and Francisella tularensis 15 NIIEG at a dose of 102 CFU induced changes in the concentration of cyclic nucleotides in the thymus and spleen of white mice. Antigen-induced changes in the cAMP/cGMP ratio in immunocompetent organs had a phase or oscillatory character, which seems to be related to the regulation of postvaccination immunoreactivity in the body. Synthetic organoselenium compound 974zh stimulated an increase in the amplitude of cAMP/cGMP oscillations, indicating its stimulating effect on the immunogenic properties of vaccine strains at doses an order of magnitude below the standard doses.

Mechanistic Study on Selenium- and Sulfur-Mediated Isomerization of Hydroxamic Acids.

An in-depth computational study reveals the intriguing mechanism of the recently reported isomerization of hydroxamic acids into para-aminophenols catalyzed by phenylselenyl bromide under mild conditions. The computations not only align with the reported experimental data, effectively explaining observed phenomena such as para-selectivity but also shed light on crucial aspects of the reaction mechanism that establish limitations on the scope of the studied rearrangement. Additionally, a joint theoretical/experimental study was performed to examine the potency of the phenylsulfenyl bromide to mediate the reaction under the same conditions.

Organoselenium Compounds: Chemistry and Applications in Organic Synthesis.

Selenium, originally described as a toxin, turns out to be a crucial trace element for life that appears as selenocysteine and its dimer, selenocystine. From the point of view of drug developments, selenium-containing drugs are isosteres of sulfur and oxygen with the advantage that the presence of the selenium atom confers antioxidant properties and high lipophilicity, which would increase cell membrane permeation leading to better oral bioavailability. In this article, we have focused on the relevant features of the selenium atom, above all, the corresponding synthetic approaches to access a variety of organoselenium molecules along with the proposed reaction mechanisms. The preparation and biological properties of selenosugars, including selenoglycosides, selenonucleosides, selenopeptides, and other selenium-containing compounds will be treated. We have attempted to condense the most important aspects and interesting examples of the chemistry of selenium into a single article.

Effectiveness of diphenyl diselenide against experimental sporotrichosis caused by Sporothrix brasiliensis.

Diphenyl diselenide (PhSe)2 is a stable organoselenium compound with promising in vitro antifungal activity against several fungi, including Sporothrix brasiliensis. This species is associated with feline and zoonotic sporotrichosis, an emergent mycosis in Latin America. We evaluated the activity of (PhSe)2, alone and in association with itraconazole, in the treatment of sporotrichosis caused by S. brasiliensis, in a murine model. Sixty mice were subcutaneously infected with S. brasiliensis in the footpad and treated by gavage for 30 consecutive days. The six treatment groups received: no active treatment, itraconazole (50 mg/kg), (PhSe)2 at 1, 5, and 10 mg/kg dosages, or itraconazole (50 mg/kg) + (PhSe)2 1 mg/kg, once a day, starting seven days post-inoculation. A significant reduction in the fungal burden of internal organs was achieved in the groups treated with (PhSe)2 1 mg/kg or itraconazole alone in comparison with the untreated group. Higher dosages (5 and 10 mg/kg) of (PhSe)2 increased the clinical manifestation of sporotrichosis and mortality rate. Treatment with both itraconazole and (PhSe)2 1 mg/kg was better than their activities alone (P < .001). This is the first demonstration of the potential use of (PhSe)2, alone or with the present drug of choice, in the treatment of sporotrichosis.

We evaluated the activity of diphenyl diselenide (PhSe)2, alone and in association with itraconazole, in the treatment of sporotrichosis caused by S. brasiliensis, in a murine model. This is the first demonstration of the potential use of (PhSe)2, alone or in an association against sporotrichosis.

Synthesis and Photophysical Study of Tetraphenyl Substituted BODIPY Based Phenyl-Monoselenide Probe for Selective Detection of Superoxide.

Selenium containing tetraphenyl substituted BODIPY probe was successfully synthesized from respective selenium aldehyde and tetraphenyl pyrrole using Knoevenagel-type condensation. The product was characterized using various spectroscopic techniques (1 H, 13 C, 77Se, 11B, and 19 F) and mass spectrometry. The probe was found to be selective and sensitive towards detection of superoxide over other ROS with a "turn-off" (quenched) fluorescence response. The detection limit of the probe was found to be 4.87 µM. The probe reacted with superoxide in less than a sec with a stoke shift of 35 nm.

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.

Antimicrobial Coatings for Medical Textiles via Reactive Organo-Selenium Compounds.

Bleached and cationized cotton fabrics were chemically modified with reactive organoselenium compounds through the nucleophilic aromatic substitution (SNAr) reaction, which allowed for organo-selenium attachment onto the surface of cotton fabrics via covalent bonds and, in the case of the cationized cotton fabric, additional ionic interactions. The resulting textiles exhibited potent bactericidal activity against S. aureus (99.99% reduction), although only moderate activity was observed against E. coli. Fabrics treated with reactive organo-selenium compounds also exhibited fungicidal activities against C. albicans, and much higher antifungal activity was observed when organo-selenium compounds were applied to the cationized cotton in comparison to the bleached cotton. The treatment was found to be durable against rigorous washing conditions (non-ionic detergent/100 °C). This paper is the first report on a novel approach integrating the reaction of cotton fabrics with an organo-selenium antimicrobial agent. This approach is attractive because it provides a method for imparting antimicrobial properties to cotton fabrics which does not disrupt the traditional production processes of a textile mill.

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.

Selected N-Terpenyl Organoselenium Compounds Possess Antimycotic Activity In Vitro and in a Mouse Model of Vulvovaginal Candidiasis.

In the present work, a series of N-terpenyl organoselenium compounds (CHB1-6) were evaluated for antimycotic activity by determining the minimum inhibitory concentration (MIC) for each compound in fluconazole (FLU)-sensitive (S1) and FLU-resistant (S2) strains of Candida albicans (C. albicans). The most active compounds in the MIC screen were CHB4 and CHB6, which were then evaluated for cytotoxicity in human cervical cancer cells (KB-3-1) and found to be selective for fungi. Next, CHB4 and CHB6 were investigated for skin irritation using a reconstructed 3D human epidermis and both compounds were considered safe to the epidermis. Using a mouse model of vulvovaginal candidiasis (VVC), CHB4 and CHB6 both exhibited antimycotic efficacy by reducing yeast colonization of the vaginal tract, alleviating injury to the vaginal mucosa, and decreasing the abundance of myeloperoxidase (MPO) expression in the tissue, indicating a reduced inflammatory response. In conclusion, CHB4 and CHB6 demonstrate antifungal activity in vitro and in the mouse model of VVC and represent two new promising antifungal agents.